Neurodegenerative Diseases - Cochran, Franczak, Hillard Flashcards
Alzheimer’s dementia is described in three stages.
What impairments are apt to be seen in Stage I?
What timespan does this generally correspond to?
Impaired learning and remote recall. Some visuospatial impairment. Anomia (language problems), and perhaps depression or delusions.
1-2 years.
Alzheimer’s dementia is described in three stages.
How does Stage II contrast with stage I?
Timespan?
Stage II has worse memory problems as well as visuospatial skills. Delusions become common.
Distinctive: Acalculia.
Alzheimer’s dementia is described in three stages.
What are the hallmarks of late-stage (III) dementia?
Severe cognitive impairment
Urinary/fecal incontinence
Limb rigidity and flexion posture; many are bedridden and die from infection.
Summarize the gross appearance of the brain of a patient with Alzheimer’s disease.
Diffuse gyral atrophy and widening of sulci.
Hydrocephalus ex vacuo–ventricles enlarge as tissue regresses.
Name 3-4 histologic hallmarks of Alzheimer’s disease.
What comprises each finding? (ie composition)
Diffuse plaque - Accumulated Aß protein.
Neuritic plaque - Accumulated Aß protein and tau.
Cerebral amyloid angiopathy - Accumulated Aß protein.
NFTs - Phosphorylated Tau.
Describe the difference between a diffuse plaque and a neuritic plaque in Alzheimer’s disease.
Both are comprised of Aß protein, but neuritic plaques also contain tau.
Neuritic plaques are more closely associated with cognitive decline than diffuse plaque.
Where are plaques generally found in Alzheimer’s disease?
Mostly in the neocortex; initially in association cortices (affects executive & higher-order functions)
Later in the primary cortices.
What is cerebral amyloid angiopathy?
What is it indicative of?
Accumulation of Aß protein around cranial vessels. Can predispose to lobar hemorrhage!
Often associated with Alzheimer’s but may be seen in the absence of clinical disease.
Describe the protein found in NFTs.
What causes it to misfold?
Tau; a microtubule associated protein that seems to be involved in maintaining microtubule stability.
The cause of unfolding is unknown, but it is not due to tau gene mutation.
How is Alzheimer’s disease diagnosed?
Clinically, with exclusion of other possibilities.
Definitive diagnosis only possible with biopsy, usually done post-mortem.
How many cases of Alzheimer’s are due to clear mendelian inheritance?
Contrast these familial ADs with sporadic AD.
1-5%.
Earlier onset (<60-65yrs), with high penetrance, but otherwise identical to late-onset AD in presentation. Autosomal dominant!
Describe how APP contributes to Alzheimer’s pathogenesis.
Why do patients with Down syndrome get AD in their 30s?
APP is a precursor that can be aberrantly cleaved by beta or gamma-secretase to form Aß, which accumulates in plaques, NFTs, amyloid angiopathy etc.
APP is located in chr 21; this can be thought of as a gene dosing effect.
Besides from trisomy 21, what genetic abnormalities comprise the small subset of familial AD?
Presenilin 1 (PSEN1; chr-14) is most common.
Amyloid precursor protein (APP; chr-14) may itself be mutated, but this is rare.
Presenilin 2 (PSEN2; chr-1) is very rare.
What gene can act as a risk factor for AD?
Which alleles are risk increase, or risk reducing?
APOE (on chr-19) encodes Apolipoprotein E. It is unclear how this affects Alzheimer’s, but the E4 allele increases risk (especially if homozygous), while the E2 allele decreases risk.
Since Alzheimer’s involves loss of cortical cholinergic neurons, name 3 treatments that can offset this to treat Alzheimer’s.
What are their mechanisms of action?
What are their side effects?
Donopezil, Rivastigmine, Galantamine.
Centrally active cholinesterase inhibitors.
GI problems, muscle cramping, abnormal dreams, and SLUDGE.
Memantine
Indication?
Mechanism of action?
Side effects?
Memantine
For AD (maybe other neurodegeneratives, too)
Blocks the NMDA channel (reduced excitotoxicity)
Headache, dizziness.
What is the prototypical frontotemporal degeneration?
What subtypes of FTD are there?
Pick’s disease.
Behavioral (involving both frontal lobes) and primary progressive aphasic (further split into PNFA and semantic, involving broca’s and wernicke’s areas?)
Describe the etiology of most FTDs; are they sporadic or inherited?
About half are sporadic.
Familial inheritance has been seen (AutDom) in Tau, progranulin, and C9orf72 (last two increase TDP-43)
What symptoms are seen in the behavioral subtype of FTD?
In the primary progressive aphasic subtypes?
Socially inappropriate behavior; impulsive, careless, without empathy. Sterotyped or ritualistic, possibly with hyperorality.
Generally aphasia of fluency or comprehension (recall the third type of aphasia, repetitive)
There are a couple of pathophysiologies of FTDs.
Describe pathology of FTD resulting from Tauopathies (eg Pick’s disease)
“Knife-edge” frontal & temporal atrophy (spares parietal & occipital lobes), with abundant astrocytosis and round tau inclusions (“Pick bodies”).
There are a couple of pathophysiologies that can cause FTD.
Describe the pathology of TDP-43 accumulation.
Very similar to that of Tauopathies; atrophic frontal & temporal lobes with TDP-43 cytoplasmic inclusions.
What are the classic four signs in Parkinsonism?
Name 2 conditions that can cause Parkinsonism.
TRAP; Tremor (resting, pill-rolling), Rigidity, Akinesia (or bradykinesia), Postural instability. Also mask facies, festinating gait?
There is a long list in the slides, but most important are Parkinson’s disease and Lewy body dementia.
Name the 3 poles and 6 lobes of the cerebral cortex
Name the size layers of (most of) the cerebral cortex from outer-to-inner
Poles: frontal, occipital, and temporal
Lobes: Frontal, parietal, temporal, occipital, insular, and limbic
Layers (outer to inner)
- Molecular
- External granular
- External pyramidal
- Internal granular
- Internal pyramidal
- Multiform
What is the function of the unimodal association cortices? Heteromodal? Give an example of each.
Unimodal: integration of function from a single area (example: Visual association cortex)
Heteromodal: higher order information processing and integration of function from multiple sensory and/or motor modalities (example: prefrontal associated cortex)
Describe Papez’s circuit
Cingulate –> hippocampus –> fornix –> mammillary bodies –> anterior thalamix nucleus –> cingulate
Describe the chief function of each:
Outer core cortical components
- Cingulate cortex
- Orbital frontal lobe
- Temporal lobe (hippocampus, parahippocampus, entorhinal cortex)
Inner core subcortical components
- Hypothalamus
- Amygdala
- Septum pellucidum
Outer core cortical components
- Cingulate cortex - rostral: emotions and motor; caudal: visual spatial and memory
- Orbital frontal lobe - personality, behavioral control, self-awareness
- Temporal lobe (hippocampus, parahippocampus, entorhinal cortex) - memory
Innter core subcortical components
- Hypothalamus - pleasure, autonomic, endocrine integration
- Amygdala - preservation-of-self behaviors
- Septum - preservation-of-species behaviors (sex)
Lesions of which structures lead to defects in declarative memory?
Describe the two major subcategories of declarative memory.
Lesions of: hippocampus, dorsal medial nucleus of the thalamus, and mamillary nuclei
**Episodic: **personal events in one’s life, associated with a time and place
**Semantic: **facts, known rather than actively recalled (the capital of Spain, etc)
Name the brain structure most closely associated with the following types of memory
- Explicit (declarative), including facts and events
- Priming
- Procedural (skills and habits)
- Associative learning and conditioning - emotional responses
- Associative learning and conditioning - skeletal musculature
- Nonassociative learning - habituation and sensitization
- medial temporal lobe
- neocortex
- striatum
- amygdala
- cerebellum
- reflex pathways
“Executive function” is controlled primarily by what lobe?
Primitive emotional responses?
Storage of emotional memories?
Frontal cortex
Hypothalamus
Amygdala and hippocampus
The striatum/neostriatum include what two major structures of the basal ganglia?
The lenticular nuclei include what two major structures of the basal ganglia?
Caudate nucleus and putamen
Putamen and globus pallidus