Alzheimer's Disease

Overview

Alzheimer disease is characterised by an insidious onset of symptoms with initial forgetfulness progressing over time to profound memory impairment with accompanying dysphasia, dyspraxia and personality change.

Definition

Dementia: Clinical syndrome that is characterised by a progressive deterioration in cognition with resulting decline in function.
Alzheimer disease: Characterised by an insidious onset of symptoms with initial forgetfulness progressing over time to profound memory impairment with accompanying dysphasia, dyspraxia and personality change.
Vascular dementia: Usually starts suddenly and will be accompanied by focal neurological signs with imaging evidence of cerebrovascular disease. Many patients with vascular dementia have evidence of atherosclerotic disease elsewhere.
Frontotemporal lobe dementia (pick’s disease): Selective brain atrophy involving the frontal and temporal lobes, requiring brain magnetic resonance imaging for accurate diagnosis. Clinically, these diseases present chiefly as progressive aphasia or as disintegration of personality and behaviour that may be misdiagnosed as a psychiatric disorder
Lewy body Dementia: Considered the second most common cause of dementia in the elderly after Alzheimer’s disease. DLB is a progressive neurological disorder characterized by core features of cognitive impairment, psychosis and Parkinsonism.

Classification

Major dementia syndromes

Alzheimer’s Disease (50-70%) – 15% are familiar in origin including early-onset dementia
Vascular Disease (10-20%) – Accumulation of small (lacunar) or large infarctions
Lewy-Body Dementia (10%) – Clinically characterised by dementia and signs of Parkinson’s disease. Often inherited – mutations in alpha-synuclein and beta-synuclein
Frontaltemporal Lobe Dementia

Anatomy and Physiology

Neuron Anatomy

Neurology – Neuron structure and function

Risk Factors

Age
Family history
- Patients with a first-degree relative with dementia have a 10 to 30 percent increased risk of developing the disorder.
Rare, dominantly-inherited mutations in genes that impact amyloid in the brain
Apolipoprotein E (APOE) epsilon 4 (e4) allele
Hypertension
Hypercholesterolaemia
Cerebrovascular disease
Type II Diabetes Mellitus
Obesity
Lifestyle and activity
Smoking
Brain trauma
Medications (Benzodiazepam, Anticholinergics and PPIs?)

It has been estimated that up to one third of AD cases worldwide might be attributable to modifiable risk factors such as diabetes, midlife hypertension, and physical inactivity.

Clinical Manifestation

Memory impairment:

Episodic (personal experiences)
Semantic (store of conceptual and factual knowledge)
Visuospatial impairment, e.g getting lost when driving.
Constructional and dressing apraxia.
Language impairment, e.g. word-finding difficulties. Alexia, agraphia, acalculia.

Mini-mental state examination (MMSE)

Physical signs:

Mild akinetic rigid syndrome
Myoclonus

Differential Diagnosis

Consider other medical causes of memory impairment including hypothyroidism, B group vitamin deficiencies, sleep apnoea, neurosyphilis, cerebral space occupying lesions and normal pressure hydrocephalus.

Vascular dementia
Thyroid Disease
Dementia with Lewy bodies
Parkinson’s Disease and Parkinson’s Plus Diseases
Prion Disease
Cerebral Syphilis
Post-cerebral radiotherapy
Wernicke-Korsakoff psychosis

Difference between Dementia and Delirium
	Dementia	Delirium
Onset	Sub-acute	Acute
Conscious level	Normal	Fluctuates
Hallucinations	Late event	Common
Agitation/agression	Uncommon until late	Common
Thought form	Poverty of thought late	Flight of ideas
Memory	Slow decline	Poor

DIFFERENTIAL DIAGNOSIS OF ALZHEIMERS
	Alzeihmers Disease	Wernicke-Korsakoff	Picks Disease (FTD)
Early Symptoms	Memory loss	Confusion most common, followed by staggering gait and ocular problems	Apathy, poor judgement/insight, aphasia
Onset	Gradual	Days-weeks	Gradual
Aetiology	Neurodegeneration	B1 deficiency relatedto alcohol and malnutrition	Neurodegeneration
Mental status	Episodic memory loss	Disorientation, minimal spontaneous speech, inattention	Frontal/executive function, language
Neuropsychiatry	Initially normal	Apathetic, lack of motivation and insight	Apathy, disinhibition, hyperorality, euphoria, depression.
Neurology	Initially normal	Confusion, ataxia, nystagmus	Progressive supranuclear palsy/cortical basal degeneration, vertical gaze palsy, dystonia
Imaging	Hippocampal and entorhinal cortex atrophy	Periventricular punctate haemorrhages affecting gray matter	Frontal and/or temporal atrophy

Investigation

Cognitive Testing Cognitive tests are vital in the diagnosis of dementia and are often used to differentiate between types of dementia. They can also be used to assess mood and may help diagnose depression.

Modified Mini-Mental Status Examination (MMSE)
Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-Cog)
General Practitioner Assessment of Cognition (GPCOG)
Rowland Universal Dementia Assessment Scale (RUDAS)
Adenbrooks Cognitive Examination
Neuropsychological Testing

Imaging

CT and/or MRI
Chest X-ray
ECG

Blood tests

FBC
ESR
EUC
Blood glucose
Calcium
LFTs
TFTs (hypothyroidism not causative but sometimes coexistent)
Vitamin B12
Venereal Diseases Research Laboratory (VDRL) test (screening for neurosyphilis is not recommended unless high suspicion)

Pathology

Generalized cortical atrophy – especially temporal lobes
Deposits of amyloid A4 protein in cortex with neuritic plaques
- Amyloid angiopathy (Amyloid within vessel walls)
Neurofibrillary tangles – tau and ubiquitin proteins

Treatment

General

Education
Family education
Support groups
Speech therapy
Physiotherapy/occupational therapy
Psychologist
Medication review
Diet
Vitamin supplements + iron

Memory is not the only complication of alzheimers. As the disease progresses behavioural and psychological symptoms of dementia, including sleep inversion, incontinence, excessive inappropriate motor activity (eg pacing), shouting and agitation manifests and all need individual treatment.

Medical treatment

Cholinesterase inhibitors
+/- Memantine (NMDA receptor blocker →↓Glutamatenergic activity
Review

Cholinesterase inhibitors improve alertness and function and can maintain cognitive scores at or above the baseline for up to 12 months. However, they do not modify the underlying progression of pathology.

Pharmacology

Cholinesterase inhibitors (Donepezil) inhibit the enzyme that normally breaks down Ach →↑Ach activity. In Alzheimer’s there is ↓Ach. Side effects: particularly anorexia, nausea and vomiting. Other adverse effects include diarrhoea, insomnia, vivid dreams, cramps, dizziness, depression, lethargy, fatigue, drowsiness, tremor, weight loss, urinary incontinence and sweating.