2 Neuroscience2.13 Neurodegeneration
2.13 Neurodegeneration
3 min read2 figures
Written by Resident Doctor Committee · Published
Shared mechanisms
Protein handling, cell metabolism, inflammation and synaptic loss interact to cause neurodegeneration.
Symptoms follow the networks affected, and psychiatric change may come before obvious cognitive or motor decline.
The visible burden of deposits does not match clinical severity.
Diseases and their proteins
Disease | Protein | Clinical features |
|---|---|---|
Alzheimer's disease | Amyloid and tau | Impaired new learning |
Dementia with Lewy bodies | Alpha-synuclein | Fluctuating cognition, well-formed visual hallucinations, rapid eye movement sleep behaviour disorder, severe antipsychotic sensitivity |
Frontotemporal lobar degeneration | Tau, TDP-43 or FUS | Behaviour-led or language-led change |
Progressive supranuclear palsy | Four-repeat tau | Early backward falls, axial rigidity, vertical gaze palsy |
Corticobasal degeneration | Four-repeat tau | Apraxia, asymmetric motor signs |
Huntington's disease | Mutant huntingtin, with striatal loss | Inherited movement, cognitive and psychiatric syndrome |
Sporadic Creutzfeldt-Jakob disease | Misfolded prion protein | Rapid decline, startle myoclonus, periodic sharp wave complexes, cortical ribboning |
Prion disease spreads when misfolded prion protein (PrPSc) recruits the normal form to misfold, which produces spongiform change.
Behavioural-variant frontotemporal dementia with motor neurone disease is almost always a TDP-43 proteinopathy, often with a C9orf72 repeat expansion.
Inclusion bodies
Inclusion | Content | Appearance and site | Disease |
|---|---|---|---|
Lewy body | Alpha-synuclein | Round, in the cytoplasm of neurones in cortex and brainstem | Dementia with Lewy bodies |
Papp-Lantos body (glial cytoplasmic inclusion) | Alpha-synuclein | In oligodendrocytes, densest in pons, cerebellar white matter and striatum | Multiple system atrophy |
Pick body | Three-repeat tau | Round, silver-staining, in neurones, densest in dentate gyrus granule cells | Pick-type frontotemporal dementia |
Bunina body | Cystatin C | Small, eosinophilic, in the cytoplasm of surviving lower motor neurones | Amyotrophic lateral sclerosis |
Progressive supranuclear palsy shows globose tangles and tufted astrocytes.
Genes and chromosomes
Gene | Chromosome | Disease and notes |
|---|---|---|
APP | 21 | Codes amyloid precursor protein |
PSEN1 | 14 | Most autosomal dominant early-onset Alzheimer's disease; presenilin 1 belongs to the gamma-secretase complex that cleaves amyloid precursor protein |
PSEN2 | 1 | Codes presenilin 2 |
APOE | 19 | Susceptibility to late-onset Alzheimer's disease |
MAPT (tau) | 17 | Dominant frontotemporal dementia with parkinsonism and tau pathology |
GRN | 17, near MAPT | Frontotemporal dementia with TDP-43 pathology |
C9orf72 | 9 | Frontotemporal dementia, motor neurone disease or both |
HTT | 4 | Huntington's disease |
PRNP | 20, short arm | Familial Creutzfeldt-Jakob disease (E200K variant); the codon 129 polymorphism shapes susceptibility to sporadic and variant disease |
APOE is a susceptibility gene, not a causal one: each ε4 allele raises the risk of late-onset Alzheimer's disease and brings onset earlier.
Motor neurone disease
The hallmark pathology is loss of lower motor neurones from the spinal anterior horn.
To the naked eye, upper motor neurone loss narrows the motor strip (precentral gyrus), and lower motor neurone loss thins the spinal cord and anterior roots.
Variant | Neurones affected | Signs |
|---|---|---|
Amyotrophic lateral sclerosis | Upper and lower | Spreads beyond the bulbar region, usually to the limbs |
Primary lateral sclerosis | Upper only | Spasticity and brisk reflexes, without wasting or fasciculation |
Progressive muscular atrophy | Lower only | Wasting, fasciculation, reduced reflexes, normal tone, flexor plantars |
Progressive bulbar palsy | Upper and lower, bulbar only | Bulbar signs and pseudobulbar affect, with the limbs spared |
Huntington's disease
The resting electrocardiogram shows an excess slow sinus rate with delayed intraventricular conduction, which reflects sympathovagal disturbance.
Once dementia is established, the electroencephalogram loses amplitude: the alpha rhythm fades first, then the record becomes diffusely low-voltage and flat, most marked frontally.
Overlap and mixed pathology
A syndrome does not identify the protein: logopenic aphasia often reflects Alzheimer pathology, and corticobasal syndrome has several causes.
Parkinson's disease dementia and dementia with Lewy bodies overlap biologically and are told apart by when dementia starts relative to parkinsonism.
Mixed vascular and protein pathology is common in older people.
Brain tumours and stroke imaging
Ependymoma grows from the ciliated ependymal lining of the ventricles and the spinal central canal.
Glioblastoma is the most common malignant primary brain tumour in adults; meningioma leads only when benign tumours are counted.
Non-contrast computed tomography of the head is first-line in suspected acute stroke, mainly to exclude haemorrhage and mimics before reperfusion treatment.