The following section reviews the cognitive and behavioral profiles associated with common neurodegenerative disorders (Table 63-3). Early identification of such disorders, many of which are diagnosed solely on these parameters, has become increasingly important due to potential therapies that may delay disease progression.
TABLE 63-3EARLY COGNITIVE SYMPTOMS ASSOCIATED WITH DIFFERENT DEMENTIA TYPES ||Download (.pdf) TABLE 63-3 EARLY COGNITIVE SYMPTOMS ASSOCIATED WITH DIFFERENT DEMENTIA TYPES
| ||SYMPTOM ONSET ||PROGRESSION RATE ||MEMORY ||ATTENTION ||EXECUTIVE FUNCTIONS ||LANGUAGE ||VISUOSPATIAL FUNCTION ||PSYCHOMOTOR FUNCTION ||BEHAVIOR |
|RECENT ||RECOGNITION INTACT? ||REMOTE INTACT? ||PROCEDURAL INTACT? |
|Alzheimer disease (AD) ||Insidious ||Steady, gradual ||Significantly impaired declarative recall ||N ||Y ||Y ||Intact primary span; impaired selective/divided attention ||Mildly impaired working memory, response inhibition, general problem solving ||Semantic organizational abilities significantly impaired, mild anomia ||Simple construction intact, complex visual reasoning impaired ||If present, symptoms are mild ||Depression common |
|Lewy body disorders |
|PD/PDD ||Insidious ||Varied ||Possible deficits ||Variable ||Y ||N—possible impairments ||Intact primary attention span, impaired selective/divided attention; fluctuations ||Difficulty planning/shifting set ||Verbal fluency, mechanical aspects of speech impaired ||May be impaired ||Resting tremor, bradykinesia, rigidity, postural instability, shuffling gait ||Depression common, may exhibit hallucinations/delusions, less common than DLB |
|DLB ||Insidious ||Steady, gradual ||Usually less than AD ||Variable ||Y ||Y ||Significant fluctuations in attention ||Variable ||Variable; fluency may be impaired ||Impaired construction, copy, visuospatial planning and problem solving ||May exhibit a range of parkinsonian symptoms ||Hallucinations, delusions, depression |
|Vascular dementia (VaD) ||May be insidious or acute ||Stepwise or gradual ||Possible deficits ||Varies ||Y ||Y ||Intact primary span; impaired selective/divided attention ||Significantly more impaired than AD and relative to performance on verbal memory tasks ||Verbal fluency impaired ||Relatively preserved, although may be affected by executive impairments ||Slowing, possible discrete motor problems depending on distribution of vascular changes ||Depression common |
|Frontotemporal lobar degeneration (FTLD) |
|Behavioral variant FTLD (FTLDbv) ||Insidious ||Steady, rapid ||Relatively preserved ||Y ||Y ||Y ||Intact primary span; impaired selective/divided attention ||Impaired across a range of executive functions ||Verbal fluency impaired ||Relatively preserved, although may be affected by executive impairments ||May exhibit ideational apraxia ||Significant behavioral changes, may include behavioral disinhibition, apathy, loss of empathy/sympathy, hyper-orality |
|Primary progressive aphasia (PPA) ||Insidious ||Steady, varied ||Preserved recall, may score poorly on verbal memory tests ||Y ||Y ||Y ||Preserved ||Preserved ||Nonfluent: poor articulation, dysarthria, relatively preserved comprehension; Logopenic: anomia, impaired repetition; Semantic: impaired comprehension, anomia, intact speech rate & prosody ||In semantic dementia, may have visual agnosia ||Nonfluent PPA: buccofacial apraxia ||Changes unlikely |
|Progressive supranuclear palsy (PSP) ||Insidious ||Steady, gradual ||Mild impairment, less than AD ||Variable ||Y ||Y ||Impaired selective/divided attention ||Impaired across a range of executive functions ||Verbal fluency impaired ||May be impaired ||Vertical supranuclear gaze palsy, postural instability ||Apathy, disinhibition |
|Corticobasal degeneration syndrome (CBS) ||Insidious ||Steady, gradual ||Variable, may be severe ||Variable ||Y ||Possible impairment ||Impaired selective/divided attention ||Impaired across a range of executive functions ||May have a variety of language disturbances ||Possible ||Asymmetric motor symptoms, alien limb syndrome ||A variety of neuropsychiatric disturbances possible |
|Alcohol-related dementias |
|Persistent alcohol dementia ||Deficits persist after d/c alcohol use ||May worsen over time ||Impairment on recall, not more than other functions ||Variable ||Y ||Y ||Impaired sustained attention ||Abstraction, mental flexibility, perseveration, confabulation, impaired judgment, reduced ability to care for self ||Preserved ||Visual scanning, visuospatial organization impaired ||May exhibit cerebellar tremor, impaired gait ||Apathy, depression |
|Wernicke-Korsakoff syndrome ||Acute (initial phase) ||Steady, gradual (chronic phase) ||Significant impairment on declarative recall relative to other deficits (semantic memory spared) ||N ||N ||Variable ||Impaired across all attentional functions ||Similar profile to persistent alcohol dementia ||Preserved ||Visual scanning, visuospatial organization impaired ||Impaired gait, abnormal reflexes, other movement abnormalities ||Personality change prominent feature, inappropriate behavior |
|Prion disease ||Insidious ||Steady, rapid ||Nonspecific impairments reported ||Y ||Y ||Y ||Nonspecific impairments reported ||Reduced problem-solving ability ||Generally preserved ||Generally intact ||May exhibit impaired reflexes and coordination ||Apathy, emotional lability, impaired sleep, appetite loss |
|Normal pressure hydrocephalus (NPH) ||Insidious ||Varied, potentially reversible ||Not prominently impaired ||Y ||Y ||Y ||Primary deficits in attention ||Nonspecific impairments in executive function reported ||Generally preserved ||Generally intact ||Wide-based gait or other balance disturbance, urinary incontinence ||May present with a confusional state |
|HIV-associated neurocognitive disorder (HAND) ||Usually later in the disease course ||Varied ||Variable ||Variable ||Y ||Y ||Nonspecific impairments reported ||Nonspecific impairments in executive function reported ||Generally preserved ||Generally intact ||Slow, loss of coordination ||Depression common |
|Neurosyphilis ||Many years after initial infection ||Varied, potentially reversible ||Variable ||Variable ||Y ||Y ||Variable ||Variable ||Generally preserved ||Generally intact ||May be ataxic ||Hallucinations, delusions, personality change, mood disturbance |
Alzheimer Disease Dementia
AD dementia, the most prevalent of the primary neurodegenerative disorders, is the clinical manifestation of underlying AD neuropathology, primarily the accumulation of β-amyloid protein and neurofibrillary tangles leading to neuronal loss and synaptic degeneration. Recently updated diagnostic criteria by the National Institutes on Aging and the Alzheimer’s Association (NIA/AA) recognize AD as a continuum, with underlying neuropathologic processes often beginning 20 years or more before the onset of clinical dementia symptoms. Thus, the revised criteria permit use of biomarkers that reflect these processes, alongside supporting clinical information, for use in early differential diagnosis. Currently, cerebrospinal fluid (CSF) and imaging studies may be used to determine the presence of β-amyloid deposition and/or neuronal injury to provide additional diagnostic evidence for or against AD as the underlying pathology. In the absence of such tools, however, conventional diagnostic criteria are considered to be reasonably accurate, particularly when the evaluation is comprehensive and includes a complete medical and psychosocial history, medical evaluation, and neurocognitive testing.
The NIA/AA criteria for AD dementia require (1) that the patient meets criteria for dementia (cognitive symptoms that interfere with daily activities that occur within at least two cognitive domains, represent a decline from previous function, and are not better explained by delirium or psychiatric disturbance), (2) evidence for or a reported insidious onset, and (3) worsening cognition by report or observation. The initial cognitive symptoms may be amnestic or nonamnestic to account for variants that present with deficits in cognitive domains other than memory, such as posterior cortical atrophy (which presents with initial visuospatial deficits) or language-predominant forms. The diagnosis is not considered “probable” if another medical/neurologic disease could account for the symptoms. “Possible” AD dementia may be diagnosed if the symptom history is atypical or unclear or if there is a mixed dementia picture.
A complete medical and psychosocial history is a vital component of any dementia assessment. Such a history should be obtained both from the patient and a reliable informant, preferably someone who has regular contact with the patient and who has an adequate opportunity to observe their daily functional abilities. Typically, a patient in the earliest stages of AD will not exhibit deficits in basic self-care. However, more complex daily tasks, including driving, finances, shopping, and other chores and activities, are likely to be affected. A gradually progressive course and insidious onset of cognitive symptoms is a hallmark of the AD, and thus a careful history regarding the nature and timing of symptom onset and progression must be obtained. An inventory of all current medical concerns, family history, past major medical problems, and medications must be evaluated in order to rule out conditions that may be either causing cognitive problems or influencing their expression.
An important goal of the medical evaluation is to exclude the presence of medical conditions that may be responsible for the observed cognitive deficits. It is critical to investigate potentially reversible causes of dementia such as uncontrolled liver or kidney disease, adverse reactions to medications, and delirium. Laboratory blood tests can aid in ruling out systemic illnesses or organ malfunction. Structural brain scans are used to evaluate major cerebrovascular events, tumors, normal pressure hydrocephalus, and other neurologic conditions, while functional brain scans identify patterns of activity that may be useful in classifying dementia type.
Neuropsychological assessment of cognitive function not only provides confirmatory evidence for cognitive impairment, but may also aid in clarification of dementia type. Given the extensive variation in rate of AD progression between patients, successive neuropsychological examinations early in the disease can also provide information regarding an individual’s rate of progression and remaining cognitive strengths. Perhaps one of the most valuable assets of neuropsychological evaluation is the sensitivity of the tests to early cognitive decline. While there has been debate regarding the usefulness of providing an early AD diagnosis, it is generally accepted that such a diagnosis will allow the patient to avail themselves of current and emerging therapies, as well as to make decisions regarding health care, finances, and legal issues while still competent. In a typical neuropsychological evaluation, patients are given tests that sample a variety of domains of cognitive function. Results are compared to normative data based on age, and also to an individual’s estimated premorbid abilities (based on educational and occupational background and performance on tests that tend to remain stable over time). Pattern analysis of test results, in combination with data from the patient history and medical evaluation, is then used to generate diagnostic possibilities. The following sections discuss cognitive impairment patterns typical in patients with AD.
The hallmark of AD, and most often the first cognitive symptom of the disorder, is anterograde amnesia, evidenced by difficulty with learning new information. Deficits are noted in declarative memory as a result of prominent impairment in information encoding, retrieval, and in particular, storage of new material. Patients are likely to exhibit deficits in recent episodic recall, and they or their caregivers often report that misplacing items, forgetting recent events or conversations, and frequently repeating questions or statements. In contrast to impaired episodic recall and difficulty learning new information, procedural memory is rarely impaired, and remote memory remains relatively intact until later stages of the disease.
In order to adequately evaluate short-term memory loss and establish a pattern of impaired retrieval, neuropsychological evaluations include tests of both immediate and delayed verbal and visual recall. Tests such as the Folstein Mini Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and other diagnostic screening instruments assess general mental status and orientation, but are not adequate for a comprehensive understanding of memory impairment. To satisfactorily assess a person’s true memory ability, Zec (1993) recommends using tasks that are high in cognitive demand, that exceed the primary memory span (such as story recall and list learning tasks that include at least 10 items), and that have a recognition component. On neuropsychological examination, verbal and visual free immediate and delayed recall and recognition are significantly impaired in AD patients relative to same-age peers, and patients typically exhibit a high number of intrusion errors and repetitions. Semantic recall is generally the most predominantly impaired, and thus verbal recall tasks are often the most sensitive to early memory loss.
Attention and Executive Function
Certain aspects of attention and concentration are often impaired early in the disease process, and recent research has supported that it may in fact be one of the earliest abilities affected in AD. While patients with AD are likely to have relatively intact simple attention (eg, primary memory span), tests requiring selective and divided attention are likely to be impaired, particularly as task demands increase. This pattern of performance strongly supports the presence of a deficit in working memory (the ability to simultaneously attend, process, and respond to multiple pieces of information) early in the disease process, and a converging body of evidence supports a primary executive component in AD.
In addition to problems on tasks of complex attention and working memory, patients are likely to exhibit mild deficits in response inhibition, evidenced by intrusion errors and perseverative responses, on neuropsychological testing. Deficits in abstract reasoning, general problem-solving ability, and making appropriate judgments are also commonly noted. In assessing for judgment and abstraction, patients may be asked the meaning of proverbs (eg, “you can lead a horse to water but you can’t make it drink”), and are often given hypothetical situations in which they must decide an appropriate course of action (eg, “What would you do if you were in a crowded shopping mall and saw smoke and fire?”). On these tasks, even early AD patients may provide incorrect or inappropriate responses.
Semantic processing is considered the primary language deficit in AD, and is present in more than half of all AD patients at the time of diagnosis. Word finding problems are commonly reported in both AD and normal aging, but patients with AD have more severe deficits and are more likely to produce a significantly higher number of semantic paraphasias and circumlocutions. Patients are generally impaired on tasks of confrontational naming, and, unlike changes that occur with normal aging, are not likely to be assisted by cues. Syntactic processing, in contrast to semantic processing, is typically unaffected in mild AD. For example, patients with early AD can typically process even complex sentences at the same level as their healthy counterparts, and generally remain unimpaired on repetition and fluent speech. Verbal fluency tasks are particularly useful in evaluating both semantic and syntactic processing. Semantic, or category, fluency (eg, “Tell me as many animals as you can”) is generally impaired disproportionately to syntactic, or phonemic, fluency (eg, “Tell me as many words that begin with the letter ___”) in AD. While decreased information processing and working memory may impair an AD patient’s responses on certain syntactic processing tasks, and comprehension and intelligible speech are likely to decline slowly as the disease advances, patients who present first with nonfluent aphasia or impaired comprehension should be carefully evaluated for other conditions.
Deficits in visuospatial abilities are frequently seen in AD patients, although they generally appear later than memory and language deficits. Patients may become lost in familiar places (eg, grocery store) or while driving. Eventually, disorientation may lead to confusion in one’s own home and subsequent wandering behavior. Early deficits however, are more likely to involve visuospatial problem solving. Neuropsychological tests commonly used involve comparing simple construction or copying, typically not impaired early in the disease, to complex visual reasoning. The presence of constructional apraxia early in the disease may indicate greater pathology in visual processing areas of the brain and has been associated with more rapid symptom progression. In general, more complex drawing tasks, such as three-dimensional figure copy, may be more precise measures of the most common early visual spatial deficits in AD than simple copying tasks.
While motor dysfunction has not been typically considered to be a defining symptom of AD, recent research suggests that AD patients may display impairments in gait, motor speed, and general level of activity, such changes may even be evident during the prodromal phase of the disease. In addition, converging evidence provides support for greater overlap between AD and Lewy body dementia, making motor changes such as tremor or gait disturbance more likely in these patients. Importantly, there have been reports of gait disturbance in patients taking cholinesterase inhibitors, a factor that should be carefully monitored when prescribing these medications.
AD patients may also exhibit mild ideomotor and ideational apraxia (deficits in skilled movements) due to concrete responses, lack of sufficient external cues, or a disruption in conceptualization ability. However, moderate-to-severe apraxia is not generally present until later stages of the disease. Incorporating an apraxia assessment into a dementia evaluation is useful, however, particularly for excluding other disorders that may initially present with more severe skilled movement disorders.
As mentioned previously, depression is common in patients with AD, and may manifest as apathy, indifference, poor initiation, or emotional lability. Irritability, agitation, and paranoid ideation are also common in AD, and may worsen with disease progression, prompting wandering behavior and aggressive outbursts. Repetitive and aimless behavior may also increase as the disease progresses. More severe psychotic symptoms, such as hallucinations and severe delusions, have been reported in some patients with early AD, but are typically rare in the absence of coexisting disorders. Given the wide range of behaviors that may be exhibited in an AD patient, it is imperative that the patient’s family be provided with ample dementia education, that they have access to social support, and that they possess the coping skills necessary to provide adequate care.
Patients in the early stages of AD typically vary in their level of deficit awareness. Whatever the starting point, deficit awareness declines with disease progression. Even when patients do acknowledge their cognitive decline, however, such awareness may not be “complete” as a result of deficits in executive function. For example, patients may be unable to translate cognitive problems into functional problems, and as a result may not understand how their deficits affect certain activities, such as driving, cooking, and finances. Again, providing the patient’s caregivers with access to education can increase the likelihood that patients will comply with physician recommendations to limit certain unsafe behaviors.
While most often the primary early deficit in AD involves recent memory, there are several reported cases of variant forms of AD that involve primary deficits in language, visuospatial function, or central executive function. In such cases, differential diagnoses, including frontotemporal dementia, primary progressive aphasia, Lewy body dementia, and others must be carefully considered prior to assigning a diagnosis of AD.
Mild Cognitive Impairment Due to AD
“Mild cognitive impairment” (MCI) describes cognitive impairment in aging that does not meet the criteria for dementia and that is not the result of a known medical condition. In its most common usage, the term is assigned to cognitive impairments thought to be related to underlying AD pathology, although criteria for prodromes of other neurodegenerative dementias (eg, Parkinson disease dementia, frontotemporal dementia) are currently proposed. Current NIA/AA criteria for MCI due to AD include the following: (1) concerns regarding a change in cognition by either the patient, informant, or a skilled clinician, (2) objective impairment in memory in one or more cognitive domains, (3) preserved independence in functional abilities, although patients may require some assistance or have mild impairments on more complex tasks such as financial management, navigation to unfamiliar places, etc, and (4) absence of dementia. Neuropsychological assessment can be particularly useful in distinguishing between normal age-related changes in cognition and MCI. Longitudinal research suggests that 80% of those diagnosed with MCI will go on to develop AD within 5 to 8 years, and will convert at a rate of approximately 10% to 15% per year compared to general population conversion rates of 1% to 2%. Amnestic forms of MCI are more likely to progress to AD than nonamnestic. However, the current criteria acknowledge that even initial nonamnestic presentations may progress to AD. Progression to AD is more likely when multiple cognitive domains are affected. In addition, MCI may progress to other forms of dementia or revert to normal cognition (Figure 63-1). Recently proposed research criteria grade the likelihood of progression to AD on the basis of biomarker outcomes: MCI due to AD-high likelihood is assigned when there are positive biomarkers for both βamyloid accumulation and neuronal injury on the basis of imaging and/or lumbar puncture, while the absence of positive biomarkers indicates a process that is unlikely to be related to AD.
A conceptual model of mild cognitive impairment (MCI) as prodromal dementia. A minority of persons diagnosed with MCI may remain stable or even improve over time. Although individuals with MCI may decline to vascular or other forms of dementia, the majority of declining MCI patients evaluated in research clinics receive a diagnosis of AD (either in pure form or mixed with other dementia subtypes). (Golomb J, Kluger A, Garrard P, Ferris S. Clinician’s Manual on Mild Cognitive Impairment. London, UK: Science Press; 2001.)
Dementia with Lewy bodies (DLB) is the second most common identified etiology for neurodegenerative dementia, behind AD. Cognitive dysfunction is also exceedingly common in Parkinson disease; thus it is increasingly recognized that Lewy body disorders account for a sizeable proportion of cognitive disability identified in aging populations. Considered a primary cause of dementia in both diseases is the presence of cortical Lewy bodies, abnormal intracytoplasmic inclusion deposits, on neuropathologic examination. However, multiple other pathologic features, including accumulation of tau protein, concurrent vascular and/or AD pathology, neurotransmitter abnormalities, and frontostriatal projections that have been disrupted by loss of dopaminergic neurons can all contribute to the cognitive decline associated with these diseases.
Although Parkinson disease and DLB have historically been considered related but separate clinical entities, many of the neuropathologic, clinical, cognitive, and psychiatric characteristics of the two diseases have considerable overlap. Thus recent debates have centered on whether or not Parkinson disease, Parkinson disease with dementia (PDD), and DLB should be placed along a clinical continuum representing the same underlying pathology. Currently, the differential diagnosis is based purely on the timing of the onset of the cognitive symptoms. A Parkinson patient who develops dementia after 1 year of motor symptoms is classified as “PDD,” while earlier cognitive symptoms may indicate DLB.
At its early stages, Parkinson disease can be difficult to differentiate from normal aging. Most patients initially present with a resting tremor. Other cardinal symptoms include bradykinesia, rigidity, and postural instability. Patients may also present with a shuffling gait, masked facies, depression, and sleep disorders. Relatively healthy older patients can present with a number of these symptoms for unrelated problems. For instance, essential tremors are not uncommon with aging, patients with arthritis often show slowed motor movements, and peripheral neuropathy, common in medical conditions such as diabetes, can impair gait.
Although motor symptoms have long been considered the defining feature of PD, a wide range of associated nonmotor symptoms are increasingly recognized as having substantial impact on functional abilities and quality of life for these patients. Of these nonmotor symptoms, cognitive dysfunction is a primary concern: dementia prevalence rates among patients diagnosed with Parkinson disease are 30% to 40%, with upwards of 80% of patients who live for 20 years or more with Parkinson disease expected to develop dementia over the course of the disease. In patients without dementia, the rate of concurrent cognitive impairment can be quite high, such that cognitive deficits, even if only slight, are now considered an inherent component of the disease. However, there is substantial variability in the nature and course of cognitive symptoms in Parkinson disease, with many patients maintaining a stable or fluctuating course and others demonstrating more rapid decline. Most patients with Parkinson disease exhibit at least some decline in attention, working memory, processing speed, or other executive functions, although the nature and degree of impairments across other domains are variable. PDD is often characterized by visuospatial deficits, impaired verbal fluency, difficulty planning or shifting to a new stimulus, slowed information processing speed, and impaired memory. Memory impairment is most frequently attributable to a retrieval deficit since recognition is often intact. Procedural learning may be impaired, a pattern atypical in normal aging or in AD. Some language skills are intact, such as vocabulary, while others that tap additional cognitive domains, such as verbal fluency, may be impaired. Mechanical aspects of speech are often impaired as well. Although PDD has been previously characterized as a “subcortical” dementia to distinguish it from cortical dementias such as AD, this characterization has been criticized more recently and may serve simply as a gross depiction of the cognitive profile. Indeed, recent research suggests that while initial mild cognitive deficits in Parkinson disease likely result from depleted dopamine in the midbrain and resulting defects in the frontostriatal loop, cortical pathology is required for the development of dementia.
Dementia with Lewy bodies
As discussed above, DLB and PDD share many of the same features, including cognitive fluctuations, neuropsychiatric features, and motor symptoms. However, the timing and severity of these symptoms may differ. Visual hallucinations often occur earlier in DLB, delusions may be more common, and a differential response to antiparkinsonian medications has been reported. In terms of cognition, prominent visuospatial and executive impairments are noted, similar to PDD. However, memory impairments are more prominent in DLB. According to consensus criteria for DLB, cognition must be carefully assessed. A progressive cognitive decline, usually over the course of a number of years, must be observed to a degree that it disables the patient. In addition the patient must show some combination of fluctuations in cognition, recurrent visual hallucinations, or spontaneous parkinsonism. Many patients may also present with other psychiatric symptoms, neuroleptic sensitivity, and a history of falls and syncopal attacks. Based on these criteria, the differential diagnosis between DLB and Parkinson disease is obviously difficult. One pattern that has emerged in patients with DLB, however, is a higher likelihood of overlap with AD pathology. Indeed, unlike PDD, a substantial majority of DLB cases have concurrent AD pathology.
The differential diagnosis between DLB and AD can thus also be difficult. The presence of visual hallucinations in patients with MMSE scores greater than 20 is highly suggestive of DLB. Neuropsychological studies have identified typical cognitive profiles that may aid in diagnosis. In DLB, patients have more difficulty than AD patients in copying complex designs, assembling pieces of an object, or completing other tasks requiring visuospatial skills. In contrast, AD subjects generally show significantly more impairment on delayed recall tasks than patients with DLB. DLB patients have attentional skills that are generally equivalent to those of AD patients; however, patients with DLB exhibit significant attentional fluctuations. As a result, evaluating attention over time is more helpful than the overall severity of attention problems in the differential diagnosis. Finally, these cognitive profiles are most evident early in the course of the diseases. As the diseases progress, all cognitive functions become impaired and neuropsychological testing is less helpful for diagnosis.
Vascular Cognitive Impairment
The construct of vascular cognitive impairment (VCI) is undergoing rapid development. The recent statement for health care professionals from the American Heart Association and American Stroke Association describes VCI as an umbrella term that uses a nosology similar to AD categorization, and subsumes the conditions of probable and possible VaD and vascular mild cognitive impairment (VaMCI). An additional category of unstable VaMCI is used to refer to patients with a diagnosis of probable or possible VaMCI who revert to normal. A diagnosis or VaD requires evidence of cerebrovascular disease on neuroimaging, decline in cognitive function in two or more domains, determined through cognitive testing, and compromise in daily function that is not attributable to the physical effects of the cerebrovascular injury. Probable VaD further requires that there be no evidence of decline prior to any vascular event that suggests underlying nonvascular neurodegeneration. Possible VaD is diagnosed when there is insufficient evidence to ascertain temporal or functional contiguity between cerebrovascular abnormalities, or to exclude other neurodegenerative processes. VaMCI subtypes are diagnosed with criteria similar to AD-related MCI.
Progress in achieving a cognitive nosology is hindered by the likely heterogenous nature of these conditions, which complicates efforts to identify characteristic cognitive profiles. According to NINDS-AIREN criteria, six vascular “subtypes” ascribe dementia to multiple large infarcts, strategic single infarcts, small vessel disease, hypoperfusion, hemorrhage, or miscellaneous vascular insult. It is likely that dementia due to small vessel disease is the most common form of vascular dementia and provides the most uniform pattern of cognitive impairment. Cognitive profiles of these patients at early stages typically reveal executive function deficits, reduced verbal fluency, and slowing, with preservation of cued memory and an absence of intrusions. Depression, irritability and lack of initiative are also common. Contrary to long-standing clinical lore, VaD does not necessarily present primarily with stepwise deterioration in cognition, rather, continuous small vessel insults can lead to slowly progressive decline in cognitive abilities. Thus, it can be difficult to differentiate VaD from AD on the basis of the clinical course of symptoms. Detailed review of cardiovascular risk factors and cognitive profile may provide better differentiation. A review of studies examining early-stage AD and VaD found that the latter group had more pronounced deficits in executive function on tests such as the Wisconsin Card Sorting Test and the executive function scale of the Mattis Dementia Rating Scale than did adults with AD. Interestingly, performance between the two groups was similar on tests of selective attention and working memory such as the Trail-Making Test and Stroop Color Word Interference test. In contrast, VaD patients had better performance than AD patients on tests of verbal learning and story recall, such as the California Verbal Learning Test and the Logical Memory subtest of the Wechsler Memory Scale-Revised (WMS-R), with fewer intrusions. However, VaD can impact the structure and function of the hippocampus thus leading to more notable memory deficits in some patients, although these impairments may not occur until later in the disease process. Because memory impairment is most often the reason patients seek evaluation, adults with VaD may have more progressed dementia and greater cognitive impairment at the time of diagnosis. It is important to note that as both VaD and AD progress, the cognitive profiles become more similar, so that differentiating mid-stage disease is very difficult. In addition, recent neuropathologic studies have shown that many patients previously diagnosed with vascular dementia due to presence of vascular risk factors such as diabetes, hypertension, and radiologic evidence of ischemia have prominent AD pathology as well. Prevalence estimates of the cooccurrence of AD and vascular dementia range from 20% to 40% of patients with dementia. Few studies have attempted to differentiate between mixed AD/VaD and either form of dementia on a neuropsychological basis, although it has been suggested that mixed dementia most closely resembles VaD from a cognitive perspective. Vascular pathology increases the likelihood that patients with neuropathologic AD will show significant cognitive impairment. Finally, cognitive profiles for other forms of VaD such as multiple large vessel or single strategic infarcts are highly idiosyncratic, depending on lesion location and volume.
Frontotemporal Lobar Degeneration
Frontotemporal lobar degeneration (FTLD) is caused by a range of underlying neuropathologic conditions (including intracellular inclusions of tau or TDP-43, among others). Various clinical presentations can be caused by FTLD, primarily resulting in gradually progressive disturbances in language and/or behavior. FTLD has been estimated to account for 3% to 20% of dementia cases, although diagnosis is often difficult, so precise estimates are unknown. The following diagnostic variants are currently recognized as most likely resulting from FTLD, although the extent to which these represent distinct disorders is not currently well defined.
This diagnostic category, which includes Pick disease, includes the prototypical symptoms of personality change and slowly progressive executive dysfunction. This variant most often presents initially with behavioral disturbance that includes at least three of the following: (a) disinhibition, (b) apathy, (c) diminished empathy/sympathy, (c) perseverative, stereotyped, or compulsive behaviors, (d) hyperorality, and (e) executive deficits on neuropsychological examination with relatively intact recall and visuospatial skills, although performance on these measures may be affected by severe executive impairments, such as disorganization. Neuropsychological testing generally reveals impaired selective and divided attention, difficulty shifting mental set, poor abstraction, and impaired verbal fluency, and perseverative errors are common. Unfortunately, the MMSE is not very helpful in screening for early behavioral variant FTLD (FTLDbv) since many patients score within normal limits early in the disease.
Primary progressive aphasia
The diagnosis of primary progressive aphasia (PPA) requires initial prominent language dysfunction with relative sparing of other cognitive domains, and the absence of radiologic evidence of cerebrovascular or other neurologic injury that would account for the aphasia. PPA variants include (1) agrammatic (nonfluent) PPA, which is characterized by labored articulation and agrammatism with preserved comprehension except for complex sentences with embedded clauses; (2) logopenic PPA, which presents with impaired naming, spontaneous speech, and repetition; and (3) semantic PPA (sometimes called semantic dementia), which involves a loss of ability to understand words and deficits in confrontational naming, often accompanied by impairment in visual recognition of objects, dyslexia, and dysgraphia. Patients with semantic dementia may display prominent visual agnosias and may not be able to demonstrate object use accurately.
Because anomia and other language deficits may occur in a number of neurodegenerative conditions, the differential diagnosis of PPA rests on the clear demonstration that nonlinguistic cognitive and behavioral functions are intact during the initial stages of the disease. The examiner must carefully determine whether poor performance on memory and other nonlanguage tests is due to language deficits such as impaired comprehension of instructions. The onset of PPA is typically in the fifth or sixth decade of life, and its rate of progression varies greatly. As the disease progresses, however, other cognitive functions become impaired, as does the patient’s ability to carry out functional activities, thus, making a diagnosis of mid-stage PPA difficult at best. Differential diagnosis is also complicated by the heterogenous etiologies of PPA demonstrated by the different subtypes. Although not consistent across all cases, agrammatic PPA is often associated with tau pathology, logopenic PPA with AD pathology (although not always in brain regions typically associated with AD), and semantic PPA with TDP-43 pathology.
Certain movement disorders, which may also include behavioral and/or language disturbance, may be caused by or associated with FTLD.
Progressive supranuclear palsy
Although Lewy bodies are found in only the minority of progressive supranuclear palsy (PSP) cases, PSP is frequently misdiagnosed as Parkinson disease. A core feature of the disorder is vertical supranuclear gaze palsy, although this symptom may not present early in the course of the disease. Patients also present with postural instability, and falls are often seen shortly after onset. Cognition is characterized by mental slowing and executive dysfunction. Memory impairments are observed, but they are not as severe as in AD. Language functions resemble those seen in PD. Visual spatial deficits and increased apathy are also observed.
Corticobasal syndrome (CBS) leads to asymmetric motor symptoms such as tremor, loss of coordination, rigidity, and spasms, and a higher prevalence of alien limb syndrome. Apraxia (most commonly ideomotor), a range of language abnormalities, and/or executive/behavioral dysfunction may be seen in CBS. Memory loss may be prominent in some patients. Neuropsychiatric symptoms are common.
In addition to the variants described above, FTD with parkinsonism and FTD associated with amyotrophic lateral sclerosis (FTD-ALS) involve symptoms of the combined diseases, and are often associated with specific genetic mutations.
Both the personality changes and cognitive dysfunction observed at early stages of FTLD exceed those seen in normal aging. As with other dementing conditions, the most difficult differential diagnosis is between FTLD and AD. Age of onset for FTLD is typically in the late 50s or early 60s, although there is a wide range observed. Therefore, on average FTLD patients show symptoms about a decade earlier than AD patients. As with AD, FTLD patients show insidious onset of symptoms with a gradual progression. Although comparisons of AD and FTLD groups do not always reveal significantly different cognitive profiles, in general, FTLD patients show relatively spared memory performance in comparison to their executive and language functioning, especially when memory cues are provided. Apraxia is also more common in FTLD than in AD. Often a multidisciplinary approach may be most helpful in the differential diagnosis since studies indicate that up to 75% of pathologically confirmed FTLD patients also appear to meet clinical criteria for probable AD.
Recent epidemiologic analyses suggest that mild-to-moderate alcohol use reduces the risk for developing certain dementias, including Alzheimer disease and vascular dementia. Chronic and profound alcohol use, however, can have a negative effect on cognition and may exacerbate the cognitive symptoms of other dementias and brain injuries. Poor nutrition (thiamine deficiency in particular) resulting from alcohol abuse is a primary contributor to the onset of cognitive problems. In addition, liver disease itself can interfere with thiamine regulation in the brain and may be a factor in the multiple cognitive and motor impairments associated with long-term alcohol use.
Persistent alcohol dementia
Alcohol dementia involves impairment in more than one area of cognitive function that persists after the patient stops drinking for a period of time. Visuospatial problem-solving deficits and executive problems, including apathy, decreased judgment, and reduced interest in self-care, are prominent in these patients. Memory problems, in particular anterograde amnesia, are also common, but are generally not more impaired than other cognitive domains, and recognition is often intact. Typical neuropsychological sequelae include impairments on tasks requiring visual scanning, visuospatial organization, perceptual-motor speed, sustained attention, abstraction, and mental flexibility, while language functions are generally preserved. Perseveration and confabulation are common indicators of impaired executive function in the responses of patients with chronic alcohol use. It is also noteworthy that chronic alcohol use may potentiate the onset of AD, and produce a clinical picture of conjoint cognitive deficits.
The most severe neurologic outcome of heavy and prolonged alcohol use, and the result of critical malnutrition, is Wernicke-Korsakoff syndrome. In contrast to patients with persistent alcohol dementia, Wernicke-Korsakoff patients exhibit an acute symptom onset, often beginning with a grave confusional state, nystagmus, and significant ataxia. During this phase, symptoms progressively and rapidly worsen if treatment (immediate thiamine replacement) is not applied. This phase is almost always followed by a chronic and progressive stage that is associated primarily with impaired frontal and cerebellar functions. Unlike persistent alcohol dementia, Korsakoff patients have significant impairments in memory relative to other cognitive effects, and memory impairment includes both retrograde and anterograde amnesia for episodic events, frequently with prominent confabulation. In contrast to AD, semantic memory is relatively spared in the Korsakoff patient. Patients show a characteristic gradient of remote memory impairment, with better recall for remote events and progressively reduced recall of recent events. As with persistent alcohol dementia, executive dysfunction and visuospatial impairments are also significant symptoms of the syndrome. Cerebellar atrophy and peripheral nerve damage lead to impaired gait, decreased or abnormal reflexes, and other movement abnormalities in these patients.
The prion diseases are a group of rare fatal spongiform encephalopathies that result from mutations and polymorphisms in the prion protein gene (PrP), causing rapid neurodegeneration. These diseases, of which Creutzfeldt-Jakob is the most well known, produce a profound and quickly progressive dementia, and may be sporadic, familial, or infectious. Sporadic cases are the most common, and are generally diagnosed in people in their 60s, with a typical age range between 40 and 80. Early cognitive signs of the prion diseases are usually vague and nonspecific, such as poor memory, concentration, and problem solving. Initially, there are also often psychiatric symptoms, including apathy, emotional lability, impaired sleep, and appetite loss. Early frank neurologic symptoms are not common, but as the disease progresses, hyperreflexia, impaired coordination, changes in saccadic eye movements, and incontinence may occur. Given the early vague symptoms and dearth of neurologic symptoms, patients are not likely to present for evaluation until they are in the more moderate-to-advanced stages, which can occur in a matter of months. Diagnosis typically involves measuring electroencephalographic changes, hyperintensities on magnetic resonance imaging, and abnormal 14-3-3 protein deposits in the CSF. The most common differential diagnoses include depression, AD, and LBD.
Normal Pressure Hydrocephalus
Normal pressure hydrocephalus (NPH) is a potentially reversible dementia that makes up about 6% of dementia cases. Abnormalities in the production, absorption, or flow of CSF result in ventricular dilatation. Patients may present with a triad of clinical symptoms that include gait or balance disturbance, urinary incontinence, and cognitive deficits. Unlike most other dementias, cognitive symptoms often present later in the course. This can make early clinical diagnosis difficult since gait abnormalities and incontinence have a variety of etiologies in geriatric populations. Radiographic evidence and intraventricular pressure measurement aid in the diagnosis. When cognitive deficits are present, they are most frequently observed in executive functioning. Although many subjects may have subjective memory complaints, memory deficits are not a prominent early symptom, and some memory declines are attributable to attention problems, which are more common. However, many of these patients may have concurrent underlying neurodegenerative disease, and thus may present with varied cognitive profiles.
When treated, a ventriculoperitoneal shunt is usually used to divert CSF for better absorption. However, surgery in geriatric populations always involves added risks, and the benefits of shunt surgery remain unclear. A wide variety of success rates have been reported, with better outcomes often reported after shorter follow-up periods. Patients with the full triad of symptoms appear to respond best to shunt surgery. Gait problems show the most frequent improvement, while cognitive function improves in the fewest patients. Recently findings from a 5-year follow-up of NPH patients with and without shunt surgery showed that at the 6-month assessment, 83% of the shunt cases improved in gait and 46% improved in memory. Of surviving shunt cases 5 years after surgery, 39% remained improved in gait, and fewer than 10% continued to show improvements on cognitive tests. Results suggested that outcomes may be improved in younger patients.
HIV-Associated Neurocognitive Disorder
Although there is often the perception that geriatric patients are not at risk for HIV infection, the Centers for Disease Control and Prevention (CDC) reported that 10% of all HIV cases in the United States are in patients of 50 years or older, and these numbers are expected to grow. The earliest cognitive areas affected are usually speed of information processing, attention, and motor speed. A subgroup of patients progress to HIV-associated dementia which is usually characterized by impairments in executive functioning, psychomotor speed, and memory, along with slowed motor function and loss of coordination. However, progression to dementia generally occurs in the absence of treatment, and is rare when antiretroviral therapy is used.
Neurosyphilis is an advanced syphilitic infection that may present with hallucinations, delusions, mood disturbance, personality change, strokes, ataxia, or cognitive decline. Deficits are observed in short-term memory and mental status with progressive cognitive decline in all areas of functioning. Although neurosyphilis is often classified as a reversible dementia, there is only limited evidence to support cognitive benefits with treatment. The onset of dementia in neurosyphilis often occurs several decades after contraction of the disease. Neurosyphilis should be considered in a differential diagnosis of dementia of unclear etiology in geriatric patients.