neurodegeneration and dementia Flashcards
features shared by NDD
progressive - once disease process has begun it continues relentlessly
fatal outcome
associtaed with aging
degeneration of neurones - dysfunction and cell death
many of these diseases are caused by
abnormal accumulation of proteins in the CNS
mostly unknown causes - genetic and environmental factors
common pathological factors
cmmonest in old age
each disease affects specific neuronal groups
clinical features relate to the anatomy and function of the affected areas
atrophy of affected areas with disease progression - seen on imaging or macroscopically at PM
regional pattern of atrophy may be pathognomonic in some cases
microscope appearance of NDD
histopathology shows neuronal loss with variable gliosis
microscopy may show distinctiive cellular inclusions containing specific proteins in either neurones of glial cells eg. NFT, lewy bodies
cortical degenerations
alzhiemer disease
frontotemporal lobar degeneration
dementia with lewy bodies
akinetic movement disorders
parkinsons disease
progressive supranuclear palsy
corticobasal degeneration
multiple ssystem atrophy (striatonigral degeneration)
hyperkinetic syndroms
huntington disease
choreoarthritis
cerebellar ataxis
inherited and sporadic
diseases of motor systems
motor neurone disease
hereditary spastic paraperesis
autonomic disorders
parkinosns disease
multiple system atrophy (shy-drager syndrome)
hippocapmus diseases
congnitive changes, memory, behaviour, language
basal ganglia diseases
movement disorders
hypokinetic
hyperkinetic
cerebellum diseases
ataxia - psinocerebellar ataxia
motor system diseases
weakness, difficulty swallowing, respiration, amyotropic lateral sclerosis
protein accumulation
Ab amyloid - alzhiemers
Tau - pick disease (3 repeat) or others with 4 repeats
alpha-synuclein
TDP-43
polyglutamine repeat expansions - huntington disease
SOD1, TDP-43
prions
dementia
an acquired progressive global impairment of intellect, memory and personality, without impairment of consciousness
the definition of dementia excludes
acute confusional state
impairment of consciousness
delirium or depression
mental impairment due to maldevelopment of the brain or due to a brain insult during development
main causes of demntia
alziemerhs
dementia with lewy bodies
frontotemporal lobar degeneration
vescular pathology
alzheimers disease
progressive and inevitably fatal within 5-15 years
immidiate cause of death often terminal infection eg. pneumonia
3rd most common death in developed world (after vascular disease and cancer)
ealry onset alzheimers
<65 yo
gold standard for alzeimhers diagnossis
post mortem pathology
changes in the brain
reduction in size and atrophy
ventricle increases in size due to decrease volume of white matter
sulci appear expanded and gyri are narrowed
reduced cerebral weight
atrophy of medial temporal lobe
histopathological features of alzheimers
amyloid b-protein accumulation - cortical neuritic plaques and cerebral amyloid angiopathy
tau accumulation - neurofibrillary tangles, plaque - associated dystrophic neurites and neuropil threads
the amyloid hypothesis
abnormal accumulation of amyloid b protein through to play a key role in initiating and perpetuating the neurotoxic events that culminate in dementia (by reduced clearance rather than increased production
released into the ECS where it aggregates to form plaques and accumulates in vessel walls as CAA
genetic risks for alzheimers
ApoE4 allele is the only recognised risk factor
familial form - mutations in presenilin 1 or presenilin 2 leading to early onset alzheimers
trisomy 21 - alzheimers by 35yrs
diagnostic criteria fro AD
ABC score
thal phase - of amyloid plaques (beta-amylloid stain)
braak stage - of neurofibillary tangles (tau AT8 stain)
CERAD stage of neuritic plaques (bielschowsky stain)
frontotemporal lobar degeneration (FTLD)
pathological correlate of FTD
progressive frontal lobe dysfunction that may be followed by temporal lobe symptomatology
behaviour and language problems precede memory problems
onset younger than for alzheimers
FTLD is divided by
divided into several subgroups that are distinguished according to type of protein deposited on immunohistochemistry (Tau, TDP-43, FUS, UPS)
FTLD macroscopic
severe frontotemporal atrophy
variable other findings
pallor of pigmented nuclei in the brainstem in some entities
NDD with clinical features of parkinsonism
several different disease affecting the same circuitries in the network of neurones in the brain can result n similar clinical findings
many of these movement disorders are sassociated with dementia
only able to be distinguished on neuropathological examination
clinical features of parkinosnism
head bent forward tremors of the head mask-like facial expression drooling rigidity stooped posture weight loss tremor akinesia loss of postural reflexes done demineralization shuffling and propulsive gait bradykinesia pill-rolling tremor festinant gait
causes of parkinsonism
parkinsons disease dementia with lewy bodies multiple system atrophy tauopathies trinucleotide repeat diseases symptomatic parkinsomism - toxic eg. carbon monoxide, carbon sulphide, manganese drug induced - butyrophenones, phenotiazines, fluraridine, reserpine vascular parkinonsim
synucleinopathies
alpha-synuclein found to be major component in several cytoplasmic inclusions
protein involved in synaptic transmission
dementia with lewy bodies
2nd most common dementia, 10-25% of cases
fluctuating cognitive impairment, visual hallucinations, parkinsonism
autonomic dysfunction
sleep difficulty - REM sleep behaviour disorder
depression
apathy
DLB = cognitive impairment first, movement later
huntington disorder
AD movement disorder - hyperkinetic degeneration of the striatum relentless progression CAG trinucleotide repeat anticipation
progression of huntington disorder
early cognitive symptoms, mood disorder
progression to severe dementia
death in 15 years on average
the prion hypothesis
PrPc is a normal cellular tranmembrane protein of uncertain function
prion disease is due to an abnormally folded form of the protein (PrPsc) with has a tendancy to aggregate in the ECS and causing spongiform change
creutzfelt jakob disease
most common prion disease
myoclonus and characteristic EEG changes occur late
can be inherited as AD trait, can bbe acquired by tranmission or occur spontaneosly
tranmission of cruetzfelt jakob disease
person to person tansmission requires parenteral innoculation of infected tissue (iatrogenic) - incubation period ranges from years to decades
diagnosis of cruetzfelt jakob disease
requires histology
CJD autopsiess
requires special decontamination procedurres
needs full PPE and self contained breathing devices
CJD histology
microscopic vacuolaton of gray matter - spongiform change
extra cellular accumulation of protease resistant peptide (PrP - prio protein)
neuronal loss and gliosis
