Common Causes of Dementia
A wide variety of diseases can produce dementia, but only a few do so commonly. In its most typical presentation—with gradual cognitive decline in an elderly (≥65 years) patient—the most common causes of dementia are Alzheimer disease, vascular (formerly “multi-infarct”) dementia, frontotemporal dementia, and Lewy body disease (Figure 5-2). Autopsy studies show that many elderly demented patients have histopathological features of more than one such dementing process, such as Alzheimer disease and vascular disease (mixed dementia). In addition, vascular factors may influence the risk or progression of neurodegenerative disease. Patients who present with dementia before age 45 years are much less likely to have Alzheimer disease or vascular dementia; in these patients, a wider range of neurodegenerative (Huntington disease, corticobasal degeneration), inflammatory (multiple sclerosis, systemic lupus erythematosus, vasculitis), and infective (prion disease) causes must be entertained. Dementia that progresses rapidly over weeks to months results most often from prion (Creutzfeldt–Jakob) disease.
Common causes of dementia based on age at presentation and rate of progression. “Mixed” refers to combined Alzheimer disease and vascular dementia. Totals of <100% reflect absence of an etiologic diagnosis in some cases. (Data from Kelley BJ, Boeve BF, Josephs KA. Young-onset dementia: demographic and etiologic characteristics of 235 patients. Arch Neurol. 2008;65:1502-1508. Garre-Olmo J, Genís Batlle D, del Mar Fernández M, et al. Incidence and subtypes of early-onset dementia in a geographically defined general population. Neurology. 2010;75:1249-1255. Geschwind MD, Shu H, Haman A, Sejvar JJ, Miller BL. Rapidly progressive dementia. Ann Neurol. 2008;64:97-108.)
Reversible causes of dementia, such as normal-pressure hydrocephalus, intracranial mass lesions, vitamin B12 deficiency, hypothyroidism, and neurosyphilis, are rare. However, they are important to diagnose because treatment can arrest or reverse intellectual decline.
Diagnosing dementia caused by Huntington disease or other heritable disorders allows patients and their families to benefit from genetic counseling. If Creutzfeldt–Jakob disease or HIV-associated dementia is diagnosed, precautions can be instituted against transmission, and HIV disease can be treated with antiretroviral drugs. Progressive multifocal leukoencephalopathy may indicate underlying immunosuppression from HIV infection, lymphoma, or leukemia and may thereby bring these disorders to attention.
Approximately 15% of patients referred for evaluation of possible dementia instead have other disorders (pseudodementias), such as depression. Depression in this setting is important to identify because it is readily treatable. Drug intoxication, often cited as a cause of dementia in the elderly, actually produces an acute confusional state, rather than dementia.
In several neurodegenerative diseases, the production of misfolded proteins and their association to form insoluble aggregates appears to play an important role in pathogenesis (Table 5-7). These abnormal proteins can arise from either genetic or acquired modifications, and their pathologic effects may result from loss of normal protein function, gain of a toxic function, or a combination of these factors. Protein aggregation may be a mechanism for sequestering proteins that the cell’s proteolytic machinery cannot process, but protein aggregates may also exert adverse effects on the cell, such as by interfering with axonal transport.
Table 5-7.Neurodegenerative Proteinopathies. ||Download (.pdf) Table 5-7. Neurodegenerative Proteinopathies.
|Protein ||Dementing Disease (s) ||Transmission ||Histopathologic Features |
|β-Amyloid (Aβ) ||Alzheimer disease ||Sporadic or inherited ||Amyloid plaques, neurofibrillary tangles |
|Tau || |
Progressive supranuclear palsy
|Sporadic or inherited ||Neurofibrillary tangles or amorphous deposits (pretangles) |
|TDP-43 || |
Frontotemporal dementia with motor neuron disease
|Sporadic or inherited ||TDP-43/ubiquitin-positive inclusions |
|Fused-in-sarcoma (FUS) ||Frontotemporal dementia ||Sporadic or inherited ||FUS-positive inclusions |
|α-Synuclein || |
Lewy body disease (Parkinson disease with dementia, dementia with Lewy bodies)
|Sporadic or inherited ||Lewy bodies |
|Huntingtin (Htt) ||Huntington disease ||Inherited ||Polyglutamine inclusions |
|Prion protein (PrP) ||Creutzfeldt–Jakob disease (CJD), Gerstmann–Sträussler–Scheinker syndrome (GSS), fatal familial insomnia, kuru ||Sporadic, infectious, or inherited ||PrP-positive plaques (variant CJD, GSS) |
Except in rare inherited or infectious cases, the underlying cause of neurodegenerative proteinopathies is unknown. However, these diseases share several features. In addition to protein misfolding and aggregation, which sometimes produces characteristic histopathologic findings (see Table 5-7), these diseases may be associated with cell-to-cell prionic transmission (Figure 5-3), which allows them to spread through the nervous system to produce characteristic anatomic patterns of involvement. Disease spread is through the release of misfolded pathogenic proteins, alone or in vesicles, from affected neurons and subsequent uptake by neighboring neurons, or through direct transfer to adjacent cells in nanotubes.
Cell-to-cell (prionic) transmission of neurodegenerative proteinopathies. Abnormal proteins associated with neurodegenerative disease may misfold, leading to the formation of protein aggregates; misfolded proteins, protein aggregates, or both may be toxic and contribute to neuronal dysfunction. In addition, toxic protein aggregates may be transferred between cells to propagate the disease.
At least two patterns of spread are observed in neurodegenerative proteinopathies: contiguous propagation, which affects anatomically adjacent areas and does not require synaptic connectivity, and network propagation, which involves synaptically (and therefore functionally) connected, and sometimes distant, regions. In Alzheimer disease, for example, β-amyloid pathology spreads centripetally from the cerebral cortex to subcortical regions, while tau pathology moves in the opposite direction, from the brainstem and entorhinal cortex to the neocortex. In Lewy body disease, α-synuclein deposits are seen first in the brainstem and olfactory bulb and ascend from there to the neocortex.
In addition to direct spread of pathogenic proteins, other mechanisms that may explain the spatial and temporal features of neurodegenerative proteinopathies include differential susceptibility of neuronal populations to proteotoxicity and different regional thresholds for symptomatic neuronal loss.
A given misfolded protein may also lead to divergent disease phenotypes. For example, tau is implicated in Alzheimer disease, frontotemporal dementia, progressive supranuclear palsy, and corticobasal degeneration, which have different clinical features. Molecular heterogeneity of abnormal prion proteins also corresponds to the clinically distinct Creutzfeldt–Jakob disease, variant Creutzfeldt–Jakob disease, fatal familial insomnia, and Gerstmann–Sträussler–Scheinker syndrome.
Alzheimer disease is the most common cause of dementia, accounting in whole or part for an estimated 60-70% of cases. Alzheimer disease affects approximately 15% of individuals of age 65 years or older and approximately 45% of those age 85 years or over. Its prevalence is >5 million cases in the United States and ~40 million cases worldwide. Men and women are affected with equal frequency, when adjusted for age. However, because women live longer, they account for approximately two-thirds of Alzheimer patients.
Alzheimer disease is defined by characteristic histopathologic features, especially neuritic (senile) plaques and neurofibrillary tangles (Figure 5-4). Neuritic plaques are extracellular deposits that contain β-amyloid (Aβ) and other proteins, including presenilin 1, presenilin 2, α1-antichymotrypsin, apolipoprotein E, α2-macroglobulin, and ubiquitin. Plaques may also be found in cerebral and meningeal blood-vessel walls, producing cerebral amyloid angiopathy. Neurofibrillary tangles are intracellular deposits containing hyperphosphorylated tau (a microtubule-associated protein) and ubiquitin. Gross inspection of the brain in Alzheimer disease shows cortical atrophy and associated ex vacuo hydrocephalus (Figure 5-5).
Characteristic extracellular neuritic plaque (arrowheads, A) and intracellular neurofibrillary tangles (arrows, A and B) in the brain of a patient with Alzheimer disease. (Used with permission of Shahriar Salamat, MD, PhD, University of Wisconsin School of Medicine and Public Health, Department of Pathology and Laboratory Medicine.)
Normal brain viewed from above (A) and in coronal section (B), compared with brain from a patient with Alzheimer disease, showing cortical atrophy (widened sulci, C) and ex vacuo hydrocephalus (enlarged ventricles, D). (Whole brain photos used with permission from Peter Anderson, D.V.M., PhD., PEIR Digital Library Image 15470. © University of Alabama at Birmingham, Department of Pathology. http://peir.net. Brain slice photos used with permission from A.C. McKee.)
Alzheimer disease is a progressive, degenerative disorder that is caused by a genetic defect in rare cases (see later), but is usually sporadic and of unknown cause. Abnormal metabolism, deposition, or clearance of two proteins—Aβ and tau—appears to be closely linked to pathogenesis.
Genetics—In ~1% of patients, Alzheimer disease is a familial disorder that results from a mutation in one of three functionally related membrane proteins (Table 5-8): β-amyloid precursor protein (APP), presenilin 1 (PS1), or presenilin 2 (PS2). Onset of the disease in these patients is typically between the ages of 30 and 60 years. Patients with Down syndrome (trisomy 21) also develop early Alzheimer disease (mean onset at age 50 years), which is thought to be related to an extra copy of the APP gene, located on chromosome 21. Although the cause of sporadic Alzheimer disease is unknown, the gene defects in familial Alzheimer disease support possible roles for both APP, a protein with neurotrophic properties, and the presenilins, which are involved in APP metabolism.
The risk of Alzheimer disease is also influenced by the inheritance pattern of apolipoprotein E (APOE) gene isoforms ε2, ε3, and ε4. Risk increases from ~10-15% when all APOE genotypes are combined to ~20-30% with a single apolipoprotein Eε4 (APOE4) allele and to ~50% with two copies of APOE4; each copy of APOE4 also lowers the age at onset by about 5 years. In contrast to APOE4, APOE2 appears to confer relative protection from Alzheimer disease. The mechanism through which APOE genotype modifies susceptibility to Alzheimer disease is unknown, but may involve APOE binding to Aβ, impairing Aβ clearance, or acting as a transcription factor.
Polymorphisms at a number of other genetic loci appear to influence Alzheimer disease risk, but their effects are small. Nevertheless, the fact that they are involved in a wide variety of functions—including lipid metabolism, inflammation, intercellular signaling, and membrane transport—suggests that diverse processes may contribute to Alzheimer disease pathogenesis.
Aβ and neuritic plaques—Aβ is the principal constituent of neuritic plaques and is also deposited in cerebral and meningeal blood vessels in Alzheimer disease. Aβ is a 38- to 43-amino acid peptide produced by proteolytic cleavage of the transmembrane protein, APP (Figure 5-6). Normal processing of APP involves its cleavage by the enzyme α-secretase, which does not produce Aβ, and by β-secretase (BACE; β-site APP cleaving enzyme) and γ-secretase, yielding primarily a 40-amino acid fragment (Aβ40), which is secreted and cleared from the brain. In Alzheimer disease, a disproportionate amount of Aβ42, a longer form of the molecule with an increased tendency to aggregate, is produced. Presenilins 1 and 2 contribute to γ-secretase activity.
Evidence for a causal role of Aβ in Alzheimer disease includes the involvement of APP mutations in some familial cases and the neurotoxicity of Aβ under some circumstances. However, there is a poor correlation between the extent of amyloid plaque deposition in the brain and the severity of dementia in Alzheimer disease. One explanation for this disparity is that soluble Aβ oligomers, rather than insoluble plaques, may be the toxic agent. Another possibility is that Aβ aggregation produces Alzheimer disease indirectly, such as by promoting the formation of tau-containing neurofibrillary tangles.
Tau and neurofibrillary tangles—Tau is a cytoplasmic protein that binds to tubulin and stabilizes microtubules, cytoskeletal structures that help maintain cell structure and facilitate intracellular transport. In Alzheimer disease and other tauopathies, tau becomes hyperphosphorylated and dissociates from microtubules; the microtubules disassemble, and hyperphosphorylated tau aggregates to form neurofibrillary tangles (Figure 5-7). How this leads to impaired neuronal function is unknown, but may involve a defect in axonal transport. A causal role for tau pathology in Alzheimer disease is supported by the observations that the abundance of neurofibrillary tangles correlates well with disease severity and that other tauopathies (eg, frontotemporal dementia), in which Aβ processing is normal, can also produce dementia.
Synaptic and neuronal network dysfunction—Alzheimer disease is accompanied by early changes in synaptic function, including altered excitatory activity, loss of dendritic spines, and ultimately loss of synapses. These changes, in turn, disrupt interneuronal connectivity and the function of brain circuits, such as the basal forebrain cholinergic, hypothalamic-hippocampal, and amygdala-hippocampal networks. Pathologic alterations at this level of brain organization may help explain memory loss and other cognitive defects in Alzheimer disease.
Neuronal loss and brain atrophy—Certain neuronal populations are preferentially lost in Alzheimer disease, including glutamatergic neurons in the entorhinal cortex and the CA1 sector of the hippocampus, as well as cholinergic neurons in the basal forebrain. Focal brain atrophy is seen in the affected areas.
Vascular involvement—The extent to which vascular pathology may contribute to Alzheimer disease is controversial. Evidence for such a connection includes the overlap between risk factors for vascular disease and Alzheimer disease (including APOE genotype), the involvement of blood vessels in amyloid pathology, and the frequent coexistence of Alzheimer and vascular histopathology.
Table 5-8.Principal Genes Implicated in Alzheimer Disease. ||Download (.pdf) Table 5-8. Principal Genes Implicated in Alzheimer Disease.
|Gene ||Gene Locus ||Protein ||Genotype ||Phenotype |
|APP ||21q21.3–q22.05 ||Amyloid β A4 precursor protein ||Various missense mutations ||Familial Alzheimer disease (autosomal dominant) |
|PS1 ||14q24.3 ||Presenilin 1 ||Various missense mutations ||Familial Alzheimer disease (autosomal dominant) with early onset (age 35-55) |
|PS2 ||1q31–q42 ||Presenilin 2 ||Various missense mutations ||Familial Alzheimer disease (autosomal dominant) in Volga Germans |
|APOE ||19q13.2 ||Apolipoprotein E ||APOE4 polymorphism ||Increased susceptibility to Alzheimer disease |
|Multiple ||21 ||Unknown ||Trisomy 21 or chromosome 21–14 or 21–21 translocation ||Down syndrome (early-onset Alzheimer disease) |
Normal and pathologic (amyloidogenic) processing of APP and Aβ. APP, a membrane-spanning protein, is normally cleaved by α-secretase (α), or by β-secretase (β) and then γ-secretase (γ, a protein complex that includes presenilin 1 or 2, nicastrin, anterior pharynx defective 1 homolog [APH1], and presenilin enhancer 2 [PEN2]) to generate β-amyloid (Aβ), a secreted protein. APP mutations associated with familial Alzheimer disease shift Aβ production from a nontoxic 40-amino acid to a toxic (amyloidogenic) 42-amino acid form, which has a greater tendency to form amyloid deposits. Aβ normally undergoes enzymatic breakdown (by neprilysin [NEP], insulin-degrading enzyme [IDE], or endothelin-converging enzyme [ECE-1]) and clearance from the brain. However, it can also aggregate to form oligomers of increasing size, which are thought to be neurotoxic. AICD, APP intracellular domain; C83 and C99, C-terminal fragments of APP; sAPP, soluble APP.
Tau hyperphosphorylation and neurofibrillary tangle formation.
The factors most conclusively associated with increased risk for Alzheimer disease are increasing age, female sex, and APOE4 genotype. Other factors that have been implicated in some studies include family history of Alzheimer disease, depression, low educational level, smoking, diabetes, obesity, hypertension, and fatty diet. Besides APOE4, several other genes that modify risk have been identified, but the magnitude of their effects is small.
Some data suggest that cognitive engagement, physical activity, a low-fat and vegetable-rich diet, and light to moderate alcohol intake may favorably affect the risk of Alzheimer disease. However, no drugs have been shown to be effective in prevention. Estrogen administration does not appear to affect cognitive function in postmenopausal women after several years of follow-up, irrespective of when treatment is begun in relation to menopause.
The clinical progression of Alzheimer disease is thought to comprise a presymptomatic phase of up to about 10 years characterized by the deposition of amyloid plaques, followed by a symptomatic phase of up to about 10 years, during which tangle formation occurs (Figure 5-8).
Relationship between plaques, tangles, and clinical progression of Alzheimer disease (AD). MCI, mild cognitive impairment.
Early manifestations—The term mild cognitive impairment (MCI) is sometimes used to describe the early phase of cognitive decline observed in patients who later receive a diagnosis of Alzheimer disease. Impairment of recent memory is typically the first sign of Alzheimer disease and may be noticed only by family members. As the memory disorder progresses over months to several years, the patient becomes disoriented to time and then to place. Aphasia, anomia, and acalculia may develop, forcing the patient to leave work or give up the management of family finances. The depression apparent in the earlier stages of the disorder may give way to an agitated, restless state. Apraxias and visuospatial disorientation ensue, causing the patient to become lost easily. Primitive reflexes are commonly found. A frontal lobe gait disorder may become apparent, with short, slow, shuffling steps, flexed posture, wide base, and difficulty in initiating walking.
Late manifestations—In the late stages, previously preserved social graces are lost, and psychiatric symptoms, including psychosis with paranoia, hallucinations, or delusions, may be prominent. Seizures occur in some cases. Examination at this stage may show rigidity and bradykinesia. Rare and usually late features of the disease include myoclonus, incontinence, spasticity, extensor plantar responses, and hemiparesis. Mutism, incontinence, and a bedridden state are terminal manifestations. Eating problems, febrile episodes, dyspnea, pneumonia, and pain are frequent complications in the final months of life, and death typically occurs from 5 to 10 years after the onset of symptoms.
Atypical variants—Several clinically atypical variants of autopsy-verified Alzheimer disease have been described in which memory is relatively preserved. These patients have early (<65 years of age) onset of symptoms, which correlate best with the density of neurofibrillary tangles. The frontal variant shows prominent behavioral and personality changes, including irritability, impulsivity, and disinhibition. The posterior variant is associated with visuospatial disorders, including Balint syndrome (optic ataxia, ocular apraxia, and simultanagnosia), Gerstmann syndrome (agraphia, acalculia, finger agnosia, and left-right disorientation), and visual agnosia. The logopenic variant exhibits anomia and impaired repetition.
Laboratory investigations should be undertaken to exclude other disorders, especially reversible or treatable conditions. Findings that may be useful in helping to establish a diagnosis of Alzheimer disease include CSF with reduced Aβ42 and increased tau and phospho-tau; MRI showing medial temporal lobe (including hippocampal) and often parietal greater than frontal lobe atrophy (Figure 5-9); positive amyloid positron emission tomography (PET) imaging; and 18F-fluorodeoxyglucose PET demonstrating glucose hypometabolism in the temporal and parietal lobes.
Axial MRI in Alzheimer disease showing (A) bilateral hippocampal and (B) parietal (bottom) more than frontal (top) lobe atrophy. (Used with permission from Berkowitz AL. Clinical Neurology and Neuroanatomy: A Location-Based Approach. New York, NY: McGraw-Hill; 2017. Fig. 22-3.)
Early Alzheimer disease may resemble depression or pure memory disorders such as the Korsakoff amnestic syndrome (see later discussion). More advanced Alzheimer disease must be distinguished from frontotemporal dementia, Lewy body disease, vascular dementia, Creutzfeldt–Jakob disease, and other dementing disorders, discussed later.
No currently available treatment has been shown to reverse existing deficits or to arrest disease progression. However, memantine (Table 5-9), an NMDA-type glutamate receptor antagonist drug, may produce modest improvement in patients with moderate or severe Alzheimer disease.
Table 5-9.Drugs Used in the Treatment of Alzheimer Disease. ||Download (.pdf) Table 5-9. Drugs Used in the Treatment of Alzheimer Disease.
|Drug Class ||Drug ||Dose ||Toxicity |
|Glutamate antagonist ||Memantine ||5 mg orally daily, increased by 5 mg each week to 10 mg orally twice daily ||Dizziness, headache, constipation, confusion |
|Acetylcholinesterase inhibitor ||Tacrine ||10 mg orally 4 times daily; may be increased to 20 mg orally 4 times daily after 6 weeks ||Abdominal cramps, nausea and vomiting, diarrhea, hepatocellular toxicity (liver enzymes should be monitored twice monthly for 4 months) |
| ||Donepezil ||5 mg orally at bedtime; may be increased to 10 mg orally at bedtime after 4-6 weeks ||Nausea, diarrhea, vomiting, insomnia, fatigue, muscle cramps, anorexia |
| ||Rivastigmine ||1.5-6 mg orally twice daily ||Nausea and vomiting, diarrhea, anorexia |
| ||Galantamine ||4-12 mg orally twice daily ||Nausea and vomiting, dizziness, diarrhea, anorexia, weight loss |
|Combination ||Memantine + Donepezil ||28 mg/10 mg orally once daily ||Same as for memantine and donepezil above |
Because cholinergic neuronal pathways degenerate and choline acetyltransferase is depleted in the brains of patients with Alzheimer disease, cholinergic replacement therapy has also been used for symptomatic treatment of cognitive dysfunction (see Table 5-9). Acetylcholinesterase inhibitors, including tacrine, donepezil, rivastigmine, and galantamine, have all been shown to produce small improvements in tests of cognitive function. Side effects include nausea and vomiting, diarrhea, and dizziness; tacrine also elevates serum transaminase levels. The better side-effect profile of donepezil and its once-daily dosage schedule are advantageous.
Experimental treatments under investigation include monoclonal antibodies directed against β-amyloid, secretase inhibitors, and tau aggregation inhibitors. Antipsychotic drugs, antidepressants, and anxiolytics may be useful in controlling behavioral disturbances associated with Alzheimer disease. However, evidence for their effectiveness is sparse, and in some cases (risperidone, olanzapine) their use is associated with an increased incidence of stroke in elderly patients.
Early in the course of the disease, patients can usually remain at home and continue social, recreational, and limited professional activities. Early diagnosis can allow patients time to plan orderly retirement from work, to arrange for management of their finances, and to discuss with physicians and family members the management of future medical problems. Patients in advanced stages of the disease may require care in a nursing facility and the use of psychoactive medications. These patients must be protected and prevented from injuring themselves and their families by injudicious actions or decisions. Death from inanition or infection generally occurs 5 to 10 years after the first symptoms.
Frontotemporal dementia (FTD) comprises a genetically and clinically heterogeneous group of dementing disorders that produce frontal and temporal lobe degeneration and affect behavior and language preferentially. FTD differs in these respects from Alzheimer disease, which involves primarily the temporal and parietal lobes and causes prominent memory disturbance. Both FTD and Alzheimer disease exhibit tau-containing inclusions, but abnormal amyloid processing and plaques are seen only in Alzheimer disease.
FTD is thought to be the third most common cause of dementia, after Alzheimer disease and vascular dementia. The average age at clinical onset is 50 to 60 years, which is younger than that for Alzheimer disease.
FTD is characterized by atrophy of the frontal and temporal lobes. Histopathologic findings include neuronal loss, gliosis, and characteristic intracellular protein inclusions. Tau inclusions in FTD differ from those found in Alzheimer disease: The former are twisted, ribbon-like structures rather than paired helical filaments and include neurofibrillary tangles, amorphous deposits (pretangles), and, in some cases, Pick bodies. Inclusions are also sometimes found in the hippocampus, subcortical nuclei, brainstem, cerebellum, or spinal cord.
In most cases, FTD is a sporadic neurodegenerative disease of unknown cause. However, 20% to 40% of patients report a family history of a neurodegenerative disorder, and approximately 10% appear to inherit frontotemporal dementia in an autosomal dominant fashion.
Genetics—Mutations in three genes—the microtubule-associated protein tau (MAPT), progranulin (GRN), and chromosome 9 open reading frame 72 (C9ORF72)—appear to be responsible for the majority of inherited cases. MAPT mutations are thought to produce disease largely by toxic gain of function, whereas GRN mutations cause loss of function through haploinsufficiency. C9ORF72 mutations, which are the most common cause of familial FTD, take the form of expanded noncoding GGGCCC hexanucleotide repeats. Processing of the corresponding RNA is impaired, producing gain-of-function RNA transcripts that sequester RNA-binding proteins and give rise to non-canonically translated toxic dipeptide-repeat proteins; loss of normal C9ORF72 function may also contribute to pathogenesis. Less common mutations producing FTD affect genes for valosin-containing protein (VCP), charged multivesicular body protein 2B (CHMP2B), TAR-DNA binding protein (TARDP), or fused in sarcoma (FUS).
Intracellular inclusions—These include tau-containing inclusions (neurofibrillary tangles or amorphous deposits; see Figure 5-7) in patients with MAPT mutations; progranulin-, TDP-43-, and ubiquitin-positive inclusions in patients with GRN mutations; p62-, ubiquitin-, and unconventionally translated dipeptide repeat-positive inclusions in patients with C9ORF72 mutations; and ubiquitin- and FUS-positive inclusions in patients with FUS mutations. In each case, the role of the inclusions in disease pathogenesis is uncertain.
Neuronal dysfunction, neuronal loss, and brain atrophy—It is unclear how much of the clinical picture in FTD results from abnormal neuronal function as opposed to neuronal loss. Eventually, however, there is marked brain atrophy affecting the frontal and anterior temporal lobes most prominently, together with neuronal loss and gliosis.
Behavioral variant frontotemporal dementia is characterized by prominent behavioral changes, including altered interpersonal interactions and personal conduct (eg, apathy and disinhibition), blunted emotions, and lack of insight. These behavioral abnormalities overshadow more modest cognitive defects, such as impaired judgment, inattention, or disorganization. This syndrome can be seen in patients with tau, TDP-43, C9ORF72, or FUS pathology.
Semantic variant primary progressive aphasia (semantic dementia) produces fluent (receptive) aphasia (see Chapter 1, Neurologic History & Examination) with word-finding difficulties, impaired comprehension, and anomia, and occurs with disease affecting the dominant temporal lobe. It is most common in patients with TDP-43 pathology.
Nonfluent variant primary progressive aphasia (progressive nonfluent aphasia) produces expressive aphasia (see Chapter 1) characterized by halting speech and agrammatism with preserved comprehension, and results from predominant involvement of the dominant frontal lobe. It is most common in patients with tau pathology.
Overlap syndromes occur in cases in which FTD is combined with features of parkinsonism (corticobasal degeneration [discussed later] or progressive supranuclear palsy [discussed later and in Chapter 11, Movement Disorders]) or motor neuron disease (amyotrophic lateral sclerosis [see Chapter 9, Motor Disorders]). Parkinsonian syndromes are seen most often in patients with tau pathology, whereas motor neuron involvement is associated with TDP-43 or C9ORF72 pathology.
MRI shows frontal and temporal lobe atrophy (Figure 5-10), and 18F-fluorodeoxyglucose PET may show hypometabolism in these regions. In both cases, the abnormalities are often asymmetric, with right-sided atrophy predominating in behavioral and left-sided atrophy predominating in language variants. CSF levels of neurodegeneration-related proteins have been studied as potential markers of FTD, but so far, none are diagnostic. Genetic screening demonstrates mutations in some patients with a positive family history.
Axial (A) and coronal (B) FLAIR MRI in frontotemporal dementia showing regional atrophy of the frontal (arrow) and temporal (arrowheads) lobes. (Used with permission from Jason Handwerker.)
In contrast to Alzheimer disease, memory disturbance does not dominate the clinical picture in FTD, and onset typically occurs at an earlier age. The diagnosis is suggested by the onset of dementia before age 60 years, with behavioral disturbance or aphasia as the primary abnormality. FTD with altered behavior may be mistaken for a primary psychiatric disorder, and language variants can raise suspicion regarding stroke.
Memantine and anticholinesterase drugs used to treat Alzheimer disease have not been shown to be effective in FTD. Antidepressants, especially selective serotonin reuptake inhibitors and trazodone, may be useful for managing behavioral symptoms. Patients with parkinsonian features (corticobasal degeneration or progressive supranuclear palsy) may benefit from carbidopa/levodopa or dopamine receptor agonists (see Chapter 11, Movement Disorders).
The duration of illness in FTD is typically 6-11 years from symptom onset and 2-5 years from clinical diagnosis.
Corticobasal degeneration is a tauopathy related to FTD with tau pathology. It produces asymmetric frontoparietal cortical atrophy and depigmentation of the substantia nigra, with tau-positive neuronal and glial inclusions, ballooned neurons, and neuronal and glia cell loss. The classic corticobasal syndrome reflects involvement of both cerebral cortex and basal ganglia and consists of unilateral limb (usually arm) clumsiness and functional impairment due to some combination of apraxia, sensory loss, and myoclonus, together with extrapyramidal rigidity, bradykinesia, and postural tremor. Limb apraxia and sensory loss may produce the alien-hand sign, in which the limb moves seemingly of its own accord. Depression, apathy, irritability, and agitation are common psychiatric features. In addition to corticobasal degeneration, the corticobasal syndrome can also be seen in progressive supranuclear palsy (see next section) and FTD. Rigidity and bradykinesia are typically unresponsive to antiparkinsonian medications.
PROGRESSIVE SUPRANUCLEAR PALSY
Progressive supranuclear palsy (PSP, or Steele–Richardson–Olszewski syndrome) is an idiopathic degenerative disorder that primarily affects the brainstem, subcortical gray matter, and cerebral cortex. Like tau-positive FTD and corticobasal degeneration, it is characterized pathologically by tau-positive intracellular inclusions. The classic clinical features are supranuclear ophthalmoplegia (especially affecting downgaze), pseudobulbar palsy, axial dystonia with or without extrapyramidal rigidity of the limbs, and dementia. Because PSP usually presents as a movement disorder with parkinsonian features, it is discussed further in Chapter 11, Movement Disorders.
Parkinson disease (see Chapter 11, Movement Disorders) is accompanied by dementia in ~25% of cases. Patients who develop dementia at least 1 year after the onset of motor symptoms (tremor, rigidity, bradykinesia, postural instability) are classified as having Parkinson disease with dementia, whereas those in whom dementia has its onset prior to or within 1 year of the first motor symptoms are given the diagnosis of dementia with Lewy bodies. However, these two diagnoses cannot be distinguished pathologically, and the term Lewy body disease is sometimes used to encompass both.
Lewy body disease is characterized histopathologically by round, eosinophilic, intracytoplasmic neuronal inclusions (Lewy bodies) in the brainstem and cerebral cortex. These inclusions contain α-synuclein, a protein that is also found in Lewy bodies in Parkinson disease without dementia, and both Lewy body disease and Parkinson disease are, therefore, classified as synucleinopathies.
Lewy body disease causes cognitive decline without prominent early memory impairment. Features include fluctuating cognitive ability, well-formed visual hallucinations, and signs of parkinsonism, especially rigidity and bradykinesia.
Motor manifestations of Lewy body disease are treated with antiparkinsonian medications (see Chapter 11); some studies suggest that memantine or anticholinesterase drugs used to treat Alzheimer disease (see Table 5-9) may also be beneficial in dementia associated with Lewy body disease.
Huntington disease is an autosomal dominant neurodegenerative disorder characterized by chorea, psychiatric symptoms, and dementia. The cause is an expanded CAG trinucleotide repeat coding for a polyglutamine tract in the huntingtin (Htt) gene. The brain shows atrophy affecting the caudate nucleus, putamen, and cerebral cortex, with Htt aggregation in cytoplasmic and nuclear inclusions. Dementia usually becomes apparent after chorea and psychiatric symptoms have been present for a few years but precedes chorea in approximately one-fourth of cases. Impaired executive function (eg, judgment) and memory are prominent features, whereas language tends to be spared until late in the course. Huntington disease is discussed further in Chapter 11, Movement Disorders.
CREUTZFELDT–JAKOB (PRION) DISEASE
Creutzfeldt-Jakob disease (CJD) produces rapidly progressive dementia with variable focal degeneration of the cerebral cortex, basal ganglia, cerebellum, brainstem, and spinal cord. It is caused by a proteinaceous infectious particle (prion) and may be sporadic (approximately 85% of cases), genetic, or infectious. In the latter case, CJD can be transmitted via prion-contaminated tissue or surgical instruments (iatrogenic CJD) or by consumption of contaminated beef (variant CJD). Documented human-to-human transmission (by corneal transplantation, cortical electrode implantation, or administration of human growth hormone) is rare. The infectious agent is present in the brain, spinal cord, eyes, lungs, lymph nodes, kidneys, spleen, liver, and CSF, but not other body fluids.
The annual incidence is approximately 1 case per million. The sporadic disease has a peak age at onset of 55-75 years, whereas the genetically acquired disease usually begins earlier. More than one member of a family is affected in only 5-10% of cases, and conjugal cases are rare.
Familial CJD is an autosomal dominant disorder caused by a mutation in the PRNP gene, which codes for the prion protein cellular isoform (PrPC), a protein of unknown function. In sporadic CJD, PrPC undergoes a conformational change to produce an abnormal prion protein (scrapie isoform, or PrPSc). PrPSc then serves as a template on which PrPC is converted to additional PrPSc. In infectious CJD, PrPSc is introduced into the brain from an external source. In each case, the result is accumulation of abnormal PrPSc prions in brain tissue. The ability of PrPSc to induce the PrPSc conformation in PrPC prions enables it to replicate without nucleic acids.
Prions have also been implicated in diseases of animals and in three other rare human disorders (Table 5-10)—kuru, a dementing disease of Fore-speaking tribes of New Guinea (apparently spread by cannibalism); Gerstmann–Straüssler–Scheinker syndrome, a familial disorder characterized by dementia and ataxia; and fatal familial insomnia, which produces disturbances of sleep and of autonomic, motor, and endocrine function.
Table 5-10.Prion Diseases. ||Download (.pdf) Table 5-10. Prion Diseases.
|Human diseases |
Creutzfeldt–Jakob disease (familial, sporadic, iatrogenic, new variant)
Fatal familial insomnia
|Animal diseases |
Bovine spongiform encephalopathy
Feline spongiform encephalopathy
Scrapie (sheep and goats)
Transmissible mink encephalopathy
Wasting disease of deer and elk
Transmissible spongiform encephalopathy of captive wild ruminants
The clinical picture may be that of a diffuse central nervous system (CNS) disorder or of more localized dysfunction (Table 5-11). Dementia is present in virtually all cases and may begin as mild global cognitive impairment or a focal cortical disorder such as aphasia, apraxia, or agnosia. Progression to akinetic mutism or coma typically ensues over a period of months. Psychiatric symptoms including anxiety, euphoria, depression, labile affect, delusions, hallucinations, and changes in personality or behavior may be prominent. Fever is absent.
Table 5-11.Clinical Features of Sporadic Creutzfeldt–Jakob Disease. ||Download (.pdf) Table 5-11. Clinical Features of Sporadic Creutzfeldt–Jakob Disease.
|Feature ||Percentage |
Lower motor neuron signs
|Visual disturbances ||42 |
|Periodic EEG complexes ||60 |
Aside from cognitive abnormalities, the most frequent clinical manifestations are myoclonus (often induced by a startle), extrapyramidal signs (rigidity, bradykinesia, tremor, dystonia, chorea, or athetosis), cerebellar signs, and pyramidal signs. Visual field defects, cranial nerve palsies, and seizures occur less often.
A distinct variant of CJD results from the transmission of bovine spongiform encephalopathy (“mad cow disease”) to humans. This variant is characterized by earlier onset (typically in the teens or young adulthood), invariable cerebellar involvement, prominent early psychiatric abnormalities, and diffuse amyloid plaques.
The most sensitive and specific tests are diffusion-weighted MRI and apparent diffusion coefficient MRI, which show hyperintense signals in the basal ganglia and cortical ribbon (Figure 5-11), and detection of PrPSc amplified by real-time quaking-induced conversion in cerebrospinal fluid or brain-biopsy tissue. The electroencephalogram (EEG) may show periodic sharp waves or spikes (Figure 5-12), which are absent in the variant form described previously, and CSF protein may be elevated (≤100 mg/dL). In familial cases, mutant prions may be detectable in DNA from lymphocytes.
Diffusion-weighted image of the brain in Creutzfeldt–Jakob disease, showing characteristic hyperintensities (white) in the basal ganglia and cortical ribbon. (Used with permission from J. Biller M.D.)
EEG in Creutzfeldt-Jakob disease with typical triphasic waves in all leads, which occur repetitively about once every second.
A variety of other disorders must be distinguished from CJD. Alzheimer disease is often a consideration, especially in patients with a less fulminant course and a paucity of cerebellar and extrapyramidal signs. Where subcortical involvement is prominent, Parkinson disease, cerebellar degeneration, or progressive supranuclear palsy may be suspected. Striking focal signs raise the possibility of an intracerebral mass lesion. Acute metabolic disorders that produce altered mentation and myoclonus (eg, sedative drug withdrawal) can mimic CJD.
No treatment is currently available. The disease is usually relentlessly progressive and invariably fatal. In most sporadic cases, death occurs within 1 year after the onset of symptoms. Depending on the specific mutation present, familial forms of the disease may have a longer course (1-5 years).
Vascular disease is generally considered the second most common cause of dementia, after Alzheimer disease, and many patients have features of both diseases. Patients with this diagnosis may have multiple large (>1 cm in diameter) cortical infarcts; strategic infarcts involving hippocampus or thalamus; multiple small (eg, lacunar) infarcts affecting subcortical white matter, basal ganglia, or thalamus; diffuse ischemic lesions of subcortical white matter (Binswanger disease); intracerebral hemorrhages (eg, cerebral amyloid angiopathy); or combinations of these.
Although vascular dementia is usually sporadic, genetic causes are also recognized. These include autosomal dominant cerebral amyloid angiopathy (usually due to mutations in the gene for amyloid precursor protein) and cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL, due to mutations in NOTCH3).
The most classic presentation of patients with vascular dementia includes a history of hypertension, a stepwise progression of deficits, a more or less abrupt onset of dementia, and focal neurologic symptoms or signs. A history of clinically apparent stroke may be absent. The neurologic examination may show pseudobulbar palsy with dysarthria, dysphagia, and pathologic emotionality (pseudobulbar affect); focal motor and sensory deficits; ataxia; gait apraxia; hyperreflexia; and extensor plantar responses. Memory disturbance is typically less prominent than in Alzheimer disease. Instead, impaired attention, information processing, and executive function, as well as depression and apathy, are common. Patients with large or strategically located infarcts may present more acutely (early-onset poststroke dementia).
The MRI (Figure 5-13) may show multiple large infarcts, multiple small (lacunar) infarcts, areas of low density in subcortical white matter, or combinations of these findings and is more sensitive than CT scan for detecting these abnormalities.
T2-weighted MRI in vascular dementia, showing foci of abnormal high signal intensity adjacent to the lateral ventricles (arrows) and within the basal ganglia (arrowheads).
Additional laboratory studies should be performed to exclude cardiac emboli, polycythemia, thrombocytosis, cerebral vasculitis, and meningovascular syphilis as underlying causes, particularly in younger patients and those without a history of hypertension.
Hypertension, when present, should be treated to reduce the incidence of subsequent infarction and to prevent other end-organ diseases. Neither antiplatelet agents nor statins have been shown to reduce the incidence or progression of vascular dementia, but may be indicated to reduce the risk of other adverse effects of thromboembolic disease or hyperlipidemia. Mean survival is 3-5 years after diagnosis.
CHRONIC SUBDURAL HEMATOMA
Chronic subdural hematoma usually affects patients aged 50 to 70 years, often after minor head trauma. Other risk factors include alcoholism, cerebral atrophy, epilepsy, anticoagulation, ventricular shunts, and long-term hemodialysis. The onset of symptoms may be delayed for months after trauma. Hematomas are bilateral in approximately one-sixth of cases.
Headache is the initial symptom in most patients; confusion, vomiting, and hemiparesis may follow, with dementia a later development. The most frequent signs are cognitive disturbance, hemiparesis, papilledema, and extensor plantar responses. Aphasia, visual field defects, and seizures are uncommon.
The hematoma can usually be seen on CT scan (Figure 5-14) as an extra-axial, crescent-shaped area of decreased density, with ipsilateral obliteration of cortical sulci and, often, ventricular compression. The scan should be carefully reviewed for evidence of bilateral subdural collections. Isodense collections may become more apparent after contrast infusion.
CT scan in chronic subdural hematoma, showing bilateral low-density collections between the inner table of the skull and the cerebral hemispheres (arrows).
Unless contraindicated by medical problems or spontaneous improvement, symptomatic hematomas should be surgically evacuated. Approaches include craniotomy and burr-hole or twist-drill craniostomy. Neither corticosteroid nor prophylactic anticonvulsant treatment has been shown to be beneficial.
Normal-pressure hydrocephalus (NPH), a potentially reversible cause of dementia, is characterized by the clinical triad of gait disorder, dementia, and urinary dysfunction. It may be idiopathic or secondary to conditions that interfere with CSF absorption, such as subarachnoid hemorrhage, traumatic brain injury, or meningitis. The mean age at onset is ~70 years. Those affected have an increased incidence of vascular risk factors, including hyperlipidemia, diabetes, obesity, and physical inactivity, and NPH often coexists with subcortical small-vessel cerebrovascular disease.
NPH is characterized by ventricular enlargement, with or without cerebral cortical atrophy, which affects the sylvian fissures out of proportion to cortical sulci. NPH is a form of communicating hydrocephalus (because the lateral, third, and fourth ventricles remain in communication) or nonobstructive hydrocephalus (because the flow of CSF between the ventricles is not impaired). In contrast, noncommunicating or obstructive hydrocephalus is caused by blockade of CSF circulation within the ventricular system (eg, by an intraventricular cyst or tumor) and is associated with increased CSF pressure and often with headache and papilledema.
NPH has been attributed to impaired absorption of CSF from the subarachnoid space over the cerebral hemispheres, through arachnoid villi, and into the venous circulation (Figure 5-15), or increased intracranial pressure pulsatility. In either case, ventricular enlargement may exert pressure on corticospinal axons mediating leg movement and urination, as well as on periventricular end arteries supplying frontal regions involved in cognition.
Circulation of cerebrospinal fluid (CSF). CSF is produced by the choroid plexus (red), which consists of specialized secretory tissue located within the cerebral ventricles. It flows from the lateral and third ventricles through the cerebral aqueduct and fourth ventricle and exits the ventricular system through two laterally situated foramina of Luschka and a single, medially located foramen of Magendie. CSF then enters and circulates through the subarachnoid space surrounding the brain and spinal cord. It is ultimately absorbed through arachnoid granulations into the venous circulation.
Normal-pressure hydrocephalus usually develops over months, and gait disorder is typically the initial manifestation. This typically takes the form of gait apraxia, characterized by difficulty in standing and initiating walking (magnetic gait), shuffling gait, unstable turns, and a tendency to fall forward (anteropulsion) or backward (retropulsion). The patient can perform the leg movements associated with walking, bicycling, or kicking a ball and can trace figures with the feet while lying or sitting but is unable to do so with the legs bearing weight. Motor perseveration (the inappropriate repetition of motor activity) and grasp reflexes in the hands and feet may occur. The gait disorder is bilaterally symmetric, there is no weakness or ataxia, and pyramidal signs (spasticity, hyperreflexia, and extensor plantar responses) are rarely present. Dementia is manifested by executive dysfunction and memory impairment, and may be accompanied by depression. Urinary symptoms include urgency and frequency, with or without incontinence, and tend to have their onset after the gait disorder and dementia are established. Fecal incontinence is uncommon.
Lumbar puncture reveals normal or low opening pressure. The CT scan or, preferably, MRI shows enlarged lateral ventricles without increased prominence of cortical sulci (Figure 5-16). Periventricular white matter lesions may be seen. The likelihood of a favorable response to treatment is best predicted by transient improvement, most often in gait, following removal of 30-50 mL of CSF by lumbar puncture (tap test). Gait should be tested immediately before and 2-4 hours after CSF removal.
CT scan at two transverse levels in normal-pressure hydrocephalus, showing enlarged lateral ventricles without enlargement of the cortical sulci.
The gait disorder, which usually appears first, may resemble that associated with Parkinson disease or other causes of parkinsonism (see Chapter 11, Movement Disorders). If both gait disorder and dementia are present, Alzheimer disease and vascular dementia must also be considered. MRI and CSF tap test should distinguish NPH from these conditions. However, it is important to note that many patients with NPH, including those who can benefit from treatment, may have more than one disorder. In particular, vascular lesions on MRI should not necessarily exclude patients from eligibility for shunting, although the extent of concurrent disease may influence post-shunt prognosis.
Treatment of NPH involves shunting of CSF, usually by the ventriculoperitoneal (VP) route. From 60-90% of patients with idiopathic NPH benefit from this procedure, and gait disorder, dementia, and urinary dysfunction can all improve. Ventricular size should be monitored for several months by serial imaging studies to confirm effective shunting. Complications of shunting include postural headache and subdural effusion (from overdrainage), shunt obstruction (which occurs in ~30% of cases and may require shunt revision), and bacterial meningitis.
BRAIN TUMOR & WHOLE-BRAIN RADIOTHERAPY
Brain tumors (see Chapter 6, Headache & Facial Pain) produce dementia and related syndromes by a combination of local and diffuse effects, including edema, compression of adjacent brain structures, increased intracranial pressure, impairment of cerebral blood flow, and disruption of neuronal connectivity. Cognitive function in patients with brain tumor can also be impaired by radiotherapy or chemotherapy. The tumors most likely to produce generalized cerebral syndromes are gliomas arising in the frontal or temporal lobes or the corpus callosum (Figure 5-17). Although such lesions tend to infiltrate subcortical white matter extensively, they may initially give rise to few focal neurologic signs.
Brain MRI (A) and postmortem horizontal brain slice (B) showing infiltrating glioblastoma multiforme crossing the corpus callosum to affect the frontal lobes of both cerebral hemispheres (butterfly glioma). (Used with permission from Reisner HM. Pathology: A Modern Case Study. New York, NY: McGraw-Hill; 2015. Fig 21-27.)
The dementia associated with brain tumor is characterized by prominent mental slowness, apathy, impaired concentration, and subtle alterations in personality. Depending on the areas of involvement, memory disorder, aphasia, or agnosia may be seen. Brain tumors ultimately produce headache, seizures, or focal sensorimotor disturbances.
Meningeal neoplasia, discussed in Chapter 4 as a cause of confusional states, may also produce dementia, which is commonly associated with headache, as well as symptoms and signs of dysfunction at multiple sites in the nervous system. The diagnosis is established by cytologic studies of the CSF.
Whole-brain radiotherapy, used to treat various tumors of the head and neck, is associated with an increased incidence of dementia, especially in patients ≤65 years of age. Factors that may be involved in pathogenesis include direct injury to brain tissue or blood vessels and inhibition of angiogenesis or neurogenesis.
CHRONIC TRAUMATIC ENCEPHALOPATHY
Severe or repetitive, concussive or subconcussive head injury may cause progressive cognitive dysfunction, sometimes leading to dementia. Histopathologic features include neurofibrillary tangles containing hyperphosphorylated tau, β-amyloid deposits in diffuse or neuritic plaques or in blood vessels, and α-synuclein-positive Lewy bodies. Although classically described in boxers (punch-drunk syndrome or dementia pugilistica), this condition is recognized increasingly in other athletes and military veterans subject to head trauma. Early features include headache and impaired attention and concentration, followed by depression, explosive behavior, and short-term memory deficits. Executive dysfunction and other cognitive impairments ensue, leading to dementia with word-finding difficulty and aggressive behavior. Suicidality is common. Associated features include dysarthria, tremor, spasticity, ataxia, and gait disturbance. Neuroimaging studies may show cortical or hippocampal atrophy, enlarged ventricles, and signs of diffuse axonal injury. Evidence of an additional neurodegenerative disease, such as motor neuron disease, Alzheimer disease, Lewy body disease, or frontotemporal dementia, is present at autopsy in about one-third of cases.
HIV-Associated Neurocognitive Disorders
Human immunodeficiency virus (HIV-1) infection of the brain can produce a range of HIV-associated neurocognitive disorders (HAND), which occur in 15-55% of HIV-infected individuals. These syndromes include asymptomatic neurocognitive impairment (demonstrable only by cognitive testing), minor neurocognitive disorder (mild to moderate cognitive and functional impairment), and HIV-associated dementia (moderate to severe cognitive and functional impairment). Combination antiretroviral therapy of HIV infection has reduced the prevalence of HIV-associated dementia, but increased the prevalence of milder forms of HAND, as patients live longer. Thus, asymptomatic neurocognitive impairment now accounts for about 70% of HAND. Cardiovascular risk factors, advanced age, and drug abuse increase the risk of HAND.
HIV-1 invades the brain in blood-borne macrophages early in the course of systemic infection and infects brain macrophages, microglia, and astrocytes, but not neurons. Neurologic, including cognitive, symptoms are thought to result from neurotoxic effects of viral proteins or of cytokines, chemokines, and other soluble factors released by inflammatory cells. Combination antiretroviral therapy inhibits viral replication, but persistent chronic inflammation and latent HIV-1 infection may continue to impair brain function in treated individuals.
Prior to the introduction of effective treatment, the brain in HIV-1-associated dementia typically showed perivascular infiltration by macrophages, multinucleated giant cells, astrogliosis, and neuronal loss, affecting the basal ganglia, subcortical white matter, thalamus, and brainstem. With combination antiretroviral therapy, histopathologic abnormalities are generally less marked. However, microglial activation is a prominent feature, and inflammation is most pronounced in the hippocampus and entorhinal and temporal cortex. Deposits of β-amyloid and hyperphosphorylated tau are also observed.
HAND usually has an insidious onset and can produce cognitive, behavioral, and motor deficits. Asymptomatic neurocognitive impairment is characterized by abnormalities on neuropsychological testing without evident functional decline. Mild neurocognitive disorder impairs memory, learning, or executive function to some degree, but typically allows the patient to continue self-care and often employment. Gait disorder, tremor, and defects in fine motor performance may occur. HIV-associated dementia is more severe, with increased memory loss and executive dysfunction, and precludes independence. Parkinsonian features (bradykinesia, postural instability) and postural or intention tremor (see Chapter 11, Movement Disorders) are sometimes present. Depression is common.
There is no definitive laboratory test for HAND. CSF may show mild to moderate elevation of protein (≤200 mg/dL); modest, usually mononuclear pleocytosis (≤50 cells/μL); and oligoclonal bands. MRI shows cortical and subcortical atrophy with diffuse signal abnormalities in subcortical white matter (Figure 5-18) and is useful for excluding other HIV-related neuropathologic processes, such as opportunistic infection. Neuropsychological testing is useful for detecting asymptomatic neurocognitive impairment and mild neurocognitive disorder.
T2-weighted MRI in HIV-associated dementia, showing increased signal intensity (arrows) in subcortical white matter.
Patients with HAND should receive combination antiretroviral therapy as described for HIV-1 meningitis in Chapter 4, Confusional States, and at https://aidsinfo.nih.gov/guidelines. Parkinsonian features may respond to antiparkinsonian drugs (see Chapter 10, Movement Disorders).
The course may be relatively static, steadily progressive, or acutely exacerbated by concurrent disease or antiretroviral treatment (immune reconstitution inflammatory syndrome; see Organ Transplantation in Chapter 4, Confusional States). Combination antiretroviral therapy can arrest but not reverse HAND-related deficits, and has extended median survival from months to years.
Syphilis is caused by Treponema pallidum and transmitted by sexual contact, which results in infection in approximately one-third of encounters with infected individuals. The incidence of syphilis is especially high in patients with HIV infection. Treponemes invade the CNS in about 40% of those infected and persist in about 12%. Dementia from neurosyphilis (general paresis), a late manifestation of neurosyphilis (Figure 5-19), was common in the prepenicillin era but is now rare.
Interval between primary syphilitic infection and neurosyphilis syndromes. (Reproduced, with permission, from Simon RP. Neurosyphilis. Arch Neurol. 1985;42:606-613. Copyright © 1985. American Medical Association. All rights reserved.)
Primary syphilis is characterized by local skin lesions (chancres) that usually appear within 1 month of exposure. Hematogenous spread of T. pallidum produces symptoms and signs of secondary syphilis, including fever, skin rash, alopecia, anogenital skin lesions, and ulceration of mucous membranes, within 1 to 6 months. Neurologic symptoms are uncommon.
Early neurosyphilis may be asymptomatic. Alternatively, it may manifest as meningeal syphilis, which occurs 2-12 months after primary infection and causes headache, stiff neck, nausea and vomiting, and cranial nerve (especially II, VII, or VIII) involvement, or meningovascular syphilis, which is seen 4-7 years into the course and usually presents with transient ischemic attacks or stroke (see Chapter 13, Stroke).
Late (parenchymatous) neurosyphilis produces the syndromes of general paresis and tabes dorsalis, which can occur separately or together (taboparesis); either one can occur in combination with optic atrophy. General paresis is a chronic meningoencephalitis caused by active spirochetal infection. Onset is with gradual memory loss or altered affect, personality, or behavior. This is followed by global intellectual deterioration with grandiosity, depression, psychosis, and focal weakness. Terminal features include incontinence, seizures, or strokes. Neurologic examination may show tremor of the face and tongue, paucity of facial expression, dysarthria, and pyramidal signs. Taboparesis is the coexistence of tabes dorsalis (see Chapter 10, Sensory Disorders) with general paresis. Signs and symptoms of tabes dorsalis include Argyll Robertson pupils (see Chapter 7, Neuro-Ophthalmic Disorders), lancinating (stabbing) pains, areflexia, posterior column sensory deficits with sensory ataxia and Romberg sign, incontinence, impotence, Charcot (hypertrophic) joints, and genu recurvatum (hyperextended knees).
Treponemal serologic blood tests (fluorescent treponemal antibody absorbed [FTA-ABS] or microhemagglutination-Treponema pallidum [MHATP]) are reactive in almost all patients with active neurosyphilis, but non-treponemal blood tests (Venereal Disease Research Laboratory [VDRL] or rapid plasma reagin [RPR]) can be negative; therefore, a treponemal blood test should be obtained in all suspected cases. If this is nonreactive, neurosyphilis is effectively excluded; if it is reactive, lumbar puncture should be performed to confirm the diagnosis of neurosyphilis and provide a baseline CSF profile against which to gauge the efficacy of subsequent treatment. The CSF in active neurosyphilis usually shows a lymphocytic pleocytosis and reactive non-treponemal CSF serology (eg, VDRL), except in early meningeal and meningovascular syphilis, isolated intracranial granuloma (gumma), and end-stage tabes dorsalis. Other CSF abnormalities include protein elevation, increased γ-globulin, and the presence of oligoclonal bands. The MRI in general paresis may show meninges-based mass lesions (gummas) or unilateral or bilateral medial temporal lobe T2 high-intensity abnormalities, with or without associated atrophy.
General paresis is treated as described earlier for syphilitic meningitis (see Chapter 4, Confusional States). Transient fever, tachycardia, hypotension, and leukocytosis may occur within hours after therapy is started (Jarisch–Herxheimer reaction). Failure of the CSF to return to normal within 6 months after treatment of neurosyphilis requires retreatment.
General paresis may improve or stabilize after treatment, but in some cases it continues to worsen. Patients with persistently reactive CSF serologic tests but no pleocytosis are unlikely to respond to penicillin therapy but are usually treated nevertheless.
Progressive Multifocal Leukoencephalopathy
Progressive multifocal leukoencephalopathy (PML) results from reactivation of JC polyoma virus infection, which is usually asymptomatic, in immunosuppressed patients. These include individuals with lymphoma, leukemia, or HIV infection and those treated with immunomodulatory drugs for multiple sclerosis or Crohn disease (eg, natalizumab) or for psoriasis (eg, dimethyl fumarate). The disease targets oligodendrocytes, leading to diffuse and patchy demyelination of the cerebral hemispheres, brainstem, and cerebellum.
The course is typically subacute and progressive, leading to death in approximately 50% of patients within 3 to 6 months, although mortality is lower (approximately 20%) in patients on natalizumab. PML associated with natalizumab does not occur until years after treatment. Fever and systemic symptoms are absent. Dementia and focal cortical dysfunction are prominent. Signs include hemiparesis, visual deficits, aphasia, dysarthria, and sensory impairment. Ataxia and headache are uncommon, and seizures do not occur.
The CSF is usually normal but may show a mild increase in pressure, white cell count, or protein. The CT scan or MRI shows multifocal white matter abnormalities, typically without enhancement or mass effect (Figure 5-20). Diagnosis is by detection of JC virus DNA in CSF or brain biopsy using the polymerase chain reaction.
Axial FLAIR MRI in progressive multifocal leukoencephalopathy, showing abnormally high signal intensity (arrows) in white matter of the right parietal and occipital lobes.
Treatment of PML is with combination antiretroviral therapy for patients with HIV infection and discontinuation of the drug for patients receiving natalizumab. Plasma exchange is also used in the latter group but its benefit is uncertain.
METABOLIC & NUTRITIONAL DISORDERS
Certain complications of alcoholism can cause dementia. These include acquired hepatocerebral degeneration from alcoholic liver disease (see Non-Wilsonian Hepatocerebral Degeneration later in this chapter), chronic subdural hematoma (discussed earlier in this chapter), and nutritional deficiency states. A dementia caused by direct toxic effects of ethanol on the brain has been proposed, but no distinctive abnormalities have been identified in the brains of demented alcoholics. Dementia in alcoholics is more likely to be explained by misdiagnosis of Korsakoff syndrome (see later in this chapter), or by the metabolic, traumatic, or nutritional complications of alcoholism mentioned previously. The latter include the following:
Pellagra, caused by deficiency of niacin, injures neurons in the cerebral cortex, basal ganglia, brainstem, cerebellum, and anterior horns of the spinal cord. Systemic involvement is manifested by diarrhea, glossitis, anemia, and erythematous skin lesions. Neurologic involvement may produce dementia; psychosis; confusional states; pyramidal, extrapyramidal, and cerebellar signs; polyneuropathy; and optic neuropathy. Treatment is with nicotinamide, 10-150 mg orally daily, but neurologic deficits may persist.
Marchiafava–Bignami syndrome is characterized by necrosis of the corpus callosum and subcortical white matter and occurs most often in malnourished alcoholics. The course can be acute, subacute, or chronic. Clinical features include dementia, spasticity, dysarthria, gait disorder, and coma. The diagnosis can sometimes be made by CT scan or MRI. No specific treatment is available, but cessation of drinking and improvement of nutrition are advised. The outcome is variable: patients may die, survive with dementia, or recover.
Hypothyroidism (myxedema) can produce a reversible dementia or chronic organic psychosis. The dementia is characterized by mental slowness, memory loss, and irritability, without focal cortical deficits. Psychiatric manifestations are typically prominent and include depression, paranoia, visual and auditory hallucinations, mania, and suicidal behavior.
Patients with myxedema may complain of headache, hearing loss, tinnitus, vertigo, weakness, or paresthesia. Examination may show deafness, dysarthria, or cerebellar ataxia. The most suggestive finding is delayed relaxation of the tendon reflexes. Diagnosis and treatment are discussed in Chapter 4, Confusional States. Cognitive dysfunction is usually reversible with treatment.
Vitamin B12 deficiency is a rare cause of reversible dementia and organic psychosis, which can occur with or without hematologic and other neurologic manifestations. The dementia consists of global cognitive dysfunction with mental slowness, impaired concentration, and memory disturbance; aphasia and other focal cortical disorders do not occur. Diminished vibration and position sense in the lower extremities is common. Psychiatric manifestations are often prominent and include depression, mania, and paranoid psychosis with visual and auditory hallucinations. Laboratory findings, CNS imaging, and treatment are discussed in Chapter 4, Confusional States.
This is a rare disorder in patients receiving chronic hemodialysis. Clinical features include personality changes, hallucinations, dysarthria, dysphagia, asterixis, myoclonus, and seizures. The EEG shows paroxysmal high-voltage slowing with intermixed spikes and slow waves. Removing aluminum from the dialysate has decreased the syndrome’s incidence.
Acquired Hepatocerebral Degeneration
Acquired (non-Wilsonian) hepatocerebral degeneration is an uncommon complication of chronic hepatic cirrhosis with spontaneous or surgical portosystemic shunting. Symptoms may be related to failure of the liver to detoxify ammonia. Neurologic symptoms precede hepatic symptoms in approximately one-sixth of patients.
Systemic manifestations of chronic liver disease are usually present. The neurologic syndrome is fluctuating but progressive over years and may be punctuated by episodes of acute hepatic encephalopathy. Dementia, dysarthria, and cerebellar, extrapyramidal, and pyramidal signs are common. Dementia is marked by mental slowness, apathy, impaired attention and concentration, and memory disturbance. Cerebellar signs include gait and limb ataxia and dysarthria; nystagmus is rare. Extrapyramidal involvement may produce rigidity, resting tremor, dystonia, chorea, or athetosis. Asterixis, myoclonus, hyperreflexia, and extensor plantar responses are common; paraparesis is rare.
Laboratory studies show abnormal hepatic blood chemistries and elevated blood ammonia, but the degree of abnormality may not correspond to the severity of neurologic symptoms. MRI may show lesions in the basal ganglia and subcortical white matter. The CSF is normal except for increased glutamine and occasional mild elevation of protein.
B. Differential Diagnosis
Wilson disease can be distinguished by its earlier onset, Kayser-Fleischer rings, and abnormal copper metabolism. Alcoholic cerebellar degeneration primarily affects gait and is not accompanied by extrapyramidal or pyramidal signs.
Treatment is as described for hepatic encephalopathy (see Chapter 4, Confusional States). Death results from progressive liver failure or variceal bleeding.
Wilson disease (hepatolenticular degeneration) is a rare but treatable autosomal recessive hereditary disorder of copper metabolism that produces dementia and extrapyramidal symptoms (see Chapter 11, Movement Disorders). The disease results from homozygous or compound heterozygous mutations in ATP7B, a gene coding for the β polypeptide of a copper-transporting ATPase.
The term “pseudodementia” is sometimes used to describe disorders that can be mistaken for dementia, especially depression. However, other conditions can mimic dementia as well. Because depression and other dementia mimics are common and often treatable, identifying them is important.
Both dementia and depression can be characterized by mental slowness, apathy, self-neglect, withdrawal, irritability, difficulty with memory and concentration, and changes in behavior and personality. Moreover, depression and other psychiatric disturbances can be a feature of dementing illnesses (Table 5-12), depression and dementia may coexist as independent disorders, and late-life depression may be a harbinger of subsequent dementia. Clinical features that help in the differentiation are listed in Table 5-13. When depression is being considered, psychiatric consultation should be obtained. If not correctable by treatment of an underlying medical disease or by a change in medication, depression should be treated directly. Treatments include cognitive behavioral therapy, antidepressant drugs, exercise, transcranial magnetic stimulation, and electroconvulsive therapy.
Table 5-12.Psychiatric Features of Selected Dementias. ||Download (.pdf) Table 5-12. Psychiatric Features of Selected Dementias.
|Disease ||Psychiatric features |
|Alzheimer disease ||Apathy, depression, anxiety, delusions |
|Frontotemporal dementia (behavioral variant) ||Disinhibition, impulsivity, gluttony |
|Progressive supranuclear palsy ||Apathy, depression |
|Lewy body disease ||Illusions, hallucinations, paranoia |
|Huntington disease ||Apathy, irritability, depression, anxiety |
|Creutzfeldt-Jakob (prion) disease ||Agitation, depression |
|Vascular dementia ||Apathy, depression, anxiety |
|Brain tumor ||Apathy, personality change |
|Chronic traumatic encephalopathy ||Depression, explosive behavior |
|HIV-associated neurocognitive disorders ||Apathy |
|Neurosyphilis ||Grandiosity, depression, illusions, hallucinations |
|Hypothyroidism ||Depression, paranoia, hallucinations |
|Vitamin B12 deficiency ||Depression, mania, paranoia, hallucinations |
Table 5-13.Dementia versus Pseudodementia of Depression: Distinguishing Features. ||Download (.pdf) Table 5-13. Dementia versus Pseudodementia of Depression: Distinguishing Features.
|Dementia ||Depression |
|Insidious onset ||Abrupt onset |
|Progressive deterioration ||Plateau of dysfunction |
|No history of depression ||History of depression may exist |
|Patient typically unaware of extent of deficits and does not complain of memory loss ||Patient aware of and may exaggerate deficits and frequently complains of memory loss |
|Somatic complaints uncommon ||Somatic complaints common |
|Variable affect ||Depressed affect |
|Few vegetative symptoms ||Prominent vegetative symptoms |
|Impairment often worse at night ||Impairment usually not worse at night |
|Neurologic examination and laboratory studies may be abnormal ||Neurologic examination and laboratory studies normal |
FUNCTIONAL COGNITIVE DISORDER
Patients with this condition complain of recurrent cognitive symptoms, despite an absence of objectively verifiable cognitive defects. Examples include name- or other word-finding difficulties, misplacing keys or other objects, and losing track of conversations or ongoing tasks. Forgotten items can often be recalled later (mnestic block). Those affected are typically of working age, well-educated, and socially and economically successful. They may have a history of anxiety or depression and recently increased psychological stress. Despite the perceived deficits, work performance has not objectively declined, friends and family members are unaware that a problem exists, and symptoms are not verifiably progressive. Neuropsychological testing (eg, Montreal Cognitive Assessment) should be performed and repeated after ~1 year to document any deterioration in function. Treatment includes reassurance, measures to reduce stress, and correction of other possible contributing factors (discussed next).
Sleep disorders associated with reduced sleep time or sleep fragmentation (obstructive sleep apnea, insomnia) can impair cognitive function by interfering with memory consolidation and, in the case of obstructive sleep apnea, causing apnea-related cerebral hypoxia. Because both obstructive sleep apnea and insomnia are more prevalent at older ages, they often affect the same population at increased risk for dementia; moreover, obstructive sleep apnea may itself increase dementia risk. Sleep-related cognitive deficits are important to identify because they are often treatable and reversible.
Obstructive sleep apnea affects ~40% of men and ~20% of women over age 40. It is caused by upper airway collapse and leads to sleep fragmentation, hypoxia, elevated blood pressure, and sympathetic hyperactivity. Associated symptoms include snoring, nocturia, and daytime sleepiness. Adverse cognitive effects include impaired attention, verbal memory, and executive function. Diagnosis is by overnight polysomnography, and treatment is with a continuous positive airway pressure (CPAP) device for ≥4-6 hours per night during sleep, which may improve cognitive deficits over several months. Obstructive sleep apnea is a risk factor for hypertension, atrial fibrillation, and stroke.
Insomnia affects up to 10% of the general population and can be caused by a wide variety of medical and psychiatric conditions, alcohol and other recreational or therapeutic drugs, and poor sleep hygiene. Patients with insomnia may experience defective verbal memory. Treatment or correction of the underlying factors listed above may improve insomnia and associated cognitive deficits.
DISORDERS OF VISION & HEARING
Sensory deficits are common in the elderly population at high risk for dementia and can interfere with both cognitive function and cognitive testing. Social isolation and depression are likely contributing factors. Visual impairment may result from presbyopia, cataract, glaucoma, or macular degeneration, and treatment (eg, cataract surgery) can improve cognition. Hearing impairment (presbyacusis) may be amenable to therapeutic cerumen disempaction, hearing aids, or cochlear implants.
The aged population most at risk for dementia is also highly susceptible to adverse drug effects, including effects on cognitive function that can be mistaken for dementia. Factors involved include the frequency of multiple medical problems (and, therefore, polypharmacy) in this population, age-related changes in pharmacokinetics (including drug distribution volume, metabolism, and clearance), and attenuation of physiologic homeostatic mechanisms. Drugs especially likely to cause confusional states that may be misdiagnosed as dementia include benzodiazepines and other sedative-hypnotics, opiate analgesics, and anticholinergics (see Chapter 4, Confusional States).