Neurodegenerative Disorders Flashcards
Dementia
Acquired global impairment of intellect, reason and personality without impairment of consciousness. Abnormalities of executive function.
Emotional lability and memory dysfunction are prominent manifestations = implies involvement of cerebral cortex and limbic system
Causes of dementia
Primary neurodegenerative disorders : Alzheimer’s disease, diffuse levy body disease , frontotemporal lobar degeneration , Huntington’s disease
Secondary causes : Cerebrovascular disease ( multi-infarct dementia ) , infection ( CJD/HIV) , drugs/toxins , metabolic disorders , vitamin deficiency ( Wernicke’s Korsakoff syndrome ) , paraneoplastic syndromes ( limbic encephalitis )
Explain Alzheimer’s disease
- Associated with age
- most cases sporadic but genetic predisposition is important because early onset is inheritable recognized with autosomal dominant forms
- Genes identified ; amyloid precursor
protein on chromosome 21, the PS 1 gene on
chromosome 14 and the PS2 gene on chromosome 1. - primary role for Aβ
protein amyloid accumulation, derived from abnormal cleavage of the
normal protein APP, encoded by the APP gene on
chromosome 21 as part of the amyloid cascade pathway.
Where is there predisposition to early onset Alzheimers
e4e4 in the Apo E gene on chromosome
19.
What does the brain show in Alzheimer’s
severe cortical atrophy with narrowing of the gyri and widening of the sulci.
White matter loss is accompanied by
dilatation of the ventricular
system (compensatory hydrocephalus).
What is amyloid
proteins/ glycoproteins that may be deposited in tissues in EC locations
- associated with B pleated sheet conformation
- systemic forms associated with significant medical complications
- localized forms may be incidental or cause significant problems eg accumulation of amyloid in the myocardium and heart failure
What can Amyloid accumulation cause
Heart failure , nephrotic syndrome , organ enlargement ( ex: hepatospenomegaly )
Which amyloid is associated with Alzheimer’s
A-beta amyloid derived from amyloid precursor protein
How does amyloid stain on Congo red staining
salmon pink colour on congo red staining which exhibits apple green birefringence under polarised light
Where else other than Alzheimer’s can amyloid appear
predisposing to spontaneous intracerebral hemorrhage
What is Parkinsonism
Impaired function of dopaminergic neurons projecting from substantia nigra to corpus striatum
What can CO poisoning cause
Parkinsonism
What mutations cause autosomal dominant Parkinson’s disease
Alpha synuclein gene mutations or duplications
What eugenic forms could cause PD
Parkin gene or UCHL1 , genetic changes in LLRK2 kinase or PARK 7 or PINK1
Substantia nigra is shown how in PD
Depigmentation of substantia nigra
Histological findings in PD
Found in the brain stem: substantia nigra - Lewy bodies - Single or multiple rounded cytoplasmic inclusions with dense core and pale halo - Contain aggregates of α synuclein with neurofilaments and ubiqutin
PD vs Lewy body dementia
PD
- Lewy bodies found lower in the brain stem in advance of nigro-striatal involvement, autonomic dysfunction and behavioural disturbances can precede the onset of motor symptoms
• Dementia can develop in idiopathic Parkinson’s disease, attributable to involvement of the cerebral cortex
Lewy body dementia
- Onset of dementia within a year of the onset of motor symptoms or if dementia preceeds the onset of motor symptoms may be termed Lewy body dementia
- Lewy bodies seen in a more widespread distribution including the cerebral cortex and limbic system
- associated with visual hallucinations, problems with confusion/sleepiness that can fluctuate, disturbed sleep, fainting spells, unsteadiness and falls
What is Huntington’s Disease and what is it associated with
Autosomal dominant condition associated with degeneration of corpus the striatum - Associated with movement disorder (choreiform movements) and behavioural changes progressing to dementia and associated with increased risk of suicide in early stages
Severe Lewy body dementia features
- A progressive dementia with prominent deficits in attention, executive function, and visuospatial abilities
- Parkinson-like features (bradykinesia, rigidity, posture, and balance)
- Visual hallucinations
- Spontaneous fluctuations in concentration and attention
- Disturbances in sleep known as REM sleep behavior disorder (i.e., acting out one’s dreams)
Causes of HD and progression
Expansion of CAG trinucleotide repeats that encode hinting tin protein
- causes alleles to have increased number of repeats
- number of repeats associated with earlier onset of disease
- intranucleaur inclusions in neurons will lead to cell death, atrophy of the caudate nucleus and the putamen within the striatum
Where in the Brian does HD affect
Caudate and Putamen in the corpus striatum
What is Chronic Traumatic encephalopathy and what is it associated with
Degenerative brain disease associated with a history of repetitive head impacts ( ex: boxing , football )
- ” punch drunk” syndrome
- associated with cognitive impairment or specific neurological syndromes eg parkinsonism,
- neurobehavioural dysregulation egimpulsivity rage, violent outbursts, emotional lability may also be associated
Finding in brain with CTE ( chronic traumatic encephalopathy )
structural abnormalities of the septum pellucidum
- thinning of the corpus callosum
- degeneration of the substantia nigra
- cerebral cortical neurofibrillary tangles.
What are Prion diseases
Group of
neurodegenerative disease including Creutzfeldt
Jakob disease (CJD) , scrapie in sheep and mad
cow disease
- can be inherited or infected with ( via being exposed to infectious prion agent )
- Agent is an abnormal form of a cellular protein; there is no nucleic acid
Explain physiology of prion disease
abnormal form PrPsc is resistant to proteolysis
and can induce conformational change in the native protein in process of propagation and aggregation
What is CJD ( NEW VARIANT )
Type of Prion disease
- primarily affects young adults
- associated with behavioural changes and slower onset of neurological signs
- new CJD variant linked with exposure to prion disease of cattle ( bovine spongiform encephalopathy ) - eating beef
- spongiform change in cerebral cortex and deep grey matter due to accumulation of abnormal proteinase resistant PrPsc and amyloid plaques
