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Dementia

Chapter 31 | Part 2: Cardinal Manifestations and Presentation of Diseases · Part 2 – Cardinal Manifestations & Presentation

Detailed clinical reference synthesised from Harrison's Principles of Internal Medicine, 22nd Edition

🔑 Key Clinical Points

  1. The single strongest risk factor for dementia is increasing age.
  2. Mild cognitive impairment (MCI) is defined as a decline in cognition confirmed on objective testing but does not disrupt normal daily activities.
  3. Mild behavioral impairment (MBI) refers to the emergence of sustained and impactful neuropsychiatric symptoms in older adults (e.g., apathy, emotional dysregulation).
  4. Rapidly progressive dementia (RPD) is applied to illnesses that progress from initial symptom onset to dementia within a year or less.
  5. The most common potentially reversible diagnoses are depression, normal pressure hydrocephalus (NPH), and alcohol dependence.
  6. CJD is suggested by the presence of diffuse rigidity, an akinetic-mute state, and prominent, often startle-sensitive myoclonus.
  7. FDG-PET in AD shows temporal-parietal or hypometabolism, often with early and prominent involvement of the posterior cingulate cortex and precuneus.
  8. A negative amyloid PET scan strongly suggests LATE as the underlying neuropathology in patients with progressive amnestic disorder and hippocampal atrophy.
  9. Lesions of frontal-striatal pathways produce specific effects: dorsolateral prefrontal/caudate lesions cause executive dysfunction; lateral orbital frontal/caudate lesions cause impulsiveness/disinhibition.
  10. Mixed pathology is common, especially in older individuals, with autopsy cohorts showing three or four different pathologies.

📑 Table of Contents

📋 Figures in This Chapter

# Type Description
1 🖼 Figure Alzheimer’s disease (AD)
2 🖼 Figure Alzheimer’s disease (AD)
3 🖼 Figure Alzheimer’s disease (AD)

1. DEFINITION & OVERVIEW

Dementia is defined as an acquired deterioration in cognitive abilities that impairs the successful performance of activities of daily living. Dementia syndromes result from the disruption of specific large-scale neuronal networks by initially focal brain lesions, including neurodegenerative changes and vascular injury. Behavior, mood, and attention are also modulated by ascending noradrenergic, serotonergic, and dopaminergic pathways, whereas cholinergic signaling is critical for attention and memory functions.

1.1 Functional Anatomy

AD typically begins in the entorhinal region of the medial temporal lobe, spreads to the hippocampus and other limbic structures, moves through the basal temporal areas, and then into lateral and posterior temporal and parietal neocortex, eventually causing a more widespread degeneration. Vascular dementia is associated with focal damage in a variable patchwork of cortical and subcortical regions or white matter tracts that disconnect nodes within distributed networks. Lesions of frontal-striatal pathways produce specific and predictable effects on behavior. The dorsolateral prefrontal cortex has connections with a central band of the caudate nucleus. Lesions of either the caudate or dorsolateral prefrontal cortex, or their connecting white matter pathways, may result in executive dysfunction, manifesting as poor organization and planning, decreased cognitive flexibility, and impaired working memory. The lateral orbital frontal cortex connects with the ventromedial caudate, and lesions of this system cause impulsiveness, distractibility, and disinhibition. The anterior cingulate cortex and adjacent medial prefrontal cortex project to the nucleus accumbens, and interruption of this system produces apathy, poverty of speech, emotional blunting, or even akinetic mutism. All corticostriatal systems also include topographically organized projections through the globus pallidus and thalamus, and damage to these nodes can likewise reproduce the clinical syndrome associated with the corresponding cortical or striatal injuries.

1.2 Clinical Course & Staging

The clinical course may be slowly progressive, as in Alzheimer's disease (AD); static, as in anoxic encephalopathy; or may fluctuate from day to day or minute to minute, as in dementia with Lewy bodies (DLB). Most patients with AD, the most prevalent form of dementia, begin with episodic memory impairment, but in other dementias, such as frontotemporal dementia (FTD), memory loss is not typically a presenting feature. When dementia is caused by a progressive neurodegenerative disease, it is preceded by a prodromal clinical stage called mild cognitive impairment (MCI), in which individuals experience cognitive decline but remain independent in most daily activities. As noted earlier, MCI is defined as a decline in cognition that is confirmed on objective cognitive testing but does not disrupt normal daily activities. MCI can be further subcategorized based on the presenting complaints and deficits (e.g., amnestic MCI, dysexecutive MCI). The term mild behavioral impairment (MBI) refers to the emergence of sustained and impactful neuropsychiatric symptoms in older adults (e.g., apathy, emotional dysregulation, impulse control, social inappropriateness, hallucinations, or delusions). Like its cognitive counterpart (MCI), MBI can reflect a neuropsychiatric prodrome to a neurodegenerative dementia.

2. EPIDEMIOLOGY

Dementia, a syndrome with many causes, affects over 6 million people in the United States and results in a total annual health care cost in excess of $300 billion. AD is the most common cause of dementia in Western countries, accounting for more than half of all patients. Vascular disease is the second most frequent cause for dementia and is particularly common in elderly patients or populations with limited access to medical care, where vascular risk factors are undertreated. The prevalence of disabling memory loss increases with each decade over age 50 and is usually associated with the microscopic changes of AD at autopsy. Yet some centenarians have intact memory function and no evidence of clinically significant dementia. Whether dementia is an inevitable consequence of normal human aging remains controversial, although the prevalence increases with every decade of life. In one large community-based autopsy cohort of individuals who presented with an amnestic dementia during life (mean age at death 89.7 years), 39% of the attributable risk for dementia was explained by AD neuropathology, 25% by cerebrovascular disease, 17% by LATE, and 12% by Lewy body disease.

2.1 Risk Factors

The risk of developing dementia in late life is associated with numerous exposures that can happen across the lifespan. Modifiable risk factors based on large-scale epidemiologic studies include low education, hearing loss, social isolation, traumatic brain injury, hypertension, diabetes mellitus, obesity, heavy alcohol use, smoking, depression, physical inactivity, and air pollution exposure. Improved management of mid-life cardiovascular risk factors has been credited with a decreasing incidence of dementia noted in North America and western European countries. The many causes of dementia are listed in Table 31-1. The frequency of each condition depends on the age group under study, access of the group to medical care, country of origin, and perhaps racial or ethnic background.

3. ETIOLOGY & PATHOPHYSIOLOGY

The major degenerative dementias include AD, DLB, LATE, FTD, and related disorders, HD, and prion diseases, including CJD. These disorders are all associated with the abnormal aggregation of a specific protein: Aβ and tau in AD; α-synuclein in DLB; TAR DNA-binding protein of 43 kDa (TDP-43) in LATE; tau, TDP-43, or the FET family of proteins (fused in sarcoma [FUS], Ewing sarcoma [EWS], and TBP-associated factor 15 [TAF15]) in FTD; huntingtin in HD; and misfolded prion protein (PrPsc) in CJD. The term rapidly progressive dementia (RPD) is applied to illnesses that progress from initial symptom onset to dementia within a year spectrum or less; confusional states related to toxic/metabolic conditions are excluded. Although the prion proteinopathy Creutzfeldt-Jakob disease (CJD) is the classic cause of a rapidly progressive dementia, especially when associated with myoclonus, more often cases of RPD are due to AD or another neurodegenerative disorder, or to an autoimmune encephalitis. Subtle cumulative decline in episodic memory is a common part of aging. This frustrating experience, often the source of jokes and humor, has historically been referred to as benign forgetfulness of the elderly. Benign means that it is not so progressive or serious that it impairs successful and productive daily functioning, although the distinction between benign and significant memory loss can be subtle. At age 85, the average person is able to learn and recall approximately one-half of the items (e.g., words on a list) that they could at age 18. The term subjective cognitive decline is used to refer to individuals who experience subjective decline from their cognitive baseline but perform within normal limits for their age and educational attainment on formal neuropsychological testing.

3.1 Molecular Basis

The molecular basis for degenerative dementia involves specific protein aggregates and genetic factors. AD involves Aβ/tau with causal genes APP (21), PS-1 (14), PS-2 (1) and susceptibility gene Apo ε4 (19). Pathologic findings include amyloid plaques, neurofibrillary tangles, and neuropil threads. DLB involves α-Synuclein with causal gene SNCA (4) and pathologic findings of α-Synuclein neuronal inclusions (Lewy bodies). LATE involves TDP-43 with no identified causal genes but susceptibility genes TMEM106B, GRN. Pathologic findings include TDP-43 neuronal inclusion bodies and neurites in neurons and glia, with or without hippocampal sclerosis. FTD involves Tau or TDP-43 or FUS family proteins. Causal genes include MAPT exon and intron mutations (17) for Tau, GRN (10% of familial cases), C9ORF72 (20–30% of familial cases) for TDP-43, and FUS for FUS. Pathologic findings include Tau neuronal and glial inclusions or TDP-43 neuronal and glial inclusions. CJD involves PrPSC with causal gene PRNP (20) and pathologic findings of PrPSC deposition, panlaminar spongiosis.

Table 1 — Table 31-2 The Molecular Basis for Degenerative Dementia

Dementia Molecular Basis Causal Genes (Chromosome) Susceptibility Genes Pathologic Findings
AD Aβ/tau APP (21), PS-1 (14), PS-2 (1) (<2% carry these mutations, most often in PS-1) Apo ε4 (19) Amyloid plaques, neurofibrillary tangles, and neuropil threads
DLB α-Synuclein Very rare SNCA (4) Unknown α-Synuclein neuronal inclusions (Lewy bodies)
LATE TDP-43 None identified TMEM106B, GRN TDP-43 neuronal inclusion bodies and neurites in neurons and glia, with or without hippocampal sclerosis
FTD Tau MAPT exon and intron mutations (17) (~10% of familial cases) H1 MAPT haplotype Tau neuronal and glial inclusions varying in morphology and distribution
FTD TDP-43 GRN (10% of familial cases), C9ORF72 (20–30% of familial cases), rare VCP, very rare TARDBP, TBK1, TIA1 TDP-43 neuronal and glial inclusions varying in morphology and distribution
FTD FUS Very rare FUS FUS neuronal and glial inclusions varying in morphology and distribution
CJD PrPSC PRNP (20) (up to 15% of patients carry these dominant mutations) Codon 129 homozygosity for methionine or valine PrPSC deposition, panlaminar spongiosis

4. CLINICAL FEATURES

Dementia is defined as an acquired deterioration in cognitive abilities that impairs the successful performance of activities of daily living. Episodic memory, the ability to recall events specific in time and place, is the cognitive function most commonly lost; 10% of persons age >70 years and 20–40% of individuals age >85 years have clinically identifiable memory loss. In addition to memory, dementia may erode other mental faculties, including language, visuospatial, motor praxis, calculation, judgment, and problem-solving abilities. Neuropsychiatric and social deficits also arise in many dementia syndromes, manifesting as depression, apathy, anxiety, hallucinations, delusions, agitation, insomnia, sleep disturbances, compulsions, or disinhibition. The clinical course may be slowly progressive, as in AD; static, as in anoxic encephalopathy; or may fluctuate from day to day or minute to minute, as in DLB. Most patients with AD, the most prevalent form of dementia, begin with episodic memory impairment, but in other dementias, such as FTD, memory loss is not typically a presenting feature. When dementia is caused by a progressive neurodegenerative disease, it is preceded by a prodromal clinical stage called MCI. The term rapidly progressive dementia (RPD) is applied to illnesses that progress from initial symptom onset to dementia within a year spectrum or less; confusional states related to toxic/metabolic conditions are excluded.

4.1 History & Onset

The history should concentrate on the onset, duration, and tempo of progression. An acute or subacute onset of confusion may be due to delirium and should trigger a search for intoxication, infection, or metabolic derangement. An elderly person with slowly progressive memory loss over several years is likely to suffer from AD and/or LATE. Nearly 75% of patients with AD begin with memory symptoms, but other early symptoms include anxiety or depression and difficulty with managing money, driving, shopping, following instructions, finding words, or navigating. Personality change, disinhibition, and weight gain or compulsive eating suggest FTD, not AD. FTD is also suggested by prominent apathy, compulsivity, loss of empathy for others, or progressive loss of speech fluency or single-word comprehension with relative sparing of memory and visuospatial abilities. The diagnosis of DLB is suggested by early visual hallucinations; parkinsonism; proneness to delirium or sensitivity to psychoactive medications; rapid eye movement (REM) behavior disorder (RBD; dramatic, sometimes violent, limb movements during dreaming); or Capgras syndrome, the delusion that a familiar person has been replaced by an impostor. A history of stroke with irregular stepwise progression suggests vascular dementia. Vascular dementia is also commonly seen in the setting of hypertension, atrial fibrillation, peripheral vascular disease, smoking, and diabetes. In patients suffering from cerebrovascular disease, it can be difficult to determine whether the dementia is due to AD, vascular disease, or a mixture of the two because many of the risk factors for vascular dementia, including diabetes, high cholesterol, elevated homocysteine, and low exercise, are also risk factors for AD.

4.2 Physical & Neurologic Examination

A thorough general and neurologic examination is essential, in the setting of dementia, to look for signs of nervous system involvement and to search for clues suggesting a systemic disease that might be responsible for the cognitive disorder. Typical AD spares motor systems until later in the course. In contrast, patients with FTD often develop axial rigidity, supranuclear gaze palsy, or a motor neuron disease reminiscent of amyotrophic lateral sclerosis (ALS). In DLB, the initial symptoms may include the new onset of a parkinsonian syndrome (resting tremor, cogwheel rigidity, bradykinesia, festinating gait), but DLB often starts with visual hallucinations or cognitive impairment, and symptoms referable to the lower brainstem (RBD, gastrointestinal or autonomic problems) may arise years or decades before parkinsonism or dementia. Corticobasal syndrome (CBS) features asymmetric akinesia and rigidity, dystonia, myoclonus, alien limb phenomena, pyramidal signs, and prefrontal deficits such as nonfluent aphasia with or without motor speech impairment, executive dysfunction, apraxia, or a behavioral disorder. Progressive supranuclear palsy (PSP) is associated with unexplained falls, axial rigidity, dysphagia, and vertical gaze deficits. CJD is suggested by the presence of diffuse rigidity, an akinetic-mute state, and prominent, often startle-sensitive myoclonus. Hemiparesis or other focal neurologic deficits suggest vascular dementia or brain tumor. Dementia with a myelopathy and peripheral neuropathy suggests vitamin B12 deficiency. Peripheral neuropathy could also indicate another vitamin deficiency, heavy metal intoxication, thyroid dysfunction, Lyme disease, or vasculitis. Dry cool skin, hair loss, and bradycardia suggest hypothyroidism. Fluctuating confusion associated with repetitive stereotyped movements may indicate ongoing limbic, temporal, or frontal seizures. In the elderly, hearing impairment or visual loss may produce confusion and disorientation misinterpreted as dementia. Profound bilateral sensorineural hearing loss in a younger patient with short stature or myopathy, however, should raise concern for a mitochondrial disorder.

4.3 Cognitive & Neuropsychiatric Assessment

Brief screening tools such as the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MOCA) can be used to capture dementia and follow progression. None of these tests is highly sensitive to early-stage dementia or reliably discriminates between dementia syndromes. The MMSE is a 30-point test of cognitive function, with each correct answer being scored as 1 point. It includes tests of orientation (e.g., identify season/date/month/year/floor/hospital/town/state/country); registration (e.g., name and restate three objects); recall (e.g., remember the same three objects 5 min later); and language (e.g., name pencil and watch; repeat no ifs, ands, or buts; follow a three-step command; obey a written command; and write a sentence and copy a design). In most patients with MCI and some with clinically apparent AD, bedside screening tests may be normal, and a more challenging and comprehensive set of neuropsychological tests will be required. When the etiology for the dementia syndrome remains in doubt, a specially tailored evaluation should be performed that includes tasks of working and episodic memory, executive function, language, and visuospatial and perceptual abilities. In AD, the early deficits involve episodic memory, category generation (Name as many animals as you can in 1 minute), and visuoconstructive ability. Usually deficits in verbal or visual episodic memory are the first neuropsychological abnormalities detected, and tasks that require the patient to recall a long list of words or a series of pictures after a predetermined delay will demonstrate deficits in most patients. Conversely, patients with FTD show hypometabolism in frontal and anterior temporal cortices. The FDG signature of DLB features hypometabolism in the occipital cortex and precuneus with sparing of the posterior cingulate (cingulate island sign), while LATE is characterized by severe medial temporal hypometabolism with sparing of association cortices. Single-photon emission computed tomography (SPECT) demonstrates spatial patterns of hypoperfusion that mirror the FDG hypometabolic patterns described above. Amyloid and tau PET imaging can support the diagnosis of AD by directly detecting amyloid plaques and neurofibrillary tangles, the neuropathological lesions that define the disease. There are currently three amyloid PET ligands (18F-florbetapir, 18F-florbetaben, 18F-flutametamol) and one tau PET ligand (18F-flortaucipir) approved by the U.S. Food and Drug Administration (FDA) for clinical use. Amyloid PET ligands bind to diffuse and neuritic amyloid plaques as well as to vascular amyloid deposits (cerebral amyloid angiopathy), while tau PET ligands bind to the paired helical filaments of tau characteristic of neurofibrillary tangles in AD. Current tau PET ligands do not reliably detect tau deposits in non-AD conditions. Because amyloid plaques are also commonly found in cognitively normal older persons (~25% of individuals at age 70), the main clinical value of amyloid imaging is to exclude AD as the likely cause of dementia in patients who have negative scans. In older patients presenting with a progressive amnestic disorder and hippocampal atrophy, a negative amyloid PET scan strongly suggests LATE as the underlying neuropathology. The spread of tau is more tightly linked to cognitive state, and thus tau PET may be more useful for ruling in AD, as well as for disease staging. Amyloid PET is also useful to identify candidates for novel anti-Aβ monoclonal antibodies (e.g., lecanemab, donanemab) that reduce amyloid plaque load and slow cognitive decline in patients in early clinical stages of AD. Amyloid and tau PET can also assist with prognosis, as patients who are positive on both modalities show the most rapid decline in cognition and function. Use of amyloid and tau PET in cognitively unimpaired older adults should for now be restricted to research studies and clinical trials testing interventions aimed at reducing the risk of future MCI and dementia in asymptomatic individuals who are positive for AD biomarkers. Recently, there has been significant progress in developing biomarkers of α-synuclein pathology, enabling a molecular diagnosis of PD or DLB. A CSF seed amplification assay for α-synuclein shows high sensitivity and specificity in clinically diagnosed PD patients and also detects pathology in a subset of individuals at risk for PD based on the presence of anosmia or RBD. α-Synuclein can also be detected with high sensitivity and specificity in living patients with PD and DLB with skin biopsies immunostained for phosphorylated α-synuclein colocalizing with nerve fiber bundles. While still in early stages of validation, these biomarkers hold promise. A functional assessment should also be performed to help the physician determine the day-to-day impact of the disorder on the patient's memory, community affairs, hobbies, judgment, dressing, and eating. Knowledge of the patient's functional abilities will help the clinician and the family to organize a therapeutic approach. Neuropsychiatric assessment is important for diagnosis, prognosis, and treatment. In the early stages of AD, mild depressive features, social withdrawal, and irritability or anxiety are the most prominent psychiatric changes, but patients often maintain core social graces into the middle or late stages, when delusions, agitation, and sleep disturbance may emerge. In FTD, dramatic personality changes with apathy, overeating, compulsions, disinhibition, and loss of empathy are early and common. DLB is associated with visual hallucinations, delusions related to person or place identity, RBD, and excessive daytime sleepiness. Dramatic fluctuations occur not only in cognition but also in arousal. Vascular dementia can present with psychiatric symptoms such as depression, anxiety, delusions, disinhibition, or apathy.

5. DIFFERENTIAL DIAGNOSIS

The major degenerative dementias can usually be distinguished by the initial symptoms; neuropsychological, neuropsychiatric, and neurologic findings; neuroimaging features; and other biomarkers. The classification of dementing illnesses into reversible and irreversible disorders is a useful approach to differential diagnosis. In a study of 1000 persons attending a memory disorders clinic, 19% had a potentially reversible cause of the cognitive impairment and 23% had a potentially reversible concomitant condition that may have contributed to the patient's impairment. The three most common potentially reversible diagnoses were depression, normal pressure hydrocephalus (NPH), and alcohol dependence; medication side effects are also common and should be considered in every patient. The term rapidly progressive dementia (RPD) is applied to illnesses that progress from initial symptom onset to dementia within a year spectrum or less; confusional states related to toxic/metabolic conditions are excluded. Although the prion proteinopathy Creutzfeldt-Jakob disease (CJD) is the classic cause of a rapidly progressive dementia, especially when associated with myoclonus, more often cases of RPD are due to AD or another neurodegenerative disorder, or to an autoimmune encephalitis. Subtle cumulative decline in episodic memory is a common part of aging. This frustrating experience, often the source of jokes and humor, has historically been referred to as benign forgetfulness of the elderly. Benign means that it is not so progressive or serious that it impairs successful and productive daily functioning, although the distinction between benign and significant memory loss can be subtle. At age 85, the average person is able to learn and recall approximately one-half of the items (e.g., words on a list) that they could at age 18. The term subjective cognitive decline is used to refer to individuals who experience subjective decline from their cognitive baseline but perform within normal limits for their age and educational attainment on formal neuropsychological testing.

5.1 Reversible vs Irreversible Causes

The classification of dementing illnesses into reversible and irreversible disorders is a useful approach to differential diagnosis. The three most common potentially reversible diagnoses were depression, normal pressure hydrocephalus (NPH), and alcohol dependence; medication side effects are also common and should be considered in every patient. Other disorders listed in Table 31-1 are uncommon but important because many are reversible. The many causes of dementia are listed in Table 31-1. The frequency of each condition depends on the age group under study, access of the group to medical care, country of origin, and perhaps racial or ethnic background.

Table 2 — Table 31-1 Differential Diagnosis of Dementia

Most Common Causes of Dementia Less Common Causes of Dementia
Alzheimer's disease Vitamin deficiencies
Alcoholism Thiamine (B): Wernicke's encephalopathy
Vascular dementia B (subacute combined degeneration)
Multi-infarct Nicotinic acid (pellagra)
Diffuse white matter disease (Binswanger's) Endocrine and other organ failure
Limbic-predominant age-related TDP-43 encephalopathy Hypothyroidism
Drug/medication intoxication Adrenal insufficiency and Cushing's syndrome
PDD/LBD spectrum Hypo- and hyperparathyroidism
Toxic disorders Renal failure
Heavy metal intoxication Liver failure
Organic toxins Pulmonary failure
Psychiatric Chronic infections
Depression (pseudodementia) HIV
Schizophrenia Neurosyphilis
Conversion disorder Papovavirus (JC virus) (progressive multifocal leukoencephalopathy)
Degenerative disorders Tuberculosis, fungal, and protozoa
Huntington's disease Whipple's disease
Multisystem atrophy Head trauma and diffuse brain damage
Hereditary ataxias (some forms) Chronic traumatic encephalopathy
Frontotemporal lobar degeneration spectrum Chronic subdural hematoma
Multiple sclerosis Postanoxia
Adult Down's syndrome with Alzheimer's disease Postencephalitis
ALS-parkinsonism-dementia complex of Guam Normal-pressure hydrocephalus
Prion (Creutzfeldt-Jakob and Gerstmann-Sträussler-Scheinker diseases) Intracranial hypotension
Miscellaneous Neoplastic
Sarcoidosis Primary brain tumor
Vasculitis Metastatic brain tumor
CADASIL, etc. Paraneoplastic/autoimmune limbic encephalitis
Acute intermittent porphyria Subacute sclerosing panencephalitis
Recurrent nonconvulsive seizures Metabolic disorders (e.g., Wilson's and Leigh's diseases, leukodystrophies, lipid storage diseases, mitochondrial mutations)
Additional conditions in children or adolescents
Pantothenate kinase–associated neurodegeneration

6. INVESTIGATIONS & DIAGNOSIS

The choice of laboratory tests in the evaluation of dementia is complex and should be tailored to the individual patient. The physician must take measures to avoid missing a reversible or treatable cause, yet no single treatable etiology is common; thus, a screen must use multiple tests, each of which has a low yield. Cost/benefit ratios are difficult to assess, and many laboratory screening algorithms for dementia discourage multiple tests. Nevertheless, even a test with only a 1–2% positive rate is worth undertaking if the alternative is missing a treatable cause of dementia. Table 31-3 lists most screening tests for dementia. The American Academy of Neurology recommends the routine measurement of a complete blood count; electrolytes; glucose; renal, liver, and thyroid functions; a vitamin B12 level; and a structural neuroimaging study (MRI or computed tomography [CT]). Neuroimaging studies, especially MRI, help to rule out primary and metastatic neoplasms, locate areas of infarction or inflammation, detect subdural hematomas, and suggest NPH or diffuse white matter disease. They also help to establish a regional pattern of atrophy. Support for the diagnosis of AD includes hippocampal atrophy in addition to posterior-predominant cortical atrophy. Marked hippocampal and medial temporal lobe atrophy is also the MRI signature of LATE. Focal frontal, insular, and/or anterior temporal atrophy suggests FTD. DLB often features less prominent atrophy, with greater involvement of amygdala than hippocampus. In CJD, magnetic resonance diffusion-weighted imaging reveals restricted diffusion within the cortical ribbon and/or basal ganglia in most patients. Extensive multifocal white matter abnormalities suggest a vascular etiology. Communicating hydrocephalus with vertex effacement (crowding of dorsal convexity gyri/sulci), gaping Sylvian fissures despite minimal cortical atrophy, and additional features suggest NPH. 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) scanning shows temporal-parietal or hypometabolism in AD, often with early and prominent involvement of the posterior cingulate cortex and precuneus. Conversely, patients with FTD show hypometabolism in frontal and anterior temporal cortices. The FDG signature of DLB features hypometabolism in the occipital cortex and precuneus with sparing of the posterior cingulate (cingulate island sign), while LATE is characterized by severe medial temporal hypometabolism with sparing of association cortices. Single-photon emission computed tomography (SPECT) demonstrates spatial patterns of hypoperfusion that mirror the FDG hypometabolic patterns described above. Amyloid and tau PET imaging can support the diagnosis of AD by directly detecting amyloid plaques and neurofibrillary tangles, the neuropathological lesions that define the disease. There are currently three amyloid PET ligands (18F-florbetapir, 18F-florbetaben, 18F-flutametamol) and one tau PET ligand (18F-flortaucipir) approved by the U.S. Food and Drug Administration (FDA) for clinical use. Amyloid PET ligands bind to diffuse and neuritic amyloid plaques as well as to vascular amyloid deposits (cerebral amyloid angiopathy), while tau PET ligands bind to the paired helical filaments of tau characteristic of neurofibrillary tangles in AD. Current tau PET ligands do not reliably detect tau deposits in non-AD conditions. Because amyloid plaques are also commonly found in cognitively normal older persons (~25% of individuals at age 70), the main clinical value of amyloid imaging is to exclude AD as the likely cause of dementia in patients who have negative scans. In older patients presenting with a progressive amnestic disorder and hippocampal atrophy, a negative amyloid PET scan strongly suggests LATE as the underlying neuropathology. The spread of tau is more tightly linked to cognitive state, and thus tau PET may be more useful for ruling in AD, as well as for disease staging. Amyloid PET is also useful to identify candidates for novel anti-Aβ monoclonal antibodies (e.g., lecanemab, donanemab) that reduce amyloid plaque load and slow cognitive decline in patients in early clinical stages of AD. Amyloid and tau PET can also assist with prognosis, as patients who are positive on both modalities show the most rapid decline in cognition and function. Use of amyloid and tau PET in cognitively unimpaired older adults should for now be restricted to research studies and clinical trials testing interventions aimed at reducing the risk of future MCI and dementia in asymptomatic individuals who are positive for AD biomarkers. Recently, there has been significant progress in developing biomarkers of α-synuclein pathology, enabling a molecular diagnosis of PD or DLB. A CSF seed amplification assay for α-synuclein shows high sensitivity and specificity in clinically diagnosed PD patients and also detects pathology in a subset of individuals at risk for PD based on the presence of anosmia or RBD. α-Synuclein can also be detected with high sensitivity and specificity in living patients with PD and DLB with skin biopsies immunostained for phosphorylated α-synuclein colocalizing with nerve fiber bundles. While still in early stages of validation, these biomarkers hold promise. Lumbar puncture is indicated when CNS infection or inflammation is a credible diagnostic possibility or to assess molecular biomarkers for AD in lieu of PET imaging. A cerebrospinal fluid (CSF) pattern that shows low levels of Aβ (or a low Aβ42/Aβ40 ratio), mild to moderately elevated CSF total tau, and elevated CSF phosphorylated tau (p-Tau at residues 181 or 217) is highly suggestive of AD and sufficient for selecting patients for anti-Aβ antibody treatment. Novel fully automated CSF Aβ and tau assays perform comparably to amyloid PET, with the Aβ42/Aβ40 or p-Tau181/Aβ42 ratios showing higher concordance with amyloid PET and neuropathology than any single CSF Aβ42/40 ratio.

6.1 Routine & Optional Evaluation

The American Academy of Neurology recommends the routine measurement of a complete blood count; electrolytes; glucose; renal, liver, and thyroid functions; a vitamin B12 level; and a structural neuroimaging study (MRI or computed tomography [CT]). The choice of laboratory tests in the evaluation of dementia is complex and should be tailored to the individual patient. The physician must take measures to avoid missing a reversible or treatable cause, yet no single treatable etiology is common; thus, a screen must use multiple tests, each of which has a low yield. Cost/benefit ratios are difficult to assess, and many laboratory screening algorithms for dementia discourage multiple tests. Nevertheless, even a test with only a 1–2% positive rate is worth undertaking if the alternative is missing a treatable cause of dementia. Table 31-3 lists most screening tests for dementia.

Table 3 — Table 31-3 Evaluation of the Patient with Dementia

Approach to the Patient Routine Evaluation Tests Optional Focused Tests Occasionally Helpful Tests
History Psychometric testing HIV, RPR, or VDRL EEG
Physical examination Laboratory tests Parathyroid function Lumbar puncture
Thyroid function (TSH) Vitamin B12 PET (FDG, amyloid, tau) Chest x-ray
Complete blood count Complete metabolic panel Apolipoprotein E Urine heavy metals
CT/MRI Blood-based AD Lab screen for autoantibodies Angiogram Urine toxin screen
RBC sedimentation rate Lab screen for autoantibodies Brain biopsy Parathyroid function
Urine toxin screen Angiogram Brain biopsy Adrenal function
Diagnostic Categories Diagnostic Categories Diagnostic Categories Diagnostic Categories
Reversible Causes Irreversible/Degenerative Dementias Psychiatric Disorders Associated Treatable Conditions
Hypothyroidism Alzheimer's Depression Depression
Thiamine deficiency Frontotemporal dementia Schizophrenia Agitation
Vitamin B12 deficiency Huntington's Conversion reaction Seizures
Normal-pressure hydrocephalus Dementia with Lewy bodies Vascular dementia Insomnia
Subdural hematoma Vascular Autoimmune encephalopathy Caregiver burnout
Chronic infection Leukoencephalopathies Parkinson's disease Drug side effects
Brain tumor LATE Capgras syndrome
Drug intoxication Parkinson's disease dementia Limbic encephalopathy
Autoimmune encephalopathy Prion (Creutzfeldt-Jakob and Gerstmann-Sträussler-Scheinker diseases) ALS-parkinsonism-dementia complex of Guam
Depression Prion (Creutzfeldt-Jakob and Gerstmann-Sträussler-Scheinker diseases) ALS-parkinsonism-dementia complex of Guam
Seizures Prion (Creutzfeldt-Jakob and Gerstmann-Sträussler-Scheinker diseases) ALS-parkinsonism-dementia complex of Guam
Insomnia Prion (Creutzfeldt-Jakob and Gerstmann-Sträussler-Scheinker diseases) ALS-parkinsonism-dementia complex of Guam
Caregiver burnout Prion (Creutzfeldt-Jakob and Gerstmann-Sträussler-Scheinker diseases) ALS-parkinsonism-dementia complex of Guam
Drug side effects Prion (Creutzfeldt-Jakob and Gerstmann-Sträussler-Scheinker diseases) ALS-parkinsonism-dementia complex of Guam

6.2 Clinical Differentiation

The major degenerative dementias can usually be distinguished by the initial symptoms; neuropsychological, neuropsychiatric, and neurologic findings; neuroimaging features; and other biomarkers. Table 31-4 provides a clinical differentiation of the major dementias.

Table 4 — Table 31-4 Clinical Differentiation of the Major Dementias

Disease First Symptom Mental Status Neuropsychiatry Neurology Imaging
AD Memory loss Episodic memory loss; Executive, language, and visuospatial functions variably affected Irritability, anxiety, depression Initially normal Entorhinal cortex and hippocampal atrophy; posterior-predominant cortical atrophy
Vascular Often but not always sudden; variable; apathy, falls, focal weakness Frontal/executive, cognitive slowing; can spare memory Apathy, delusions, anxiety Usually motor slowing, spasticity; can be normal Cortical and/or subcortical infarctions, confluent white matter disease
DLB Visual hallucinations, REM sleep behavior disorder, delirium, Capgras syndrome, parkinsonism Drawing and frontal/executive; spares memory; delirium-prone Visual hallucinations, depression, sleep disorder, delusions Parkinsonism Posterior parietal atrophy; hippocampi larger than in AD
LATE Memory loss Episodic memory loss; Mild semantic deficits None described Normal Medial temporal and hippocampal atrophy, anterior predominant
FTD Apathy; poor judgment/insight, speech/language; hyperorality Frontal/executive and/or language; spares drawing Apathy, disinhibition, overeating, compulsivity May have vertical gaze palsy, axial rigidity, dystonia, alien hand, or MND Frontal, insular, and/or temporal atrophy; usually spares posterior parietal lobe
CJD Dementia, mood, anxiety, movement disorders Variable, frontal/executive, focal cortical, memory Depression, anxiety, psychosis in some Myoclonus, rigidity, parkinsonism Cortical ribboning and hyperintensity on diffusion/FLAIR MRI

7. MANAGEMENT & TREATMENT

Accurate diagnosis guides effective therapy. The management of mid-life cardiovascular risk factors has been credited with a decreasing incidence of dementia noted in North America and western European countries. Amyloid PET is also useful to identify candidates for novel anti-Aβ monoclonal antibodies (e.g., lecanemab, donanemab) that reduce amyloid plaque load and slow cognitive decline in patients in early clinical stages of AD. Amyloid and tau PET can also assist with prognosis, as patients who are positive on both modalities show the most rapid decline in cognition and function. Use of amyloid and tau PET in cognitively unimpaired older adults should for now be restricted to research studies and clinical trials testing interventions aimed at reducing the risk of future MCI and dementia in asymptomatic individuals who are positive for AD biomarkers. Recently, there has been significant progress in developing biomarkers of α-synuclein pathology, enabling a molecular diagnosis of PD or DLB. A CSF seed amplification assay for α-synuclein shows high sensitivity and specificity in clinically diagnosed PD patients and also detects pathology in a subset of individuals at risk for PD based on the presence of anosmia or RBD. α-Synuclein can also be detected with high sensitivity and specificity in living patients with PD and DLB with skin biopsies immunostained for phosphorylated α-synuclein colocalizing with nerve fiber bundles. While still in early stages of validation, these biomarkers hold promise. The choice of laboratory tests in the evaluation of dementia is complex and should be tailored to the individual patient. The physician must take measures to avoid missing a reversible or treatable cause, yet no single treatable etiology is common; thus, a screen must use multiple tests, each of which has a low yield. Cost/benefit ratios are difficult to assess, and many laboratory screening algorithms for dementia discourage multiple tests. Nevertheless, even a test with only a 1–2% positive rate is worth undertaking if the alternative is missing a treatable cause of dementia. Table 31-3 lists most screening tests for dementia. The American Academy of Neurology recommends the routine measurement of a complete blood count; electrolytes; glucose; renal, liver, and thyroid functions; a vitamin B12 level; and a structural neuroimaging study (MRI or computed tomography [CT]).

7.1 Reversible Causes

The three most common potentially reversible diagnoses were depression, normal pressure hydrocephalus (NPH), and alcohol dependence; medication side effects are also common and should be considered in every patient. Other disorders listed in Table 31-1 are uncommon but important because many are reversible. The many causes of dementia are listed in Table 31-1. The frequency of each condition depends on the age group under study, access of the group to medical care, country of origin, and perhaps racial or ethnic background. The classification of dementing illnesses into reversible and irreversible disorders is a useful approach to differential diagnosis. In a study of 1000 persons attending a memory disorders clinic, 19% had a potentially reversible cause of the cognitive impairment and 23% had a potentially reversible concomitant condition that may have contributed to the patient's impairment.

7.2 Biomarkers & Therapeutic Targets

Amyloid and tau PET imaging can support the diagnosis of AD by directly detecting amyloid plaques and neurofibrillary tangles, the neuropathological lesions that define the disease. There are currently three amyloid PET ligands (18F-florbetapir, 18F-florbetaben, 18F-flutametamol) and one tau PET ligand (18F-flortaucipir) approved by the U.S. Food and Drug Administration (FDA) for clinical use. Amyloid PET ligands bind to diffuse and neuritic amyloid plaques as well as to vascular amyloid deposits (cerebral amyloid angiopathy), while tau PET ligands bind to the paired helical filaments of tau characteristic of neurofibrillary tangles in AD. Current tau PET ligands do not reliably detect tau deposits in non-AD conditions. Because amyloid plaques are also commonly found in cognitively normal older persons (~25% of individuals at age 70), the main clinical value of amyloid imaging is to exclude AD as the likely cause of dementia in patients who have negative scans. In older patients presenting with a progressive amnestic disorder and hippocampal atrophy, a negative amyloid PET scan strongly suggests LATE as the underlying neuropathology. The spread of tau is more tightly linked to cognitive state, and thus tau PET may be more useful for ruling in AD, as well as for disease staging. Amyloid PET is also useful to identify candidates for novel anti-Aβ monoclonal antibodies (e.g., lecanemab, donanemab) that reduce amyloid plaque load and slow cognitive decline in patients in early clinical stages of AD. Amyloid and tau PET can also assist with prognosis, as patients who are positive on both modalities show the most rapid decline in cognition and function. Use of amyloid and tau PET in cognitively unimpaired older adults should for now be restricted to research studies and clinical trials testing interventions aimed at reducing the risk of future MCI and dementia in asymptomatic individuals who are positive for AD biomarkers. Recently, there has been significant progress in developing biomarkers of α-synuclein pathology, enabling a molecular diagnosis of PD or DLB. A CSF seed amplification assay for α-synuclein shows high sensitivity and specificity in clinically diagnosed PD patients and also detects pathology in a subset of individuals at risk for PD based on the presence of anosmia or RBD. α-Synuclein can also be detected with high sensitivity and specificity in living patients with PD and DLB with skin biopsies immunostained for phosphorylated α-synuclein colocalizing with nerve fiber bundles. While still in early stages of validation, these biomarkers hold promise.

8. PROGNOSIS & COMPLICATIONS

The clinical course may be slowly progressive, as in AD; static, as in anoxic encephalopathy; or may fluctuate from day to day or minute to minute, as in DLB. Most patients with AD, the most prevalent form of dementia, begin with episodic memory impairment, but in other dementias, such as FTD, memory loss is not typically a presenting feature. When dementia is caused by a progressive neurodegenerative disease, it is preceded by a prodromal clinical stage called MCI. The term rapidly progressive dementia (RPD) is applied to illnesses that progress from initial symptom onset to dementia within a year spectrum or less; confusional states related to toxic/metabolic conditions are excluded. Although the prion proteinopathy Creutzfeldt-Jakob disease (CJD) is the classic cause of a rapidly progressive dementia, especially when associated with myoclonus, more often cases of RPD are due to AD or another neurodegenerative disorder, or to an autoimmune encephalitis. Subtle cumulative decline in episodic memory is a common part of aging. This frustrating experience, often the source of jokes and humor, has historically been referred to as benign forgetfulness of the elderly. Benign means that it is not so progressive or serious that it impairs successful and productive daily functioning, although the distinction between benign and significant memory loss can be subtle. At age 85, the average person is able to learn and recall approximately one-half of the items (e.g., words on a list) that they could at age 18. The term subjective cognitive decline is used to refer to individuals who experience subjective decline from their cognitive baseline but perform within normal limits for their age and educational attainment on formal neuropsychological testing. In one large community-based autopsy cohort of individuals who presented with an amnestic dementia during life (mean age at death 89.7 years), 39% of the attributable risk for dementia was explained by AD neuropathology, 25% by cerebrovascular disease, 17% by LATE, and 12% by Lewy body disease. Mixed pathology is common, especially in older individuals. The poor outcome of persistent vegetative and minimally conscious states has already been mentioned, but reports of a small number of patients displaying cortical activation on functional MRI in response to salient stimuli have begun to alter the perception of such individuals. In one series, about 10% of vegetative patients (mainly following traumatic brain injury) could activate their frontal or temporal lobes in response to requests by an examiner to imagine certain visuospatial tasks. Another series demonstrated that up to 15% of patients with various forms of acute brain injury and absence of behavioral responses to motor commands showed EEG activation in response to these commands. It is prudent to avoid generalizations from these findings, but the need for future studies of novel techniques to help communication and possibly recovery is needed.

8.1 Rapidly Progressive Dementia

The term rapidly progressive dementia (RPD) is applied to illnesses that progress from initial symptom onset to dementia within a year spectrum or less; confusional states related to toxic/metabolic conditions are excluded. Although the prion proteinopathy Creutzfeldt-Jakob disease (CJD) is the classic cause of a rapidly progressive dementia, especially when associated with myoclonus, more often cases of RPD are due to AD or another neurodegenerative disorder, or to an autoimmune encephalitis. CJD is suggested by the presence of diffuse rigidity, an akinetic-mute state, and prominent, often startle-sensitive myoclonus.

9. SPECIAL CONSIDERATIONS

The age at symptom onset can also aid in the differential diagnosis of dementia. AD and FTD are the most common neurodegenerative causes of early-onset (age at symptom onset 65) are AD, DLB, and vascular dementia. LATE neuropathological changes are increasingly common with older age and are found in ~20% of individuals with dementia who die at age 50% of individuals with dementia who die at age >90. Most late-onset dementia is associated with multiple pathologies; it is common for individuals who suffered from dementia to show three or four different pathologies at autopsy. In the elderly, hearing impairment or visual loss may produce confusion and disorientation misinterpreted as dementia. Profound bilateral sensorineural hearing loss in a younger patient with short stature or myopathy, however, should raise concern for a mitochondrial disorder. Alcohol abuse creates risk for malnutrition and thiamine deficiency. Certain occupations, such as working in a battery or chemical factory, might indicate heavy metal intoxication. Careful review of medication intake, especially for sedatives and analgesics, may raise the issue of chronic drug intoxication. An autosomal dominant family history is found in HD and in familial forms of AD, FTD, DLB, or prion disorders. A history of mood disorder, the recent death of a loved one, or depressive signs such as insomnia or weight loss raise the possibility of depression-related cognitive impairment.

9.1 Early vs Late Onset

The age at symptom onset can also aid in the differential diagnosis of dementia. AD and FTD are the most common neurodegenerative causes of early-onset (age at symptom onset 65) are AD, DLB, and vascular dementia. LATE neuropathological changes are increasingly common with older age and are found in ~20% of individuals with dementia who die at age 50% of individuals with dementia who die at age >90. Most late-onset dementia is associated with multiple pathologies; it is common for individuals who suffered from dementia to show three or four different pathologies at autopsy.

10. KEY PEARLS & CLINICAL TRAPS

The single strongest risk factor for dementia is increasing age. The three most common potentially reversible diagnoses were depression, normal pressure hydrocephalus (NPH), and alcohol dependence; medication side effects are also common and should be considered in every patient. CJD is suggested by the presence of diffuse rigidity, an akinetic-mute state, and prominent, often startle-sensitive myoclonus. DLB is associated with visual hallucinations, delusions related to person or place identity, RBD, and excessive daytime sleepiness. Dramatic fluctuations occur not only in cognition but also in arousal. Vascular dementia can present with psychiatric symptoms such as depression, anxiety, delusions, disinhibition, or apathy. In the elderly, hearing impairment or visual loss may produce confusion and disorientation misinterpreted as dementia. Profound bilateral sensorineural hearing loss in a younger patient with short stature or myopathy, however, should raise concern for a mitochondrial disorder. The term rapidly progressive dementia (RPD) is applied to illnesses that progress from initial symptom onset to dementia within a year spectrum or less; confusional states related to toxic/metabolic conditions are excluded. Although the prion proteinopathy Creutzfeldt-Jakob disease (CJD) is the classic cause of a rapidly progressive dementia, especially when associated with myoclonus, more often cases of RPD are due to AD or another neurodegenerative disorder, or to an autoimmune encephalitis. Subtle cumulative decline in episodic memory is a common part of aging. This frustrating experience, often the source of jokes and humor, has historically been referred to as benign forgetfulness of the elderly. Benign means that it is not so progressive or serious that it impairs successful and productive daily functioning, although the distinction between benign and significant memory loss can be subtle. At age 85, the average person is able to learn and recall approximately one-half of the items (e.g., words on a list) that they could at age 18. The term subjective cognitive decline is used to refer to individuals who experience subjective decline from their cognitive baseline but perform within normal limits for their age and educational attainment on formal neuropsychological testing.

Figures & Illustrations

Reproduced from Harrison's 22nd Edition.

Figure 1

Alzheimer’s disease (AD)

Caption: FIGURE 31-1 Alzheimer’s disease (AD). Axial T1-weighted MRI and 18F-florbetapir amyloid PET images from a 62-year-old healthy control (left) and 60-year-old with dementia due to AD (right panels). Note the reduction in medial temporal volumes and prominent sulci on MRI in the patient with AD. Amyloid PET demonstrates a white matter only binding pattern in the healthy control (negative scan), whild the patient with AD demonstrates diffuse neocortical binding and blurring of gray/white matter contrast (positive scan). (Images courtesy of Gil Rabinovici, University of California, San Francisco.) — Figure 31-1: Axial T1-weighted MRI and 18F-florbetapir amyloid PET images comparing a 62-year-old healthy control (left) and a 60-year-old with dementia due to AD (right). The healthy control shows white matter only binding (negative scan), while the AD patient shows diffuse neocortical binding and blurring of gray/white matter contrast (positive scan). MRI shows reduction in medial temporal volumes and prominent sulci in the AD patient.

Figure 2

Alzheimer’s disease (AD)

Caption: FIGURE 31-1 Alzheimer’s disease (AD). Axial T1-weighted MRI and 18F-florbetapir amyloid PET images from a 62-year-old healthy control (left) and 60-year-old with dementia due to AD (right panels). Note the reduction in medial temporal volumes and prominent sulci on MRI in the patient with AD. Amyloid PET demonstrates a white matter only binding pattern in the healthy control (negative scan), whild the patient with AD demonstrates diffuse neocortical binding and blurring of gray/white matter contrast (positive scan). (Images courtesy of Gil Rabinovici, University of California, San Francisco.) — Figure 31-2: Magnetic resonance imaging (MRI) findings in vascular dementia. Extensive multifocal white matter abnormalities suggest a vascular etiology, often seen in the setting of hypertension, atrial fibrillation, peripheral vascular disease, smoking, and diabetes.

Figure 3

Alzheimer’s disease (AD)

Caption: FIGURE 31-1 Alzheimer’s disease (AD). Axial T1-weighted MRI and 18F-florbetapir amyloid PET images from a 62-year-old healthy control (left) and 60-year-old with dementia due to AD (right panels). Note the reduction in medial temporal volumes and prominent sulci on MRI in the patient with AD. Amyloid PET demonstrates a white matter only binding pattern in the healthy control (negative scan), whild the patient with AD demonstrates diffuse neocortical binding and blurring of gray/white matter contrast (positive scan). (Images courtesy of Gil Rabinovici, University of California, San Francisco.) — Figure 31-3: Magnetic resonance imaging (MRI) findings in normal-pressure hydrocephalus (NPH). Communicating hydrocephalus with vertex effacement (crowding of dorsal convexity gyri/sulci), gaping Sylvian fissures despite minimal cortical atrophy, and additional features suggest NPH.

Generated from Harrison's Principles of Internal Medicine, 22nd Edition.