Behavioral Science - dementias (combined lectures) Flashcards
What defines MCI vs normal aging?
MCI must have:
Memory complaint corroborated by an informant
Objective memory impairment for age and education
Preserved general cognition
Normal activities of daily living
Not demented
normal aging:
Difficulty retrieving words and names
Slower processing speed
Difficulty sustaining attention when faced with competing environmental stimuli
Learning something new takes a bigger effort
No functional impairment
DSM criteria for dementia (Neurocognitive Disorder):
1) decline in memory, complex attention, exec function, learning/memory, language, perceptual/motor, social cognition
2) Cognitive deficits must impact social and occupational function
3) Diagnosis must be made in the presence of intact sensory systems
two DSM5 suptypes of neurocognitive disorder
Meets 3 criteria (decline, social/ocupational impact, not due to focal neurological defecit in sensory systems)
MAJOR patient not capable of independent living
MINOR capable of independent living
When does early onset AD present? Late onset?
30 - 60 Yrs of age
>60
Is early onset AD usually sporadic or familial?
familial (older than 60, cases are much more likely to be sporadic)
What are the associated genetic mutations in early onset AD? Genetics (sex linked, autosomal, recessive, dominant)?
1- abnormal presenilin 2
14- abnormal presenilin 1
21- abnormal amyloid precursor protein
Autosomal dominant
What chromosome is APOE4 located on?
19
What is AD? How does it usually present clinically?
The most common cause of senile dementia.
presents with deficits in recent memory, progressing to global impairment of cognition.
What is a hallmark feature of AD suspected to account for clinical symptoms?
Neuronal and synaptic loss affecting cortical and some subcortical areas (e.g. nucleus basalis of Meynert).
Which type of neuron is thought to contribute to loss of cognitive function in AD?
cholanergic neurons
What enzymes is responsible for cleaving APP?
beta and gama secretase
What enzymes is responsible for cleaving APP?
beta and gama secretase
beta secretase is also called BACE1 (Beta-site APP Cleaving Enzyme 1)
A-beta deposits in cortical and leptomeningeal arteries and arterioles - disease?
cerebral amyloid angiopathy
development of abnormal proteinaceous (alpha-synuclein) cytoplasmic inclusions
Lewy bodies
what is Granulovacuolar degeneration (GVD) - what disease?
grainy deposits within neurons surrounded by a clear zone
AD (also lewey body dementia but LBD is often associated with AD hippocampal features)
what is Granulovacuolar degeneration (GVD) - what disease?
grainy deposits within neurons surrounded by a clear zone
AD (also lewey body dementia but LBD is often associated with AD hippocampal features)
Because of association with other dementias GVD and also Hirano bodies are not considered diagnostically important disease features
rapid or acute onset dementia, with especially rapid decline in the first few months - overlapping loss of cognitive and motor function, diffuse alpha-synuclein rich cytoplasmic inclusions throughout the brain (cortex and basal ganglia), sometimes cortical atrophy/ventriculomegaly, loss of Ach and DA neurons (in SN not VTA)
Lewy body dementia
Presinilin (what, where is it?)
component of gamma secretase complex (multimeric transmembrane protein complex responsible for cleaving the membraine associated region of amyloid precursor protein)
forms the catalytic/proteolytic site - mutations of presenlin 2 (chromasome 1) and preseilin 1 (chromasome 4) are involved in familial AD
Presinilin (what, where is it?)
component of gamma secretase complex (multimeric transmembrane protein complex responsible for cleaving the membraine associated region of amyloid precursor protein)
forms the catalytic/proteolytic site - mutations of presenlin 2 (chromasome 1) and preseilin 1 (chromasome 14) are involved in familial AD
1st and 2nd greatest risk factors for AD
Age, APOE4
Which APOE allele is thought to be protective against AD?
APOE 2
dense central core of compact amyloid, surrounded by a clear zone and a peripheral corona or halo consisting of non-compact amyloid and neurites, including axon terminals
neuritic/senile plaque
Apple-green birefringence of what stain under polarized light confirms presence of amyloid.
congo red
stain for neurofibrillary hyperphosphorylated tau tangles
silver
what is Tau? What is it’s function?
microtubule associated protein - stabilizes microtubules
How are neurofibrillary tangles formed?
hyperphosphorilation by microtubule associated kinases result in deassociation with MT fillament, MT depolimerization, and assemblage of hyperphosphorylated tau into paired helical filaments, which bundle to form neurofibrillary tangles
what are neuropil threads?
the dystrophic neurites at the periphery of neuritic plaques - major component is paired helical filaments of hyperphosphorylated tau
What are the gross features of Frontotemporal Lobar Degeneration as seen in frontotemporal dementia?
atrophy in the frontal lobe and temporal lobe of the brain, with sparing of the parietal and occipital lobes.
has so-called knife edge
what are the common accumulation products seen in frontotemporal lobular dengeneration/frontotemporal dementia?
*FTLD-Tau (Numerous tau containing neurons) Most common
*FTLD-TDP (TAR-DNA binding protein 43)
FTLD-FUS and other (less common)
Relative to AD what is the onset profile for FTD?
Earlier onset compared to AD
What are Pick bodies?
What diseases are they associated with?
Where are they seen?
intraneuronal inclusions of Tau
AD and FTD
Dentate gyrus of hippocampus
What are the stages of AD?
asympomatic, podromal (early, possible disease sympotms),
What are early cognitive symptoms of AD?
Trouble keeping appointments
Difficulty finding words
Misplacing objects
What are early functional symptoms?
Difficulty driving
Difficulty selecting clothes
Missing appointments
Problems at work
cognitive retardation from primary depression and dementia differ in that depressed patients usually
1
2
3
Demonstrate less motivation during cognitive testing
Express cognitive complaints that exceed measured deficits
Maintain language and motor skills
What are the indications for neuroimaging in a suspected demented patient?
1
2
3
Focal findings on exam
Rapid onset/decline
Falls, head trauma by history
What are 3 common features seen in both vascular dementia and AD?
Lacunar infarcts,
small vessel disease
white matter
Compared to AD, memory loss in FTD occurs earlier or later in the disease course?
later! (earlier onset in FTD and more rapid progression, but behavioral/emotional changes, not memory impairments, are not the initial clinical findings)
Are cholinesterase inhibitors useful for FTD?
no
What medication can help with behavioral control in FTD patients?
(anticonvulsants) Divalproex or valproic acid
Are SSRIs used for FTD?
yes - for irratability, depression, impulsive behaviors
Can atypical atipsychotics be used?
Yes, carefully
What are the most common pharmacologic treatments for AD?
Cholinergic therapy.
NMDA receptor antagonists
Are current pharmacologic treatments disease modifying based on biomarkers (CSF-Tau Amyoid/FDG-PET?)?
no - for management of cognitive/behavioral symptoms symptoms
Degeneration of ______ results in “Inwide-spread” of acetylchoiline deficiency in AD
the basal nucleus of Meynert
memory deficits in AD are thought to be caused by_____?
Loss of Ach neurons
Which class of agents and which drugs in particular are used to address consequences of degeneration in the basal nucleus of Meynert in AD?
anticholinergic agents
donepezil
rivastigmine
galantamine
What drug is FDA approved for treatment of severe AD?
donepezil
- AChE inhibitor - metabolized by CyP450
- side effects are nausia, vomiting, sleep disturbance
What neurodegenerative disease is memantine used for an why (pathophysiology of neuronal death/ drug MOA)?
AD - because loss of cholanergic neurons and symptoms cascade is thought to be caused by glutamatergic excitotoxicity
thinking is that excess glutamate signaling results in excess Ca 2+ influx into cytoplasm and activation of signalling pathways that lead to increased expression of phosphatases/kinases, which in turn disrupt microtubule stabiizing proteins and form intracellular filament aggregates that alter metabolic function and damage mitochondria triggering apoptosis
memantine is an NMDA receptor antagonist
Can memantine be used alongside donepezil?
yes - combo of AChE blocker + NMDA blocker is most beneficial
which antidepressants are used for AD?
sertraline and venlafaxine
What anxiolytics are used for AD?
buspirone and lorazepam.
what antipsychotics are used for AD?
risperidone and haloperidol
Multi-infarct dementia
diffuse small infarctions that result from small vessel disease and lead to neuronal death and cognitive decline
feature of vascular dementia
what are the common histologic features of vascular dementia?
diffuse lacunar infarcts caused by hypertension related small vessel pathology
white matter pathology
neuronal death
cerebral amyloid angiopathy
What is a leukoencephalopathy? What type of dementia is it commonly associated with?
broad term that describes any disease that affects brain white matter (leuko = white)
common in vascular dementia
What vessel branches are particularly susceptible to hypertensive small vessel pathology?
branchges of lenticulostriate arteries that supply basal ganglia and internal capsule
what form of dementia can result from arteriosclerosis of small arteries?
subcortical dementia
what are features of subcortical dementia
Cognitive slowing.
Impaired problem solving.
Visuospatial abnormalities.
Disturbances of mood and affect
How common is vascular dementia relative to other dementias?
Most common after Alzheimer’s
Progression of vascular dementia is usually _____
Step-wise - but can be abrupt after CVA
what is a common association with vascular dementia?
cardiovascular risk factors - atherosclerosis, hypertension, hyperlipidemia, diabetes
T/F “Mixed” dementia with AD or Lewy Body is not unusual
true
T/F emotional lability (inapropriate ouburst of crying/laughing) is a common feature of subcortical vascular dementia
true
T/F first line pharmacologic treatment for vascular dementia is anticholanergic agents
false! cholinesterase inhibitors are used to increase Ach
donepezil, glalantamine, rivastigmine
T/F exercise (both physical and mental) is useful in treatment of vascular dementia
true
T/F a “Mediterranean” diet is recommended for prevention/treatment of vascular dementia
true
T/F focus of vascular dementia is control of cardiovascular risk factors
true
what primary sporadic diseases are caused by intracellular missaccumulation of pre-synaptic protein alpha-synuclein?
parkinsons disease
lewy body dementia
what is the site of apearance of lewy bodies in lewy body dementia vs parkinsons disease
LBD = cortex Parkinsons = SN
What are the cardinal symptoms are parkinsons disease?
resting tremor, difficulty initiating movement (akinesia), slowed movement (bradykinesia), rigidity, shuffling gait postural instability.
parkinsons disease ever associated with dementia
yes, occasionally (probably underdiagnosed)
Pallor of substantia nigra with degeneration and loss of pigmented dopaminergic neurons of substantia nigra pars compacta (SNpc) that contain eosinophilic inclusions called lewy bodies
what disease?
parkinsons
palor of substantia nigra with degeneration or loss of substantia nigra pars compacta without lewy bodies is seen in what disease?
cortical basal degeneration or progressive cerebral palsy
What are the 2 features necessary for making histologic diagnosis of parkinsons disease?
palor of substantia nigra
with lewy bodies!
what is more common fronto temporal dementia or lewy body dementia?
lewy body dementia (3rd most common)
T/F dual diagnosis of AD and LBD is possible
true
T/F lewy body dementia can be associated with little or no atrophy
true
What is a hallmark and distinctive feature of lewy body dementia?
visual hallucinations with significant cognative fluctuations from day to day
T/F antypsychotic drugs are used to address conitive/behavioral fluctuations in LBD
False! antipsychotics are contraindicated due to increased sensitivity
What drug is used to treat REM sleep disorder in LBD?
clonazepam
what is the diagnostic criterion used to difference between LBD and PD?
uses time frame of appearance of parkinsonian symptoms
Onset of dementia within 12 months of parkinsonism
LBD
Onset of dementia more than 12 months after the diagnosis of PD
PD (w/ dementia)
what is the Mini Mental Status Examination (MMSE)?
Standardized 30 point rating scale that SCREENS (does not diagnose) for dementia
What factors can influence the MMSE results?
age, education, ethnicity
T/F a higher number (1-30) indicates more severe cognitive impairment
False
low numbers are worse
how is the MMSE result categorized?
normal
mild
moderate
severe
MMSE of 20-10
possible moderate dementia
What are early behavioral symptoms?
Subtle changes in personality
Social withdrawal
Depression
MMSE score categorizing possible severe dementia
Cognitively normal person’s MMSE score
30-27
possible mild dementia MMSE score
30-20
T/F MMSE scores can be used to discern the type of dementia
False - only severity
What are the 5 categories of the MMSE?
Orientation Registration Attention and Calculation Recal Language
What is the MoCA?
Montreal cognitive assessment
Standardized 30 point rating scale
Screening tool … NOT a diagnostic tool
Not specific for dementia type
Scoring- can be impacted by age, education, ethnicity
What is different about the MoCA and MMSE
Catagories and scoring
MoCA is more sensitive
What are the catagories of the MoCA?
Misuospatial/executive naming memory attention language abstraction delayed recal orientation (optional)
Is it possible to get a 30 on the MMSE and still have dementia?
yes (mild 30-20) – also test is NOT diagnostic
What is the mini-cog? How is it performed? Interpreted?
stripped down version of MMSE
As Pt. to repeat 3 unrelated words (mushroom cannon flamingo)
then ask them to draw a clock showing a particular time
then ask to repeat words
Interpretation is subjective - if they have some difficulty on either they probably have some degree of cognitive impairment
What is the scoring system on the MoCA?
Normal >26
Mild 18-26
Moderate 10-17
Severe
What is included on the MoCA that is missing from MMSE?
assessment of executive function
How does the MoCA assess working memory?
ask Pt. to repeat reverse number sequences
What categories are functional assessment divided into?
ADLs - activities of daily living
IADLs - instrumental activities of daily living (allow people to engage with their environment and facilitate daily needs)
ADL or IADL?
Dressing Eating Ambulating Toileting Hygiene
ADL
D E A T H
ADL or IADL?
Shopping Housekeeping Accounting Food Preparation Transportation
IADL
S H A F T
