Dementia: Clinical Syndromes
Dementia of the Alzheimer's type (AD), frontotemporal dementia (FTD), and diffuse Lewy body disease are primary degenerative processes occurring within the CNS. These syndromes are progressive and lead inevitably to severe disability and death. Other degenerative dementias are associated with diseases that affect other neurological systems; these include Huntington's disease, Parkinson's disease (PD), progressive supranuclear palsy, corticobasal degeneration, and multiple system atrophy.
Dementia of the Alzheimer's Type
The most widely applied criteria for the clinical definition of AD are those of the National Institute of Neurological and Communicative Disorders and Stroke and those of the AD and Related Disorders Association. The diagnosis of probable AD requires the presence of dementia established by clinical examination, documented by standardized mental status assessment, and confirmed by neuropsychological tests. These tests must demonstrate deficits in two or more areas of cognition, with progressive worsening of memory and other cognitive functions in the absence of delirium. The onset must be between ages 40 and 90 years, and there must be no other brain disease that could account for the clinical observations (this implies a work-up, including the blood studies and brain imaging tests discussed above). The disorder must also be progressive and associated with disability in routine activities. Supportive features include family history, specific progressive deficits in cognitive functions, and laboratory data such as PET or SPECT scans. PET ligands that bind to amyloid, such as the Pittsburgh Compound, may provide more accurate AD diagnosis in the future.
AD is the most common form of dementia, accounting for over half of all dementias. Oddly enough, just 25 years ago, many textbooks considered AD to be rare, likely because the disease was confined to “presenile” cases, younger than age 65. We now know that the neuropathology of presenile and senile dementia is the same. There has been a veritable explosion in research in AD.
Although memory problems dominate the early stages of the disorder, AD affects cognition, mood, and behavior. Cognitive impairment affects daily life because patients are unable to perform normal activities of daily living. Behavioral manifestations of the disease such as temper outbursts, screaming, agitation, and severe personality changes are more troubling than the cognitive difficulties. No two patients with AD are exactly alike when it comes to the behavioral manifestations of the disorder. Only recently has this aspect of the disease received substantial attention.
AD is the most common type of progressive dementia. This degenerative disease reaches 20% prevalence in 80-year-olds, as much as 48% prevalence in one study of community-dwelling elderly people over age 85, and afflicts over four million Americans. It is projected to affect 8–14 million by the year 2030. The disease affects women more often than men. The economic impact of AD has been estimated at over $100 billion annually.
In general, AD represents an imbalance between neuronal injury and repair. Factors contributing to injury may include free radical formation, vascular insufficiency, inflammation, head trauma, hypoglycemia, and aggregated β-amyloid protein. Factors contributing to ineffective repair may include the presence of the apolipoprotein E (ApoE) E4 gene, altered synthesis of amyloid precursor protein, and hypothyroidism. Some researchers hypothesize that β-amyloid causes chronic inflammation. AD also involves formation of tau-containing neurofibrillary tangles; most researchers feel that the tau protein changes (see below) are a secondary phenomenon in AD, though they may be primary in FTD and other diseases. Ultimately, the deficit of key neurotransmitters, especially acetylcholine, plays a major role in the cognitive symptoms.
Plaques and tangles identify the illness at the microscopic level. Amyloid plaques occur in vast numbers in severe cases. Amyloid plaques were first recognized in 1892. PAS or Congo Red stains identify these structures. β-Amyloid peptide, which is concentrated in senile plaques, has been linked to AD. The β-amyloid protein, in the form of pleated sheets, appears early in the brain and in blood vessels in AD. Some studies suggest that β-amyloid is toxic to mature neurons in the brains of Alzheimer's patients. Neurons in these areas begin to develop neurofibrillary tangles. Amyloid plaques and neurofibrillary tangles gradually accumulate in the frontal, temporal, and parietal lobes. The density of plaques determines postmortem diagnosis. Amyloid binding can now be imaged in PET studies, using the Pittsburgh compound and other ligands. The number of neurons and synapses is reduced. This is particularly true of acetylcholine-cholinergic-containing neurons in the basal nucleus of Meynert, which project to wide areas of the cerebral cortex. PET studies demonstrate a reduction in acetyl cholinesterase and decreased binding of cholinergic ligands. Hirano bodies and granulovacuolar degeneration occur in the hippocampus and represent further degeneration.
Neocortical neurofibrillary tangles are extremely rare in normal individuals, however, neuropil threads and neurofibrillary tangles appear at the onset of dementia. These intracytoplasmic filaments displace the nucleus and the cellular organelles. Neurofibrillary tangles contain an abnormally phosphorylated protein named tau. The abnormal phosphorylation of tau protein probably causes defective construction of microtubules and neurofilaments. The neurofibrillary tangles in brains affected by AD abnormally express Alz-50, a protein antigen commonly found in fetal brain neurons. Neural thread protein is present in the long axonal processes that emerge from the nerve cell body and is found in association with neurofibrillary tangles. This protein may be involved in neural repair and regeneration.
Neurons bearing neurofibrillary tangles often project to brain regions that are rich in senile plaques containing β-amyloid. These plaques are found in areas innervated by cholinergic neurons. Cholinergic neurons in the hippocampus and the basal nucleus of Meynert degenerate early in AD, causing impairment of cortical and hippocampal neurotransmission and cognitive difficulty. The affected cortical areas become anatomically disconnected. One of the earliest areas to be disconnected is the hippocampus, which explains why memory disorder is one of the early manifestations of AD. As time goes on, there is a loss of communication between other cortical zones and subsequent loss of higher cognitive abilities.
These basal forebrain cholinergic projections not only mediate cognitive function but also mediate brain responses to emotionally relevant stimuli. In the late stages of AD, a wide range of behavioral changes occur, including psychosis, agitation, depression, anxiety, sleep disturbance, appetite change, and altered sexual behavior. These changes are mediated by cholinergic degeneration and by degeneration in other neural systems. Serotonergic neurons and noradrenergic neurons degenerate as the disease progresses. Degeneration of these systems also contributes to some of the later cognitive and behavioral manifestations of the disorder. Because dopaminergic neurons are relatively immune to degeneration in AD, the performance of well-learned motor behaviors is preserved well into the late stages of the disease.
AD has demonstrated genetic diversity. Chromosome 21 has been implicated for many years because it is well known that patients with Down syndrome are very likely to develop the histological features of AD. Genetic mutations usually cause familial, autosomal dominantly transmitted, early-onset AD. Several mutations of the amyloid precursor protein gene on chromosome 21 have been described. These mutations increase the production of an abnormal amyloid that has been associated with neurotoxicity. Another form of early-onset disease has been localized to a variety of defects on chromosome 14. These mutations are associated with presenilin 1 and account for the majority of familial Alzheimer's cases. A mutation on chromosome 1 is associated with presenilin 2. Both of these mutations also cause increased production of amyloid, in that the presenilins are now known to be secretase enzymes involved in the formation of beta-amyloid peptide, a 40–42 amino acid peptide, from the amyloid precursor protein.
The ApoE E4 allele is associated with the risk of late-onset familial and sporadic forms of AD. ApoE; a plasma protein involved in the transport of cholesterol is encoded by a gene on chromosome 19. Disease risk increases in proportion to the number of ApoE E4 alleles. The population that is positive for ApoE E4 has a lower age at onset. The ApoE E2 allele may offer some protection. Although patients with the ApoE E4 allele may be more likely to have AD, a full diagnostic evaluation including imaging, laboratory tests, and neuropsychological evaluation is still indicated when the clinical situation warrants. It is premature to regard ApoE testing as a screening tool for AD, and it is not recommended for presymptomatic screening in family members of patients with AD. Another gene, SORL1, has recently been described as a marker for sporadic AD.
A subjective sense of memory loss appears first, followed by loss of memory detail and temporal relationships. All areas of memory function deteriorate including encoding, retrieval, and consolidation. Patients forget landmarks in their lives less often than other events. Amnesia for names and specific nouns is the earliest language abnormality in AD, and a mild anomic aphasia is often found in patients with early AD. Agnosia (failure to recognize or identify objects), more severe aphasia (language disturbance), apraxia, and visuospatial-topographical impairments such as getting lost while walking or driving occur later in the disease.
In the early stages of AD, a subjective memory deficit is difficult to distinguish from benign forgetfulness. Considerable research has examined patients with impaired memory but otherwise normal cognitive function, a disorder called “mild cognitive impairment.” These patients are more likely to develop AD over time than age-matched controls. Deficits in memory, language, concept formation, and visual spatial praxis evolve slowly. Later, patients with AD become passive, coarse, and less spontaneous. Many become depressed, and depression may worsen the patient's cognitive function. Depressed Alzheimer's patients often exhibit degeneration of the locus coeruleus or substantia nigra.
More than half of patients with mild Alzheimer's patients present with at least one psychiatric symptom, and one-third present with two or more symptoms. After the initial stage of the disease, patients enter a stage of global cognitive deterioration. Denial or loss of self-awareness replaces anxiety, and cognitive deficits are noticeable to family and friends. In the final stages, patients become aimless, abulic (unable to make decisions), aphasic, and restless. At this stage, abnormal neurologic reflexes, such as the snout, palmomental, and grasp reflexes, are common.
The clinical assessment and staging of AD have always been difficult. The MMSE is often used but sometimes seriously underestimates cognitive impairment. The Standardized MMSE has better reliability than the MMSE. The Blessed Dementia Scale uses collateral sources and correlates well with postmortem pathology. The interrater reliability of the Blessed Dementia Scale is low.
The Extended Scale for Dementia is a rating scale designed to distinguish the intellectual function of dementia patients from normal seniors. The Neurobehavioral Cognitive Status Examination (NCSE) is a tool that assesses a patient's cognitive abilities in a short amount of time. This instrument uses independent tests to estimate functioning within five major cognitive ability areas: language, constructions, memory, calculations, and reasoning. The Mattis Dementia Rating Scale (DRS) is useful in staging dementia. Both the NCSE and the DRS are sensitive, but they are more time consuming than the MMSE. In most clinical practices, the MMSE is used for assessment of dementia and for following the patient's progress, and common recommendations for drug therapy are based on the MMSE score.
Comprehensive scales combine clinical judgment, objective data, and specific rating criteria. The Reisberg Brief Cognitive Rating Scale and the Global Deterioration Scale are brief comprehensive scales. The Clinical Dementia Rating Scale (CDR) is a more extensive instrument that includes subject interview, collateral interview, brief neuropsychological assessment, and interview impression. Patients with a CDR score of 0.5 are likely to have “very mild” AD. The CDR has a complicated scoring algorithm and is best reserved for research.
The Alzheimer's disease Assessment: Cognitive (ADAS COG) and the Behavioral Pathology in AD (Behave-AD) instruments are used in clinical drug trials to determine pharmacologic efficacy in cognitive areas or behavioral areas, respectively.
The Consortium to Establish a Registry for Alzheimer's disease Criteria (CERAD) examination includes general physical and neurologic examinations as well as laboratory tests. Specified neuropsychological tests and a depression scale are also administered.
Laboratory Findings and Imaging
Although CT scans reveal atrophy in Alzheimer's patients as a group, atrophy alone does not reliably predict AD in individual patients. Atrophy can be quantified using appropriate ratios and progresses on serial evaluation, but this information adds little to the patient's clinical care.
MRI region-of-interest techniques reveal reduced brain volume and higher CSF volume in patients with AD. AD may be associated with enlarged CSF spaces or atypical signal intensity in the medial temporal lobes. These findings imply that advancing AD is associated with increased brain water, where either the atrophy leads to an increase in CSF spaces, or there are associated ischemic changes in the deep cerebral white matter. Finally, volumetric studies may show hippocampal sclerosis in the brains of Alzheimer's patients. Hippocampal atrophy may be relatively specific to AD and may be useful for early detection and differential diagnosis.
31P–nuclear magnetic resonance (NMR) spectroscopy profiles may be helpful in the evaluation of AD. 31P NMR profiles of AD patients show elevated ratios of phosphomonoesterase to phosphodiesters in the temporoparietal region.
In the early stage of dementia, functional brain imaging (i.e., PET and SPECT scans) is more sensitive than structural brain imaging (i.e., MRI and CT scan). PET scans reveal changes in temporoparietal metabolism that differentiate patients with AD from the normal elderly. PET scans reveal the following abnormalities in AD: (1) reductions in whole-brain metabolism (paralleling dementia severity), (2) hypometabolism in the association cortex exceeding that in the primary sensorimotor cortex, and (3) metabolic asymmetry in suitable cortical areas accompanying neuropsychological deficits. In AD metabolic deficits start in the parietal cortex. Frontal metabolism decreases as dementia progresses. AD spares the primary motor cortex, sensory cortex, and basal ganglia.
SPECT scans can reveal information about regional brain function at a much lower cost and degree of complexity than PET scans, but the spatial resolution is not as good. In more advanced AD cases, SPECT scans reveal decreased perfusion in the bilateral temporoparietal regions.
EEG abnormalities are not common early in AD, but they develop as the disease progresses. Diffuse slow wave abnormalities occur first in the left temporal regions and become more frequent and longer as the disease progresses. EEG abnormalities that occur early in dementia suggest a coexisting delirium. Because dementia often presents first in association with delirium, infectious, toxic, or metabolic disturbances should be considered if the EEG slowing is severe.
Evoked potentials are an EEG technology that average many signals following a specific stimulus. In AD, the auditory P300 amplitude in the posterior parietal regions is suppressed on evoked potential maps. Other studies have not demonstrated clinically useful abnormalities of the P300 component in dementia. Compared to control subjects, AD patients show longer P100 latencies of pattern-reversal visual evoked potentials. The flash P100 distinguishes them only marginally. The long-latency auditory evoked potential helps differentiate between cortical and subcortical dementias. Patients with subcortical dementias exhibit prolonged latencies.
Differential Diagnosis (Including Comorbid Conditions)
Clinicians have traditionally used a battery of laboratory tests to differentiate AD from a variety of medical conditions that cause memory impairment. These tests include complete blood count, comprehensive metabolic panel, thyroid function tests, and vitamin B12. In appropriate cases, the erythrocyte sedimentation rate, serological tests for syphilis, and even a lumbar puncture may be indicated. In many cases, a careful history and bedside mental status examination can reliably diagnose presumed AD and distinguish it from other forms of dementia. A detailed drug history is necessary because drugs, especially those with anticholinergic properties, can cause Alzheimer-like symptomatology. A normal neurologic examination is entirely consistent with AD. Neurologic abnormalities are much more common in other dementing illnesses. The relationship between AD and depression is complex and is discussed later in this chapter.
Memory loss is common in nondemented seniors. Many of these patients become terrified that they have AD and seek medical help. Physicians have difficulty distinguishing normal age-associated memory loss, benign forgetfulness, and early AD.
Benign senile forgetfulness is a condition that occurs when effects of aging on memory are greater than expected. Elderly patients with benign forgetfulness forget unimportant details. This contrasts with Alzheimer's patients, who forget events randomly. Seniors who experience benign senile forgetfulness have trouble remembering recent information; typically, Alzheimer's patients have difficulty with recent and remote memory. The most important aspect of the treatment of benign senile forgetfulness is reassurance, but cognitive retraining can sometimes be helpful. When the memory loss is clearly more than normal for age, the diagnosis should be “mild cognitive impairment” (MCI). As mentioned earlier, this condition is not as benign, in that almost half of patients with MCI progress to AD over a 3–4-year period. Drug treatment for patients with MCI is the subject of active research, but no specific recommendation exists, as yet. Treatment should be considered when the cognitive disorder becomes disabling, or by common insurance company guidelines, when the MMSE drops below 24.
Although AD can be diagnosed accurately in clinical settings, inaccuracy of diagnosis continues to plague clinical care. AD is over-diagnosed. Patients with FTD, PD, diffuse Lewy body disease, or even metabolic conditions mistakenly receive the diagnosis of AD. Unfortunately, even patients taking multiple medications and those who have delirium may receive the diagnosis of AD.
The aim of pharmacotherapy in AD is as follows: (1) to prevent the disease in asymptomatic individuals, (2) to alter the natural course of the disease in those already diagnosed, and (3) to enhance patients’ cognition and memory. As yet, no treatment has been shown to be effective in preventing the disease, though general health measures such as exercise, healthy diet, treatment of hypertension and hyperlipidemia, and avoidance of tobacco and excessive alcohol are all suggested to delay or prevent the disease. Treatment to enhance memory in Alzheimer's patients has focused on improving cholinergic activity. Cholinergic enhancement can occur through the administration of acetylcholine precursors, choline esterase inhibitors, and combinations of AChE with precursors, muscarinic agonists, nicotinic agonists, or drugs facilitating AChE release. To date, only cholinesterase inhibitors have proved effective in clinical trials.
Early attempts to treat dementia with ergoloid mesylates were of limited benefit. In some studies, ergoloid mesylates were more effective than placebo. The dose-response relation suggests that the effective dosage may be higher than currently approved. Unfortunately, the original clinical trial designs were flawed, leaving their benefit unproved.
Attempts to enhance acetylcholine transmission with precursors such as lecithin and choline failed to show benefit in AD. Cholinomimetic substances such as arecoline were more successful but have had limited use because of adverse side effects, short half-life, and narrow dose range. Physostigmine, an acetylcholinesterase inhibitor, has limited benefit because of its short half-life and significant side effects.
The first acetylcholinesterase inhibitor approved for use in mild to moderate AD was tetrahydroaminoacridine (Tacrine). Tacrine frequently causes adverse side effects, particularly gastrointestinal hyperactivity. Elevation of liver transaminase is another significant side effect. Of the patients who take tacrine, 25% will experience elevations (up to three times the normal) in alanine amino transferase levels. For these reasons, tacrine is rarely used currently.
Second-generation cholinesterase inhibitors such as donepezil are more specific for CNS acetylcholinesterase than for peripheral acetylcholinesterase. These drugs do not have the limitations associated with tacrine. Donepezil has the additional advantage of daily dosing. It does not cause significant hepatotoxicity. Donepizil has an orally dissolving tablet form and has been approved for mild, moderate, and severe AD. Rivastigmine is a cholinesterase inhibitor that has a relative specificity for both acetylcholinesterase and butyrylcholinesterase, an effect shared only with tacrine. There is evidence that butyrylcholinesterase is present at high concentrations in the brains of patients with AD, but the relevance of this factor to its clinical effect is unknown. The drug has more gastrointestinal side effects than donepizil. It is given twice daily at doses of 1.5, 3, 4.5, and finally 6 mg, with dose advances made every four weeks. A last cholinesterase agent, galantamine, has similar effects on the acetylcholinesterase enzyme, but may also increase presynaptic release of acetylcholine. This agent is available in both twice daily and extended release preparations. The daily doses are 8, 16, and 24 mg. The gastrointestinal side effects of this agent are intermediate between those of donepizil and rivastigmine, but individual patients may tolerate one better than another.
New delivery mechanisms for the anticholenesterase medications have made them more tolerable. Galantamine is available in an extended release formulation. Rivastigmine will be available in a patch formulation that provided similar efficacy to that achieved at the highest doses of the capsule with three times fewer reports of nausea and vomiting.
Muscarinic M1 receptors are relatively intact in AD, despite the degeneration of presynaptic cholinergic innervation. Several muscarinic agonists have been studied in clinical trials, but none has been approved, to date. Finally, stimulation of nicotinic receptors may have a protective effect in AD.
The newest drug to be USFDA approved for AD is memantine, an antagonist at the NMDA receptor. The exact mechanism of action of this drug is not known; the NMDA effect could represent a neuroprotective effect on “excitotoxicity” of glutamate on surviving neurons, but this drug appears to have other beneficial effects on learning and memory. It has been approved for moderate to advanced AD, that is, patients with MMSE <20.
Treatment of behavioral complications of AD is problematic. Depression should always be treated, usually with an SSRI agent. Anxiety can be helped with trazodone at bedtime, but benzodiazepines tend to worsen the memory loss and may cause paradoxical agitation. Valproic acid has been found helpful in some, but not all studies. Both donepezil and memantine appear to ameliorate behavioral disturbances in patients with AD. The same therapeutic considerations discussed under delirium are relevant in the treatment of psychosis in AD. Atypical antipsychotic agents are not greatly effective and have a black box warning. In general, we recommend low doses of olanzapine, risperidone, aripiprazole or quetiapine, with increases in dosage or shifting to another agent if symptoms persist. In the CATIE trial, the benefit for those taking active drug compared to placebo, was small. While antipsychotic medications were more often associated with distressing adverse effects. Patients and families must be warned of the potential risks of these agents.
Therapeutic strategies intended to slow progression of AD have not been very successful. Early studies suggested that the incidence of AD was reduced in postmenopausal women taking estrogen, but the Women's Health Initiative studies found the opposite: postmenopausal estrogen and progesterone hormone replacement therapy appears associated with a higher incidence of cognitive deficits and dementia. Use of non-steroidal anti-inflammatory drugs has been inversely associated with incidence of dementia in population studies, but a therapeutic use of these agents in AD has not been proved. The Cox II inhibitor refoxicib (Vioxx) was taken off the market because of increased cardiovascular events, and one of the two studies with this finding involved patients with AD. Antioxidants such as vitamin E and selegiline have shown a beneficial effect in some studies, but several recent studies have failed to establish any role for these agents. In particular, a study of mild cognitive impairment showed a limited benefit for donepizil, but none whatsoever for Vitamin E. Nicotine may have protective properties, but the toxic effect of the drug on other body systems currently precludes its use as treatment. Attempts to treat AD with nerve growth factor have been limited by the inability of the substance to cross the blood–brain barrier.
Treatments to reduce the deposition of amyloid protein in the brain have not proved effective as yet, but this field has great promise. A trial of a vaccine against amyloid had to be stopped because of the development of an encephalitis in about 10% of the recipients; one case, studied at autopsy, had little remaining amyloid staining. More selective vaccines and passive immunity with monoclonal antibodies against amyloid are currently in testing. An experimental drug called Alzhemed represents another attempt to reduce amyloid deposition; this clinical trial is still in progress. In general, AD is a very active area of clinical research.
An early-onset form of AD occurs in some people in their 40s, 50s, or 60s. A prolonged, indolent, subtle deterioration in mental function characterizes the clinical course of illness. From the time of clinical diagnosis the course is variable, but survival is possible up to 20 years from clinical recognition. Early-onset cases tend to progress more rapidly. Ultimately, functional performance declines. The patient's ability to drive becomes impaired, and he or she becomes unable to manage personal finances or to produce a complete meal. In general, studies suggest that patients with a MMSE score below 20 are probably not safe drivers. Later, impairment of language and inability to recognize familiar people lead to agitation, restlessness, and wandering. Hallucinations and other disruptive behaviors may make management difficult. In the final stages of the disease, the patient is generally mute and completely devoid of comprehension. Death most often results from a comorbid illness such as pneumonia.
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- FTDs represent a cluster of related disorders associated with degeneration of the frontal and temporal lobes. These disorders differ from AD primarily in the presentation with focal symptoms such as frontal lobe dysfunction or aphasia, rather than memory loss. In the frontal lobe variants of this disorder, personality changes usually precede or overshadow the patient's cognitive problems. Many patients become apathetic and stop caring about hygiene or social involvement. Others become disinhibited or impulsive. Sexual inappropriateness is common. Executive functions such as planning and judgment may also be abnormal in some patients. Alternatively, patients may tend to exhibit anger, irritability, and even mania. In rare cases, the Klüver-Bucy syndrome may develop with hyperorality, hypersexuality, and a compulsion to attend to any visual stimulus; this syndrome is associated with bilateral temporal lobe pathology. These patients also have impaired visual object recognition. Many FTD patients present with progressive aphasia. In the U.S., these patients have been referred to under the diagnosis “primary progressive aphasia.” The term “FTD” is now considered a more general category, of which primary progressive aphasia is one subtype.
- The variety of presentations is the result of the segmental nature of the pathology. Some areas of the frontal lobe may be devastated, whereas adjacent areas may be entirely normal. Therefore, any behavioral syndrome compatible with damage to a specific frontal region is possible.
FTDs represent about 10% of degenerative dementias. About 40% of patients with these disorders have a family history of dementia, which suggests dominantly inherited illness. Other risk factors include electroconvulsive therapy (ECT) and alcoholism. Pick's disease is historically the most recognized frontal lobe dementia. It is often familial.
FTDs are pathologically heterogeneous conditions. Only rare patients with this type of presentation have AD, and those represent primarily patients who present with fluent aphasia. One variant is “semantic dementia,” in which patients not only become unable to name objects, but they lose the meaning of words said to them. These patients have either AD or one of the other variants of FTD at autopsy. Most FTD cases have a lobar atrophy pattern involving one or both frontal and temporal lobes. The microscopic pathology is variable. Some have intraneuronal, intracytoplasmic, silver-staining inclusions called Pick bodies; these cases are traditionally diagnosed as “Pick's disease”. In some patients, neuropathologic evaluation shows no specific histopathologic changes, other than neuronal loss, microvacuolation of the neuropil, and gliosis. Many of these patients have abnormal tau proteins within neurofibrillary tangles. These disorders are often familial, and several gene mutations involving the tau gene on Chromosome 17 have been described. Some families have been described with features of progressive aphasia, FTD, and Parkinsonism. Other cases are tau-negative, but ubiquitin-positive. In other patients, frontal lobe dementia occurs simultaneously with lower motor neuron disease as in amyotrophic lateral sclerosis. The genetic and molecular biogical characterization of these variants of FTD is an active field of research at present.
Core features of frontal lobe dementias include insidious onset and gradual progression. There is early decline in social interpersonal conduct. Emotional blunting and apathy also occurs early without insight. There's a marked decline in personal hygiene and significant distractibility and motor impersistence (failure to maintain a motor activity). In the types associated with aphasia, language is affected more significantly than personality.
Personality change, lack of insight, and poor judgment dominate the early stages of frontal lobe dementias. Frontal lobe dementias cause patients to be apathetic when medial frontal damage occurs and disinhibited when basal-frontal dysfunction predominates. Social withdrawal and behavioral disinhibition may precede the onset of dementia by several years. Sometimes memory is impaired, but attention, language, and visuospatial skills are spared.
In patients whose frontal lobe dementia primarily affects frontal language, loss of spontaneity of speech is often the first noticeable symptom. Selective language defects may occur in the absence of significant cognitive decline. In these patients, the clinical picture resembles a progressive aphasia.
Most patients with frontal lobe dementias lack drive and motivation. Others are tactless or insensitive in the early stages of the illness. Some patients develop symptoms of Klüver-Bucy syndrome with hypersexuality and hyperorality, going on later to exhibit perseverative speech, apathy, or stereotyped behavior. The memory disorder of frontal lobe dementias is more prominent concerning recently acquired material. Remote memory remains intact until later in the disease. Behavioral symptoms are usually more prominent in frontal lobe dementias, whereas parietal lobe symptoms such as receptive aphasia and agnosia are less common.
On psychological testing, patients exhibit features consistent with frontal lobe dysfunction. Useful tests include the Wisconsin Card Sorting Test, the Stroop Test, another test in which the subject is asked to list words beginning with the letters F, A, and S (FAS test) and the response is timed, the Trail Making Test, and other tests designed to ferret out frontal lobe dysfunction. Some measures of aphasia should also be included in the neuropsychological test battery.
Laboratory Findings and Imaging
In classic cases of Pick's disease, the patient's brain exhibits marked atrophy of the frontal and temporal lobes, resulting in a knife-like appearance of the gyri. MRI may show a dramatic frontal pole or temporal pole atrophy that clearly differentiates Pick's and other frontal lobe dementias from the pattern of temporoparietal atrophy seen in Alzheimer's patients. In frontal lobe dementias, the EEG may remain normal despite severe pathology. PET and SPECT imaging also show the focal, lobar nature of the degeneration.
PET scans in patients with Pick's disease show bilateral frontal hypometabolism without temporoparietal defects. These findings are not always observed in early Pick's disease. In some patients the findings may be unilateral. In cases with progressive aphasia, left frontal and temporal hypometabolism or hypoperfusion are evident.
At a microscopic level, cell loss is particularly marked in the outer layers of the cortex. Degenerating neurons may have Pick's bodies. The structural changes of AD, including amyloid plaques and tangles, are entirely lacking. Frontal lobe dementias are not associated with Lewy bodies, however, areas of spongiform degeneration, similar to those found in Creutzfeldt-Jakob disease, may be observed. The pathology is patchy: Some frontal lobe areas remain normal. From a histopathologic point of view, frontal lobe dementia (Pick's disease) is characterized by gliosis, microvacuolation, neuronal atrophy loss, and 40–50% loss of synapses in three superficial cortical laminae of the frontal convexity and anterior temporal cortex. The deeper laminae are little changed.
Other conditions can present with frontal lobe behaviors and dementia, for example, vascular dementias, normal pressure hydrocephalus, Huntington's disease, and mass lesions. Butterfly gliomas are particularly likely to present with pure frontal lobe behaviors and dementia. Frontal lobe dementias can also be confused with personality disorder, mania, and depression. This is particularly true early in the course of the illness when the cognitive involvement is minimal.
Treatment of frontal lobe dementias is limited to psychosocial interventions, such as protecting the patient from his or her indiscretions, and symptomatic psychiatric treatment. At times an associated depression occurs. Treatment of this depression with SSRIs may be helpful. Psychostimulants, such as methylphenidate, may help motivate apathetic patients. Carbamazepine may be helpful for Klüver-Bucy syndrome by reducing the frequency of behaviors. Olanzapine may be helpful when extreme disinhibition occurs. In patients with memory disorder, donepezil may be helpful, but no treatment trials have confirmed a benefit of either anticholinesterase medications or memantine in FTDs, and it is not clear that degeneration of the cholinergic system is prominent in this condition.
FTDs often have primarily a presenile onset. Progression is quite variable but, generally speaking, slow. Memory functions may be retained until later in the illness. Patients with frontal lobe dementias can later develop motor neuron disease, although the clinical features of motor neuron disease may accompany or occasionally precede the onset of dementia.
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Lewy bodies are cytoplasmic inclusions seen in the neurons of the substantia nigra and other pigmented nuclei in patients with PD. In recent years, similar neuronal inclusions have been discovered in cortical neurons in patients with dementia. The term “Lewy body dementia” refers to patients who present with dementia symptoms before or simultaneously with motor disturbances suggestive of PD. Patients with Lewy body disease typically demonstrate fluctuating cognitive impairment, with active confusion and hallucinations, in addition to deterioration of memory and higher cortical functions. This fluctuating, delirium-like presentation distinguishes this disorder from AD. Associated features include visual or auditory hallucinations, mild extrapyramidal signs, or repeated and unexplained falls. Autonomic findings are common, and diffuse Lewy body disease may present as part of the multiple systems atrophy or Shy-Drager syndrome. The illness progresses at a variable rate to an end stage of severe dementia. Vascular dementias and other physical illness must be excluded.
The prevalence of diffuse Lewy body disease may have been underestimated in the past because of the difficulty of making the neuropathologic diagnosis. Lewy bodies may occur in the cortex or in subcortical regions. They may also be intermixed with plaques and tangles. When Lewy bodies occur together with the pathology of AD, the term Lewy body variant of AD is used. This condition is also referred to as the common form of Lewy body disease. The pure form of Lewy body disease lacks Alzheimer's pathologic features. This form is sometimes referred to as diffuse Lewy body disease. Both disorders are included in the more general term Lewy body dementia. Diffuse Lewy body disease may underlie the dementia associated with PD, but many such cases have AD pathology at autopsy.
The disease represents approximately 15% of dementias seen at autopsy. The age at onset is somewhat earlier than Alzheimer's and shows a greater degree of variability. There is substantial overlap with AD, and many patients exhibit mixed pathology. The mean age at onset is 68 and at death is 75 years. Men are affected more often than women.
The ApoE E4 allele is over-represented in patients with Lewy body disease. The mutant allele of CYP2D6B is a risk factor for both PD and Lewy body disease. This gene encodes an enzyme that is involved in detoxifying environmental toxins. The mutation eliminates the active form of the enzyme.
In the early stages of diffuse Lewy body disease, memory loss, inattention, and difficulty in sustaining a train of thought are characteristic. Psychiatric signs are prominent in many patients with diffuse Lewy body disease and may be the first indication of the disorder. Psychiatric symptoms include personality change, depression, hallucinations, or delusions. Weight loss is common. Extrapyramidal signs are less severe in diffuse Lewy body disease than in PD. Bradykinesia is more common than the tremor. Sometimes extrapyramidal signs are limited to the patient's gait. The anatomic location of the Lewy bodies explains some characteristics of the disorder. Diffuse Lewy body disease affects both cholinergic and dopaminergic systems.
Patients with diffuse Lewy body disease present with both cortical and subcortical neuropsychological findings. The subcortical features distinguish the condition from AD. Although not a pure subcortical dementia, diffuse Lewy body disease has prominent subcortical features.
The primary symptoms of subcortical dementias include forgetfulness, slowed thinking, and apathy. In addition, the patient's ability to manage information efficiently is reduced. Executive functions are also diminished. Memory is more disturbed for free recall than recognition. Patients with subcortical dementias are unable to profit from feedback because of poor concentration and inability to maintain set. They have difficulty sequencing and conceptualizing ideas. Another symptom is perseveration. Memory problems and visual spatial disturbances are also common but are not as severe as in AD. Subcortical dementias differ from AD in that the former are not associated with aphasia, recognition deficits, and denial of illness.
Laboratory Findings and Imaging
The hallmark of diffuse Lewy body disease is extensive Lewy body formation in the neocortex. The severity of dementia is related to the density of cortical Lewy bodies. Lewy bodies are usually found in the pigmented neurons of the substantia nigra in PD. Cortical Lewy bodies are much easier to overlook. Staining with anti-ubiquitin antibodies simplifies identification and increases the recognition of diffuse Lewy body disease. In contrast, Alz-50 immunoreactivity is small or nonexistent.
The EEG can be helpful in distinguishing between diffuse Lewy body disease and AD. Diffuse slowing and frontal intermittent delta activity are common in Lewy body disease. Significant slowing and frontal intermittent rhythmic delta are not usually present in early AD, however, slowing of the background EEG does occur in vascular dementias. Vascular dementias, particularly those caused by stroke, are likely to demonstrate focal EEG changes consistent with the underlying structural damage. Focal EEG findings are not consistent with either diffuse Lewy body disease or AD. Even though the EEG may provide useful information, EEG alone cannot reliably differentiate vascular dementias from AD or diffuse Lewy body disease.
A noninvasive diagnostic test does not exist for Lewy body disease. The most distinctive feature of the disease is the delirium-like episodes with psychotic features that occur and then remit spontaneously. Diffuse Lewy body disease shares some features with progressive supranuclear palsy, FTD, PD, AD, and normal pressure hydrocephalus. The dementia caused by the later stages of small vessel disease may also bear a striking resemblance to Lewy body dementia. Late-life psychosis, delirium, syncope, and drug toxicity must also be considered.
Because diffuse Lewy body disease affects neocortical dopamine systems, typical neuroleptic treatment of the psychiatric symptoms is usually not successful and can produce significant extrapyramidal side effects. Severe and often fatal neuroleptic sensitivity may occur in some elderly patients with dementia of the Lewy body type. Neuroleptic sensitivity may be manifested as neuroleptic malignant syndrome. Although the typical neuroleptics are not well tolerated, atypical neuroleptics such as olanzapine, clozapine, or quetiapine may produce significant antipsychotic effect without serious side effects.
The response to l-dopa is less dramatic than in other Parkinson's syndromes. Higher doses of l-dopa often produce or aggravate psychosis, and this is even more true of dopamine agonist drugs such as pramipexole or ropinirole. In contrast, depression is treatable and responds readily to antidepressant agents, often with a corresponding improvement in cognition. Antidepressants that cause orthostasis should be avoided. Some patients may need fludrocortisone to support blood pressure. Anticholinesterase agents may be of benefit for the memory disorder of Lewy body dementia; rivastigmine has recently been approved by the USFDA for the treatment of patients with PD and dementia. Neuroprotective agents such as vitamin E or selegiline may be tried, but there is no proof of their benefit.
Diffuse Lewy body disease has quite a variable course but generally progresses more rapidly than AD. The average time from diagnosis to death is approximately 6 years. The disease often presents as a psychiatric condition because of the strange and complex hallucinations and delusions. The psychiatric symptoms occur much earlier in the course of diffuse Lewy body disease than in AD. Cardinal features of fully developed Lewy body dementia include delirium, hallucinatory-delusional states, disturbed behavior, akinesia, rigidity, and orthostatic hypotension. Aphasia is notably absent. Although the cognitive impairment is progressive, there is marked daily variability. As the disease progresses, parkinsonian signs may become more severe. Involuntary movements, myoclonus, quadriparesis in flexion, and dysphagia (difficulty swallowing) occur in the final stages.
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Patients with subcortical dementias have a diagnosed disorder of deeper brain structures in the presence of a relatively unaffected cerebral cortex. These patients have problems with arousal, attention, mood, motivation, language, and memory. Subcortical dementias may occur in PD, Huntington's disease, progressive supranuclear palsy, cortical basal ganglia degeneration (now called corticobasal degeneration), Hallervorden-Spatz disease, idiopathic basal ganglia calcification, and the spinocerebellar degenerations. Subcortical dementias have also been identified in inflammatory, infectious, vascular, and demyelinating illness.
The concept of subcortical dementias unifies conceptually those conditions affecting the relationship of deeper structures to the cortex. In subcortical dementias, cerebral cortical functioning is relatively intact, but the basal ganglia are dysfunctional or disconnected. Subcortical dementias are not entirely homogeneous entities, and specific features will depend on the pathologic causes. Thus the features of the cognitive disorder observed in PD are not exactly the same as that seen in Huntington's disease or in progressive supranuclear palsy.
Estimates of the prevalence of dementia in Parkinson's patients depends on the population studied and criteria used. Estimates ranging from 30% to 50% have frequently been reported, but if neuropsychological testing criteria are used, prevalence may reach 90%. The overall prevalence rate of PD with dementia is estimated to be about 40 per 100,000.
The prevalence of Huntington's disease is about six per 100,000. Dementia is a ubiquitous feature of Huntington's disease, but the severity of impairment varies greatly among patients. There are other degenerative diseases of the basal ganglia frontal circuits that lead to subcortical dementia. Progressive supranuclear palsy, the disease in which subcortical dementia was first described, is less common than PD. Striatonigral degeneration and corticobasal degeneration can also cause subcortical dementia, though corticobasal degeneration also affects cortical structures and often presents with language and cognitive deficits. Corticobasal degeneration is associated with tau protein abnormalities and often overlaps with the FTD syndrome. Parkinsonism and apraxia of one upper limb are associated symptoms. These entities are more widely recognized with improved diagnostic techniques.
Subcortical dementias involve primarily the thalamus, basal ganglia, and related brainstem nuclei with relative sparing of the cerebral cortex. Patients with basal ganglia disease or with disease affecting basal ganglia frontal circuits develop subcortical dementias. PD is always associated with neuronal loss in the substantia nigra, leading to destruction of dopaminergic connections to the basal ganglia. As a result, subcortico–cortical pathways function defectively. Striatal dopamine depletion disrupts the normal pattern of basal ganglia function in PD and, consequently, interrupts normal transmission of information through frontostriatal circuitry. Dopaminergic transmission, along the nigrostriatal pathway, may be implicated in sustaining various cognitive and motor processes.
In addition, neuronal loss occurs throughout the CNS. Patients with dementia due to PD have significant cell loss in many other CNS structures, particularly in the basal nucleus of Meynert. The depletion of acetylcholine in the cortex is less severe than in AD. There is significant damage to the locus coeruleus, secondary loss of cortical norepinephrine, and cell loss in the raphe nucleus leading to serotonin depletion. This may explain the anxiety and depression so commonly associated with PD.
Huntington's disease has an autosomal dominant mode of inheritance. An excess number of CAG trinucleotide repeats in the 5′-translated region of chromosome 4 causes Huntington's disease. A DNA test can detect the gene before symptoms appear. Virtually 100% of patients with more than 40 repeats of the gene will manifest the disease at some point in their lives, however, the age at which the disease manifests itself is quite variable. Huntington's disease exhibits an earlier onset in successive generations of a pedigree, especially when transmitted through the father. There is greater variability of repeat length with paternal transmission, and the gene tends to have everincreasing CAG repeats. The change in repeat length with paternal transmission is correlated significantly with decreasing age at onset between the father and offspring.
The genetics of progressive supranuclear palsy have recently been clarified. Studies suggest that progressive supranuclear palsy is an autosomal recessive condition that maps to a polymorphism in the tau gene. It has been reported that a genetic variant of tau, known as the A0 allele, was represented excessively in patients with progressive supranuclear palsy in comparison to control subjects. A highly significant overrepresentation of the A0/A0 genotype and a decrease in the frequency of the A0/A3 genotype were found in patients with progressive supranuclear palsy. The presence of the tau A0/A0 genotype is a risk factor for developing the disorder, whereas A3 may be protective. PSP, made famous by the comedian and actor Dudley Moore, is also a tauopathy.
Hallervorden-Spatz syndrome is a rare, autosomal recessive neurodegenerative disorder in which iron accumulates in the basal ganglia. Extrapyramidal signs are dominant and include dystonia. Mental deterioration occurs as the disease progresses. MRI reveals marked overall low signal from the globus pallidus.
The genetics of PD are extremely complex and reflect the fact that the disorder has multiple etiologies. Several genes have been discovered in families with more than one member with PD; to date, these genetic types of PD account for less than 10% of the cases. There may be genetic factors influencing susceptibility to PD. In addition, it has long been believed that PD represents an interaction between genetic and environmental factors. A large twin study also suggests that genetic influences are less important in patients with disease beginning after the age of 50 years. In contrast, genetic influences are larger in earlier-onset disease.
Several purely genetic forms of PD have been identified. The g209a mutation in the alpha-synuclein gene has been associated with autosomal dominant PD in a number of families. Other gene loci have been reported. Different mutations in the microtubule-associated tau protein gene have been identified in several families with hereditary FTD and Parkinsonism (ftdp-17) linked to chromosome 17q21–22. Another gene, Gstp1–1, expressed in the blood–brain barrier, may influence response to neurotoxins and explain the susceptibility of some people to the parkinsonism-inducing effects of pesticides. The dopamine receptor gene has also been implicated in PD. Autosomal recessive juvenile parkinsonism and early-onset parkinsonism with diurnal fluctuation are other forms of PD with relatively clear genetic causes.
In contrast to cortical dementias such as AD, subcortical dementias are relatively circumscribed syndromes. The principal features of subcortical dementias include slowed mentation, impairment of executive function, recall abnormalities, and visuospatial disturbances. Recall is better than in AD, and overall memory impairment is not as severe. At each functional stage, patients with subcortical dementias are less intellectually impaired than are patients with AD. Subcortical dementias do not involve aphasia, agnosia, or apraxia.
Subcortical dementias may constitute a group of partially treatable forms of dementia. Subcortical dementias create a cognitive picture similar to that of major affective disorder. Moreover, if the patient becomes depressed, his or her cognitive abilities are reduced even further. Psychiatric consultation may be obtained to treat depression and apathy. Depression aggravates the memory and language impairments associated with subcortical dementias. Antidepressants may improve cognition in subcortical syndromes. Specific subtypes of cognitive impairment are related directly to the neuropathology of each disease. In progressive supranuclear palsy, behavioral and cognitive changes resemble those associated with lesions of the frontal lobes.
Symptoms of subcortical dementias may respond to psychotropic medication. Mood disorders are extremely common in subcortical dementias and may respond to antidepressants. Sometimes the cognitive deficits improve along with the mood disorder. The response of psychotic symptoms to neuroleptics is more variable. The choice of neuroleptic must be thought out more carefully. Antipsychotics may be required to control psychotic symptoms and agitation, however, many of these patients have associated movement disorders and antipsychotics may affect motor symptoms in either a positive or a negative manner depending on the specific movement disorder.
The dementias associated with PD and Huntington's disease are discussed in detail in the sections that follow. Normal pressure hydrocephalus and AIDS dementia complex also present as subcortical dementias, but will be discussed in later sections.
Cognitive changes, particularly mild impairment in memory, executive functions, attention, and information processing, occur early in Parkinson's disease. The time required to make decisions is prolonged. These effects are more noticeable if the primary symptoms are bradykinesia and rigidity. Patients who complain primarily of tremors have fewer cognitive abnormalities.
Some Parkinson's patients have only a subcortical dementia. Others are more seriously mentally impaired, and these patients appear to have either cortical Lewy bodies or plaques and tangles, suggesting AD. These patients also differ from others with the disorder in that they present a more marked severity of the extrapyramidal syndrome with predominant bradykinesia and an earlier deteriorating response to l-dopa treatment. The presence of dysphasia or other cortical deficits early in the course of the illness suggests the presence of coexisting AD. These patients are also more likely to develop a significant depression early in the course of the illness. In the presence of depression, Parkinson's patients are more likely to develop a cognitive disorder that persists even when the depression is treated.
Very early in the disease course, Parkinson's patients demonstrate mild impairment on tests sensitive to information processing speed, maintaining set, and visuospatial discrimination. Neuropsychological tests suggest that an underlying perceptual motor deficit exists in PD. Personality changes occur early whereas recall abnormalities and apathy tend to occur later. These subtle cognitive difficulties might underlie the mental inflexibility and rigidity associated with PD and could be attributed to destruction of the ascending dopaminergic and mesocorticolimbic pathway.
Parkinson's patients whose disease develops relatively late in life are prone to develop comorbid dementing illness such as AD, diffuse Lewy body disease, or vascular dementia. Neuropsychological testing can help determine whether these patients are developing a mixed syndrome, sometimes referred to as Parkinson's plus.
Laboratory Findings and Imaging
PET scans using [18F]fluorodeoxyglucose will often show hypofrontality in nondemented Parkinson's patients or in those with mild subcortical dementia. The presence of bilateral temporoparietal deficits in addition to hypofrontality suggests the coexistence of either Lewy body disease or AD.
PET scans can be used to examine glucose metabolism through the use of [18F] fluorodeoxyglucose and to examine dopamine metabolic patterns through the use of [18F] fluorodopa. [11C] raclopride can be used to examine dopamine D2 receptor binding; this ligand is not routinely available in clinical practice. These techniques hold promise for future diagnostic clarification.
In Parkinson's patients, SPECT scans demonstrate decreased frontal lobe blood flow that is more significant on the left side than on the right. Basal ganglia decrements are also visible. These changes appear to be particularly accentuated in the early stages of PD with subcortical dementia. SPECT binding studies demonstrate decreased basal ganglia binding in demented Parkinson's patients compared to nondemented Parkinson's patients. Bilateral temporoparietal deficits probably indicate concomitant AD.
NMR spectroscopy indicates an increase in cerebral lactate in patients with PD, especially in those with dementia. Finally, evoked potential studies indicate some difference between Parkinson's patients with and without dementia. Reaction time is prolonged in both groups of patients. The event-related P300 evoked potential is normal in nondemented Parkinson's patients but is prolonged in demented Parkinson's patients. Visual evoked potentials show an increased latency of P100 in demented Parkinson's patients compared to nondemented Parkinson's patients.
PD with subcortical dementia must be distinguished first from PD with coexisting Alzheimer's or diffuse Lewy body disease. Functional imaging may help. Other conditions to consider include vascular dementias and other parkinsonian syndromes such as progressive supranuclear palsy.
Many medications affect cognition in PD patients. As a rule, anticholinergic medication impairs cognition, whereas dopaminergic medication may mildly enhance it. The dosage of dopaminergic medication is important, because at higher dosages patients may become confused or hallucinate. Levodopa–carbidopa or direct dopamine agonists such as pramipexole and ropinirole are the standard initial treatments for PD. Neuroleptics may cause significant rigidity in patients with PD or diffuse Lewy body dementia. Atypical neuroleptics are usually preferred in these patients because standard neuroleptics cause extrapyramidal side effects, tardive dyskinesia, and neuroleptic malignant syndrome. Clozapine or quetiapine may be preferred neuroleptics for patients with subcortical dementias because these atypical agents may improve psychotic symptoms without adverse motor effects.
ECT has been used in the management of psychiatric complications in PD. Not only do affective symptoms respond, but motor symptoms improve. Unfortunately patients with dementia due to PD may develop post-ECT delirium. Nonetheless, ECT remains an occasionally used treatment for intractable depression associated with PD. The dosage of antidepressant or number of ECT treatments should be considered together with anti-parkinsonian therapies. Demented parkinsonian patients often experience side effects after taking anti-parkinsonian medication. As a result, the clinician should be inclined to treat the motor symptoms conservatively in order to minimize cognitive side effects. The use of rivastigmine for dementia associated with PD was discussed above, under Lewy body dementia.
Patients with PD who become demented are older, have a longer duration of disease, and a later age at onset than those who do not become demented. Age is the biggest risk factor. The development of dementia is strongly related to the age at which the patient developed motor manifestations. In some patients, cortical Lewy bodies cause the dementia. Although most patients with PD do not have AD, some Parkinson's patients have dementia that is due to the coexistence of AD. The dual diagnosis of Parkinson's and AD is associated with a particularly poor prognosis.
The cognitive deficits evident in early PD do not progress to dementia in all patients. When dementia does develop, the symptoms are quite heterogeneous. Patients with Parkinson's dementia have a great deal of difficulty with tasks that involve visual and spatial orientation. Intellectual ability begins a global decline in PD with dementia, but memory is more severely impaired than are language and other cortical functions. Episodic memory (i.e., memory for items relating to date and time) is especially distorted. Although the patient can drive an automobile, decline in spatial memory may make following directions difficult and slowed reaction time makes driving dangerous.
The association between depression and PD has been recognized for more than 150 years. Depression affects up to 50% of Parkinson's patients and is more pronounced during the early stages of the illness. Affective disorder aggravates the poor concentration and impaired information processing associated with PD. The treatment of depression tends to improve some of these cognitive deficiencies.
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Progressive Supranuclear Palsy
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Dementia Due to Huntington's Disease
Huntington's disease often has a delayed onset, with a mean age at onset of about 40 years. Progressive cognitive decline is a cardinal feature of Huntington's disease, however, mild deficits in cognitive function are an early finding. Severe mental deterioration is apparent later in the disease. The onset is proportional to the number of cytosine-adenine-guanine (CAG) repeats in the Huntington's disease allele, although the degree of cognitive deficit is not proportional to the number of CAG repeats but rather to chronicity of the illness.
Huntington's disease usually presents with choreiform movements, but it can present as incipient dementia or depression. As the disease progresses, all patients become demented. The cognitive changes are quite varied, even in the late stages of the illness.
The dementia develops slowly and is consistent with damage to pathways linking the frontal areas to the striatum. Prominent complaints are apathy, slow information processing, and problems in maintaining attention. Difficulty with attention and concentration is more pronounced than in PD. Compared to patients with AD, those with Huntington's disease have less memory impairment. Cortical symptoms such as aphasia, agnosia, and apraxia are less common in Huntington's than in AD.
Most patients with Huntington's disease develop prominent psychiatric symptoms. Depression is the most common symptom, but up to 10% of patients have symptoms resembling bipolar disorder. Irritability, personality change, and other behavioral problems are also common. Frontal lobe impairment results in poor judgment that may lead to embarrassing or even illegal activities. A paranoid psychosis is common in Huntington's patients.
Huntington's patients initially show difficulty with attention tasks. Other early deficits include psychomotor speed and the ability to shift set. Go/no-go tasks are impaired early as are other tasks that require internal cues. Huntington's patients are unable to maintain divided attention and to perform tasks in which multimodal sensory information is provided. When compared to Alzheimer's patients, Huntington's patients demonstrate greater impairment on the initiation/perseveration subscale of the DRS. Alzheimer's patients demonstrate greater impairment on the memory subscale than do Huntington's patients. Constructional praxis becomes apparent at moderate and severe levels of dementia in Huntington's patients but appears relatively early in Alzheimer's patients.
Laboratory Findings and Imaging
At autopsy, there is a marked decrease in small cholinergic neurons in the striatum, with low levels of choline acetyl transferase. The disease also damages the small cells containing GABA. Consequently the basal ganglia have decreased concentrations of GABA. Acetylcholine-containing neurons in the basal nucleus of Meynert are preserved. The dopaminergic system is also spared. In Huntington's disease, brain imaging reveals atrophy in the caudate nucleus, reflecting this loss of neurons.
CT scans and MRI show atrophy of the basal ganglia years before the development of symptoms. The putamen is less affected than the caudate. PET scans show striatal hypometabolism in the brains of Huntington's patients early in the course of the disease. Asymptomatic carriers can be identified with 86% sensitivity and 100% specificity. Glucose metabolism decreases at a rate of about 2% per year. Raclopride binding is decreased by about 6% per year and correlates with the number of CAG repeats. The easy availability of the genetic test for Huntington's disease has made brain imaging less crucial in this disease.
Huntington's disease must be differentiated from other choreiform disorders. The existence of a specific genetic test has aided greatly in diagnosis. The most compelling question of differential diagnosis is whether to perform this test on asymptomatic individuals who have not yet developed the disease; in general, this should be reserved for genetics clinics with counseling readily available.
Patients with Huntington's disease may experience an improvement in chorea from neuroleptics but may concurrently experience cognitive decline. Affective disorder is extremely common in HD patients. Mood-stabilizing agents, particularly lithium, can be helpful. Ten percent of patients become psychotic. Clozapine can be used effectively in psychotic Huntington's patients. Other patients show prominent obsessive–compulsive features. Chlorimipramine may be effective for associated obsessive–compulsive disorder. An interesting finding is that psychiatric illness is increased significantly in patients who are at risk for the disease but in whom later genetic testing reveals the absence of the HD gene. This finding emphasizes the need for considerable counseling and social support in this disease.
The prognosis of HD is universally fatal. The later the onset of Huntington's disease the greater the probability that cognitive decline will be minimal, however, 60% of Huntington's patients develop features typical of subcortical dementia. Initially chorea predominates, but later the patient becomes rigid. Striatal damage progresses at a rate that is determined by the length of the CAG repeat. If the patient is affected by psychiatric illness, particularly affective disorder, there is a high prevalence of suicide. The relationship between the severity of chorea and dementia is robust, particularly regarding memory loss. The degree of cognitive disability is ultimately related to the chronicity of the illness but not to the length of the CAG repeat.
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Vascular dementias are a varied group of disorders. The true incidence of dementia cases that represent pure vascular dementia is unknown. Because of the variety of types of vascular diseases, the diagnosis of this disorder has been problematic. Cases with mixed vascular disease and AD are likely the second most common dementia, after AD itself.
DSM-IV Diagnostic Criteria
The development of multiple cognitive deficits manifested by both
memory impairment (impaired ability to learn new information or to recall previously learned information)
one (or more) of the following cognitive disturbances:
aphasia (language disturbance)
apraxia (impaired ability to carry out motor activities despite intact motor function)
agnosia (failure to recognize or identify objects despite intact sensory function)
disturbance in executive functioning (i.e., planning, organizing, sequencing, abstracting)
The cognitive deficits in Criteria A1 and A2 each cause significant impairment in social or occupational functioning and represent a significant decline from a previous level of functioning.
Focal neurological signs and symptoms or laboratory evidence indicative of cerebrovascular disease that are judged to be etiologically related to the disturbance.
The deficits do not occur exclusively during the course of a delirium.
(Adapted with permission from Diagnostic and Statistical Manual of Mental Disorders, 4th edn. Copyright 1994 American Psychiatric Association.)
- Diagnostic subclassifications and the concept of vascular dementia are very much in flux. The Hachinski Scale is used primarily to exclude vascular dementia when studying AD. The criteria from the National Institute of Neurological Disorders and Stroke and from the European Association Internationale pour la Recherche et l’Enseignement en Neurosciences are more specific in regard to etiology and are more flexible.
Because such a large number of possible etiologic mechanisms exist, the clinical features related to vascular dementia differ from one patient to another. Vascular dementias have many causes: Small vessel disease, multi-infarct dementia, strategic strokes, cerebral hypoperfusion, vasculitis, subarachnoid hemorrhage, genetic causes, and cerebral amyloid angiopathy. Recent neuroimaging studies have revealed that vascular dementias may be more common than previously supposed.
Factors in cerebrovascular disease leading to vascular dementia include (1) volume of lesion (e.g., one large lesion or several small lesions), (2) number of cerebral injuries, (3) location of cerebral injury (e.g., cortical lesions produce a different form of dementia than do subcortical lesions; strokes in strategic locations may produce dementia), (4) white-matter ischemia due to small vessel disease, and (5) co-occurrence of vascular disease and AD or another dementing process.
Vascular dementias may be more amenable to prevention and treatment than is AD. Generally, the risk factors for vascular dementias are the same as those for strokes: Hypertension, diabetes mellitus, advanced age, male sex, smoking, and cardiac disease.
Dementia Due to Small Vessel Disease
Small vessel disease can cause a subcortical dementia syndrome. Personality and mood changes are frequent. Psychomotor retardation and poor judgment accompany memory deficits. Binswanger's disease is an extreme form of this condition and is characterized by pseudobulbar signs, abulia, and significant mood and behavior change. Binswanger's disease is associated with multiple small areas of hemispheric softening and demyelination. It occurs mainly in hypertensive males. In most cases, there is not only atherosclerosis of the extracranial arteries but also fibrous and muscular thickening of the small vessels.
Small vessel disease can cause cortical and subcortical lesions. Imaging studies can identify these lesions, often referred to as leukoaraiosis, or ischemic deep white-matter disease. Imaging studies identify excessive CNS water caused by damage to the capillaries and postcapillary venules: Collagen is deposited in the media and adventitia and may eventually block the lumen of the arteriole, ultimately affecting the regulation of blood flow in the brain parenchyma. The result is a characteristic pathologic change in the nervous system: rarefication of the white matter. This finding on MRI scans is extremely common in elderly people, whereas Binswanger's disease is rare in autopsy series. To qualify as a stroke, white matter lesions must be clearly dark on CT or on T1-weighted MRI. Most ischemic changes in the white matter are bright on T2 and Fluid-Attenuated Inversion Recovery (FLAIR) but not clearly dark on T1. The correlates of ischemic white matter changes with behavioral and cognitive measures have been controversial. The presence of these lesions correlates both with age and with vascular risk factors such as hypertension. In some series, cognitive decline has correlated with the degree of white matter ischemic change, but many normal people have some degree of white matter change. Neurologists and psychiatrists spend a great deal of time explaining the significance of “ischemic white matter changes” on MRI to patients and families. Anxiety, depression, and overall severity of neuropsychiatric symptoms are also associated with white-matter ischemia.
The effects of small vessel disease are synergistic with lacunar infarcts. PET research has shown that reduction in cortical metabolism is related to the severity of subcortical pathology. Pathology in the subcortical nuclei greatly influences the metabolism of the frontal cortex.
Lacunar infarcts are small, punctate lesions usually found in the deep white matter, basal ganglia, and brainstem. Multiple lacunar strokes or a few larger strokes can lead to multi-infarct dementia. Hypertension is the greatest risk factor. Previous strokes or myocardial infarction often precede dementia; as compared to AD, most patients have had abrupt, stroke-like events. Previous strokes and cortical atrophy are also correlated with dementia.
Multi-infarct dementia advances in stepwise fashion. The clinical signs and symptoms of the disease are associated with changes in MRI, CT scan, and EEG. The Hachinski Scale is a rating scale based on clinical course and illness features that is intended to assess the probability of multi-infarct dementia. Mean Hachinski ischemic scores of 10 predict the presence of infarcts in 93% of patients. Small, localized strokes in brain areas that are functionally important cause well-recognized conditions such as Weber's or Wallenberg's syndromes, however, these lesions may not cause dementia. In patients with multi-infarct dementia, the deep middle cerebral artery territory supplied by the lenticulostriate branches is most likely to be affected. Bilateral infarcts are very common.
A subcortical dementia can sometimes develop in patients with strokes. Paramedial mesencephalic and diencephalic infarcts cause cognitive and affective disorder closely resembling that associated with subcortical degenerative disorders. In these cases, CT scans or MRI sometimes delineate clinical anatomic relationships that account for specific constituents of the syndrome. Dementia resulting from small deep infarctions may involve disease in the same cholinergic projections from the deep frontal nuclei to the cerebral cortex involved in AD. Multiple lesions are thought to have a cumulative effect on mental function.
Dementia Due to Strategic Strokes
Strategic single infarcts in specific areas of the brain can cause dementia. Patients who have strokes in the left supramarginal or angular gyrus may develop profound difficulties with comprehension. Strategic strokes in the frontal lobes or in the nondominant parietal lobe can lead to significant reduction in cognitive abilities. Right temporal lesions can be associated with acute confusional states. One or more strategically placed strokes can therefore lead to dementia. The most common single strokes associated with dementia would be major middle cerebral artery strokes on either side, posterior cerebral strokes that affect the hippocampus, and frontal lobe strokes.
Stroke patients are prone to affective disorder that can affect recovery. About 40% of stroke patients develop poststroke depression. In some studies, depression correlates with infarctions in the left hemisphere and frontal more than posterior location. Systemic vascular disease, drug therapy, and psychological reactions to disability contribute to poststroke depression. Subcortical atrophy may predispose to the development of poststroke depression. Patients with ventricular enlargement may be more likely than those without atrophy to develop major depression following a left frontal or left basal ganglia lesion. Whereas left-hemisphere injury leads to early depression, right-hemisphere lesions and preexisting subcortical atrophy predispose to delayed onset of depression, and occasionally to mania.
Each brain hemisphere has a different biochemical response to injury. PET scan findings suggest the biochemical response of the two hemispheres to stroke may be different. Right-hemisphere stroke increases serotonin-receptor binding. This does not occur following comparable left-hemisphere stroke. The lower the serotonin binding within the left hemisphere, the more severe the depression is likely to be. This finding suggests that the right, not the left, hemisphere produces biochemical “compensation” for damage by increasing serotonin binding in the noninjured regions. After a stroke, depression may be a result of the failure to up-regulate serotonin receptors. Other factors influencing the differences between hemispheres in poststroke depression undoubtedly include the dominance of the right hemisphere for emotions, such that damage to the right hemisphere causes emotional flatness or apathy, and the presence of neglect of deficit in right hemisphere stroke patients (see below), which often results in a delayed onset of poststroke depression. Nondepressed patients experience less cognitive impairment than do depressed patients. Structural neurologic damage may produce either classic affective disorder or disorders of affective expression and personality that bear little resemblance to classic affective disorder. Stroke patients with depression often respond to antidepressant treatment.
The expression and understanding of affect are right-hemisphere functions. Evaluation of mood disorders in patients with right-hemisphere damage requires consideration of alterations of affective communication. Depression may be underdiagnosed in patients with right temporoparietal lesions. These patients are often unable to understand nuances of affect. Common cognitive complications of right parietal dysfunction include denial of illness, hemi-inattention (lack of attention to one side of the body), constructional apraxia, and spatial discrimination. Patients with right posterior lesions may not verbally acknowledge depressed feelings. They may appear emotionally flat, or indifferent. A late-onset depression may occur in these patients.
Right frontal lobe damage causes expressive aprosodia (impairment in the normal variations of speech), an inability to express nuances of affect. Affective explosiveness, a temporal lobe function, is preserved. Depressed patients with expressive aprosodia do not appear depressed during a psychiatric interview.
With left-hemisphere lesions, language impairment complicates the diagnosis of affective disorder. Patients with Broca's aphasia exhibit nonfluent speech, impaired writing, defective naming, and (usually) hemiparesis (one-sided paralysis). Verbal acknowledgment of a depressed mood may be difficult to elicit. In spite of diagnostic difficulties, the incidence of depression in patients with unilateral left frontal lobe damage is striking. The putative mechanism is interruption of catecholamine axons to, and arborization in, the cerebral cortex. Comprehension deficits in patients with posterior aphasia make accurate diagnosis of affective disorder difficult. Clinically, posterior aphasia can resemble either dementia or affective disorder. Speech is fluent and associated neurologic deficits often subtle, however, neologisms and paraphasic errors punctuate the speech of patients with Wernicke's aphasia. In addition, Wernicke's patients exhibit impaired reading, writing, naming, repetition, and comprehension. Patients with left posterior lesions display exaggerated affect because the main remaining vehicle of communication is affective expression. When their speech is not understood, they may become angry or even paranoid.
Left parietal dysfunction can mimic AD because it produces ideomotor apraxia, right-left disorientation, finger agnosia, amnestic aphasia, dyslexia (inability to read, spell, and write words), dysgraphia (difficulty in writing), and acalculia (inability to do simple arithmetic calculations). Right parietal dysfunction causes left spatial neglect and “dressing apraxia.” These patients do not usually have as great a memory impairment as do AD patients. Some visuospatial disruption attends normal aging. Neuropsychological evaluation distinguishes normal elders from those with parietal disorder or dementia.
Clinical deterioration may occur in brain-disordered patients without a new lesion. Erratic recovery and poor cooperation during rehabilitation suggest affective disorder. Pathologic laughing or crying, depressive propositional language, and perhaps abnormal dexamethasone suppression test suggest depression. Bilateral hemispheric dysfunction may cause excessive crying.
Differentiating Frontal Lobe Disorder from Depression
Several characteristics differentiate frontal lobe disorder from depression. Frontal patients are apathetic and not deeply depressed. Frontal personality changes are more dramatic than are those in depression. Frontal lobe systems are responsible for affect modulation. When these systems disconnect from brainstem centers, pseudobulbar affect develops. Patients who feel a fleeting emotion may be unable to inhibit a prolonged affective display such as crying. The phrase “emotionally incontinent” is sometimes applied to these patients because of their inability to inhibit emotional expression. Patients with frontal lobedisease often have impaired insight and judgment. They are perseverative concerning some social responses, yet they may be unable to initiate others. As a result, they can appear bizarre in social settings.
Dementia Due to Cerebral Hypoperfusion of Watershed Areas
Hypotension, decreased volume of body fluids, cardiac arrhythmias, and other causes of hypoperfusion can cause ischemia in the watershed areas between the major sources of cerebral arterial supply. Significant watershed strokes can lead to serious disconnection syndromes. Lesions circling Broca's area cause a transcortical motor aphasia. Transcortical motor aphasia displays elements of Broca's aphasia with intact repetition. Patients with transcortical motor aphasia have decreased speech production (abulia). Mild forms of the disorder can be identified by poor performance on the FAS test and on other frontal lobe tests.
Watershed lesions surrounding Wernicke's area cause transcortical sensory aphasia. This syndrome is similar to Wernicke's aphasia, but repetition remains intact. The most severe form of watershed infarct causes isolation of the speech area. In this condition the entire language apparatus is disconnected from other brain structures. Echolalia is the only form of speech of which the patient is capable.
Bilateral strokes in the posterior parts of the hemispheres can result in complex neurobehavioral deficits such as visual agnosia, prosopagnosia (inability to recognize familiar faces), or auditory agnosias. These deficits are often explained by disconnections between sensory input and centers that interpret the information. Unilateral left posterior cerebral artery territory strokes are associated with alexia without agraphia, and severe memory disorder. These cognitive deficits can contribute to vascular dementia.
Dementia Due to Cerebral Vasculitis
Autoimmune vasculitis is an uncommon cause of dementia. Systemic vasculitis that affects the CNS occurs most often in conjunction with collagen vascular disease (such as polyarteriitis nodosa).The most common autoimmune disease associated with stroke is systemic lupus erythematosus, but this disease is associated with antineuronal antibodies that cause delirium and antiphospholipid antibodies associated with stroke; a true vasculitis is rare. Antiphospholipid antibodies can also be associated with stroke syndromes in patients who do not have lupus. CNS vasculitis can occur in isolation (e.g., granulomatous angiitis or isolated CNS vasculitis). Infectious diseases such as neurosyphilis and Lyme disease can cause CNS vasculitis, which can be extremely difficult to diagnose but should be considered in the presence of any rapidly progressing dementia.
Dementia Due to Subarachnoid Hemorrhage
Subarachnoid hemorrhage causes intense vasospasm, which can lead to significant ischemia. This ischemia can cause a dementing syndrome that persists after the subarachnoid hemorrhage has resolved.
Dementia Due to Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts & Leukoencephalopathy (CADASIL)
CADASIL is an inherited arterial disease of the brain recently mapped to chromosome 19p13.1. Features of the disorder include recurrent subcortical ischemic events, progressive or stepwise subcortical dementia, pseudobulbar palsy, migraine with aura, and severe depressive episodes. Attacks of migraine with aura occur earlier in life than ischemic events. The diagnosis should be considered in patients with recurrent small subcortical infarcts leading to dementia that also have transient ischemic attacks (TIAs), migraine with aura, and severe depression. Demented patients exhibit frontal, temporal, and basal ganglia deficits on SPECT scans despite the relative absence of focal neurologic findings.
Dementia Due to Cerebral Amyloid Angiopathy
Cerebral amyloid angiopathy is the term given to a condition in which amyloid is deposited on the walls of small arteries and arterioles, weakening the blood vessels and leading to an increased incidence of intracerebral hemorrhage. Amyloid angiopathy can also interfere with blood flow in small vessels and contribute to deep white-matter ischemic changes. The hemorrhages are lobar, may be recurrent, and often occur in patients without hypertension. Cerebral amyloid angiopathy often occurs within the context of AD and is a cause of mixed vascular-Alzheimer's dementia.
See discussions of individual dementias.
The neuropsychological deficits in vascular dementias tend to be variable and depend on both the underlying pathology and the location of the lesion. Although memory is almost always affected, executive, subcortical, and frontal lobe functions may exhibit significant deterioration. Patients with vascular dementias generally have better language function and better memory than do those with AD (unless the language areas are directly affected by strokes).
Neuropsychological findings in vascular dementias depend heavily on the volume and location of the infarct. Usually multiple forms of vascular pathology contribute concurrently to the overall findings of vascular cognitive impairment.
Laboratory Findings and Imaging
A variety of clinical laboratory findings may be indicated in the investigation of vascular dementias. A complete blood count, sedimentation rate, blood glucose, and ECG are obtained routinely. Often a carotid Doppler, transesophageal echocardiography, and Holter monitor (recording ambulatory ECG) add to the investigation. In some cases, coagulation screen, lipid profile, lupus anticoagulant, anticardiolipin antibodies, and autoantibody screens may be necessary. Cerebral angiography may be necessary to diagnose cerebral vasculitis but is not routinely obtained. If an infection or inflammation is suspected, then a spinal tap may be helpful.
MRI is the most helpful radiologic tool in the diagnosis of vascular dementias, but CT scans may be helpful in some cases. Patchy diffuse white-matter lucency on CT scan or hyperintensity on MRI suggests leukoaraiosis. Normal scans may show lesions that are punctate or partially confluent. The aging brain becomes susceptible to an assortment of changes in the periventricular and subcortical white matter. These changes are radiolucent on CT scans and hyperintense on T2-weighted MRI. White-matter changes are common in patients with chronic hypertension. Examination of affected tissues reveals dilated perivascular (Virchow-Robin) spaces, mild demyelination, gliosis, and diffuse neuropil vacuolation. The associated clinical abnormalities are usually not serious, but defects of attention, mental processing speed, and psychomotor control may be evident, although usually only through neuropsychological testing. As a result, significant overlap occurs between the scans of normal patients and those who have clinically significant vascular disease. These changes also appear in early AD, making the interpretation of early disease more difficult. Leukoaraiosis is associated with increased age, hypertension, limb weakness, and extensor-plantar responses. Some patients have extensive deep white-matter brain lesions without detriment to cognitive, behavioral, or neurologic functioning.
Pathology becomes evident when periventricular capping and plaque-like hyperintensities become confluent. When these changes are at their most severe, the diagnosis of Binswanger's disease can be suspected. Lesions that distinguish patients with vascular dementias include definite infarctions, dark on T1 and bright on T2 weighted MRI scans. Irregular periventricular hyperintensities extending into the deep white matter and large confluent areas of deep white-matter hyperintensity likely contribute, but these alone cannot be used to diagnose vascular dementia. These abnormalities are associated with extensive arteriosclerosis, diffuse white-matter rarefication, and even necrosis. In general, the hyperintensities associated with AD are smaller.
A relationship exists between the extent of MRI abnormality and dementia, in population studies, but not in individual patients. MRI white matter abnormalities relate to advanced age, vascular risk factors, and loosely to degree of cognitive impairment. In CADASIL, MRI reveals prominent signal abnormalities in the subcortical white matter and basal ganglia. Cognitive impairment is linked to signal abnormalities and hypoperfusion in the basal ganglia.
31P NMR spectroscopy profiles may be helpful in the evaluation of vascular dementias. Patients with vascular dementias exhibit elevations of the phosphocreatine/inorganic orthophosphate ratio in tempo roparietal and frontal regions.
PET scans may be helpful in diagnosing vascular dementias. They may demonstrate focal areas of hypometabolism that correspond roughly to areas of impairment discovered on neuropsychological testing. Hypometabolism, even without atrophy, is visible on anatomic images. Areas of hypometabolism seen on PET scans conform to cortical high-signal intensity on MRI. In addition, cerebral metabolism is reduced globally because isolated lesions have extensive and distant metabolic effects. The pattern of hypometabolism observed in vascular dementias is distinct from that observed in AD. Vascular dementias are associated with multiple defects in the cortex, deep nuclei, subcortical white matter, and cerebellum. Dementia increases as global and frontal hypometabolism evolve. Consequently, PET scans detect more widespread brain involvement than does structural imaging. In AD, hypometabolism can involve areas that appear structurally normal on MRI, but in vascular dementia the two imaging modalities correlate better. SPECT scans of patients with vascular dementias show varying degrees of irregular uptake in the cerebral cortex, similar to that seen in PET scans. In SPECT studies of individuals affected with CADASIL, cerebral blood flow reduction matched with MRI signal abnormalities.
EEG often shows focal slowing corresponding to areas of cerebral ischemia or infarction. These areas of slowing may be demonstrated visually on EEG brain maps. Computer-analyzed EEGs use mathematical formulas to break the EEG into power distributions across frequencies. This technique reveals decreased alpha power and increased theta power and delta power that parallel the degree of dementia. The ratio of high-frequency to low-frequency electrical activity in the left temporal region is decreased. Compared to AD, vascular dementias are associated with lower EEG frequency and reduced synchronization. Somatosensory evoked potentials show prolonged central conduction time and a reduction of the primary cortical response amplitude in multi-infarct dementia but not in AD.
Prevention is important in vascular dementias. Control of hypertension is probably the single most important preventive measure, however, caution must be taken not to lower the blood pressure too much and thus cause hypoperfusion. Control of diabetes, cholesterol and lipid management, and abstinence from cigarettes are also important. Treatment of atrial fibrillation can prevent embolic strokes. Although anticoagulants are highly effective for preventing cardioembolic strokes, their effectiveness in noncardioembolic strokes is uncertain. Antiplatelet agents, including aspirin, clopidogrel, or aspirin and extended release dipyridamole have been shown to reduce the incidence of second strokes. These agents are likely beneficial also in patients with vascular dementia. Diagnosis and surgical or endovascular treatment of carotid disease is also important in patients with TIA and stroke secondary to carotid artery stenosis. Pentoxifylline has been tested but has demonstrated limited efficacy. In cases of either systemic or cerebral vasculitis, high-dose corticosteroids may prevent further cognitive loss. As yet, no specific agent has been approved for vascular dementia itself, though clinical trials have supported efficacy of anticholinesterase medications.
Vascular dementias shorten life expectancy. Three-year mortality is almost three times greater in the very elderly than in age-matched controls. About one-third of patients die from dementia itself; the others die from cerebral vascular disease, cardiac disease, or other, unrelated conditions (Tables 14–1 and 14–2).
Table 14–1. Hachinski Ischemic Score* ||Download (.pdf)
Table 14–1. Hachinski Ischemic Score*
Relative preservation of personality
History of hypertension
History of strokes
Evidence of associated atherosclerosis
Focal neurological symptoms
Focal neurological signs
Table 14–2. California Criteria for Ischemic Vascular Dementia (IVD) (Chui ET Al., Neurology, 1992) ||Download (.pdf)
Table 14–2. California Criteria for Ischemic Vascular Dementia (IVD) (Chui ET Al., Neurology, 1992)
Dementia established by clinical examination
Progressive worsening of cognitive function
Evidence of at least two strokes by clinical or neuroradiological criteria
Evidence of at least one hemisphere infarct by CT or MRI (T1-weighted)
Diagnosis of definite IVD requires neuropathology
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Dementia Due to Cerebral Infection & Inflammation
Infectious processes can cause a sustained, progressive loss of intellectual function. The diagnosis of dementia due to cerebral infection or inflammation is made when the infectious process can be established as a causal agent of the dementia.
Neurosyphilis is the classic dementia due to an infectious process. More recently, the AIDS dementia complex has become the most common form of infectious dementia. Other viral causes of dementia include herpes simplex, progressive multifocal leuko encephalopathy, and subacute sclerosing panencephalitis. Any severe encephalitis can cause a subsequent dementia. Creutzfeldt-Jakob disease is an uncommon cause of rapidly developing dementia caused by a prion, a novel infectious entity that produces a spongiform encephalopathy.
Dementia Due to HIV Disease, Opportunistic Infection, or Multifocal Leukoencephalopathy
Dementia due to HIV disease is often referred to as the AIDS dementia complex, which eventually affects about 15% of AIDS patients.
Early in HIV infection, patients are likely to experience an acute encephalitis or aseptic meningitis. In HIV-infected patients, impaired memory and reduced psychomotor speed are more common than is global intellectual deterioration. HIV-induced neuropsychological impairment does not correlate with subjective complaints, neurologic signs, reduced T4 lymphocytes, CSF abnormalities, EEG slowing, atrophy on brain CT scan, or nonspecific hyperintensities on brain MRI. Dementia, cancer of the CNS, and opportunistic infection present later in HIV infection.
AIDS dementia complex is characterized by a clinical triad of progressive cognitive decline, motor dysfunction, and behavioral abnormality. Early symptoms include memory difficulty and psychomotor slowing. Behavioral symptoms include apathy and social withdrawal. It can be difficult to distinguish the AIDS dementia complex from depression, and the pattern of dementia is subcortical. Eventually, cognitive and motor impairment progresses, leading in the final stages to global dementia and paraplegia. Although the AIDS dementia complex may present at any stage of HIV infection, it usually appears relatively late in the course of the disease. The mean survival time in patients with AIDS dementia complex was 7 months before the introduction of protease inhibitors.
Patients with the AIDS dementia complex have a neuropsychological profile consisting of decreased motor speed, decreased memory, and failure on frontal lobe tasks. The HIV Dementia Scale tests specific abilities including timed motor tasks, frontal lobe function, and memory. The test is easy to administer and may be used to follow the patient's progress and response to treatment. Physical findings in the HIV dementia complex include hyperreflexia and hypertonia.
Laboratory Findings and Imaging
In the AIDS dementia complex, HIV probably enters the CNS through macrophages that cross the blood–brain barrier. These macrophages infect microglia. In the AIDS dementia complex, the HIV virus can be detected in macrophage- and glial-activated cells in the white matter and deep gray matter. Activated macrophages and microglia probably cause dementia through the secretion of neurotoxins that cause neuronal depopulation and a loss of dendritic arborization. The most common neuropathologic finding is a diffuse destruction of white matter and subcortical gray matter.
Sixty percent of patients show a slightly elevated spinal fluid protein. There may also be an elevated IgG fraction and oligoclonal bands. CSF lymphocytosis may occur; the CD4/CD8 ratio mirrors that of the peripheral blood. HIV can usually be isolated directly from the CSF.
Brain imaging is essential in the evaluation of patients with the AIDS dementia complex because infection with the human immunodeficiency virus-type 1 (HIV-1) predisposes the individual to a number of opportunistic CNS infections and tumors. In order to diagnose the AIDS dementia complex, the clinician must exclude these opportunistic infections, including progressive multifocal leukoencephalopathy, toxoplasmosis, tuberculosis, and cryptococcosis. On MRI and CT scans, the brains of patients with the AIDS dementia complex demonstrate atrophy. MRI shows scattered white-matter abnormalities.
Diagnostic uncertainty may exist in severe cases. Progressive multifocal leukoencephalopathy produces focal white-matter abnormalities due to multiple foci of demyelination. PET brain imaging techniques help to distinguish opportunistic infections from intracerebral lymphoma.
The most effective therapy is to reduce the number of viruses with antiretroviral agents such as 3′-azido-3′deoxythymidine (AZT). AZT can improve the mental function of HIV-infected patients. If AZT therapy is not initially effective, the dosage can be increased to the patient's ability to tolerate side effects or another antiviral agent can be added. Protease inhibitors have a similar effect, and multidrug regimens are now the standard treatment of HIV. Psychostimulants have been reported to provide symptomatic relief in some patients.
In the early stages of the illness, the AIDS patient experiences forgetfulness, lapses in concentration, and social withdrawal. Cognitive and motor slowing are prominent. The memory problem is mild compared to that observed in AD. Patients retain a relatively good sense of self-awareness and rarely experience the denial of illness that often occurs in other dementias. As the disease progresses patients become unable to perform activities of daily living. Motor function is affected simultaneously. Patients become unable to walk or require a walker and personal assistance. In the final stages of the disease, patients are nearly vegetative.
Dementia Due to Other Viruses
Herpes simplex encephalitis damages the temporal lobes. The disease can present initially with confusion or psychiatric symptomatology. Later the patient develops a severe headache, fever, often seizures, and confusion. MRI and CSF examination are helpful for early diagnosis. A specific EEG pattern is associated with the disorder. Early recognition is essential so that antiviral therapy can be initiated. If the disease progresses, the patient may be left with rather severe deficits. Klüver-Bucy syndrome, an amnestic syndrome, or global dementia are common residuals of herpetic encephalitis.
Progressive multifocal leukoencephalopathy generally occurs in older immunocompromised patients. It may also occur in the later stages of AIDS. This disorder proceeds extremely rapidly, and death usually occurs within months. Subacute sclerosing panencephalitis is a rare disease of late childhood caused by measles virus. It has become extremely rare since the measles vaccine was introduced. Sporadic encephalitis is another uncommon cause of dementia.
Dementia Due to Neurosyphilis
Neurosyphilis, caused by the spirochaete bacterium Treponema pallidum, was historically a major cause of dementia, but it is a rare diagnosis in the current era. Neurosyphilis presents as a vascular occlusive disease. The meninges may appear thickened and inflamed. Neuroimaging may show infarction, arteriitis, cortical lesions, or meningeal enhancement. The basal areas of the brain are preferentially affected, leading to frontal and temporal lobe dysfunction.
Neurosyphilis frequently causes psychiatric symptoms such as labile affect, depression, or mania. Patients are usually moderately demented but experience a preponderance of personality disturbances. The Argyll Robertson pupil (the pupil accommodates but does not react to light) is observed occasionally, but many patients become demented without exhibiting this sign. Tabes dorsalis, with posterior column sensory loss and lightening pains, is an associated finding in some patients.
A variety of screening tests are used to establish the possibility of syphilitic infection. Once the infection is suspected, a spinal tap is indicated. The diagnosis of neurosyphilis is made by performing the Venereal Disease Research Laboratory (VDRL) test on the patient's CSF.
The principal mode of treatment for neurosyphilis is intravenous penicillin. The decision to retreat a patient who has already had a course of penicillin is difficult to make and is usually based on the patient's clinical response, CSF cell count, and protein concentration. Even after successful treatment of the infection, the patient may continue to have significant deficits. VDRL titer may be an indicator of continued T. pallidum activity in patients without obvious clinical deterioration.
Neurosyphilis can occur decades after the original infection. It is not uncommon for an elderly woman to present with this disorder, having been infected many years earlier by her spouse. Early symptoms include fatigue, personality change, and forgetfulness. Neurosyphilis is a great imitator and can produce almost any psychiatric or cognitive disorder. Late in the disease the patient becomes confused and disoriented. Myoclonus, seizures, and dysarthria are common.
Dementia Due to Lyme Disease
Lyme disease is a multisystemic illness that can affect the CNS, causing neurologic and psychiatric symptoms. It is caused by the spirochaete Borrelia burgdorferi, which enters the host after a bite by a deer tick.
Lyme disease may involve either the peripheral or the CNS. Dissemination to the CNS can occur within the first few weeks after skin infection. Like syphilis, Lyme disease may have a latency period of months to years before symptoms of late infection emerge. A broad range of psychiatric reactions have been associated with Lyme disease including dementia, psychosis, and depression.
Dementia Due to Creutzfeldt-Jakob Disease
An unusual infectious agent, known as a prion, leads to Creutzfeldt-Jakob disease (CJD), a condition associated with a rapidly progressive dementia. There are three forms of Creutzfeldt-Jakob disease: Infectious, sporadic, and inherited. Until recently, the infectious variety was usually iatrogenic, however, the addition of sheep brain to cow feed in Britain has led to an outbreak of an atypical variant of the disease, bovine spongiform encephalopathy (“mad cow disease”) among beefeaters in Britain.
The majority of patients with CJD present with myoclonus, exaggerated startle responses, seizures, and pyramidal signs. Although most cases are sporadic, 10–15% are familial. Gerstmann-Straussler syndrome is a rare familial dementia caused by a prion and related to Creutzfeldt-Jakob syndrome. It resembles olivopontocerebellar degeneration. Spongiform encephalopathy accompanies both Gerstmann-Straussler syndrome and CJD. Mutation in the prion protein (PrP) gene occurs in Gerstmann-Straussler syndrome. Fatal familial insomnia is another rare inherited dementia caused by the prion. Patients with this disorder experience a complete lack of sleep in the year or two prior to death. PrP gene analysis is potentially useful for diagnosis and genetic counseling.
Creutzfeldt-Jakob disease is the only dementia that can be distinguished by characteristic electrical patterns. EEG shows triphasic bursts, sometimes correlating with myoclonic jerks. PrP genetic analysis can be helpful in some cases of prion disease. MRI also shows lesions early in the course, often affecting the basal ganglia and cortex; in relatively acute cases, the diffusion weighted MRI shows bright lesions resembling strokes.
Prion disease is uniformly fatal. The time between diagnosis and death is generally less than 2 years. There are no treatments. Because the disease has been transmitted through careless production and processing of meat, primary prevention is possible.
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Dementia Due to Other General Medical Conditions
Metabolic causes of dementia include dialysis dementia, repeated episodes of diabetic hypoglycemia, prolonged hepatic encephalopathy, hypothyroidism, and hypoxia. Many diseases can cause dementia in older people, for example, pernicious anemia, thyroid disorder, systemic infection, collagen disease, brain hypoxia, and toxic exposure.
Vitamin B12 deficiency causes subacute combined degeneration. Subacute combined degeneration causes demyelination in the posterior columns and loss of pyramidal cells in the motor strip. Often a peripheral neuropathy is present. Slow information processing, confusion, memory changes, delirium, hallucinations, delusions (“megaloblastic madness”), depression, and psychosis have been observed in patients with vitamin B12 deficiency.
Anemia is not necessary for the syndrome to develop. Sometimes a familial pattern occurs. Antiparietal-cell antibodies are often present. Current state-of-the-art testing uses serum cobalamin levels as a screening test and serum or urine homocysteine and methylmalonic acid determinations as confirmatory tests. Homocysteine abnormalities are associated with neurologic deficits and psychiatric symptomatology. A Schilling test follows the patient's vitamin B12 level to help determine etiology.
Depression and dementia respond rapidly to the administration of vitamin B12 when the condition is diagnosed in its early stages. Vitamin B12 deficiency is treatable with monthly injections, daily oral supplements, or an intranasal gel. If the condition is not diagnosed in the early stages, neurologic, psychiatric, and cognitive impairment may persist and become irreversible. The prevalence of low cobalamin levels is significantly increased in AD. Contrary to widely accepted beliefs, subnormal serum vitamin B12 levels are a rare cause of reversible dementia.
Older people frequently have mildly decreased thyroid function. This does not cause an irreversible dementia. In some people, hypothyroidism exacerbates a depression. Thyroid deficiency can also hasten a severe melancholic depression that causes a patient to appear demented. Consequently, thyroid function tests (including thyroid stimulating hormone level) should be obtained. On exceedingly rare occasions, hyperthyroidism or hypothyroidism cause a delirium that can be mistaken for dementia. Patients with vascular dementias often have hypothyroidism. The reason for this association is unclear, but thyroid replacement can improve the performance of patients who have this condition.
Patients who are undergoing dialysis may experience impaired mental functioning that can be secondary to a parathyroid hormone abnormality and its effect on calcium metabolism. Patients who have been on dialysis for extended periods may experience a general decline in intellectual function that is usually mild. True dialysis dementia has become rare since aluminum was eliminated from the dialysate.
Many toxins can cause dementia. Organic solvents inhaled in the workplace cause cognitive deficits. Organic solvents can occasionally cause dementia when used as intoxicants. Carbon monoxide and heavy metals are other toxins that affect mental function. Appropriate history, physical examination, and toxicology evaluation are necessary for the diagnosis of toxin-induced dementias.
Dementia can be caused by the direct or indirect effect of cancer. Patients with cancer develop dementia as a result of intracranial tumors, cerebral metastases, carcinomatous meningitis, progressive multifocal leukoencephalitis, opportunistic infections, and paraneoplastic effects (“limbic encephalitis”). Tumors can lead to noncommunicating hydrocephalus by obstructing the outflow of CSF. Some patients develop progressive dementia as a complication of whole-brain radiotherapy.
Dementia Due to Normal Pressure Hydrocephalus
Normal pressure hydrocephalus causes a relatively distinct syndrome consisting of gait difficulty, sometimes called gait apraxia, urinary incontinence, and dementia. Normal pressure hydrocephalus may be idiopathic, but it may follow a subarachnoid hemorrhage, meningitis, or other entity that can cause altered spinal fluid dynamics.
Normal pressure hydrocephalus is the most common type of hydrocephalus diagnosed in people over age 60 years.
Normal pressure hydrocephalus occurs when the CSF pressure inside the ventricles is higher than that in the subarachnoid space, and the ventricles expand.
The clinical diagnosis of hydrocephalus as a cause of dementia is confusing because many conditions can cause similar symptoms. Nonetheless, a timely diagnosis is important because dementia caused by normal pressure hydrocephalus can sometimes be reversed if the diagnosis is made early enough.
The patient presents the classic triad of dementia, incontinence, and gait disturbance. The dementia develops at a rapid pace. The patient's gait becomes magnetic in quality, and he or she is likely to experience frequent falls.
Patients with normal pressure hydrocephalus are impaired on tests designed to detect frontal lobe involvement. The pattern of dementia suggests a subcortical process. Successful ventriculoperitoneal shunt placement improves the patient's cognitive function in 50–67% of cases, in published series.
Laboratory Findings and Imaging
The clinical picture associated with vascular dementias can closely resemble that associated with normal pressure hydrocephalus. Unfortunately, MRI findings in patients with normal pressure hydrocephalus overlap those seen in patients who have small vessel disease. Both conditions are associated with increased ventricular size and significant periventricular hyperintensity, as shown on T2-weighted MRI. Normal pressure hydrocephalus differs from small vessel disease in that in the former the MRI can show a large cerebral aqueduct when the pulsation of CSF creates a flow void.
When radioisotope-labeled albumin (RISA) is injected into the lumbar sac (the RISA cisternogram test), it usually diffuses readily over the cerebral convexities. Patients with normal pressure hydrocephalus have abnormal CSF dynamics: Radioactivity appears in the ventricles but is absent over the convexities. Although this test may sometimes be useful, it is not often used today.
Cerebral fluid drainage procedures are sometimes used to help predict whether surgery will be successful. If the patient's gait improves after removal of a large amount of CSF, then the patient is judged to be a better candidate for surgery. Lack of improvement militates against surgery.
Normal pressure hydrocephalus can be difficult to distinguish from vascular dementias and AD. Although imaging tests help, there is some overlap between the findings of normal pressure hydrocephalus and other forms of dementia. Tests of spinal fluid dynamics help clarify the matter, but ultimately, improvement after shunt placement clarifies the issue. Unfortunately, clinical experience with shunt placement may not be as favorable as that seen in published reports. Improvement may be more transient.
Dementia from normal pressure hydrocephalus may respond to shunting, the treatment of choice, however, shunting is associated with significant morbidity. Thus the procedure should probably be carried out only in cases in which the indications are clear and in which the dementia has not progressed to an irreversible degree.
Patients whose normal pressure hydrocephalus has a defined etiology, such as previous head trauma or subarachnoid hemorrhage, respond more reliably to shunting than patients with idiopathic hydrocephalus. Variables associated with a positive outcome from CSF shunting include CSF pressure, duration of dementia, and gait abnormality preceding dementia.
Dementia Due to Traumatic Brain Injury
Dementia due to traumatic brain injury refers to a wide range of alterations in thinking, mood, and behavior resulting from specific neurologic damage associated with brain trauma. The severity of the injury is an important determinant of outcome. Specific vulnerabilities such as age, preexisting neurologic or psychiatric disease, and social support determine the ultimate prognosis.
The annual rate of traumatic brain injury among the general population is about 200 per 100,000 people in the United States. Traumatic brain injuries are most common among young adult males and most often are the result of automobile accidents. Older adults also represent a significant risk group. Falls are the most common cause of injury in children and older adults. Most head injuries are considered to be mild. Older adults are more likely than younger adults to have a severe injury.
Head trauma severe enough to cause brief loss of consciousness or posttraumatic amnesia can produce long-lasting cognitive and behavioral changes.
The principal mechanisms underlying traumatic brain injury have been well established. Forces of deceleration and acceleration act within the cranial compartment to produce injury. The swirling movement of brain tissue causes diffuse injury to axons and contusions to cortical areas adjacent to jagged bone. Because the hippocampus is found near the sphenoid ridge, it is especially susceptible to damage when the brain is set in sudden motion. Memory mechanisms fail, and both anterograde and retrograde amnesia follow. The length of posttraumatic amnesia is closely related to the overall severity of diffuse brain damage. The frontal lobes are also susceptible to contracoup injury. Closed head trauma causes both diffuse and focal brain injury. Subarachnoid hemorrhage and subdural hematoma may produce additional damage, and cerebral edema further complicates the picture.
Beyond structural changes, biochemical alterations also develop. For example, free acetylcholine may appear in large quantities in the CSF, or anoxic damage may produce an increase in CSF lactate.
Fatigue, headache, and dizziness may occur shortly after a mild head trauma. Later a postconcussive disorder may develop. The most significant features of postconcussive syndrome are slowing of information processing, impaired attention, and poor memory.
More severe head injuries are rated according to the Glasgow coma scale. This is a measure of consciousness that analyzes eye opening response, verbal response, and motor response. Head trauma is categorized on this scale as mild, moderate, or severe. The Glasgow coma scale gives a rough judgment regarding prognosis.
Recovery from moderate and severe head trauma is an extremely long process. Recovery is most rapid during the first year or two, and it can continue for many years. In the initial stages of recovery, progress can be followed with the Rancho Los Amigos scale. In the later stages of recovery, measurement of recovery is based on clinical indicators such as return to work.
Recovery from head trauma is also affected by secondary brain injury. Intracranial hematomas, brain edema, and vasospasm affect prognosis by causing occlusion of intracranial vessels, thus producing secondary strokes. Infection, seizures, or metabolic imbalance may affect the postinjury course. Traumatic brain injury produces physical disability ranging from sensory and motor deficits to posttraumatic epilepsy. In addition, there is usually some deterioration in cognitive ability. Emotional or behavioral deviation usually produces the most significant disability. Some individuals show personality disturbance characterized by anxiety, depression, or irritability. Others may demonstrate a classic frontotemporal syndrome with memory impairment, apathy, lack of motivation, and indifference to the environment. Physicians must consider these emotional difficulties when providing treatment and rehabilitation to these patients.
Neuropsychological test data are used to develop treatment strategies tailored for an individual's strengths and deficits. Neuropsychological testing can sometimes reveal subtle changes in information processing in patients who otherwise appear normal. A commonly used test is the paced auditory serial addition task. During this exercise, subjects listen to digits presented at a standard rate and add each digit to the one immediately preceding. Head trauma patients are both slower and less accurate than are normal subjects.
Patients with mild to moderate postconcussive disorder may become irritable or even aggressive, and exhibit blunt affect, apathy, or lack of spontaneity. The effects of mild to moderate head trauma can be subtle, and both patients and practitioners may make light of the cognitive impairment associated with mild head trauma despite sometimes devastating consequences.
In more severe forms of head trauma, neuropsychological testing can be used to measure the extent of secondary injury. To some extent this helps establish the prognosis. Neuropsychological testing can then be used to measure progress. Because cognitive rehabilitation is an important part of recovery, neuropsychological testing can help the psychologist focus on the particular areas of deficit.
Laboratory Findings and Imaging
The EEG is sensitive to brain changes following trauma. Local suppression of the alpha rhythm may extend bilaterally. In more severe injury, EEG discharges become progressively slower and delta activity may predominate. The EEG is not a reliable guide to prognosis, and other clinical features must be considered. An EEG that becomes normal early in the course of the illness usually predicts good recovery following head trauma. MRI is invaluable in detecting areas of structural damage.
Recovery from head trauma is a dynamic process rather than a static one. As a result, treatment evolves during the course of recovery. In mild head trauma, treatment consists in determining the neuropsychological deficit and giving appropriate counseling. In addition, symptomatic treatment of headaches, dizziness, and mood alteration is useful. Intervention with the patient's employer may help foster understanding and help encourage work conditions that are more conducive to success.
In moderate or severe head trauma, the goals of treatment change as the patient recovers. The early stages of treatment may be oriented to merely suppressing violent outbursts and improving sleep. Later, therapy is tailored to improving memory, impulsiveness, irritability, and affective disorder. Both pharmacotherapy and psychotherapy are useful in this regard. Carbamazepine is generally useful for impulsiveness and may be combined with an atypical neuroleptic. Sleep disturbance may respond to trazodone. The affective disorders respond to SSRIs and other antidepressants. In general, these agents should be started at low doses, with gradual increases. Head trauma patients tend to be sensitive to medication side effects.
Complications/Adverse Outcomes of Treatment
Depression and anxiety are common in outpatients with traumatic brain injuries. These symptoms add to the morbidity of closed head trauma because depressed or anxious patients perceive themselves as more severely disabled. Death by suicide is a risk after head injury.
Alcohol and substance abuse also alter the outcome of traumatic brain injury. Alcohol intoxication is present in up to one-half of patients hospitalized for brain injury. Two-thirds of rehabilitation patients have a history of substance abuse preceding their injuries. Untreated substance abuse adversely affects cognitive status in rehabilitation patients.
Repeated head trauma in boxers produces dementia pugilistica. In its fully developed form, the disorder consists of cerebellar, pyramidal, and extrapyramidal features, along with intellectual deterioration. The syndrome may progress even after the boxer has retired from the sport.
Periods of unconsciousness may last several hours yet still be compatible with complete recovery. The longer the patient is unconscious, the poorer the outcome. As the patient recovers from severe head trauma, a period of confusion may follow lasting from hours to months. Some patients pass through a period of extremely disturbed behavior that poses severe management problems. The patient may be abusive, aggressive, or uncooperative. The patient may appear delirious during this time with vivid audiovisual hallucinations. When head trauma is associated with prolonged unconsciousness, recovery is usually followed by some degree of dementia. Recovery from mild to moderate head trauma is more variable and difficult to predict.
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Depressed seniors often deny mood disorder and focus on memory problems, complaining of memory loss disproportionate to their actual decrement in memory functioning. Because depressed seniors commonly exhibit impaired attention, perception, problem solving, or memory, psychometric testing may not distinguish depression from AD. This lack of diagnostic clarity has led to the term pseudodementia. This term creates unrealistic expectations for a psychiatric cure for dementia. Cognitive disorder seen during late-life affective disorder is real and not simulated. Depressive cognitive dysfunction is a more accurate term. In most cases, depression is a factor worsening dementia rather than the sole cause.
The cognitive decline encountered in depressed older people is more precipitous than in demented patients. The history often reveals previous depression. The combined effects of age and depression produce a pattern of deficits distinct from that found in younger depressed patients and less severe than that in Alzheimer's patients. The actual memory impairment is modest in depressed patients, but the level of subjective complaint is high. In contrast, organically impaired patients have more memory loss and less subjective complaints. The cognitive dysfunction encountered in depressed patients is probably secondary to decreased arousal with associated deficits in motivation and attention. Depressed patients do well on simple tasks but poorly on tasks requiring sustained attention or concentration. Following drug treatment, their performance improves. Patients’ cognitive complaints correlate with depressive symptoms rather than with MMSE scores.
Patients with depressive dementia often exhibit early morning awakening, anxiety, weight loss, psychomotor retardation, and decreased libido. Patients with dementia present with disorientation, and their daily activities are more seriously impaired. Despite these differences, there is no definitive diagnostic tool. Cognitive decline in depressed older people commonly has a multifactorial etiology. In fact, depression may be the presenting symptom of a degenerative disorder.
The dexamethasone suppression test is not useful in discriminating between depression and dementia or between subtypes of dementia. Sleep studies distinguish depression from dementia with about 85% accuracy. Depressed seniors experience shorter rapid eye movement (REM) latency, higher REM sleep percentage, less non-REM sleep disturbance, and early morning awakening. Patients with AD experience less REM sleep. Computerized techniques, including amplitude frequency measures and spectral analyses, permit new approaches to the examination of delta sleep. Many depressed patients show lower delta wave intensity during the first non-REM period than during the second period.
Several studies have shown an association between depressive dementia and degenerative dementia. The longer the follow-up, the more likely that depressive dementia will evolve into degenerative dementia. Elderly depressed patients also display a remarkable increase in prevalence of cortical infarcts and leukoencephalopathy. Depressed patients tend also to have basal ganglia lesions, sulcal atrophy, large cerebral ventricles, and subcortical white-matter lesions. Nevertheless, AD patients have more prominent cortical atrophy compared to those with major depression.
PET scans distinguish dementia from late-life depression more clearly than does structural imaging (i.e., CT scan and MRI). The temporoparietal pattern observed in patients with primary degenerative dementia is not observed in those with affective disorder. In severely depressed patients, PET scans show left-right prefrontal asymmetry in resting-state cerebral metabolic rates. Successful drug therapy reduces the asymmetry. In depression, the decrease in glucose metabolism is more pronounced in prefrontal areas, and these changes persist despite clinical improvement, suggesting that the abnormality is not state dependent.
Both mania and depression can present as pseudodelirium. Vegetative signs are not helpful in distinguishing depression from delirium. Laboratory investigations are required. Mania may present with symptoms of dementia, but delirium is more common. About one quarter of manic patients over age 65 years have no history of affective illness. Cognitive changes often persist even after the patient has “switched” into depression.
Treatment with lithium, carbamazepine, or valproate resolves both mania and cognitive impairment. Antidepressant medication for affective disorder is usually effective, however, side effects are troublesome in older patients. Previous treatment response should help guide therapy. Unfortunately, one-third of the seniors hospitalized for mania experience a permanent decline in their MMSE scores. This suggests that late-life mania is related to structural changes in the brain.
Because TCAs are likely to cause adverse drug reactions in seniors, SSRI's or SNRI's are generally preferred. Occasionally, monoamine oxidase inhibitors, alprazolam, and bupropion are useful. For mild depression, SSRIs are the first-line agents. Psychostimulants such as methylphenidate and dextroamphetamine present yet another treatment option. These drugs appear to be of particular benefit when used in the short term for the treatment of depression that complicates medical illness.
Lithium is effective in treating bipolar disorder, but its side effect of impairing renal function limits its use. In elderly patients, lithium has a very narrow therapeutic index. Lithium toxicity can occur quickly, damaging already-compromised kidneys. Valproate may be preferred if the patient has a new-onset illness and has not previously been exposed to treatment. If lithium is used, very close monitoring is required. When other therapies have failed, ECT may reverse pseudodementia or pseudodelirium dramatically. ECT is safe and effective, even in patients older than 80 years or in those with poststroke depression. Common complications of ECT in the elderly include severe confusion, falls, and cardiorespiratory problems.
Delusions & Behavioral Disturbance
As dementia worsens, behavioral problems emerge. Problem behavior often stems from the inability of staff to understand patients’ needs. It is important to identify the cause of the dementia before rushing into pharmacologic treatment. Patients can exhibit behavioral disturbances because they are hungry, thirsty, bored, constipated, tired, sexually aroused, or in pain. Patients with dementia, like all of us, need to feel loved, and they benefit from opportunities to develop self-esteem. An initial psychosocial approach to these problematic patients should assess whether these needs are being met.
A multidisciplinary team setting is the most appropriate format for setting treatment goals that are then communicated to the family. It is essential to involve the family in order to educate them and to initiate social interventions. Patients and family members need to believe that a meaningful life is possible despite dementia. This is particularly true if family members are taught to validate the patient's emotional experience. Very little can be gained by approaches aimed at reorientation or enforcing confrontation with reality. Support groups help family members learn not only to cope with the negative outcomes but also to understand their loved one in the context of the illness.
Drug therapy of abnormal behaviors associated with dementia are problematic. First, the anticholinesterase agents and memantine have been demonstrated to improve behavior to some degree. Psychotropic medications must be used cautiously. The Omnibus Reconciliation Act of 1990 introduced specific restrictions on the use of psychotropic medication in the care of nursing home residents. Nonetheless, pharmacotherapy is often essential for treatment of the behavioral disorders that accompany dementia. Psychiatrists are frequently asked to treat agitation in demented patients. Antipsychotics, antidepressants, and sedative-hypnotics are used widely for this purpose, however, data from double-blind clinical trials are limited.
Neuroleptics are effective in some patients with dementia related psychosis. In many other patients they are of absolutely no benefit and may even be harmful. Although atypical agents have a lower incidence of extrapyramidal side effects including tardive dyskinesia, these newer agents all carry a black box warning regarding an increase in death rate in treated patients. A review of 17 placebo-controlled studies involving four of the atypical antipsychotics showed that the death rate for elderly patients with dementia was about 1.6–1.7 times that of placebo.
There is no evidence that atypical agents offer convincing benefits in this population. Despite many millions of dollars spent by pharmaceutical companies on double blind placebo controlled trials, these agents demonstrate limited or no efficacy when compared to placebo. In the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study, a large government study of atypical antipsychotics in AD, about 30% of those taking the active medications improved, compared to 21% of those taking placebo. But atypical antipsychotic medications also were more often associated with troubling side effects, such as sedation, confusion, and weight gain, compared to placebo. All neuroleptics should be used in as low doses as possible and for as short a duration as possible. Neuroleptics should be reduced periodically or discontinued in order to determine ongoing need. Dementia is a progressive and dynamic process. Patients who required therapy at an early stage of the illness may no longer benefit at a later stage.
Short-acting benzodiazepines control agitation and may be used on occasion in the short term to treat agitation or as a hypnotic in severely demented patients. They can be used in conjunction with antipsychotics. Benzodiazepines are effective for only a minority of patients, and they cause drowsiness, paradoxical agitation, memory loss, an increased risk of falling, and potential habituation. Their use should be reserved for the management of short-term crisis situations in which a rapid response is necessary.
Trazodone has been used to control aggression in demented patients on the theory that aggression is related to serotonergic depletion. Patients generally receive a mild benefit with nighttime doses of 50–100 mg/day. Because some elderly patients experience gait disturbances immediately after the nighttime dose, fall precautions must be taken. Buspirone reduces agitation in dementia in dosages of 20–40 mg/day. Some patients respond preferentially to valproic acid. These patients often have manic symptoms associated with agitation, including pressured speech, flight of ideas, and sleeplessness.
There are few placebo-controlled studies of the drugs used to treat agitation in older people, but the use of psychopharmacology is common in patients who have failed conventional treatment. Carbamazepine or valproate may be best for patients with manic symptoms, buspirone for patients with anxiety, and antidepressants for patients who appear depressed. Because these medications often are given to dementia patients for prolonged periods, studies are needed to define their long-term clinical efficacy.
Some behaviors such as wandering, purposeless repetitive activity, stealing, and screaming are not amenable to pharmacologic intervention. These behaviors must be dealt with by environmental design such as the wander-guard system (a wristband alarm system) or appropriate soundproofing. Clinicians can reduce the occurrence of sundowning by promoting daytime activity, preventing daytime napping, and enforcing a regular sleep schedule. The medical treatment of sundowning can be frustrating, however, sedatives are sometimes helpful.
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