Dementia
- Degenerative diseases are characterised by;
- Progressive loss of neurones
- Selective pattern of neurone loss
- No clear inciting event resulting in disease onset
- Commonly there is development of degradation resistant protein aggregates – inclusions
- Clinically dementia is the progressive loss of cognitive function independent of the state of attention
- Causes of dementia;
- Alzheimer disease
- Frontotemporal dementia
- Vascular disease (multi-infarct)
- Dementia with Lewy bodies
- Creutzfeldt-Jakob disease
- Neurosyphilis
- Alzheimer disease
DEMENTIA IS NOT A CONSEQUENCE OF
Alzheimer Disease
- Most common cause of dementia in the elderly
- Prevalence is 1% in 60-64 year old, doubles every 5 years
- Accounts for 65% of the dementia in the
UK - Most cases are sporadic but 5-10% are familial
- Pathology occurs in all trisomy 21 patients who live beyond 45
Clinical features
- Progression is slow but relentless
- Symptomatic course runs 10 years
- Initial symptoms are forgetfulness and other memory losses
- With progression there are language deficits, loss of mathematical skills, loss of learned motor skills
- In the final stages patients may be mute, unable to walk and incontinent
- Terminal event for these patients is generally intercurrent illness e.g. pneumonia
Morphology
- Cortical atropy of brain – widening of sulci which is most pronounced in the frontal, temporal and parietal lobes
- Ventricular enlargement secondary to atrophy
- Major microscopic abnormalities are;
- Neuritic (senile) plaques
- Neurofibrillary tangles
- Amyloid angiopathy
- Neuritic (senile) plaques
- Time course of areas undergoing pathological changes;
- Entorhinnal complex
- Hippocampal formation
- Neocortex
- Entorhinnal complex
Neuritic plaques
- Focal, spherical collections of dilated, tortuous dystrophic neurites (a neurite any projection from a neurone cell body), surrounding central amyloid core
- The dominant component of the plaque core is Ab (either Ab40 or Ab42), a peptide derived from APP
- Around the periphery are microglial cells and reactive astrocytes
- Diffuse plaques are amyloid peptide deposits without any surrounding neuritic reaction, they may represent an early stage of plaque formation
Neurofibrillary tangles
- Bundles of filaments in the cytoplasm of the neurones that displace or encircle the nucleus
- Viable as basophilic fibrillary structures with H&E staining but are dramatically visible with silver stain
- Neurofibrillary tangles are insoluable and resistant to clearance in vivo
- A major component of the tangles is abnormally hyperphosphorylated forms of tau
Cerebral amyloid angiopathy
- Almost always found in Alzheimer disease but also found in individuals without Alzheimer disease
- Vascular amyloid is predominantly Ab40
Pathogenesis
- Centred on the properties of Ab
- Ab peptide readily aggregates, forms b-pleated sheets, is resistant to degradation, is inflammatory and neurotoxic
- APP is a protein, the function of which is unclear and which has a single transmembrane domain and is expressed on the cell surface
- Regarding the fate of surface APP;
- It can be cleaved by a-secretase to a soluable form that cant give rise to the Ab fragment
- It can be endocytosed and cleaved by b and g-secretase to generate Ab
- Several genes have been associated with familial Alzheimer disease;
- APP on chromosome 21
- Presenilin-1 on chromosome 14
- Presenilin-2 on chromosome 1
- (presenilins are components of g-secretase)
- ApoE on chromosome 19
Frontotemporal dementias
- Group of disorders with shared clinical features and pathology;
- Progressive deterioration of language
- Changes in personality
- Degeneration and atrophy of frontal and temporal lobes
- Types
- Frontotemporal dementia with Parkinsonism linked to Chromosome 17
- Pick disease
- Progressive supranuclear palsy
- Corticobasal degeneration
- Frontotemporal dementia with Parkinsonism linked to Chromosome 17
Frontotemporal dementia with Parkinsonism linked to chromosome 17
- Frontotemporal dementia accompanied by parkinsonian symptoms
- Linked to chromosome 17 and a variety of mutations in the tau gene
- Morphology
- Evidence of frontal and temporal lobe atrophy
- Atrophy due to neuronal loss and gliosis as well as the presence of tau containing neurofibrillary tangles
- Tangles may contain either 4 repeat tau or a mixture of 3 or 4 repeat tau
- Nigral degeneration may occur
- Inclusions can be found in glial cells in some forms of the disease
- Evidence of frontal and temporal lobe atrophy
Pick disease
- Rare, distinct progressive dementia charcterised clinically by early onset of behavioural and personality disturbances as well as language disorders
- Most cases are sporadic but there have been some familial forms identified linked with tau mutations
- Morphology
- Pronounced frequently asymmetric atrophy of the frontal and temporal lobes with conspicuous sparing of the posterior 2/3 of the superior temporal gyrus and only rare involvement of the occipital and parietal lobes
- Atrophy is more severe than Alzheimer disease reducing gyri to a thin wafer appearance
- There may also be bilateral atrophy of the caudate and putamen
- Neuronal loss is most severe in the outer 3 layers of cortex
- Some of the surviving cells show a characteristic swelling and are called Pick cells
- Some cells contain Pick bodies which are round cytoplasmic filamentous inclusions
- Unlike neurofibrillary tangles of Alzheimer’s Pick cells do not survive the death of the cell and do not remain as markers of disease
- Pronounced frequently asymmetric atrophy of the frontal and temporal lobes with conspicuous sparing of the posterior 2/3 of the superior temporal gyrus and only rare involvement of the occipital and parietal lobes
Progressive supranuclear palsy (PSP)
- Characterised clinically by truncal rigidity, balance disturbance, nuchal dystonia, pseudobulbar palsy, abnormal speech, ocular disturbances (vertical gaze palsy) and mild progressive dementia
- Onset between 5th and 7th decade
- Males twice more commonly affected than females
- Disease fatal 5 to 7 years after onset
- Morphology
- Widespread neuronal loss in the;
- Globus pallidus
- Subthalamic nuclei
- Substantia nigra
- PAG
- Dentate nucleus of cerebellum
- Associated with neurofibrillary tangles and 4 repeat tau
- Widespread neuronal loss in the;
Corticobasal degeneration
- Mostly a disease of the elderly with clinical and neuropathic heterogenicity
- The extrapyramidal signs mean it is also grouped with syndromes of basal ganglia dysfunction
- Morphology
- Cortical atrophy, mainly of motor, premotor and anterior parietal lobes
- In the cortex there is neuronal loss, gliosis and ‘ballooned’ neurones
- Tau-positive processes present (4 repeat)
- Disease is characterised by extrapyramidal rigidity, asymmetric motor disturbances, sensory cortical dysfunction and cognitive decline
- Cortical atrophy, mainly of motor, premotor and anterior parietal lobes
Frontotemporal dementias without tau pathology
- In motor neurone disease there is tau-negative, ubiquitin-positive inclusions found in the superficial cortical area of the temporal and frontal lobe and the dentate gyrus
- This pattern of pathology is called motor neurone disease inclusion dementia
- Other cases show no specific inclusions but rather cortical atrophy with some thalamic gliosis. This pattern of pathology has been termed dementia lacking distinctive histology (DLDH)
Vascular dementia
- Various types of vascular injury can result in dementia
- Vasculitis can result in progressive cognitive decline and improve with treatment
- Accounts for 10% of
UK dementia
Parkinsonism
- Characterised clinically by;
- Diminished facial expression
- Stooped posture
- Slowness of voluntary movement
- Festinating gait (progressive, shortened, accelerated steps)
- Rigidity
- ‘pill-rolling’ tremor
- Dementia
- Due to damage to the nigrostriatal dopaminergic system
- Diminished facial expression
Morphology
- Macroscopically there is pallor of the substantia nigra and locus ceruleus
- Microscopically there is loss of pigmented catecholaminergic neurones in these regions associated with gliosis
- Lewy bodies may be found. These are cytoplasmic eosinophilic round inclusions that often have a dense core surrounded by a pale halo. They are composed of fine filaments of a-synuclein, parkin and ubiquitin
Pathogenesis
- Degeneration of the substantia nigra is associated with a reduction in striatal dopamine content
- Severity of motor syndrome is proportional to the dopamine deficiency
- Some familial cases associated with mutation in a-synuclein, a lipid binding protein associated with synapses
- Mutation is parkin is associated with juvenile onset autosomal recessive PD
- Parkin acts as an E3 ubiquitin ligase with a-synuclein as one of its substrates
- UCH-LI is encoded by another susceptibility locus, it is a deubiquitination enzyme
- Altogether there seems to be a link between altered protein degradation and the disease
Clinical features
- 10-15% of patients with PD develop dementia, with increasing incidence with age
- Features include;
- Fluctuating course
- Hallucinations
- Prominent frontal signs
- Dementia is associated with Lewy bodies in the cerebral cortex and involving the amygdala and brainstem
- Fluctuating course
- There is also a group of patients with cortical Lewy bodies in whom dementia is their primary complaint – dementia with Lewy bodies. The relationship between this and PD is unclear
- Dementia with Lewy bodies accounts for 15% of dementia in the
UK