Alzheimer and Neurodegenerative Diseases Flashcards
Alzheimers disease
incidence
Alzheimer’s disease (AD) is the most common type of senile dementia and accounts for 50-60% of all dementias.
Most cases of AD are sporadic (90%) and 10% are familial.
Prevalence increases with age:
People over 65 years of age 10%
People over 85 years of age 50%
Alzheimers disease
Early sx
Difficulty in finding words (dysnomia)
Impaired visuospatial memory (misplace things, not finding their way home)
Impaired recent memory
Delusions, insomnia, depression
Alzheimers disease
Late changes
Increasingly impaired remote memory
Non confluent speech
Agitation, aggression
Alzheimers disease
Final stages
Recent and remote memory obliterated
Mute
Severe rigidity
Alzheimers disease
Clinical course
Relentless progression over 5-10 years
Alzheimers disease
imaging
- MRI:
Marked reduction in brain volume Cortical atrophy, frontal, parietal Ventricular dilatation (hydroceplus ex vacuo) - Positron emission tomography (PET): (fluorodeoxyglucose study) Early changes: impaired glucose utilization in posterior cingulate gyrus and parietal cortex (cf. DLBD: anterior cingulate gyrus).
Alzheimers disease
Differential diagnosis
Multiple infarct dementia: Intermittent step-wise progression. Imaging.
Diffuse Lewy Body Disease: 30% of all dementia. Fluctuation in cognitive function day to day but progressive course. Often associated with extrapyramidal symptoms. PET scan: anterior cingulate gyrus affected
Disorders commonly assoc with AD
a. Down syndrome (trisomy 21): chromosome 21 includes amyloid precursor protein (APP) gene
b. Cerebrovascular disease (2xAD)
c. DLBD (60% incidence of AD)
d. ALS (2 xAD)
e. Idiopathic Parkinson’s disease (PD) (50% incidence of AD)
f. Diabetes (2.5 times higher incidence of AD)
AD
Pathology
How is definitive dx made
Definitive diagnosis of AD is a post-mortem pathological diagnosis.
AD
Key pathological markers
Neurofibrillary tangles: Flame-shaped or globose structures of hyperphosphorylated neurofilament + tau + -amyloid. Found in neuronal cytoplasm: hippocampus, cerebral cortex, basal nucleus of Meynert, amygdala. Ultrastructurally paired-helical filaments.
Senile plaques (neuritic plaques): These evolve from diffuse plaques which consist of focal deposits of -amyloid in the neuropil to primitive plaques which show neurite degeneration to mature plaques with neurite degeneration and a central -amyloid core to finally burnt-out plaques, which consist of an amyloid core only (the previously degenerated neurites have died-back).
AD
Associated pathological changes
AD can be regarded as a progressive dying-back degenerative process which affects at least initially the cholinergic system. Hence the earliest changes are synaptic degeneration which progresses to neurite degeneration to neuronal degeneration.
AD
pathological changes
list
Senile plaques
Neurofibrillary tangles
Hirano-bodies
Granulo-vacuolar degeneration
Congophilic angiopathy
Neuronal loss and gliosis
AD
Hirano-bodies
Crystalloid cytoplasmic inclusions which consist of 10 nm filaments. Seen in hippocampus mainly.
AD
Granulo-vacuolar degeneration
Granulo-vacuolar degeneration: Small vacuoles with dense argyrophilic material in the center, which consist of tau protein. Seen in hippocampus and entorhinal cortex.
AD
Congophilic angiopathy
Congophilic angiopathy: (also called amyloid angiopathy). Deposition of -amyloid in meningeal and intra-parenchymal arteries and arterioles. Seen particularly in occipital and parietal lobes.
AD
Neuronal loss and gliosis
Neuronal loss and gliosis. The ultimate fate of the degenerative dying back process is neuronal loss with gliosis. This is most pronounced in CA1 and subiculum of hippocampus and in entorhinal, temporal and parietal cortices. It also involves key limbic and deep gray structures such as nucleus basalis of Meynert, amygdala, and anterior and dorsomedial thalamus.
Histopathological changes in AD that can also be seen in normal aging
Hirano bodies
Granulo-vacuolar degeneration
Congophilic angiopathy
Neuronal loss and gliosis
AD
Pathologic-clinical correlations
Pathologic changes that correlate most closely with cognitive function
The pathologic changes that correlate most closely with cognitive function are 1) synaptic density, 2) senile plaques; and 3) neurofibrillary tangles, in that order.
AD
Definitive pathologic dx
How is it made
Therefore based on the density of senile plaques, criteria have been set-up for the definitive pathologic diagnosis of AD. These differ with age and are based on evaluation of the four most severely affected areas of the brain (usually entorhinal, parietal and insular cortices and amygdala)
For the positive diagnosis of AD at age 50 years or less, 5 or more senile plaques per x200 field are required; for 50-65 years of age, 8 or more; for 66-75 years, 10 or more; and for individuals older than 75 years, 15 or more senile plaques per x200 field are required.
Pathogenesis of AD
genetics
APP gene is located on chromosome 21. Almost all patients with Down’s Syndrome (who harbor three copies of APP) develop AD pathology at an early age.
Mutations of the APP gene are associated with familial AD.
Mutations or polymorphisms of apoE (chromosome 19); presenilin 1 (chromosome 14); and presenilin 2 (chromosome 1), which induce increased production of amyloid A, have been implicated in AD.
Amyloid Hypothesis Diagram
239
AD therapy
AD is primarily a disorder affecting the cholinergic systems believed to be responsible for several of the cognitive symptoms.
*Several controlled trials have been performed using cholinesterase inhibitors. Meta-analysis of these studies shows a modest beneficial impact on functional outcomes.
*Limited trials using glutamate receptor inhibitors or acetyl-L-
carnitine have shown small effects in patients with early AD.
*Untested therapies: Antioxidants. Cholesterol lowering agents
AD
Therapy
Future developments
Proteins or chaperones are being developed to block to transformation of the physiological conformer of the amyloid-β peptide to the pathological β-sheet conformer, so called “β-sheet breaker peptides”. One such peptide “peptide-X” has shown promising results in rats and mice
Tauopathies
examples
AD Diffuse lewy body disease Transient cerebral ischemia Pick's disease Cortico-basoganglionic degeneration Amyotrophic lateral sclerosis Progressive supranuclear palsy Chromosome 17-linked dementia Multiple system atrophy
