Parkinson's Disease - Cortical or Subcortical Dementia?
Subcortical Dementia
Alzheimer's Disease- Cortical or Subcortical Dementia?
Cortical Dementia
Cortical or Subcortical Dementia? :
Predominantly involves memory, language, thinking, and social behavior
Cortical Dementia
Cortical or Subcortical Dementia? :
Psychomotor slowing-- slowness of thinking and movement and emotional changes
Subcortical Dementia
(also "some problem w/ memory")
Top 4 common causes of dementia?
1. Alzheimer's Disease
2. Vascular Dementia
3. Dementia w/ Lewy Body
4. Frontotemporal Dementia
Are most cases of Alzheimer's Disease hereditary or sporadic?
Sporadic
* Apolipoprotein E4 allele = risk factor
(~80% AD patients have one apoE4 allele)
Alzheimer's:
____-onset may be genetic
Early
Established risk factors of Alzheimer's Disease?
- Age
- Family history
- Specific genetic mutations
Possible (not proven):
- Head trauma
- Environmental toxins
1 abnormal cellular mechanism that is a feature of almost all neurodegenerative diseases?
Abnormal protein folding with production of intracellular aggregates or "inclusions" resistant to degradation
2 disorders primarily affecting extrapyramidal system?
Parkinson's & Huntington's
(Other: progressive supranuclear palsy, multiple system atrophy)
3 disorders primarily affecting cerebral cortex?
- Alzheimer's disease
- Lewy body dementia
- Frontotemporal dementias
2 disorders primarily affecting the motor system?
- Amyotrophic lateral sclerosis
- Spinal muscular atrophy
Alzheimer's Disease: Major pathologic feature includes production and deposition of the misfiled proteins ____ & ____
Tau & ? amyloid
Alzheimer's Disease:
~ 0.1% are Early-onset Familial (Aut. Dominant) cases due to mutations in one of 3 genes. What are the 3 genes?
Amyloid precursor protein (APP) & Presenilins 1 and 2
Known gene risk factor in sporadic AD?
Inheritance of the ?4 allele of the apolipoprotein E gene (APOE)
T or F? The gross appearance of the brain in early Alzheimer's disease may be indistinguishable from normal aging.
True
Normal function of Tau protein?
Assembly & stabilization of microtubules
What are neurofibrillary tangles?
Insoluble tau aggregates that form within neurons and their processes in Alzheimer's Disease
Alzheimer's Disease:
Cause of destabilization and disintegration of microtubules? Effect on neurons?
Cause = abnormal (misfolded hyperphosphorylated) tau protein
Effect = dysfunction and loss of synaptic spines and neuronal processes (axons & dendrites)
AD-related protein whose normal functions include primarily:
� Synaptic formation and repair
� Neuronal differentiation
� Repair after neural injury
Amyloid precursor protein
Cause of senile plaques seen in AD?
Beta-Secretase cleavage --> Soluble ?-amyloid oligomers --> insoluble amyloid fibrils which aggregate into plaques
The earliest and most severe neurofibrillary changes in AD involve what system?
The limbic system:
- Medial temporal cortex
- Hippocampus
- Amygdala
Why are Acetylcholine esterase inhibitors (donepezil) used in AD?
Neuronal loss in nucleus basalis ? ? Ach in cortex
T or F? Clinical symptoms in autosomal dominant Alzheimer's disease occur around the time that A? deposition begins to occur.
False.
A? deposition in autosomal dominant Alzheimer's disease occurs years before expected clinical symptoms
Chronic Traumatic Encephalopathy - pathology? (3 things)
- Frontal and temporal atrophy
- Axonal degeneration
- Widespread tau-positive inclusions in neurons & astrocytes
T or F? In CTE, ?-amyloid plaques occur in fewer than half the cases.
True
Is Parkinson's mostly hereditary or sporadic?
90% of cases are sporadic
(mutations in genes including alpha synuclein, parkin, LRRK2, glucocerebrosidase)
2 possible protective factors of Parkinson's disease?
Smoking & Caffeine
Diagnosis? Deposition of aggregates of misfolded alpha synuclein protein (Lewy bodies) in brainstem (esp. Substantia Nigra), DMS nuclei, Autonomic nuclei, cerebral cortex, & Limbic system.
Parkinson's Disease
Gross changes in brain of Parkinson's Disease (3 things)?
- Pallor of substantia nigra and locus ceruleus
- Normal striatum and globus pallidus
- Cerebrum normal or cortical atrophy
Lewy Body Dementia refers to pathology of what 2 neurodegenerative diseases?
- Parkinson's disease dementia
- Dementia with Lewy bodies
T or F? Lewy Body Dementia is a rare neurodegenerative disease.
False - it affects an estimated 1.3 million individuals in US and is the 2nd most common form of degenerative dementia after Alzheimer's disease
T or F? Many patients w/ Lewy Body Dementia also have Alzheimer-type pathology (tangles, plaques).
True
Diagnosis? Hereditary neurodegenerative disorder affecting entire brain with prominent early changes involving neostriatum (caudate nucleus, putamen), cerebral cortex, substantia nigra, hippocampus, cerebellum, thalamus, hypothalamus.
Huntington's Disease
Huntington's Disease genetics?
Autosomal Dominant (HTT gene - 4p16.3)
- Gene encodes protein = huntingtin (htt)
- Mutation ? CAG trinucleotide repeats (polyglutamine region of htt)
- Correlation between number of CAG repeats, occurrence of symptoms and age of disease onset (e.g. 36 or
Diagnosis? Pathophysiology includes loss of inhibitory GABA-ergic striatal neurons ? reduced inhibition by striatum within indirect pathway, overdriving of the subthalamic nucleus, and causing excess activity in thalamocortical circuits
Huntington's Disease
Gross pathology of Huntington's Disease?
Atrophy of caudate nucleus and putamen with enlargement of lateral ventricles
Microscopic pathology of Huntington's Disease?
Loss of small GABA-ergic spiny neurons in striatum - most severe in caudate, less in putamen
(stratal degeneration = clinical severity of disease)
Diagnosis? Progressive age-dependent neurodegenerative disorder characterized by loss of upper and lower motor neurons in the spinal cord and brain
Amyotrophic Lateral Sclerosis
ALS:
Loss of __(UMN or LMN)__ in __(location)__ ? spasticity and hyperreflexia
UMNs (Betz cells) in precentral gyrus
ALS:
Loss of __(UMN or LMN)__ in __(location)__ ? skeletal muscle denervation and atrophy
LMNs in brainstem and spinal cord
ALS prognosis?
Usually fatal in 3-5 yrs.
Is ALS usually hereditary or sporadic?
~ 90% cases are sporadic & 10% are familial
T or F? Vascular dementia is characterized by:
- Subcortical Dementia
- Relatively preserved personality and insight until the later stages of the disease
- Focal deficits may be present on exam
Vascular Dementia
(may coexist with Alzheimer's disease)
In Vascular Dementia, cases caused by a single infarct (as opposed to multiple infarcts) are more common w/ ____-sided stroke involving the ____.
left-sided stroke involving the hippocampus
What is Leukoaraiosis?
Cause of Vascular Dementia.
Diffuse ischemic involvement of subcortical white matter secondary to liphyalinosis of the small vessels
What is Creutzfeldt-Jakob Disease (CJD)?
Related to Bovine spongiform encephalopathy (BSE) or mad cow disease
�
Rapidly progressive dementia, ataxia, and myoclonus
Ddx of Dementia vs. Depression?
Depressed mood, anxiety, sleep, and appetite disturbances more common versus apathy and psychomotor slowing in AD
Delirium - how is it different from Dementia?
Prominent fluctuating deficits of attention and awareness (contrast to dementia), identifiable trigger
Diagnosis:
55-yr old patient presents w/ disinhibition, inappropriate behavior, and trouble expressing himself with some memory impairment.
Frontotemporal Dementia