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Week 4: Dementia and Neuropsychological Assessments, Screenshot 2023-11-21…
Week 4: Dementia and Neuropsychological Assessments
Alzheimer's
Biological Processes
Amyloid-Beta
linked to plagues
protein fragments from amyloid precursor proteins in neurons
Amyloid cascade hypothesis
Impacts on episodic Memory
Neurodegeneration
Neuronal Dysfunction
fMRI studies
disrupts network circuitry in the brain
especially in the DMN => active at rest & suppressed with :arrow_up: cognitive challenge
:arrow_down: ability to control brain networks in response to task demands associated w
episodic memory
effects of amyloid on fMRI BOLD activity in specific regions
Effects
poorer
connectivity
among regions in networks
lower brain activity in brain regions associated with AD
FDG-PET
:arrow_down: metabolic activity in temporoparietal regions usually impaired in AD
metabolic activity indicated by glucose levels utilised for energy
Neuronal Loss
measures
:arrow_down: in hippocampal volume
:arrow_down: in cortical thickness
Tau tangles
amyloid known to induce tau tangles in rats
little known about tau effects in humans due to lack of data on in vivo tau
hypothesised that amyloid induces spread of tau throughout neocortex
tangles in the soma that kill neurons
measured through
CSF from lumbar punctures indirectly
found to be more predictive of cognitive decline than amyloid
possibly PET imaging
:arrow_up: amyloid burden associated with
:arrow_down: cortical thinning
mixed results for :arrow_down: hippocampal volume
Interventions
must occur before tipping point
Drug trials have
99.6%
failure rate
Continuum
:one: Preclinical
:two: Mild Cognitive Impairment (MCI)
:three: Dementia
Model of Preclinical AD
:one: Asymptomatic Amyloidosis
:two: Amyloidosis + Neurodegeneration
:three: Amyloidosis + Neurodegeneration + Subtle cognitive decline
amyloid deposition has passed tipping point & cognitive decline evident
evidence of subtle changes from baseline cognition levels
:arrow_down: performance on more challenging cognitive tests
not meet criteria for MCI
amyloid continues to accrue & detectable neurodegeneration evidence
cortical thinning and hippocampal atrophy on sMRI
neuronal dsyfunction on FDG-PET/fMRI
:arrow_up: tau/p-tau in CSF
amyloid starts to deposit
:arrow_down: amyloid beta in CSF
:arrow_up: PET amyloid tracer retention
Amyloid cascade hypothesis
amyloid as intiating event that begins a cascade of neurodegeneration
leads to cognitive decline and AD
Symptoms
memory loss from damage in mediotemporal regions
entorhinal cortex
hippocampus
memory dysfunction :arrow_right: inability to recognise others :arrow_right: loss of bodily function :arrow_right: death
Vascular Dementia :<3:
Strokes
large stroke enough to cause dementia
Multi-infarct Dementia
infarct :arrow_right: small stroke
dementia caused by multiple smaller strokes
decline
Factors
Risk factors
Age
Sleep
SWS
CSF clears metabolic
positive feedback loop
amyloid accumulation disrupts sleep and more sleep increases amyloid accumulation
Cardiovascular Health
aerobic exercise shown to decrease amyloid accumulation in animal studies
Protective Factors
Neuroplasticity
NUN study
high level of cognitive ??
redundancy in neural connections
too many synapses for Alzheimer's to affect
active life
Diet
Scaffolding Theory of Aging and Cognition
Modifiers
Neural Depletion
APOE ε4 allele
:arrow_up: risk of AD & :arrow_down: age of onset
associated with impaired clearance of soluble amyloid from brain
resulting in :arrow_up: rapid amyloid accumulation and deposition
associated with earlier onset of amyloid positivity & :arrow_up: rate of amyloid deposition across age
Amyloid+ APOE carriers :arrow_up: cognitive decline over 1.5 years than amyloid+ non-carriers, amyloid- carriers & noncarriers.
Age
Autopsy studies
amyloid plaque deposition :arrow_up: with age
Amyloid imaging
age primary risk factor amyloid deposition
most of population is amyloid-negative
from age
60
amyloid deposition high enough for
subpopulation
of amyloid-positive individuals to appear
Lifestyle
:arrow_down: cognitive engagement
associated with :arrow_up: amyloid deposition but
only for APOE ε4 carriers
no effect on non-carriers
:arrow_down: Exercise
no effect on non-carriers
associated with :arrow_up: amyloid but
only for APOE e4 carriers
Uncontrolled hypertension
Significantly :arrow_up: amyloid burden was detected tgt with uncontrolled hypertension in APOE ε4 carriers
no impact on those with controlled hypertension or without hypertension
suggests gene-environment interaction
Neural Enrichment
allow for build-up of
cognitive reserve
that is protective and allows individuals to withstand negative effects of pathology
demonstrated that people with :arrow_down: cognitive reserve had :arrow_down: memory with :arrow_up: amyloid burden
memory in those with :arrow_up: cognitive reserve seemed unaffected by :arrow_up: amyloid burden
education and IQ on American
National Adult Reading Test as measures of cognitive reserve
higher levels of education and sustained engagement in intellectually challenging activities delay the age of onset of AD
Alzheimer’s Association research indicated that delaying AD diagnosis by
5
years would :arrow_down: number of cases by over 40%.
5 more years of independence and vitality valuable to AD sufferers and family
Features
Both models
encompass both normal and pathological aging
Normal decline
modest :arrow_down: in brain structure & function
experience some compensatory scaffolding that help maintain cognitive function
Pathological
Pronounced :arrow_down: in hippocampal volume
:arrow_up: aggregation of amyloid
Strong path from brain structure & function to
rate of cognitive change
Compensatory Scaffolding
build up of lots of cognitive reserves in brain
serves as a buffer for adverse effects off Alzheimer's or vascular dementia
neuroplasticity education
:arrow_up: in neural activity in frontoparietal regions of the brain with age-related structural decline
Evidence that older adults recruit :arrow_up: neural circuitry than younger people for same tasks
both models include pathways that allow changes in brain structure & function to be mitigated by compensatory scaffolding
Biological Aging
Brain structure eg.
dopamine depletion
volumetric shrinkage
white matter lesions
cortical thinning
Brain function eg.
age-related :arrow_down: in hippocampal activity
Dedifferentiation => :arrow_down: specialisation of neuronal activity with age
related to deterioration in brain structure & function
STAC-r
Cognitive function & cognitive change
accounted for through life course approach
both related to brain structure & function
Purpose
integrate structural and functional neuroimaging data with cognitive aging findings
provide relatively complete view of how age-related changes in brain structure & function affect cognition
provide concrete, testable hypotheses
Reasons
findings that healthy older adults
no symptoms of cognitive impairment in life
substantial amyloid deposition in brains during autopsy
25-30% of older adults w normal cognitive function => same amyloid levels as adults with AD symptoms
neural enrichment & CS explain preservation of cognitive function despite :arrow_down: brain structural integrity
Interventions
Psychosocial
Self-guided meditation (
B
)
ineffective for memory or executive functioning
relative to control conditions over 6 months (one lower ROB study) or 6–8 weeks (3 higher ROB studies)
Creative art therapy (
B
)
small effect on global cognition or memory (verbal learning)
relative to usual treatment in 1 study and to socially active control in other study (w MCI)
creative art or art and story-telling groups led by trained therapists delivered over 16–26 weeks
6 months of weekly piano lessons (
C
)
effective at improving executive functioning (w or w/o MCI)
1 high ROB study
In-Home-reminiscence (
C
)
ineffective at improving global cognition
1 high ROB study
Goal-focused or problem-focused interventions (
B
)
setting goals to improve lifestyle, improve mood or address cognitive limitations
ineffective at improving executive functioning or memory scores (w & w/o MCI)
3 higher ROB studies
Lifestyle
Multidomain
6 weeks home-based mental activities & clinician-delivered lifestyle advice (
B
)
ineffective in improving cognition
1 low ROB study
2-year, intensive intervention with dietary, exercise, cognitive training & social components (
B
)
improved cognition with small effect size relative to usual treatment (people w dementia risk)
1 low ROB study
Single
Dietary
Mediterranean-style diets (
D
)
ineffective for cognitive outcomes
2 low (w/o MCI) and 1 high ROB study (w or w/o MCI) over 6–33 months
improvements for global frontal & executive cognitive outcomes w :arrow_down: effect sizes
1 high ROB study over 4 years (w/o MCI)
Exercise
Aerobic exercise programmes (
A
)
for 16 weeks or more at least twice a week with ≥ 70 % adherence to sessions
moderate-sized, positive effect on global cognition relative to control (w or w/o MCI)
2 low % 2 high ROB studies (3x a week in low ROB studies)
Combined cognitive & motor challenges (
A
)
improved memory orglobal cognition by small to moderate effect sizes (MCI)
3 low & 5 high ROB studies
1−3 weekly group interventions lasting six months or more
dance/dumbbell training simulated task exercise
Pharmacological
Lecanemab
small gains of
27%
over
18 months
Small benefit-risk ratio
slows but does not halve progression of the disease
potential risks including death
On 6 Jul 2023 FDA fully approved lecanemab(Leqembi) for very early AD
Not yet approved by SG's HSA but doctors may request to import the drug
Aducanamab
used Centre for Evidence Based Medicine guidelines
Grade A:
consistent evidence from :arrow_down: ROB studies
Grade B:
consistent evidence from :arrow_up: ROB studies
Grade C:
extrapolations from :arrow_up: ROB studies
Grade D:
inconsistent/inconclusive evidence at any level
Risk of Bias
modified Cochrane ROB tool
affirmative answers to asterisked questions
Statistics
SG
WISE study: dementia in Singaporeans over 60 (Subramaniam et al., 2015)
10/66 dementia:
10%
DSM-IV dementia:
4.6%
:arrow_up: risk of dementia associated with
stroke history
homemaker and retired (vs employed)
:arrow_down: education levels (no formal or only primary education)
10/66 has :arrow_up: validity than DSM-IV dementia compared against gold standard
Singapore cost of dementia
Woo, Thompson & Magadi (2017)
Mean informal cost of care:
$44,530.55
Higher than mean formal cost of care:
$25,654.11
:arrow_up: costs with :arrow_up: dementia severity
informal care makes up
63.4%
of costs
ADA and SMU study
1 in 10
people over 60 have AD
1 in 2
people over 85 have AD
over 100,000
diagnosed with dementia
72%
of dementia patients feel rejection and loneliness
56%
worry about being incompetent
Global
Global costs of dementia (WHO)
50%
of costs in informal care
projected to increase from
1.3 trillion USD
(2019) to
2.8 trillion USD
(2030)
Frequency (WHO)
about
10 million
new cases every year
one every 3 seconds
