Dementia Notes

NOTES NOTES DEMENTIA GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Acquired, progressive cognitive impairment ▪ Involving one/more cognitive functions ▫ Memory, concentration, language, learning, praxis, judgment, executive functions, social cognition ▪ Previous functional-level deterioration; consciousness remains intact CAUSES ▪ Increasing age; most important risk factor ▪ Alzheimer disease ▪ Vascular dementia including multi-infarct dementia, Binswanger’s disease ▪ Lewy body dementia (DLB) ▪ Frontotemporal dementia (e.g. Pick disease) COMPLICATIONS ▪ Inability to function independently in everyday life ▪ Debilitated state infections (death secondary) ▪ See mnemonic for summary MNEMONIC: DEMENTIA Common causes of Dementia Diabetes Ethanol Medication Environmental (eg CO poisoning) Nutritional Trauma Infection Alzheimer’s SIGNS & SYMPTOMS ▪ Memory loss, difficulty retaining new information ▪ Language impairment ▪ Executive dysfunction ▫ Difficulty in handling complex tasks, concentration loss, poor judgement ▪ Visuospatial ability impairment ▪ Apraxia (inability to perform an action) ▪ Behavioral disturbance ▪ Personality change DIAGNOSIS DIAGNOSTIC IMAGING CT scan ▪ Reveals microinfarcts indicative of vascular dementia OTHER DIAGNOSTICS ▪ Mental status examination ▫ Identify cognitive impairment with standardized mental status scales ▪ Montreal cognitive assessment (MoCA), mini-mental state examination (MMSE) ▪ Neuropsychological testing ▫ Quantitate cognitive impairment degree/ domains involved (e.g. animal-naming test) ▪ Post-autopsy brain biopsy OSMOSIS.ORG 555

TREATMENT ▪ Treatment/control of reversible causes MEDICATIONS ▪ Acetylcholinesterase inhibitors ▫ ↑ acetylcholine (brain’s primary neurotransmitter) levels; used for Alzheimer disease, DLB ▪ Memantine ▫ N-methyl-D-aspartate (NMDA) receptor antagonist (neuroprotective, diseasemodifying drug) for advanced dementia ALZHEIMER'S DISEASE (AD) osms.it/alzheimers-disease PATHOLOGY & CAUSES ▪ Neurodegenerative disease; beta amyloid plaque, neurofibrillary tangle formation → impaired neuronal signaling, neuron apoptosis ▪ Most common form of dementia ▪ Sporadic (95% of cases), typically > 60 years old ▫ Early AD onset unusual, mostly familial ▪ Amyloid precursor protein (APP) ▫ Normally located in neuronal membrane ▫ Growth, neuron-repair contributor ▫ Abnormal APP degradation via beta secretase (normally degraded by gamma, alpha secretase) → APP cut into insoluble fragments → create beta amyloid plaque → AD results ▫ Beta amyloid plaque pathology: signalling obstruction → deposits around vessels (amyloid angiopathy), ↑ hemorrhage risk → initiates inflammatory response ▪ Tau proteins ▫ Intracellular microtubule-associated proteins ▫ In AD, Tau proteins become pathologically hyperphosphorylated → aggregate, stop supporting microtubules → form neurofibrillary tangles → obstruct neuronal signaling → neuron apoptosis 556 OSMOSIS.ORG RISK FACTORS ▪ ↑ age (> 60 years old → risk doubling every five years) ▪ Family history ▪ Trisomy 21 (Down syndrome) ▪ Gene mutations affecting APP, presenilin 1 and 2 (gamma secretase subunits) ▪ Apolipoprotein E-e4 alleles (ApoEe4) ▫ ApoE normally breaks down beta amyloid, e4 alleles encode less effective ApoE ▪ History of hypertension, dyslipidemia, cerebrovascular disease, altered glucose metabolism, brain trauma COMPLICATIONS ▪ Complete debilitation, dependence on others ▪ Debilitation → dehydration, malnutrition, infection ▪ Death occurs 5–10 years after symptoms onset MNEMONIC: RONALD Features of AD Reduction of Ach Old age Neurofibrillary tangles Atrophy of cerebral cortex (diffuse) Language impairment Dementia (MC in elderly)/ Down’s syndrome

Chapter 72 Dementia SIGNS & SYMPTOMS ▪ Insidious onset, symptom progression Early stages ▪ Initial symptom ▫ (Commonly) recent memory impairment; inability to acquire, remember new information ▪ Executive dysfunction ▫ Impaired reasoning, handling complex tasks, concentration/motivation loss, difficulty making/executing plans, poor judgement ▫ Impaired visuospatial skills ▫ Reduced insight into cognitive deficit (anosognosia) ▫ Sleep disturbance Intermediate/later stages ▪ Behavioral, psychological symptoms ▫ Apathy, social disengagement, irritability, agitation, aggression, wandering, psychosis (hallucination, delusion) ▪ Motor task completion ▫ Difficulty (dyspraxia)/inability (apraxia) ▫ Impaired language function (e.g. wordfinding deficit) ▫ Remote memory loss ▫ Seizure ▫ Motor signs (e.g. pyramidal signs) MNEMONIC: ALZHEIMER'S Characteristics of AD Anterograde amnesia Life expectancy increase in population shows increased prevalence Zapped (loss of) acetylcholinergic neurons Hereditary disease Entire hippocampus affected Identified by neurofibrillary tangles Mutation in amyloid genes Entorhinal areas degenerate first Retrograde amnesia Senile plaques at synapse OTHER DIAGNOSTICS ▪ Mental status scale clinical assessment (e.g., MoCA, MMSE) ▪ Neuropsychological testing ▫ Confirm cognitive impairment diagnosis ▪ Post-autopsy brain biopsy ▫ Shows characteristic beta-amyloid plaque, neurofibrillary tangle Advanced ▫ Complete debilitation, dependence on others, urinary/fecal incontinence DIAGNOSIS ▪ Diagnosis of exclusion DIAGNOSTIC IMAGING CT scan/MRI ▪ Exclude other dementia causes ▪ Brain scans show diffuse cortical (especially hippocampus) atrophy, gyri narrowing, sulci widening, ventricle enlargement Figure 72.1 An MRI scan in the axial plane demonstrating prominent sulci and gyri in an individual with Alzheimer’s disease. OSMOSIS.ORG 557

TREATMENT ▪ No cure MEDICATIONS ▪ Acetylcholinesterase inhibitors ▪ Vitamin E supplementation may provide benefit ▪ Memantine (advanced stages) Figure 72.2 A histological section of the hippocampus from an individual with Alzheimer’s disease demonstrating a neurofibrillary tangle. Figure 72.3 A histological section of brain from an individual with Alzheimer’s disease demonstrating multiple amyloid plaques. LEWY BODY DEMENTIA osms.it/lewy-body-dementia PATHOLOGY & CAUSES ▪ Degenerative disease ▫ Early dementia, visual hallucinations onset; later parkinsonian clinical feature onset, presence of Lewy bodies ▪ Occurs at 50–85 years old (typically) ▪ More rapid cognitive decline than AD CAUSES ▪ Alpha-synuclein protein aggregation in neurons (particularly cortex, substantia nigra) forming Lewy bodies, → apoptosis 558 OSMOSIS.ORG COMPLICATIONS ▪ Persistent psychotic symptoms, especially visual hallucinations ▪ Depression ▪ Complete debilitation, dependence on others ▪ Debilitation infection often → death; life expectancy ↓ ▪ Neuroleptic-agent sensitivity ▫ Adverse effects (parkinsonism) ↑ severity, symptom exacerbation

Chapter 72 Dementia TREATMENT SIGNS & SYMPTOMS Early stages ▪ Progressive, fluctuating cognitive function impairment ▫ Attention, executive, visuospatial functions; memory affected later ▪ Visual hallucination, disorganized speech, depression Later stages ▪ Motor symptoms mimic Parkinson’s disease ▫ Resting tremor, stiffness, slow movement, reduced facial expressions ▪ No cure MEDICATIONS Alleviate symptoms ▪ Acetylcholinesterase inhibitors ▫ Cognitive symptoms ▪ Dopamine analogue ▫ Motor symptoms ▪ Atypical neuroleptic agents ▫ Persistent disabling hallucinations, psychotic features (used very cautiously) Other clinical features ▪ Rapid eye movement (REM) sleep behavior disorder ▫ Sleep disturbance (sleep walking, talking) ▪ Autonomic nervous system dysfunction ▫ Orthostatic hypotension, syncope, urinary incontinence/retention, constipation, impotence ▪ Repeated falls (parkinsonism), cognitive fluctuation/orthostatic hypotension ▪ Neuroleptic sensitivity DIAGNOSIS ▪ Exclude other dementia causes Figure 72.4 A histological section of the brain demonstrating a Lewy body. They are caused by the abnormal deposition of the protein alpha synuclein. DIAGNOSTIC IMAGING Single-photon emission computerized tomography (SPECT) scanning ▪ Dopamine transporter ligand ioflupane I-123 (DaTSCAN) shows ↓ transporter perfusion OTHER DIAGNOSTICS ▪ Neuropsychological testing ▫ Confirms cognitive-impairment diagnosis ▪ Mental status scale assessment (e.g. MoCA, MMSE) ▪ Post-autopsy brain biopsy ▫ Shows Lewy bodies as eosinophilic intracytoplasmic inclusions in cortical neurons Figure 72.5 Immunohistochemical tain for the protein alpha synuclein highlights the Lewy bodies in the brain tissue of an individual with Lewy body dementia. OSMOSIS.ORG 559

FRONTOTEMPORAL DEMENTIA (FTD) osms.it/frontotemporal-dementia PATHOLOGY & CAUSES SIGNS & SYMPTOMS ▪ Heterogeneous degenerative frontal/ temporal lobe disease ▫ Presents with personality/behavioral disturbances/aphasia ▪ Occurs < 65 years old (typically) ▫ Memory loss develops later ▪ Inherited/sporadic ▪ Associated with specific-protein cellular inclusions ▫ Tau proteins (Pick disease) ▫ TAR DNA-binding protein 43 (TDP43) ▪ Protein buildup → stop neuronal signaling, lead neurons to apoptosis ▪ Concomitant motor disease: 15–20% (e.g. parkinsonism, motor neuron disease) ▪ Frontal lobe involvement → behavior/ emotional changes ▪ Disinhibition, emotional blunting, apathy/ empathy-loss, hyperorality, compulsive behavior, family/friend dissociation (argumentative/hostile behavior) ▪ Temporal lobe involvement → language impairment, emotional disturbance ▪ Difficulty finding correct word, progressive aphasia, impaired word comprehension, emotional impairment (anxiety/irrational fear), sarcasm-recognition difficulty ▪ Later stages → cognitive decline ▪ Worsening memory, inability to learn new things, concentration loss TYPES Pick disease ▪ Specific pathological FTD subtype characterized by presence of Pick bodies (tangles of abnormal Tau proteins—3R tau isoforms) ▫ 3R tau isoforms (particular amino-acid sequence repeated three times) are hyperphosphorylated, stop supporting microtubules, tangle into round silverstaining inclusion bodies (Pick bodies) Figure 72.6 An MRI scan of the head in the axial plane demonstrating frontotemporal volume loss. 560 OSMOSIS.ORG

Chapter 72 Dementia DIAGNOSIS ▪ Exclude other dementia causes ▫ Laboratory, imaging tests DIAGNOSTIC IMAGING MRI ▪ Structural imaging ▪ Unilateral frontal/temporal atrophy, may → both hemispheres, ventricle enlargement SPECT/perfusion-MRI/PET ▪ Functional imaging ▪ Affected-lobe hypometabolism, hypoperfusion LAB RESULTS Genetic testing ▪ Familial FTDs Pick disease-specific biopsy findings ▪ Pick bodies ▫ Round/oval, Tau-positive, neuronal cytoplasmic inclusions ▪ Pick cells ▫ Swollen (ballooned) neurons TREATMENT ▪ No cure MEDICATIONS Symptom alleviation ▪ Antidepressants ▫ Severe behavioral symptoms ▪ Atypical antipsychotic drugs have significant side effects ▪ Cholinesterase inhibitors ▫ No convincing evidence of benefit OTHER INTERVENTIONS ▪ Physical exercise; physical, occupational, speech therapy; ↑ supervision MNEMONIC: PICK Features of Pick disease Progressive degeneration of neurons Intracytoplasmic Pick bodies Cortical atrophy Knife edge gyri OTHER DIAGNOSTICS ▪ Neuropsychological tests ▫ Normal in early stages ▪ Mental status scale assessment (e.g. MoCA, MMSE) ▪ Post-autopsy brain biopsy shows characteristic microscopic findings ▫ Microvacuolation, neuronal loss, swollen neurons, myelin loss, astrocytic gliosis, abnormal protein inclusions Figure 72.7 A brain at post mortem with frontotemporal degeneration. OSMOSIS.ORG 561

VASCULAR DEMENTIA osms.it/vascular-dementia PATHOLOGY & CAUSES ▪ Heterogenous dementia ▫ Results from multiple cerebrovascular events/chronic ischemia ▪ Second most common dementia cause in elderly ▪ High Alzheimer disease comorbidity ▪ Multiple, bilateral, cortical, subcortical infarcts/chronic ischemia → ↓ brain blood supply → stepwise cognitive function decline, gait abnormality, focal neurological deficits ▫ Prominent executive function deficit ▫ Late-onset memory impairment ▪ Binswanger’s disease ▫ Large subcortical white matter areas involved CAUSES ▪ Cerebral artery atherosclerosis ▪ Carotid artery/heart embolization ▪ Chronic hypertension → cerebral arterioles sclerosis ▪ Vasculitis RISK FACTORS ▪ Smoking, hypertension, diabetes, insulin resistance, hyperlipidemia, hyperhomocysteinemia SIGNS & SYMPTOMS ▪ Progressive, stepwise cognitive function impairment (affected cortical areadependent) ▫ Frontal: executive dysfunction (frontal) ▫ Left parietal: aphasia, apraxia, agnosia ▫ Right parietal: hemineglect, confusion, agitation, visuospatial, constructional difficulty ▫ Temporal: anterograde amnesia 562 OSMOSIS.ORG ▪ Deficits due to subcortical infarcts ▫ Focal motor signs ▫ Gait disturbance ▫ Urinary frequency/urgency ▫ Personality, mood change ▫ Relatively mild memory deficit ▫ Improvements may occur between cerebrovascular events DIAGNOSIS DIAGNOSTIC IMAGING MRI/CT scan ▪ Show multiple cortical, subcortical infarcts ▪ Microinfarcts identified ▫ Initiate evaluation to define etiology ▫ Carotid Doppler ultrasound: reveal carotid plaques ▫ Echocardiogram: reveal cardiogenic emboli OTHER DIAGNOSTICS ▪ Neuropsychological testing ▫ Detects cognitive impairment, domains involved ▫ Similar language, construction, memory registration deficits with AD, but more impaired executive functioning ▪ Microinfarcts identified ▫ Initiate evaluation to define etiology ▫ Holter monitor (detect arrhythmias) ▫ Risk factor screening

Chapter 72 Dementia TREATMENT ▪ No cure MEDICATIONS ▪ Vascular risk factor control ▫ Antihypertensive drugs, antidiabetic agents, statins, antiplatelet agents ▪ Acetylcholinesterase inhibitors/memantine OTHER INTERVENTIONS ▪ Vascular risk factor control ▫ Lifestyle changes Figure 72.8 An MRI scan in the axial plane of the head of an individual with cognitive impairment. There are multiple small white matter infarcts and an absence of cortical atrophy. OSMOSIS.ORG 563