02 Neurodegeneration & Dementia Flashcards
preventive factors of non-degenerative dementia
- high educational attainment
- healthy lifestyle (no smoking)
- social life
- no depression
- being under 80
- high blood pressure, diabetes and obesity not really associated with dementia
degenerative vs. non-degenerative dementia
- degenerative dementia happens over time, most-common form/cause: Alzheimer’s
- non-degenerative: acute, caused by e.g. stroke, endocrine conditions, metabolic disorders, nutritional deficiencies, toxins
(neurodegenerative) diseases leading to dementia
- Alzheimer’s dementia (55,6%): only few patients have pure Alzheimer’s
- mixed dementia (20%): vascular dementia + neurodegenerative dementia
- vascular dementia (3,3%):
- Parkinson dementia (1,1%): 1/3 of Parkinson patients, closely related to Lewis body dementia (typical feature: hallucinations)
- Fronto-temporal dementia (4,4%): Pick’sche atrophy, early onset, longer patients
- other dementia (15,6%): genetics, trauma, alcohol (Korsakov syndrome), normal-pressure hydrocephalus)
stages of dementia/Alzheimer’s
- preclinical disease: no symptoms, but abnormal biomarkers
- subjective cognitive decline: patients report impairments, but cannot be detected by tests
- mild cognitive impairment: state of cognition and functional ability between normal aging and very mild AD
- clinical disease
dementia - psychometric tests
clock test:
- test visuo-spatial / temporo-parietal function
- 6 steps, suspicion at stage 3 (erhaltene visuell-räumliche Darstellung - geringe kognitive Einbußen)
- hippocampus
- entorhinal cortex responsible, damaged by Alzheimer’s very early on
- patient have memory problems (hippocampus) but also visuo-spatial impairments (entorhinal cortex)
Neuropathology of Alzheimer’s dementia
- hippocampus (memory), entorhinal cortex (orientation) and temporal cortex are shrinking (atrophy)
familial vs. sporadic Alzheimer’s
- familial: numerous mutations on 3 genes responsible, possible to become clinically obvious in 30s, massive metabolic problem
- sporadic: genetic risk factors are minor or unclear, most common form of Alzheimer’s
Amyloid Hypothesis
abnormal metabolism of APP (beta- and gamma-secretase) -> increase in Abeta40 and Abeta42 -> formation of soluble Abeta-oligomers -> amyloid plaques (drop in Abeta1-42) -> neuroinflammation -> increase in pTau -> neurodegeneration
Baptists vs. Taoists
- baptists: Störung Amyloidstoffwechsel -> Amyloidablagerungen -> Inflammation -> neurofibrilläre Tangles
- taoists: Störung des axonalen Transportes -> Störung des Proteinmetabolismus -> Amyloidablagerungen
Evidence Taoists
geordnetes und vorhersagbares Muster der Degeneration, reflektiert Grad der Myelinisierung
Evidence Baptists
- injection of tau protein does not lead to spreading in mouse
- in transgenic mouse model, spreading starts if APP is overexpressed and therefore, amyloid is present
- amyloid is needed for enhanced tau pathology
biomarker model for AD
- Abeta1-42 starts dropping first
- then amyloid plaques increase
- then increase in tau protein (pTau)
- then atrophy starts
- and finally, clinical symptoms arise
genetics of sporadic AD
- APOE most important genetic factor
- worst form e4e4 leads to symptoms alread in 30-40s, 90% chance of getting AD at the age of 90
- 3% of population has this genotypoe
AT(N) system for preclinical AD diagnosis
A = Amyloid pathology, T = tau pathology, N = neurodegeneration
- AD = A+T+N+ or A+T+N-
- Alzheimer’s pathologic change: A+T-N- (risk factor)
- Alzheimer’s and concomitant suspected non Alzheimer’s pathologic change: A+T-N+
Standardized lumbar puncture
- needle size (21G), time (morning, before noon), volume (12ml)
- polypropylene-tubes (prevent adhesion of proteins
- without delay further processing (within 30min)
- freezing of aliquots in -80 degrees fridge
