2 Neuroscience2.13 Neurodegeneration
2.13.1 Controversies in the pathophysiology of neurodegeneration
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Written by Resident Doctor Committee · Published
Classifying disease by the aggregating protein
Neurodegenerative disorders are classed by the misfolded protein in their defining inclusions.
Protein | Disorders |
|---|---|
Tau (tauopathies) | Alzheimer's disease, Pick's disease, progressive supranuclear palsy, corticobasal degeneration, chronic traumatic encephalopathy |
Alpha-synuclein (synucleinopathies) | Parkinson's disease, dementia with Lewy bodies, multiple system atrophy |
TDP-43 (TDP-43 proteinopathies) | Most frontotemporal dementia with motor neurone disease |
Amyloid beta | Alzheimer plaques, cerebral amyloid angiopathy |
Prion protein | Prion diseases, with spongiform degeneration |
Tau and the tauopathies
Normal tau binds tubulin and stabilises microtubules, promoting their assembly; its gene, MAPT, lies on chromosome 17.
Hyperphosphorylation lowers tau's affinity for microtubules, so it detaches and self-aggregates into intracellular filamentous inclusions, the mechanism all tauopathies share.
Disorder | Tau isoforms | Hallmark pathology |
|---|---|---|
Progressive supranuclear palsy | Four-repeat | Globose neurofibrillary tangles and tufted astrocytes in midbrain, subthalamic nucleus and basal ganglia |
Corticobasal degeneration | Four-repeat | Astrocytic plaques and ballooned neurones |
Pick's disease | Three-repeat | Pick bodies and ballooned Pick cells |
Alzheimer's disease | Mixed three-repeat and four-repeat | Neurofibrillary tangles |
Progressive supranuclear palsy (Richardson syndrome) is defined by impaired vertical gaze, downward first, and its brainstem tau also explains early backward falls and axial rigidity.
Corticobasal syndrome (asymmetric rigidity, limb apraxia, alien limb, cortical sensory loss) usually reflects corticobasal degeneration.
Pick bodies are round, argyrophilic neuronal inclusions of three-repeat tau, dense in the granule cells of the dentate gyrus.
Chronic traumatic encephalopathy is a tauopathy defined by phosphorylated tau tangles around small vessels at the depths of cortical sulci, not by synuclein, copper, huntingtin or prion pathology.
Synucleinopathies
Parkinson's disease, dementia with Lewy bodies and multiple system atrophy all deposit alpha-synuclein but in different cells.
Lewy bodies are round neuronal inclusions with a dense pink core and pale halo on haematoxylin and eosin staining.
In dementia with Lewy bodies, Lewy bodies and Lewy neurites lie in the cortex, limbic system and brainstem.
In multiple system atrophy, argyrophilic glial cytoplasmic inclusions (Papp-Lantos bodies) form in oligodendrocytes.
These inclusions degenerate the striatonigral, olivopontocerebellar and autonomic systems, giving parkinsonism, ataxia, early autonomic failure and the hot cross bun sign.
Multiple system atrophy is told from the Lewy body disorders by its glial, not neuronal, inclusions.
TDP-43 proteinopathies
Frontotemporal dementia with motor neurone disease is almost always a TDP-43 proteinopathy with ubiquitinated inclusions.
A C9orf72 repeat expansion is its commonest familial cause.
Genetic, metabolic and developmental neighbours
Disorder | Gene and inheritance | Mechanism | Pathology and features |
|---|---|---|---|
Huntington's disease | Autosomal dominant CAG expansion in HTT, chromosome 4 | Polyglutamine tract; 40 or more repeats fully penetrant | Loss of GABAergic medium spiny neurones of the striatum, caudate first |
Wilson's disease | Autosomal recessive, ATP7B copper transporter | Hepatocytes cannot load copper onto apoceruloplasmin or excrete it in bile | Copper in liver, basal ganglia and cornea; not a tauopathy |
Fatal familial insomnia | PRNP: D178N with methionine at codon 129 on the same allele | Inherited prion disease | Neuronal loss in anterior ventral and mediodorsal thalamic nuclei |
CADASIL | NOTCH3, chromosome 19 | Damaged smooth muscle of small penetrating arteries; granular osmiophilic deposits | Migraine with aura, recurrent subcortical infarcts, mood disorder, early subcortical dementia |
Doublecortin disorder | DCX, a microtubule-associated protein guiding neuronal migration | Disturbed cortical development | Lissencephaly, subcortical band heterotopia; not neurodegenerative |
Other named inclusions
Inclusion | Appearance | Where and when found |
|---|---|---|
Hirano bodies | Rod-shaped, eosinophilic, containing actin | Normal ageing, more in Alzheimer's disease; not diagnostic alone |
Rosenthal fibres | Elongated, carrot- or corkscrew-shaped, eosinophilic, in astrocytic processes | Long-standing gliosis, low-grade gliomas, some metabolic disorders |
Negri bodies | Round eosinophilic aggregates of viral protein | Hippocampal pyramidal and cerebellar Purkinje cells; diagnostic of rabies encephalitis |
Macroscopic pathology
Disorder | What the naked eye shows |
|---|---|
Alzheimer's disease | Generalised atrophy, worst in hippocampus, entorhinal cortex and amygdala, then parietal association cortex; widened sulci, enlarged temporal horns |
Pick's disease | Sharply bounded knife-edge atrophy of frontal and anterior temporal lobes, sparing posterior superior temporal gyrus, parietal and occipital lobes |
Huntington's disease | Neuronal loss and gliosis in caudate and putamen; caudate atrophy squares off the frontal horns of the lateral ventricles |
Parkinson's disease | Pale substantia nigra from loss of pigmented dopaminergic neurones of the pars compacta; faded locus coeruleus; striatum keeps its bulk |
Thiamine deficiency (Wernicke-Korsakoff) | Petechial haemorrhages in mammillary bodies acutely; shrunken brown mammillary bodies in chronic Korsakoff syndrome; damage around third ventricle, aqueduct and medial thalamus |
Huntington's disease shrinks the striatum, whereas Parkinson's disease loses the substantia nigra and spares striatal bulk.
Open questions about mechanism
Pathology and symptoms diverge: deposits may precede symptoms by years, and synaptic loss tracks impairment more closely than aggregate burden.
Deposits might drive injury, mark toxic soluble oligomers, sequester harmful material or reflect failed clearance.
Braak staging describes recurring anatomical patterns of tau or Lewy pathology, although not every case follows them.
Neither seeded spread through connections nor selective vulnerability of metabolically demanding cells fully explains these patterns alone; a combined account has spread through connections, with injury set by the receiving cells' vulnerability.
Prion disease shows a misfolded protein can transmit its conformation, but "prion-like" spread elsewhere does not imply person-to-person transmission.
Cognitive reserve describes differing clinical expression at the same pathological burden; resistance means avoiding pathology and resilience means tolerating it.
The amyloid cascade is supported by familial genetics and APP gene dose, but challenged by weak plaque-severity correlation, asymptomatic deposition and negative trials.