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Case 22.3 – Alzheimers

Category: Medicine | Discipline: Neurology | Setting: Memory Clinic

Case

Amanda Wilson is a 65 year old woman who has been referred to you by her GP with "memory problems". Her daughter informs you that her mother has been becoming more forgetful over the last few years. She is struggling to remember what she needs to buy at the shops. She has also become less active and less confident and is now having some trouble looking after her finances. She finds difficult coping with paying bills, managing her bank account. Her daughter is very concerned about her mother's welfare. The GP tells you in a referral that her mother's MMSE (mini mental state examination) was 22 out of 30. Physical examination was unremarkable except that you noticed she had some difficulty drawing a clock face and placing the hands at "10 past eleven", which you requested as part of the assessment.

Questions

1. What clinical history and examination would you want to do with Amanda and her family?

History (from patient AND informant/family member):

Cognitive symptoms:

  • Memory: Recent vs remote memory; examples of forgetfulness; repetitive questions; forgetting appointments/events
  • Language: Word-finding difficulties, naming problems
  • Visuospatial skills: Getting lost in familiar places, difficulty with directions
  • Executive function: Problems with planning, organization, complex tasks
  • Praxis: Difficulty with learned motor tasks (e.g., using tools, getting dressed)

Timeline:

  • Onset: When did symptoms first start?
  • Progression: Gradual vs stepwise vs rapid
  • Duration: Weeks, months, years?
  • Course: Progressive, static, or fluctuating?

Functional impact:

  • Activities of Daily Living (ADLs): Washing, dressing, toileting, eating, mobility
  • Instrumental ADLs: Shopping, cooking, housework, managing finances, managing medications, using telephone, driving
  • Employment/hobbies - has patient stopped activities?

Behavioral and psychological symptoms:

  • Depression, anxiety, apathy
  • Personality changes
  • Psychotic symptoms (hallucinations, delusions)
  • Sleep disturbance
  • Agitation, aggression, disinhibition
  • Wandering

Other neurological symptoms:

  • Parkinsonism (tremor, rigidity, bradykinesia, gait disturbance)
  • Seizures
  • Falls, syncope
  • Visual hallucinations (especially in Lewy body dementia)
  • REM sleep behavior disorder

Past medical history:

  • Vascular risk factors: hypertension, diabetes, hyperlipidemia, smoking, previous stroke/TIA
  • Head injury
  • Psychiatric history (depression can mimic or coexist with dementia)
  • Thyroid disease
  • Vitamin B12 deficiency
  • Alcohol history

Drug history:

  • Medications that can impair cognition: anticholinergics, benzodiazepines, opioids
  • Over-the-counter medications

Family history:

  • Dementia, Parkinson's disease, other neurological conditions
  • Early-onset dementia in family (before age 65) suggests genetic causes

Social history:

  • Living situation, support network
  • Carer stress/burden
  • Safety concerns (wandering, leaving gas on, etc.)
  • Driving status

Examination:

Cognitive/Mental State Examination:

  • Formal cognitive testing: MMSE, MoCA (Montreal Cognitive Assessment), ACE-III (Addenbrooke's Cognitive Examination)
  • Clock drawing test: Tests visuospatial and executive function
  • Orientation to time, place, person
  • Attention and concentration
  • Memory: immediate recall, short-term, long-term
  • Language: naming, repetition, comprehension, fluency
  • Visuospatial skills
  • Executive function: planning, abstract reasoning

Neurological Examination:

  • Cranial nerves: Visual fields, pupil responses, eye movements, facial strength
  • Motor: Tone (rigidity?), power, reflexes, plantar responses
  • Extrapyramidal signs: Bradykinesia, tremor, rigidity, postural instability (suggests Parkinson's/Lewy body dementia)
  • Gait: Parkinsonian, apraxic, ataxic, hemiplegic
  • Primitive reflexes: Grasp, palmomental, glabellar tap (suggest frontal lobe involvement)

General Examination:

  • Cardiovascular: BP, heart rhythm (AF - vascular dementia risk), carotid bruits
  • Signs of systemic disease that might contribute to cognitive impairment
2. What investigations would be needed and why?

Essential Blood Tests (to exclude reversible causes):

  • Full Blood Count: Anemia can impair cognition
  • ESR/CRP: Inflammatory/infective causes, vasculitis
  • Urea and Electrolytes: Hyponatremia, renal failure can cause confusion
  • Liver Function Tests: Hepatic encephalopathy
  • Thyroid Function (TSH, free T4): Hypothyroidism is a treatable cause of cognitive impairment
  • Vitamin B12 and Folate: Deficiency can cause cognitive impairment and is reversible
  • Calcium: Hypercalcemia can cause confusion
  • Glucose/HbA1c: Diabetes control; hypoglycemia/hyperglycemia
  • Lipid profile: Vascular risk assessment

Other Blood Tests (if clinically indicated):

  • Syphilis serology (VDRL/TPPA): Neurosyphilis is rare but treatable cause
  • HIV serology: If risk factors present
  • Autoimmune screen (ANA, ANCA): If suspecting vasculitis or autoimmune encephalitis
  • Paraneoplastic antibodies: If rapidly progressive or atypical features

Neuroimaging:

1. MRI Brain (preferred) or CT Brain:

  • Essential in all patients with dementia
  • Exclude:
    • Structural lesions: tumor, subdural hematoma, hydrocephalus
    • Vascular disease: previous strokes, small vessel disease
  • Support diagnosis:
    • Alzheimer's disease: Medial temporal lobe (hippocampal) atrophy, generalized cortical atrophy, posterior predominance
    • Vascular dementia: Multiple infarcts, extensive white matter changes, strategic infarcts
    • Frontotemporal dementia: Frontal and/or temporal lobe atrophy
    • Normal pressure hydrocephalus: Dilated ventricles without sulcal enlargement
  • MRI superior to CT for detecting early changes and small vessel disease

Other Investigations (specialist use):

Functional Brain Imaging:

  • FDG-PET scan: Shows glucose hypometabolism
    • Alzheimer's: Temporoparietal and posterior cingulate hypometabolism
    • Frontotemporal dementia: Frontal/temporal hypometabolism
  • Amyloid PET scan: Detects amyloid plaques (hallmark of Alzheimer's); negative scan effectively excludes Alzheimer's
  • DaTscan (dopamine transporter scan): Distinguishes Lewy body dementia/Parkinson's dementia from Alzheimer's

CSF Analysis (lumbar puncture):

  • Usually reserved for atypical cases or research
  • In Alzheimer's: Low Aβ42, elevated total tau and phosphorylated tau
  • Useful to exclude infection (chronic meningitis), inflammation, or prion disease

Genetic Testing:

  • Usually only for early-onset dementia (\<65 years) with strong family history
  • Alzheimer's: APP, PSEN1, PSEN2 mutations (rare, autosomal dominant)
  • APOE genotyping NOT routinely recommended (APOE ε4 is risk factor, not diagnostic)
  • Frontotemporal dementia: C9orf72, MAPT, GRN mutations

EEG:

  • Not routinely required
  • Consider if suspecting: seizures, Creutzfeldt-Jakob disease (CJD), encephalitis
3. Assuming normal blood tests and imaging, what would be the most likely diagnosis? What are the differential diagnoses?

Most Likely Diagnosis: Alzheimer's Disease (AD)

Rationale:

  • Gradual onset and progressive decline over years
  • Prominent memory impairment (forgetting shopping items, appointments)
  • Impaired complex tasks (managing finances, paying bills)
  • Visuospatial dysfunction (difficulty with clock drawing)
  • Age 65 (typical age of onset for late-onset AD)
  • MMSE 22/30 indicates mild-moderate cognitive impairment
  • No features suggesting other causes (no stepwise decline, no parkinsonism, no behavioral changes)

Alzheimer's Disease - Clinical Features:

  • Insidious onset, gradual progressive decline
  • Memory impairment (episodic memory affected early)
  • Other cognitive domains affected: language, visuospatial, executive function
  • Functional impairment in ADLs
  • Neurological examination usually normal (until late stages)
  • Behavioral and psychological symptoms common (apathy, depression, agitation, psychosis)

Differential Diagnoses of Dementia:

1. Vascular Dementia (VaD) / Mixed Dementia:

  • Second most common cause after AD (~15-20% of dementia; mixed AD + VaD ~10%)
  • Risk factors: hypertension, diabetes, smoking, previous stroke
  • Clinical features:
    • Stepwise deterioration (sudden declines corresponding to vascular events)
    • Focal neurological signs (e.g., hemiparesis, visual field defects)
    • Gait disturbance (small-stepped, shuffling)
    • Emotional lability, depression
    • Executive dysfunction and slowed processing often prominent early
  • Imaging: Multiple infarcts, extensive white matter changes, strategic infarcts (thalamus, basal ganglia)

2. Dementia with Lewy Bodies (DLB):

  • ~5-10% of dementia
  • Core features (2 of 4 required for probable DLB):
    • Fluctuating cognition: Marked variations in attention and alertness
    • Visual hallucinations: Recurrent, well-formed, detailed
    • REM sleep behavior disorder: Acting out dreams
    • Parkinsonism: Bradykinesia, rigidity, tremor (usually develops with or after cognitive symptoms)
  • Supportive features: Severe sensitivity to antipsychotics, autonomic dysfunction, falls
  • DaTscan abnormal (reduced dopamine transporter uptake)

3. Frontotemporal Dementia (FTD):

  • ~5% of dementia; often presents <65 years (early-onset)
  • Subtypes:
    • Behavioral variant FTD (bvFTD): Early behavioral changes (disinhibition, apathy, loss of empathy, compulsive behaviors); memory relatively preserved initially
    • Primary progressive aphasia: Language impairment (non-fluent or semantic variant)
  • Imaging: Frontal and/or temporal lobe atrophy
  • Strong genetic component (~40% have family history)

4. Parkinson's Disease Dementia (PDD):

  • Dementia developing in established Parkinson's disease (motor symptoms precede cognitive symptoms by >1 year)
  • Features: Executive dysfunction, visuospatial impairment, memory problems
  • Visual hallucinations, fluctuations common

5. Normal Pressure Hydrocephalus (NPH):

  • Classic triad: Gait disturbance (magnetic gait, first symptom), cognitive impairment, urinary incontinence
  • CT/MRI: Ventriculomegaly out of proportion to sulcal atrophy
  • May improve with CSF shunting (potentially reversible)

6. Depression ("Pseudodementia"):

  • Can mimic dementia or coexist with dementia
  • Features suggesting depression: Rapid onset, subjective complaints of memory loss greater than objective deficits, poor effort on testing, depressed mood, history of depression
  • Important to treat depression even if underlying dementia present

7. Other Rarer Causes:

  • Prion diseases (Creutzfeldt-Jakob disease): Rapidly progressive, myoclonus, ataxia
  • Chronic subdural hematoma (history of head injury)
  • Brain tumor
  • Chronic meningitis/encephalitis (TB, cryptococcus, syphilis, HIV)
  • Metabolic: B12 deficiency, hypothyroidism, chronic hypoxia
  • Toxic: Alcohol-related dementia, heavy metal exposure
  • Autoimmune encephalitis
  • Huntington's disease (family history, chorea)

Mild Cognitive Impairment (MCI):

  • Cognitive impairment beyond normal aging but does NOT significantly impair ADLs/independence
  • Amnestic MCI (memory impairment) has high risk (~10-15% per year) of progression to Alzheimer's dementia
  • Amanda has significant functional impairment (finances, shopping), so this is dementia, not MCI
4. What medications may be used for patients with dementia?

MEDICATIONS FOR ALZHEIMER'S DISEASE:

1. Cholinesterase Inhibitors:

Mechanism: Increase acetylcholine levels in brain by inhibiting acetylcholinesterase

Three drugs available:

  • Donepezil (Aricept):
    • Once daily dosing (5mg, 10mg)
    • Most commonly prescribed
    • Generally well tolerated
  • Rivastigmine (Exelon):
    • Oral (twice daily) or transdermal patch
    • Patch may have fewer GI side effects
  • Galantamine (Reminyl):
    • Twice daily or once daily extended release
    • Also has nicotinic receptor modulating activity

Indications:

  • Mild to moderate Alzheimer's disease (MMSE 10-26)
  • Also licensed for: Dementia with Lewy bodies (rivastigmine), Parkinson's disease dementia (rivastigmine)

Efficacy:

  • Modest symptomatic benefit (2-4 point improvement in MMSE, or slowing of decline)
  • About 40-50% of patients show measurable improvement or stabilization
  • Benefits may include: improved cognition, functional ability, behavior
  • Do NOT alter disease progression (symptomatic treatment only)
  • Effect size modest; clinical significance debated

Side effects:

  • Gastrointestinal: Nausea, vomiting, diarrhea, anorexia (most common; take with food to minimize)
  • Bradycardia (caution in conduction abnormalities)
  • Insomnia, vivid dreams (take in morning)
  • Muscle cramps
  • Increased gastric acid (caution in peptic ulcer disease)
  • Urinary frequency

Contraindications/Cautions:

  • Sick sinus syndrome, conduction abnormalities
  • Active peptic ulcer
  • Severe asthma/COPD (theoretical increased bronchial secretions)

2. Memantine (Ebixa/Namenda):

Mechanism: NMDA receptor antagonist; reduces glutamate excitotoxicity

Indications:

  • Moderate to severe Alzheimer's disease (MMSE <14)
  • Can be used in combination with cholinesterase inhibitors

Dosing:

  • Start 5mg daily, titrate up to 10mg twice daily (or 20mg once daily extended release)

Efficacy:

  • Modest benefit in moderate-severe AD
  • May slow functional and cognitive decline
  • May reduce behavioral symptoms
  • Combination with cholinesterase inhibitor may offer additional modest benefit

Side effects:

  • Generally well tolerated
  • Dizziness, headache, confusion
  • Constipation
  • Fewer side effects than cholinesterase inhibitors

NICE Guidance (UK):

  • Cholinesterase inhibitors recommended for mild-moderate AD
  • Memantine recommended for moderate-severe AD, or for those intolerant of/contraindicated for cholinesterase inhibitors
  • Specialist initiation; can be continued by GP
  • Review response after 3-6 months; continue if beneficial
  • MMSE used to stage severity but clinical judgment paramount

MEDICATIONS FOR BEHAVIORAL AND PSYCHOLOGICAL SYMPTOMS OF DEMENTIA (BPSD):

General Principles:

  • Non-pharmacological approaches FIRST: identify and address triggers, structured activities, environmental modification, support for carers
  • Medications should be used ONLY when non-pharmacological approaches fail AND symptoms cause significant distress or risk
  • Use lowest effective dose for shortest duration

1. Antipsychotics (for agitation, aggression, psychosis):

  • Risperidone: Only antipsychotic licensed for short-term use in dementia (for severe aggression/psychosis unresponsive to other measures)
  • Cautions:
    • Increased risk of stroke (1-2% absolute increase)
    • Increased mortality (1.6-1.7x)
    • Extrapyramidal side effects, sedation, falls
    • AVOID in Lewy body dementia (severe sensitivity reactions)
    • Should be time-limited (review after 3 months)

2. Antidepressants:

  • SSRIs (citalopram, sertraline) for depression and anxiety in dementia
  • Citalopram may help agitation even without depression
  • Avoid TCAs (anticholinergic, worsen cognition)

3. Other medications:

  • Trazodone: For agitation, sleep disturbance (off-label use)
  • Avoid benzodiazepines: Worsen cognition, increase falls, dependence
  • Avoid anticholinergic medications: Worsen cognition (e.g., TCAs, antihistamines, bladder antimuscarinics)

DISEASE-MODIFYING THERAPIES (New/Emerging):

  • Aducanumab (Aduhelm): Monoclonal antibody against amyloid; controversial approval in US (2021); not approved in EU/UK; high cost, modest/unclear benefit, significant side effects (ARIA - amyloid-related imaging abnormalities)
  • Lecanemab: Another anti-amyloid antibody showing modest slowing of decline in early AD trials (2022)
  • These target underlying pathology (amyloid plaques) but clinical benefits remain modest and controversy exists about risk-benefit

NON-PHARMACOLOGICAL MANAGEMENT:

(Often more important than medications!)

  • Cognitive stimulation therapy
  • Physical exercise
  • Social engagement
  • Occupational therapy (home adaptations, memory aids)
  • Carer education and support (essential!)
  • Advanced care planning
  • Management of vascular risk factors (BP, diabetes, lipids, smoking)