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Parkinson's Disease (Neurobiological Markers (Basal Forebrain…
Parkinson's Disease
Motor Markers
Positive:
Tremor at rest
Muscular rigidity
Involuntary movements: continual changes in posture, small movements (akathisia), involuntary turns of the head
chorea: irregular, repetitive, jerking movements
dystonia: muscles contract uncontrollably
myoclonus
ballismus
Negative:
postural: disorder of fixation (difficulty maintaining a body part in its normal position in relation to other body parts) eg. person's head may drop forwards, disorder of equilibrium (difficulty standing & sitting unsupported), postural instability, gait issue, reduced adjustments of posture
locomotive: difficulty initiating stepping (they shuffle with short footsteps)
Bradykinesia: slowness of movement
Akinesia: blank facial expression, lack of blinking, sitting motionless
speech disturbance: almost complete absence of tone in speaker's voice
Cognitive Markers (heterogenous cognitive profiles) -> before motor features
ca. 30 % of PD patients have dementia (up to 80% of PD patients will eventually develop dementia according to longitudinal studies)
fatigue
early changes: reduced attention, executive dysfunction eg. working memory, set shifting, planning, slowed processing speed, alterations in visuospatial functioning (search & organization) -> mental flexibility is lacking (seen on Tower of London, WCST)
as PDD progresses, memory deficits in recall, encoding & retrieval (resembling AD)
MCI as transitional stage (17-30% of PD patients)
language functions quite preserved (if not, then related to semantic & phonemic fluency)
Psychological Markers
mood disorders, apathy --> leading to reduced motivation
sleep disturbance (up to 80%): REM sleep behavior disorder
psychosis ie. hallucinations & delusions
distress, decreased Quality of Life
impoverishment of feeling: they may sit for hours lacking the will to continue any activity
Depression affects 30-60% of PDD & DLB
affects cognition, contributes to a more rapid cognitive decline
associated wth increased mortality
worsens motor functioning
ca. 90% of PDD patients experience at least one neuropsychiatric feature & 75% have two or more
Neurobiological Markers
Basal Forebrain cholinergic neurons: cel loss, attention & executive deficits
Substantia Nigra loses its pigmentation (less dark)
Pontine Serotonergic neurons: linked to depression in PD, my contribute to REM sleep behavior disorder
degenerating neurons contain Lewy Bodies: alpha-synuclein is a protein that is not cleared normally from the neurons 7 it clumps together inside the neurons to form Lewy Bodies -> abnormal accumulation of alpha-synuclein
Olfactory DA neurons: olfactory transmission is inhibited by DA
also amyloid & tau contribute to pathology eg. amyloid plaque deposition in the striatum in DLB
Retinal DA neurons: visual impairment eg. color perception, contrast sensitivity
Midbrain/nigral DA neurons: motor deficits
Lewy Body pathology begins in the Autonomic NS, then extends to the brainstem (mood issues), limbic system (memory issue & psychotic symptoms) & finally the neocortex (dementia)
relevant loops: dorsal -> motor (putamen, SMA), spatial (caudate, dlPFC, PPC)
visual & affective loops maybe affected in the latest progression stages
gradient of dopamine depletion: greatest in dorsal striatum & weakest in ventral striatum
CSF biomarkers don't yield conclusive results: not sure if higher or lower alpha-synuclein levels
cholinergic deficits in temporal cortex: visual hallucinations
atrophy in GM & WM (more for DLB than for PDD): atrophy of the hippocampus & parietal-temporal cortex associated with cognitive performance & predicts decline in non-demented patients on 2-year follow-up
Hypometabolism in frontal & parietal regions: executive changes & visuospatial deficits (early metabolic changes in visual & posterior cingulate cortices are predictive of dementia in PD)
Neurotransmitter systems overall:
frontostriatal DA dysfunction mediates the dysexecutive syndrome in MCI of early PD
noradrenergic dysfunction underlies the attentional set shifting deficit
frontal cholinergic deficit compromises early PD cognition, especially visuospatial & mnemnonic deficits
cholinergic modulation probably has a key role in the progression to PDD
Progression from healthy to PDD
1) Healthy
2) cognitive issues/ MCI (can occur at all stages until PDD occurs): attention, planning, set shifting
3) PD: motor issues eg. bradykinesia, rigidity, tremor at rest (cognition not relevant)
neurobiology: hippocampal atrophy, gray & white matter atrophy
4) DLB & PDD: neuropsychiatric features, sleep disturbance, psychosis
rating scales & research focused predominantly on movement symptoms: from mild symptoms occurring at one side of the body to stiffness leading to impossibility to walk
possible causes of Parkinsonism
postencephalic form: unique patterns brain damage, viral cause most probable
drug-induced PD: especially when ingesting tranquilizers, symptoms are reversible
idiopathic PD: cause is unknown, maybe familial or viral
Treatment
Pharmacological treatment has two objectives:
increase the activity in dopamine synapses
suppress the activity in structures that show heightened activity in the absence of adequate DA action
L-Dopa enhances DA transmission
no cure exists: it is still unknown what are the factors that produce the progressive deterioration of Substantia Nigra-> treatment is symptomatic & directed toward support & comfort
Anticholinergics block the cholinergic activating systems that show heightened activity in the absence of adequate DA activity
Deep Brain Stimulation
What are the side effects/differential effects of PD treatment?
DA-replacement medication improves processes that implicate substantia nigra-innervated dorsal striatum BUT it impairs processes that depend upon VTA-supplied ventral striatum --> motor symptoms are improved but some cognitive functions are hindered ( reward processing & learning)
beneficial effects of DA medication on planning, spatial working memory but not on visual recognition memory or set shifting
detrimental effects on probabilistic reversal learning following L-Dopa medication but improvements in task switching
Gambling task: L-Dopa led to increased, impulsive, delay-aversive behavior
psychotic symptoms are often worsened by DA medication in DLB
DA medication can cause overall increase in tonic DA but it masks phasic DA dips evoked by error-correcting feedback
reduction in reward sensitivity after medication
risk factors for dementia in PD
older age, disease severity, non-tremor predominant parkinsonian symptoms, later age of PD onset, longer duration of symptoms, MCI, visual hallucinations, olfactory dysfunction, depression, family history of dementia
Why would we want to conduct a cognitive assessment in PD?
Differentiate between PDD & DLB
DLB:
more deficits in memory than PDD
more deficits in visuospatial functions & to lesser degree attention, executive functions eg. verbal fluency
more conceptualixation deficits & fluctuations in EF, arousal, attention
more anxiety (65%)
hallucinations & delusions (76% & 57% respectively)
higher amyloid plaque deposition in the striatum
more frequent alpa-synuclein in hippocampus area CA2 & CA3
less marked cell loss in substantia nigra
lack of D2 receptor upregulation in striatum
more atrophy in GM & WM
PDD: always motor symptoms present (we need a well-established PD)
difficult to differentiate on the basis of NP tests
usually differentiation on the temporal basis:
PDD has an established temporal sequence: MCI -> PD -> PDD
in DLB motor symptoms may come after cognitive symptoms
What are the best predictors of cognitive decline in PD patients based on MMSE?
Pentagon copying (involving motor & spatial loop)
Semantic Verbal Fluency (involving spatial/executive loop)
Dual Syndrome Hypothesis
PD:
tremor-dominant phenotype
deficit on tests of planning, WM, EF
reflecting fronto-striatal dysfunction
could be improved with DA medication
PDD:
akinetic subgroup
gait disturbance
early deficits in visuospatial function & semantic fluency
posterior cortical & temporal lobe dysfunction
rapid cognitive decline to dementia
cholinergic treatment might be beneficial
to understand the heterogeneity of cognitive impairment in PD