Primary Neurodegenerative Disease

Primary neurodegenerative disease      Conditions with selective (i.e. not all CNS regions equally affected) and progressive loss of neurones. Can be inherited or sporadic (i.e. acquired). A common theme in these conditions is the brain accumulation of a particular protein. Examples include: o AD (Aβ peptide, tau). o Dementia with Lewy Bodies (α-synuclein). o Frontotemporal dementia (tau – not in all subtypes). Damage to different regions elicit different symptoms. Alzheimer’s disease Epidemiology  Most common cause; 50 – 80%.  Increases in incidence with age, with risk exceeding 1:3 over the age of 85.  AD + cerebrovascular disease (mixed dementia) represents a further 13 – 17%.  About 10% of all cases have a strong family history of AD. Aetiology  Sporadic late onset (most common).     Familial late onset (uncommon). Familial early onset (rare). Associated with Down syndrome. Associated with other degenerative disease. Natural history  Not due to other causes (e.g. cerebrovascular disease, hypothyroidism, vitamin B12/folate deficiency).  Not due to other psychiatric diagnosis (e.g. major depression, schizophrenia).  Gradual onset and continuing cognitive decline.  Increased confusion, dysphagia, poor gait and increased falls. Clinical features  Forgetfulness: o Slowly progressive memory loss for recent events. o ‘Short term memory loss’. o Problems with remembering conversations, dates, appointments, and misplacing items at home. o Changes in normal ageing should not interfere with function.  Language deficit: o In 40 – 50% of cases at presentation. o Word finding difficulty, paraphasic errors (substitute words with similar concept, table for chair or boat for boot), circumlocution. o Expressive aphasia. o Later, receptive and global aphasia. o Early language deficit  poor prognosis.  Executive function impairment: o Poor judgement, organisation, reasoning and abstract thinking. o Inability to complete complex, demanding tasks. o Less prominent initially than other dementias.  Poor concentration and attention.  Deficits in visuospatial abilities: o Problems with driving, dressing, usual eating utensils.  Personality changes: o Passivity, lack of interest, restlessness and overactivity. o Depression in up to 30%.  Worsening symptoms in the evening; ‘sundowning’.  Later: marked agitation and aggression. Later stages  Frail and dependent for self-care and activities of daily living and/or bed-bound.  Bowel and bladder incontinence.  Median survival: 8 – 10 years. Pathogenesis  Amyloid β (Aβ) peptide. o Appears to be the critical molecule. o Derived through particular cleavage (β, γ) of amyloid precursor protein (APP, a normal neuronal membrane protein with transmembrane domain). o Insoluble Aβ aggregate and accumulate, elicit reaction from glial cells and are directly toxic to neurones. o Forms the amyloid core of neuritic plaques.  Tau proteins. o Normal tau proteins are microtubule binding proteins. o Tau protein gene in chromosome 17. o In normal brain, phosphate groups are rapidly removed by phosphatases. o In AD, aggregated tau protein in PHF is resistant to dephosphorylation. Molecular genetics Type AD1 AD2 AD3 AD4 Mutation in APP gene on chromosome 21. ApoE on chromosome 19. Presenilin-1 gene on chromosome 14. Presenilin-2 gene on chromosome 1. Normal brain vs. AD brain Histology – macroscopic features  Widened sulci and dilated ventricles secondary to loss of parenchymal volume, mostly temporal cortex, amygdala and hippocampus. Histology – microscopic features  Neuritic plaques (NPs) – deposition of specific amyloid. o Located in neuropil, extracellular. o Deposition of Aβ amyloid. o Clusters of abnormally distended, radially orientated tortuous neuronal processes surrounding amyloid cores. o Reactive astrocytes and microglia at the plaque periphery.  Neurofibrillary tangles (NFTs) – intraneuronal inclusions of paired helical filaments tau. o Located in the cytoplasm of neurones. o Insoluble bundles of paired helical filaments, composed mainly of abnormally phosphorylated tau (microtubule associated protein responsible for cytoskeleton stability and axonal signal transport). o NFTs are not specific to AD; also seen in FTD. o Paired helical filaments are also found within the abnormal neuronal processes in neuritic plaques.  Congophilic angiopathy. o Aβ deposition in the walls of cerebral arteries and arterioles. o Present to some degree in virtually all cases of AD. o Can occur without AD (especially in elderly).    Dystrophic neurites and neuropil threads. Loss of synapses and neurons in cerebral cortex. Other associated changes: o Granulovascular degeneration. o Hirano bodies. o Lipofuscin deposition. o Corpora amylacae. Risk    factors Age. Family history. Genetic factors. o APOE (on chromosome 19) mediates neuronal protection and repair. o Mutation involved in early beta amyloid deposition.   o APOE4: heterozygote = 4 fold increase; homozygote = 30 fold increase. o APOE2: may be protective. Mild cognitive impairment. Others: o Hypercholesterolaemia. o Hypertension. o Diabetes. o Smoking. o Obesity. o Reduced activity. o Low education. Screening  Comprehensive assessment.  History and examination.  Corroborative history.  Cognitive assessment: o Multiple domains. o MMSE.  Exclusion of reversible (and other) causes. o Medications. o Alcohol (Wernicke-Korsakoff syndrome). o Metabolic disorders (e.g. thyroid disease, vitamin B12 deficiency, folate deficiency). o Depression. o CNS neoplasia, chronic subdural haematomas, chronic meningitis. o Tertiary syphilis. o Normal pressure hydrocephalus. o HIV. o CJD (not reversible). Cognitive assessment  Attention, concentration.  Orientation.  Memory.  Language.  Calculation.  Visuospatial skills.  Executive function.  Conceptual thinking, abstraction. MMSE  A score out of 30.     Remains standard screening tool; MMSE <24 suggestive of dementia. It is used only to screen for dementia; does not give definitive diagnosis. o Score can be abnormal in the absence of dementia; score can be normal in the presence of dementia. Limitations: o Patients from culturally and linguistically diverse backgrounds. o Low levels of educational attainment. o Frontal lobe domains are arguably not really tested. Clock face construction: Frontal lobe assessment  History (from family): social behaviour, problems crossing the road, etc.  Judgement.  Similarities.  Differences.  Proverb interpretation.  Luria sequence.    List of animals, ‘S’ words. Following instructions. Trail A and B. Neurological examination  Appearance: o Tremor. o Involuntary movements.  Power; tone; reflexes; sensations: o Focal signs. o Asymmetry. o Proximal myopathy. o Peripheral neuropathy. o Rigidity; cog-wheeling. o Ataxia; dysmetria. o Fine motor skills. Treatment: ACh-esterase inhibitors  E.g. donepezil, rivastigmine, galantamine).    Increase levels of ACh in synapses, enhancing cholinergic activity in the affected break regions. Majority of patients do not have any noticeable improvement. o 18 – 48% of persons may experience improvements in cognition. o Plateau/slowing rate of cognitive decline. Controversial, but may lead to: o Improvements in quality of life. o Reduced caregiver burden. o Reduced economic cost associated with care. Pathological diagnosis  Post-mortem neuropathological assessment of the whole brain that can confirm the diagnosis.  The more frequent and widespread the NPs and/or NFTs, the greater the likelihood of having had AD. o Debate as to which gives best indication.  Some accumulation does occur in normal ageing brain.