Alzheimer Disease

Diseases, ,

Clinical features:

Clinical features in general:

  • Episodic memory loss: This is usually the first symptom  to develop. It preceeds the dysfunction in activities of daily living. In most cases Alzeimer disease develops from amnestic mild cognitive impairment.
  • Later on other cognitive domains are involved this leads to:
    • Executive dysfunction
    • Agnosia
    • Apraxia
    • Aphasia
    • Neuropsychiatric symptoms: depression, apathy, agitation, anxiety, delusions.
  • In the end stages the patient becomes akinetic and mute.
  • Other features: physical frailty
Other criteria:

DSM-IVR criteria:

  • Multiple cognitive deficits:
  • Memory impairment must be present
  • Plus one or more of:
  • Aphasia
  • Apraxia
  • Agnosia
  • Disturbance in executive functioning e.g. planning, organising, abstracting
  • Must rule out other causes of dementia, must rule out delirium, rule out substance abuse
  • Early onset if = or <65 y.o.
  • Late onset if >65 y.o.
  • With our without behaviour problems

ICD-10 criteria:

  • There are separate criteria for ICD-10

NINCD-ADRDA criteria for Alzheimer:

  • Definite: clinically typical +histology
  • Probable clinically –histology
  • Possible: clinically atypical -histology -other diagnosis

Pathology:

Gross:

  • Decreased weight, gyral atrophy, ventricular dilation especially in medial temporal structures.

Microscopic pathology:

  • Neuritic plaques: found in the cortex. extracellular Abeta-amyloid protein aggregations (made from Amyloid precursor protein APP which is cleaved by Beta & gamma secretases to Abeta peptides which polymerizes into plaques) with Tau positive neurites (axons & dendrites).
  • Neurofibrillary tangles NFTs: found in the hippocampus, entorinal cortex, amygdala & neocortex, then temporal & parietal lobes. Intracellular Tau positive accumulation of abnormally phosphorylated tau, shaped like the neuron.
  • Other features:
    • Hirano bodies: in pyramidal neurons of hippocampus. Eosinophilic rod shaped bodies. Tau positive, Abeta amyloid positive, neurofilament positive.
    • Granulovacuolar degeneration of pyramidal neurons of the hippocampus. Cytoplasmic vacuoles and granules positive for tau, neurofilament, ubiquitin, tubulin.
    • Decreased acetylcholine neurons in forebrain nucleus basalis of Myenert
    • Cerebral amyloid angiopathy: Abeta-amyloid protein accumulation in media & externa of arteries & arterioles of the Cortex & meninges, sparing the white matter vessels.

CSF analysis:

  • Tau, p-tau (posphorylate tau), and isoprostanes: elevated
  • Abeta amyloid  1-42 (fibrillogenic) Abeta42: reduced in AD
  • Phosphorylated tau: increased in AD
  • Tau/Abeta42 ratio: increased in AD

Genetic forms:

  • Amyloid precursor protein= amyloid beta a4 precusor protein, APP chr. 21q21
  • Presenilin 1 protein, PSEN1 gene chr. 14q24.3
  • Presenilin 2 protein, PSEN2 gene chr. 1q31-q42
  • Microtubule associate protein tau MAPT, MTPT1 chr. 17q21.1

Genetic factors:

  • APOE gene, chr. 19q13.2:
  • ApoE4 haplotype: predisposes
  • ApoEe2 haplotype: protective
  • ApoE3 haplotype

MRI:

  • Hippocampal atrophy may occur

SPECT:

  • Regional hypoperfusion in posterior temporal & parietal lobes

Neuropsychological testing:

Mini-Mental Status Examination (MMSE)
Other neuropsychological tests:
  • Weschler Memory Scale: impaired verbal episodic memory, impaired delayed verbal episodic memory
  • Digit span forward & backward: impaired attention
  • Trailmaking test B: Impaired executive function
  • Trailmaking test A: Impaired psychomotor speed
  • Boston naming test & Category fluency test: impaired language
Clinical Dementia Rating (CDR):

A measure of functional status used to quantify the severity of dementia. Assess six areas: memory, orientation, judgment & problem solving, community affairs, home & hobbies, and personal care. Scores in each of these are combined to obtain a composite score ranging from 0 through 3 as follows
0 : no dementia
0.5: very mild dementia
1: mild dementia
2: moderate dementia
3: severe dementia

Geriatric depression scale:
  • Used for behavioural assessment

Treatment:

Institute general measures for controlling dementia, include:

  • Exercise training for physical health & depression

Memory impairment:

  • Acetylcholine esterase inhibitor e.g. rivastigmine, BID or TID. Donepezil in moderate & severe cases.
  • Galantamine. [SERAD RCT]
  • NMDA receptor antagonist e.g. memantine

Debatable efficacy:

  • Some consider adding high dose vitamin E (alpha tocopheraol) 2000 IU daily, [evidence of harm exists].

Depression:

  • SSRI: for example Sertraline or citaloparam

Agitation & psychosis:

  • Non-pharmacological therapies first, rule out pain
  • Avoid antipsychotics: quetiapine as it accelerates cognitive decline. Other atypical antipsychotics have an unfavourable risk/benefit ratio.[CATIE-AD, DART-AD] Typical antipsychotics are likely to have the same poor profile. However, often these medications are still necessary when non-pharmacological measures fail.
  • Donepezil isn’t effective for antigation [CALM-AD] [135]

Drugs that failed to show benefit:

  • Ginkgo Biloba
  • NSAIDs
  • Statins
  • Oestrogen replacement
  • Steroids

Related Articles:

References:

  1. Buchman, A.S., et al., Physical frailty in older persons is associated with Alzheimer disease pathology. Neurology, 2008. 71(7): p. 499-504.
  2. Burns, A., et al., Safety and efficacy of galantamine (Reminyl) in severe Alzheimer’s disease (the SERAD study): a randomised, placebo-controlled, double-blind trial. Lancet Neurol, 2009. 8(1): p. 39-47.
  3. Ballard, C., et al., The dementia antipsychotic withdrawal trial (DART-AD): long-term follow-up of a randomised placebo-controlled trial. Lancet Neurol, 2009. 8(2): p. 151-7.
  4. Burns, A., et al., Safety and efficacy of galantamine (Reminyl) in severe Alzheimer’s disease (the SERAD study): a randomised, placebo-controlled, double-blind trial. Lancet Neurol, 2009. 8(1): p. 39-47
  5. Ballard, C., et al., The dementia antipsychotic withdrawal trial (DART-AD): long-term follow-up of a randomised placebo-controlled trial. Lancet Neurol, 2009. 8(2): p. 151-7.
  6. Cummings, J.L., Alzheimer’s disease. N Engl J Med, 2004. 351(1): p. 56-67.
  7. Black, S.E., et al., Donepezil preserves cognition and global function in patients with severe Alzheimer disease. Neurology, 2007. 69(5): p. 459-69
  8. Feldman, H.H. and R. Lane, Rivastigmine: A placebo-controlled trial of BID and TID regimens in patients with Alzheimer’s disease. J Neurol Neurosurg Psychiatry, 2007.
  9. Howard, R.J., et al., Donepezil for the treatment of agitation in Alzheimer’s disease. N Engl J Med, 2007. 357(14): p. 1382-92
  10. Buchman, A.S., et al., Physical frailty in older persons is associated with Alzheimer disease pathology. Neurology, 2008. 71(7): p. 499-504
  11. Auchus, A.P., et al., Galantamine treatment of vascular dementia: a randomized trial. Neurology, 2007. 69(5): p. 448-58.
  12. Miller, E.R., 3rd, et al., Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med, 2005. 142(1): p. 37-46.
  13. Pollock, B.G., et al., A double-blind comparison of citalopram and risperidone for the treatment of behavioral and psychotic symptoms associated with dementia. Am J Geriatr Psychiatry, 2007. 15(11): p. 942-52.
  14. Kales, H.C., et al., Mortality risk in patients with dementia treated with antipsychotics versus other psychiatric medications. Am J Psychiatry, 2007. 164(10): p. 1568-76.