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Dementia¶

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

Key Clinical Points¶

The single strongest risk factor for dementia is increasing age.
Mild cognitive impairment (MCI) is defined as a decline in cognition confirmed on objective testing that does not disrupt normal daily activities.
Mild behavioral impairment (MBI) refers to the emergence of sustained and impactful neuropsychiatric symptoms in older adults (e.g., apathy, emotional dysregulation).
Rapidly progressive dementia (RPD) is applied to illnesses progressing from initial symptom onset to dementia within a year or less; excludes toxic/metabolic conditions.
Common potentially reversible diagnoses include depression, normal pressure hydrocephalus (NPH), and alcohol dependence.
CJD is suggested by diffuse rigidity, an akinetic-mute state, and prominent, often startle-sensitive myoclonus.
FDG-PET in AD shows temporal-parietal hypometabolism, with early/prominent involvement of the posterior cingulate cortex and precuneus.
A negative amyloid PET scan in a patient with progressive amnestic disorder and hippocampal atrophy strongly suggests LATE as the underlying pathology.
Frontal-striatal pathways: Dorsolateral prefrontal/caudate lesions → executive dysfunction; Lateral orbital frontal/ventromedial caudate lesions → impulsiveness/disinhibition; Anterior cingulate/medial prefrontal → apathy, poverty of speech, or akinetic mutism.
Mixed pathology is common in older individuals, with autopsy cohorts often showing three or four different pathologies.

1. DEFINITION & OVERVIEW¶

• Definition: An acquired deterioration in cognitive abilities that impairs the successful performance of activities of daily living. • Pathophysiology: Result from disruption of specific large-scale neuronal networks by initially focal brain lesions (neurodegenerative changes or vascular injury). • Neurotransmitter Roles: ◦ Noradrenergic, serotonergic, and dopaminergic pathways → modulate behavior, mood, and attention. ◦ Cholinergic signaling → critical for attention and memory functions.

1.1 Functional Anatomy¶

• AD Progression: Entorhinal region → hippocampus/limbic structures → basal temporal areas → lateral and posterior temporal and parietal neocortex. • Vascular Dementia: Focal damage in a variable patchwork of cortical/subcortical regions or white matter tracts that disconnect nodes within distributed networks. • Frontal-Striatal Pathways (Specific Effects): ◦ Dorsolateral prefrontal + Caudate → Executive dysfunction (poor organization, planning, decreased cognitive flexibility, impaired working memory). ◦ Lateral orbital frontal + Ventromedial caudate → Impulsiveness, distractibility, and disinhibition. ◦ Anterior cingulate + Medial prefrontal → Nucleus accumbens; damage leads to apathy, poverty of speech, emotional blunting, or akinetic mutism.

1.2 Clinical Course & Staging¶

• Course Types: ◦ Slowly progressive (e.g., AD). ◦ Static (e.g., anoxic encephalopathy). ◦ Fluctuating daily/minutely (e.g., DLB). • Prodromal States: ◦ Mild Cognitive Impairment (MCI): → Defined as a decline in cognition confirmed on objective testing but does not disrupt normal daily activities. → Subcategories: amnestic MCI, dysexecutive MCI. ◦ Mild Behavioral Impairment (MBI): → Emergence of sustained and impactful neuropsychiatric symptoms (apathy, emotional dysregulation, impulse control, social inappropriateness, hallucinations, or delusions). • Terminology: ◦ Subjective Cognitive Decline: Individuals with perceived decline but performance within normal limits on formal testing. ◦ Benign Forgetfulness of the Elderly: Non-progressive/non-serious memory loss that does not impair daily functioning.

2. EPIDEMIOLOGY¶

• Impact: Affects over 6 million people in the US; annual healthcare cost exceeds $300 billion. • Prevalence: AD is the most common cause of dementia (>50% of cases). Vascular disease is the second most frequent cause. • Age Factor: Prevalence increases with every decade of life. While some centenarians have intact memory, 10% of individuals >70 years and 20–40% of individuals >85 years have clinically identifiable memory loss.

2.1 Risk Factors¶

• Modifiable Risk Factors: Low education, hearing loss, social isolation, traumatic brain injury (TBI), hypertension, diabetes mellitus, obesity, heavy alcohol use, smoking, depression, physical inactivity, and air pollution exposure. • Clinical Context: Improved management of mid-life cardiovascular risk factors has been linked to decreased incidence of dementia in North America and Western Europe.

3. ETIOLOGY & PATHOPHYSIOLOGY¶

• Major Degenerative Dementias: AD, DLB, LATE, FTD, HD, and prion diseases (CJD). • Rapidly Progressive Dementia (RPD): → Progression from initial symptom onset to dementia within a year or less. → Excludes: confusional states related to toxic/metabolic conditions. → Causes: Often AD, other neurodegenerative disorders, or autoimmune encephalitis. CJD is the classic cause of RPD with myoclonus.

3.1 Molecular Basis (Table 31-2)¶

• AD: Aβ/tau; Genes: APP (21), PS-1 (14), PS-2 (1); Susceptibility: Apo \epsilon4 (19). Findings: Amyloid plaques, neurofibrillary tangles, and neuropil threads. • DLB: α-Synuclein; Gene: SNCA (4). Findings: α-Synuclein neuronal inclusions (Lewy bodies). • LATE: TDP-43; Susceptibility: TMEM106B, GRN. Findings: TDP-43 inclusion bodies and neurites. • FTD: ◦ Tau: MAPT mutations (10% of familial cases); H1 MAPT haplotype. ◦ TDP-43: GRN (10%), C9ORF72 (20–30%), rare VCP, TARDBP, TBK1, TIA1. ◦ FUS: Rare FUS mutations. • CJD: PrPsc; Gene: PRNP (20); Susceptibility: Codon 129 homozygosity. Findings: PrPsc deposition, panlaminar spongiosis.

4. CLINICAL FEATURES¶

• Cognitive Domains: Memory (most common loss), language, visuospatial, motor praxis, calculation, judgment, and problem-solving. • Neuropsychiatric Symptoms: Depression, apathy, anxiety, hallucinations, delusions, agitation, insomnia, sleep disturbances, compulsions, or disinhibition.

4.1 History & Onset¶

• Acute/Subacute Confusion: Suggests delirium → check for infection, tox, or metabolic issues. • AD Profile: 75% start with memory loss; others include anxiety, depression, and difficulty managing money/driving. • FTD Profile: Personality change, disinhibition, weight gain, compulsivity, loss of empathy, impaired speech fluency. • DLB Profile: Early visual hallucinations, parkinsonism, REM behavior disorder (RBD), Capgras syndrome. • Vascular Profile: History of stroke; irregular stepwise progression; associated with HTN, DM, smoking.

4.2 Physical & Neurologic Examination¶

• AD: Typically spares motor systems until late. • FTD: Axial rigidity, supranuclear gaze palsy, or motor neuron disease (MND) features. • DLB: Parkinsonian syndrome (tremor, bradykinesia), RBD, autonomic problems. • CBS: Asymmetric akinesia/rigidity, dystonia, myoclonus, alien limb, nonfluent aphasia. • CJD: Diffuse rigidity, akinetic-mute state, startle-sensitive myoclonus. • Systemic Clues: ◦ Vitamin B12 deficiency → myelopathy/peripheral neuropathy. ◦ Hypothyroidism → dry cool skin, hair loss, bradycardia.

5. DIFFERENTIAL DIAGNOSIS¶

• Categorization: 1. Reversible Causes 2. Irreversible/Degenerative Dementias 3. Psychiatric Disorders

5.1 Reversible vs Irreversible Causes¶

• Reversible (Table 31-1): ◦ Depression (pseudodementia), NPH, alcohol dependence. ◦ Medication side effects, Vitamin deficiencies (B12, Thiamine). ◦ Endocrine: Hypothyroidism, Adrenal insufficiency/Cushing's, Hyper/Hypoparathyroidism. ◦ Organ Failure: Renal, Liver, Pulmonary failure. ◦ Infections: HIV, Neurosyphilis, T-berg, fungal, protozoal, Whipple's. ◦ Toxins: Heavy metals, organic toxins. ◦ Other: Subdural hematoma, autoimmune encephalopathy. • Irreversible/Degenerative: AD, DLB, LATE, FTD, Huntington's, Parkinson's, ALS-parkinsonism-dementia complex of Guam.

Clinical Differentiation (Table 31-4)¶

• AD: First Symptom: Memory loss; Neuropsych: Irritability/anxiety; Imaging: Medial temporal atrophy, posterior-predominant cortical atrophy. • DLB: First Symptom: Visual hallucinations, RBD, parkinsonism; Neuropsych: Hallucinations, depression; Imaging: Posterior parietal atrophy, larger hippocampi than AD. • FTD: First Symptom: Apathy, judgment/insight, speech; Neuropsych: Disinhibition, overeating; Imaging: Frontal, insular, and/or temporal atrophy.

6. INVESTIGATIONS & DIAGNOSIS¶

Initial Screening:
Use MMSE or MoCA to capture dementia and track progression.
Clinical Evaluation:
History: Determine onset, duration, and tempo (e.g., sudden → delirium; slow → AD/LATE).
Physical Exam: Rule out motor signs (FTD/DLB) or systemic issues (hypothyroidism, B12 deficiency).
Laboratory Workup (Table 31-3):
Routine: TSH, Vitamin B12, CBC, CMP, CT/MRI.
Optional: HIV, RPR/VDRL, Chest x-ray, Urine toxin screen.
Advanced Imaging & Biomarkers:
FDG-PET: Identify patterns (e.g., posterior cingulate/precuneus for AD; 'cingulate island' sparing for DLB).
Amyloid PET: Rule out AD; if negative in a patient with hippocampal atrophy → suspect LATE.
Tau PET: Rule in AD and used for staging.
Biomarkers: CSF seed amplification assay (α-synuclein) or skin biopsy (phosphorylated α-synuclein) for PD/DLB.

7. MANAGEMENT & TREATMENT¶

Identify and Treat Reversible Causes:
Depression (pseudodementia).
Normal pressure hydrocephalus (NPH).
Alcohol dependence.
Medication side effects.
Address Systemic Deficiencies:
Correct Vitamin B12 or Thiamine deficiencies.
Treat thyroid dysfunction (hypothyroidism).
Symptom Management:
Manage agitation, insomnia, and sleep disturbances.
Address caregiver "burnout" and patient safety.
Clinical Monitoring:
Use MMSE/MoCA to track progression of cognitive decline.

8. PROGNOSIS & COMPLICATIONS¶

• Rapidly Progressive Dementia (RPD): → Often due to AD, other neurodegenerative disorders, or autoimmune encephalitis. → CJD is the classic cause of RPD with myoclonus.

Clinical Differentiation Summary¶

• AD: Memory loss → Posterior-predominant atrophy. • DLB: Visual hallucinations/Parkinsonism → Occipital hypometabolism. • FTD: Apathy/Disinhibition → Frontal/Temporal atrophy.

9. KEY PEARLS & CLINICAL TRAPS¶

• Rule of Exclusion: Use Amyloid PET primarily to exclude AD; a negative scan in the presence of hippocampal atrophy strongly points toward LATE. • Clinical Distinction: FTD is characterized by behavioral changes (apathy, disinhibition) and motor signs (axial rigidity), whereas AD typically begins with memory loss. • Diagnostic Clues: - Myoclonus + Rapid progression → CJD. - Parkinsonism + Visual hallucinations → DLB. - Stepwise decline + HTN/DM → Vascular dementia. • Neuroimaging Logic: - FDG-PET 'Cingulate Island' (sparing of posterior cingulate) → DLB. - Medial temporal hypometabolism → LATE.

Reference Tables¶

TABLE 31-1 Differential Diagnosis of Dementia Most Common Causes of Dementia Alzheimer’s disease Vascular dementia¶

Harrison's 22e, p.194

Most Common Causes of Dementia
Alzheimer’s disease	Alcoholisma
Vascular dementia	PDD/LBD spectrum
Multi-infarct	Drug/medication intoxicationa’
Diffuse white matter disease (Binswanger’s)	Limbic-predominant age-related TDP-43 encephalopathy
Less Common Causes of Dementia
Vitamin deficiencies Thiamine (B): Wernicke’s 1 encephalopathya B (subacute combined 12 degeneration)a Nicotinic acid (pellagra)a Endocrine and other organ failure Hypothyroidisma Adrenal insufficiency and Cushing’s syndromea Hypo- and hyperparathyroidisma Renal failurea Liver failurea Pulmonary failurea Chronic infections HIV Neurosyphilisa Papovavirus (JC virus) (progressive multifocal leukoencephalopathy) Tuberculosis, fungal, and protozoala Whipple’s diseasea Head trauma and diffuse brain damage Chronic traumatic encephalopathy Chronic subdural hematomaa Postanoxia Postencephalitis Normal-pressure hydrocephalusa Intracranial hypotension Neoplastic Primary brain tumora Metastatic brain tumora Paraneoplastic/autoimmune limbic encephalitisa	Toxic disorders Drug, medication, and narcotic poisoninga Heavy metal intoxicationa Organic toxins Psychiatric Depression (pseudodementia)a Schizophreniaa Conversion disordera Degenerative disorders Huntington’s disease Multisystem atrophy Hereditary ataxias (some forms) Frontotemporal lobar degeneration spectrum Multiple sclerosis Adult Down’s syndrome with Alzheimer’s disease ALS-parkinsonism-dementia complex of Guam Prion (Creutzfeldt-Jakob and Gerstmann-Sträussler-Scheinker diseases) Miscellaneous Sarcoidosisa Vasculitisa CADASIL, etc. Acute intermittent porphyriaa Recurrent nonconvulsive seizuresa Additional conditions in children or adolescents Pantothenate kinase–associated neurodegeneration Subacute sclerosing panencephalitis Metabolic disorders (e.g., Wilson’s and Leigh’s diseases, leukodystrophies, lipid storage diseases, mitochondrial mutations)

TABLE 31-2 The Molecular Basis for Degenerative Dementia DEMENTIA AD¶

Harrison's 22e, p.195

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
	α-Synuclein	Very rare SNCA (4)	Unknown
LATE	TDP-43	None identified	TMEM106B, GRN	TDP-43 neuronal “inclusion bodies” and neurites in neurons and glia, with or without hippocampal sclerosis
	Tau	MAPT exon and intron mutations (17) (~10% of familial cases)	H1 MAPT haplotype
	TDP-43	GRN (10% of familial cases), C9ORF72 (20–30% of familial cases), rare VCP, very rare TARDBP, TBK1, TIA1
	FUS	Very rare FUS
CJD	PrPSC	PRNP (20) (up to 15% of patients carry these dominant mutations)	Codon 129 homozygosity for methionine or valine	PrPSC deposition, panlaminar spongiosis

TABLE 31-3 Evaluation of the Patient with Dementia¶

Harrison's 22e, p.195

ROUTINE EVALUATION	OPTIONAL FOCUSED TESTS	OCCASIONALLY HELPFUL TESTS
History Physical examination Laboratory tests Thyroid function (TSH) Vitamin B 12 Complete blood count Complete metabolic panel CT/MRI	Psychometric testing HIV, RPR, or VDRL Lumbar puncture PET (FDG, amyloid, tau) Chest x-ray Urine toxin screen Apolipoprotein E Blood-based AD biomarkers	EEG Parathyroid function Adrenal function Urine heavy metals RBC sedimentation rate Lab screen for autoantibodies Angiogram Brain biopsy
Diagnostic Categories
REVERSIBLE CAUSES	IRREVERSIBLE/ DEGENERATIVE DEMENTIAS	PSYCHIATRIC DISORDERS
Examples Hypothyroidism Thiamine deficiency Vitamin B deficiency 12 Normal-pressure hydrocephalus Subdural hematoma Chronic infection Brain tumor Drug intoxication Autoimmune encephalopathy	Examples Alzheimer’s Frontotemporal dementia Huntington’s Dementia with Lewy bodies Vascular Leukoencephalopathies Parkinson’s LATE	Depression Schizophrenia Conversion reaction
Associated Treatable Conditions
	Depression Seizures Insomnia	Agitation Caregiver “burnout” Drug side effects

TABLE 31-4 Clinical Differentiation of the Major Dementias DISEASE AD¶

Harrison's 22e, p.196

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
	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
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
	Memory loss	Episodic memory loss Mild semantic deficits	None described	Normal
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
	Dementia, mood, anxiety, movement disorders	Variable, frontal/executive, focal cortical, memory	Depression, anxiety, psychosis in some	Myoclonus, rigidity, parkinsonism