CNS pathology - Neurodegenrative Diseases Flashcards
What is the definition of ND?
‘Types of disease in which neurons &/or glial cells of the central (or peripheral) nervous system cease functioning or die’
What are the general features / symptoms of ND?
Associated symptoms usually first appear at older ages (e.g., after 65 years) & get progressively worse over time, with available treatments providing some (variable) relief but no ultimate cure
Why is the differential diagnosis problematic?
: Symptoms can be quite similar in different diseases, with their definitive diagnosis once reliant on post-mortem examinations of the underlying cellular pathology. New genetic analyses or neuro-imaging methods can now be used to provide such diagnoses in some selected cases or particular disease processes
What are the most common CNS diseases by classification ?
Cognitive Impairment/Dementia
Alzheimer’s Disease*
Lewy Body Disease*
Motor/Movement Impairment Parkinson’s Disease* Huntington’s Chorea Amyotrophic Lateral Sclerosis Friedreich Ataxia
What are the 3 diseases that increase in prevalence with age & are associated with ocular problems ?
Parkinson’s Disease*
Alzheimer’s Disease*
Lewy Body Disease*
What are the causes of CNS ND?
Genetics (rarely primary)
Autosomal dominant, with full penetrance
Huntington’s Chorea; early-onset Alzheimer’s Disease
+ ‘Risk factor’ genes, with incomplete penetrance (susceptibility)
Environmental (more often primary)
But mostly unknown causes = sporadic or idiopathic
Except for Head injury/brain trauma
Dementia Pugilistica (boxers)
Chronic §Traumatic Encephalopathy (footballers)
Alzeihmer disease case :
First described by German psychiatrist & neuroanatomist Alois Alzheimer in 1906.
Case study of early-onset (pre-senile) dementia in a 50-year old woman suffering confusion, spatial dis-orientation, memory loss, paranoid delusions & aggression.
Post-mortem revealed cortical atrophy & 2 characteristic degenerative neuron losses in her brain: amyloid-beta plaques and neurofibrillary tangles
What is the gross neuropathology of AD?(Alzeihmers Disease)
by Brian atrophy
Neuron loss in Cerebral Cortex grey matter leading to reduced gyral thickness tissue& wide sulci + enlarged ventricles general brain atrophy
What is Definitive Cellular Neuropathology of AD (Alzeihmers Disease)
based on ?
ceulluar neuropathology
Deposition of [1] amyloid- (Aβ) protein forming extracellular ‘plaques’ (5-200 m diameter) & [2] toxic clumps intracellular hyperphosphorylated tau protein as ‘neurofibrillary tangles’:
Causes: Neuron cell death by apoptosis
What is the new combined neuroimaging methods for diagnosis of AD invivo?
Temporo-Parieto-Frontal atrophy (blue) in AD associated with selective fluorodeoxyglucose (FDG) hypo-metabolism (green) and amyloid & tau marker deposition in the same areas, with generalized reactive glial inflammatory translocator protein (TSPO) & synapse (SV2A) loss, revealed by protein binding of radiolabelled markers with Positron Emission Tomography (PET)
What re the causes of AD?
Causes: Mainly sporadic/idiopathic, but…
Early-onset, ~10% cases hereditary, autosomal dominant (APP, Presenelin-1 or -2) or risk factor (APOE-e4) genes
What is the prevalence of the AD?
Prevalence: 1 in 15 adults
~1,000,000 cases in UK (200,000 new cases/year)
20% pre-senile, 80% aged 65 years or older
What is the progression of AD?
intellectual functions gradually deteriorate
New/old memory impairment, spatial disorientation
Visual agnosias, paranoid delusions>hallucinations, dysphasias
Immobility, incontinence, apathy, dysphagias
What are the AD genes
Amyloid Precursor Protein (APP): chr 21, autosomal dom’t
APP is trans-membrane, role in neuron growth & repair
But accumulates & extruded as extra-cellular plaques; toxic to neurons
Presenilin (PS) -1 & -2: chr 14 & 1, autosomal dom’t
PS proteins part of gamma secretase enzyme complex, role in
APP clearance, but incomplete digestion; so accumulates and forms
APOE-e4: chr 19, risk factor, 50% AD cases mutation both genes
Apolipoprotein E, like PS, role in the APP clearance, but also in
Packaging cholesterol: Mediterranean diet reduces the risk!
How is AD affect the eye?
cause Cataract: Aβ-protein deposited in lens
Early marker? Prior to dementia, but correlates with brain plaques
affect Retina: extension of the CNS, Aβ-plaques
All cell body layers (ONL, INL, GCL)
RGC degeneration & thinning of NFL, correlating with
Pattern ERG P50 wave: reduced amplitude, increased latency
Inflammatory responses, with microglia reactivity
cause Vascular damage: amyloid angiopathy, Aβ-protein deposited
In retinal blood vessels, reduced circulation
How does the AD affect the retina ?
Aβ-plaques (brown) in all 3 cell layers and deposit in capillary (bv) wall - check slide
Superior & inferior peripheral retinal quadrants most affected (why? unknown) with associated VF deficits (confused with glaucoma)
How does AD affect Visual Dysfunctions?
Also different Neuron susceptibilities to degeneration:
[1] SW/blue cones: tritan colour deficits
[2] Parasol/Magno RGCs: reduced contrast & motion sensitivity
[3] Melanopsin RGCs: circadian disturbances & reduced/slower pupillary light responses
Primary (V1) Visual Cortex rarely atrophic, but
[4] InferoTemporal Cortex: object & face agnosias
[5] Posterior Parietal Cortex: Delayed, slow & inaccurate saccadic and smooth pursuit eye movements + visuo-spatial disorientation
What is Posterior Cortical Atrophy (PCA) ?
PCA may be a relatively rare (prevalence unknown) variant of AD with Aβ plaques & tangles selectively affecting the Occipital Cortex
Whereas……atrophy of the Frontal, Temporal & Parietal lobes is most common in AD, with less Occipital involvement
How does PCA affect AD?
Onset of PCA is typically early (ages 50-65 years). Because neurodegeneration extends into the Occipito-Temporal (LOC, Fusiform Face Area) & Occipito-Posterior Parietal Cortex (PEF, SPL), Px’s typically have more marked visual disturbances – in acuity, visual fields & agnosias with hallucinations, in reading, hand & eye movements - than in AD
What is Lewy Body Dementia (LBD)?
First described in 1912 by Frederich Lewy, a German neurologist working with Alzheimer
Post-mortem brains of patients with dementia, some with amyloid plaques & tau tangles, but also abnormal intracellular inclusions in degenerating neurons = the definitive characteristic of the disease
What are the LBD: Cause, Symptoms & Risks?
10-15% of dementia cases in people aged >65 years
3rd most common after AD & vascular dementia
Widespread brain neuron death by apoptosis
Cognitive impairment, depression, insomnia
Attentional deficits, autonomic dysfunctions
Visual Hallucinations (less than PCA, more than AD)
Lewy bodies = accumulated alpha-synuclein protein
Normally regulates vesicle trafficking & transmitter release
Bodies = toxic clumped misfolded α-synuclein ‘protofibrils’
Cause is unknown/sporadic: male > female prevalence
What is Parkinsons? (Parkinsons disease : PD)
First described in 1817 by James Parkinson, an English surgeon & anthropologist, as the ‘Shaking Palsy’ or paralysis agitans
What are the symptoms of movement disorder ?
Limbs: 4-8 Hz tremor (worse when anxious) rigidity of muscle tone difficulty initiating movement (akinesia) movements slow (bradykinesia) with a shuffling gait Hand: ‘pill-rolling’ action at rest Face: Immobile, expressionless
What is Definitive Neuropathology of PD associated with ?
Apoptotic death of dopamine (& melanin) producing neurons in the substantia nigra (SN) of the basal ganglia (BG) base of midbrain, which normally make excitatory connections with other BG neurons in the caudate & putamen nuclei via nigro-striatal pathways
