Neurodegenerative disorders Flashcards
If only one cognitive domain is affected without functional impairment, it is more likely to be _ rather than dementia
If only one cognitive domain is affected without functional impairment, it is more likely to be mild cognitive impairment rather than dementia
Dementia is an acquired, persistent, progressive impairment in intellectual function that affects _ cognitive domain(s)
Dementia is an acquired, persistent, progressive impairment in intellectual function that affects multiple cognitive domain(s)
* One of which is usually memory
* Also see a decline in function
* Interference with work or social life
By definition, neurodegenerative disorders are _
By definition, neurodegenerative disorders are loss of neurological function (dementia, loss of movement control, paralysis) due to loss of neurons
* The most common is Alzheimer disease
* All neuronal death is linked to the deposition of abnormal proteins
Lewy body dementia is often associated with [symptoms]
Lewy body dementia is often associated with visual hallucinations, parkinson-like symptoms
* Tremor, shuffling gait, mask-like facies
CJD is associated with [neuro exam finding] and [neuro exam finding]
CJD is associated with myoclonus and ataxia
Progressive supranuclear palsy is sometimes referred to as _
Progressive supranuclear palsy is sometimes referred to as Parkinson plus
* Postural instability, bradykinesia, oculomotor findings
Supranuclear palsy is distinguished from parkinson disease by the presence of _
Supranuclear palsy is distinguished from parkinson disease by the presence of oculomotor findings (impaired downward gaze, loss of vertical saccades)
* They often fall backwards
Progressive supranuclear palsy is associated with accumulation of [protein] and formation of [structure]
Progressive supranuclear palsy is associated with accumulation of tau and formation of neurofibrillary tangles
* It is another “tauopathy”
The three most important proteinopathies associated with neurodegenerative dementias are:
The three most important proteinopathies associated with neurodegenerative dementias are:
1. Tau
2. Amyloid
3. Alpha synuclein
Alzheimer disease specifically affects [locations]
Alzheimer disease specifically affects cerebral cortex, hippocampus, amygdala
Plaques seen in Alzheimer disease are composed of [protein]
Plaques seen in Alzheimer disease are composed of beta-amyloid
Neurofibrillary tangles seen in Alzheimer disease are composed of [protein]
Neurofibrillary tangles seen in Alzheimer disease are composed of hyperphosphorylated tau
Lewy bodies are composed of [protein]
Lewy bodies are composed of alpha-synuclein
* Seen in Lewy body dementia and Parkinson disease
* “Lew” “Synu”
Diffuse lewy bodies is suggestive of _
Diffuse lewy bodies is suggestive of lewy body dementia
* Parkinson disease has lewy bodies in the basal ganglia
Huntington disease is associated with [protein] and specifically affects [locations]
Huntington disease is associated with mutant huntington protein and specifically affects caudate and putamen
* Intranuclear inclusions with polyglutaminated huntingtin due to CAG repeat expansion
CJD is an issue of [proteins]
CJD is an issue of prions forming amyloid
Diagnosis
Alzheimer disease: neurofibrillary tangles
* Hyperphosphorylated tau protein
Diagnosis
Alzheimer disease: amyloid plaques
Diagnosis
CJD: spongiform change
Ach gets made in [nucleus]
Ach gets made in basal nucleus of meynert
Dopamine is made in [nucleus]
Dopamine is made in ventral tegmentum (and the SNc)
GABA is made in [nucleus]
GABA is made in nucleus accumbens
NE is made in the [nucleus]
NE is made in the locus ceruleus
* In the pons
Serotonin is made in [nucleus]
Serotonin is made in raphe nuclei
* In the medulla, pons
Anxiety is associated with an increase in [NTs] and decrease in [NTs]
Anxiety is associated with an increase in NE and decrease in GABA, Serotonin
Depression is associated with an increase in [NTs] and decrease in [NTs]
Depression is associated with an increase in nothing and decrease in dopamine, NE, serotonin
Schizophrenia is associated with [NT change]
Schizophrenia is associated with increased dopamine
Alzheimer disease is associated with [NT change]
Alzheimer disease is associated with decreased Ach
Huntington disease is associated with an increase in [NTs] and decrease in [NTs]
Huntington disease is associated with an increase in dopamine and decrease in Ach, GABA
Parkinson disease is associated with an increase in [NTs] and decrease in [NTs]
Parkinson disease is associated with an increase in Ach and decrease in dopamine, serotonin
Cognitive fluctuation is a feature of [neurodegenerative disease]
Cognitive fluctuation is a feature of dementia with lewy bodies
Visual hallucination is a feature of [neurodegenerative disease]
Visual hallucination is a feature of dementia with lewy bodies
REM sleep behavior disorder is associated with [neurodegenerative disease]
REM sleep behavior disorder is associated with dementia with lewy bodies
Alzheimer disease may be detectable on MRI by the presence of _
Alzheimer disease may be detectable on MRI by the presence of hippocampal atrophy
* Also see widened sulci, enlarged ventricles, and shrinkage of cortex
Frontotemporal dementia is associated with _ and _ (cell inclusions)
Frontotemporal dementia is associated with Tau and TDP-43 (cell inclusions)
The pattern of atrophy in Alzheimer disease is _
The pattern of atrophy in Alzheimer disease is diffuse and symmetric;
* Seen in frontal, temporal, parietal and usually spares the occipital
Individuals with [chromosomal abnormality] are at an increased risk for Alzheimer
Individuals with down syndrome are at an increased risk for Alzheimer
* Due to third copy of chromosome 21 –> APP gene
* All patients with downs will eventually develop AD
What is APO-E and how is it related to Alzheimer?
APO-E is involved in cholesterol transport to neurons & breakdown of beta-amyloid
_ form of APO-E increases the risk of Alzheimer while _ form decreases risk
E4 form of APO-E increases the risk of Alzheimer while E2 form decreases risk
Alpha secretase/ alpha cleavage results in soluble, nontoxic protein whereas beta secretase/beta cleavage results in _
Alpha secretase/ alpha cleavage results in soluble, nontoxic protein whereas beta secretase/beta cleavage results in insoluble protein –> A-beta deposits
_ is a functional subdivision of the prefrontal cortex that is involved in moedulation of emotional behavior, decision making, and social recognition
Orbitofrontal cortex is a functional subdivision of the prefrontal cortex that is involved in moedulation of emotional behavior, decision making, and social recognition
Grossly, the brain would appear with _ in frontotemporal dementia
Grossly, the brain would appear with asymmetric atrophy of frontal and temporal lobe in frontotemporal dementia
* Note that it tends to be asymmetric (unlike Alzheimer)
* It tends to spare the parietal lobes
Frontotemporal dementia presents with [signs]
Frontotemporal dementia presents with market personality change > memory loss
* Apathy, disinhibition, loss of insight and emotional control
* Global cognitive decline
Frontotemporal dementia involves tau-positive spherical _ cytoplasmic neuronal inclusions called _
Frontotemporal dementia involves tau-positive spherical intracytoplasmic neuronal inclusions called pick bodies
Hereditary frontotemporal dementia (common) tends to be [inheritance]
Hereditary frontotemporal dementia (common) tends to be autosomal dominant
Three types of primary progressive aphasias include:
Three types of primary progressive aphasias include:
* Agrammatic Nonfluent, impaired repetition but preserved naming
* Logopenic Reduced fluency, impaired word retrieval (AD) and impaired repetition
* Semantic fluent speech and repetition but impaired word comprehension (naming)
Progressive supranuclear palsy is caused by _
Progressive supranuclear palsy is caused by midbrain atrophy, “hummingbird sign”
Huntington disease is an autosomal dominant trinucleotide repeat: _
Huntington disease is an autosomal dominant trinucleotide repeat: CAG
Huntington disease involves a repeat expansion in the [gene] on [chromosome]
Huntington disease involves a repeat expansion in the HTT on chromosome 4
* Variable penetrance depending on repeats
* Anticipation results from expansion of CAG
Huntington symptoms usually present around age _ and include _
Huntington symptoms usually present around age 20-50 and include chorea, athetosis, aggression, depression, dementia
In huntington disease we see atrophy of the _ structures with ex vacuo ventriculomegaly
In huntington disease we see atrophy of the caudate and putamen with ex vacuo ventriculomegaly
Neuronal cell death in huntington occurs via NMDA-R binding and _ excitotoxicity
Neuronal cell death in huntington occurs via NMDA-R binding and glutamate excitotoxicity
The clinical hallmark of ALS is _ motor neuron findings
The clinical hallmark of ALS is mixed upper and lower motor neuron findings
* Muscles will undergo denervation atrophy
Degeneration of lower motor neurons in ALS occurs in the _
Degeneration of lower motor neurons in ALS occurs in the anterior horn cells
Degeneration of upper motor neurons in ALS occurs in the _
Degeneration of upper motor neurons in ALS occurs in the corticospinal tract
_ are small eosinophilic intraneuronal inclusions in the remaining lower motor neurons of ALS patients
Bunina bodies are small eosinophilic intraneuronal inclusions in the remaining lower motor neurons of ALS patients
ALS can also affect _ , resulting in bulbar muscle dysfunction (dysphagia, dysarthria, difficulty chewing/breathing)
ALS can also affect motor nuclei in brainstem , resulting in bulbar muscle dysfunction (dysphagia, dysarthria, difficulty chewing/breathing)
ALS will spare the extraocular muscles and _
ALS will spare the extraocular muscles and spincters (no incontence)
Many sporadic and familial cases of ALS involve a mutation in [gene]
Many sporadic and familial cases of ALS involve a mutation in SOD1
Mutations in [gene] is linked to both ALS and FTD
Mutations in C9ORF72 is linked to both ALS and FTD
The pyramidal system involves _ and _ tracts
The pyramidal system involves corticospinal and corticobulbar tracts
The extrapyramidal system involves (4 tracts):
The extrapyramidal system involves (4 tracts):
1. Rubrospinal
2. Tectospinal
3. Reticulospinal
4. Vestibulospinal
Name 5 parts of the basal ganglia:
Name 5 parts of the basal ganglia:
1. Caudate nucleus
2. Putamen
3. Globus pallidus
4. Substantia nigra
5. Subthalamic nucleus
ID the substantia nigra and the subthalamic nucleus
All input to the basal ganglia comes through the _
All input to the basal ganglia comes through the striatum
* Recall that the striatum is caudate + putamen
The [globus pallidus i or e] is the major output from the basal ganglia
The globus pallidus internus is the major output from the basal ganglia
The direct basal ganglia pathway _ movement
The direct basal ganglia pathway facilitates/increases movement
The indirect basal ganglia pathway _ movement
The indirect basal ganglia pathway inhibits movement
The GPi is involved in the (direct/ indirect) pathway
The GPi is involved in the direct pathway
The substantia nigra pars compacta uses _ to project to the striatum
The substantia nigra pars compacta uses dopamine to project to the striatum
The substantia nigra reticulata uses _ to project to the globus pallidus
The substantia nigra reticulata uses GABA to project to the globus pallidus
The subthalamic nucleus uses _ to project to the globus pallidus
The subthalamic nucleus uses glutamate to project to the globus pallidus
The motor symptoms of parkinson disease can be remembered with the mneumonic:
The motor symptoms of parkinson disease can be remembered with the mneumonic: TRAP
* Tremor
* Rigidity
* Akinesia
* Postural instability
Benign essential tremors are characterized by occuring with (rest/action)
Benign essential tremors are characterized by occuring with action
* Includes both postural and intention tremors
* Difficulty with eating, drinking, fine motor tasks
* Worse with emotional distress and relieved by alcohol
Treatment for benign essential tremor is _
Treatment for benign essential tremor is beta-blockers (propranolol)
Cerebellar tremors are coarse and are often worse during _
Cerebellar tremors are coarse and are often worse during end of purposeful movement
Parkinsonism-associated tremor is activated by (rest/action)
Parkinsonism-associated tremor is activated by rest
Differential for conditions that cause chorea:
Differential for conditions that cause chorea:
* Huntington’s
* Parkinson’s meds
* Antipsychotics
* Post-strep infection (sydenham’s chorea)
* Lupus associated
* Chorea gravidarum
Antipsychotic drugs can cause a chorea movement called _
Antipsychotic drugs can cause a chorea movement called tardive dyskinesia
When extension of the wrists causes “flapping” motion we call it _
When extension of the wrists causes “flapping” motion we call it asterixis
* Can be associated with Wilson disease
Restlessness or intense urge to move is called _ ; can be seen as a side effect of Parkinson treatment
Restlessness or intense urge to move is called akathisia; can be seen as a side effect of Parkinson treatment
Slow, snake-like, writhing movements (especially in the fingers) is called _ and is a feature of _ disease
Slow, snake-like, writhing movements (especially in the fingers) is called athetosis and is a feature of Huntington disease
* Suggests issue of basal ganglia
_ are sudden, jerky, purposeless movements
Chorea are sudden, jerky, purposeless movements
* Seen in Huntington
Dystonia is _
Dystonia is sustained, involuntary muscle contractions
* Ex: writher’s cramp, blepharospasm, torticollis
* Treat with botox
Sudden, wild flailing of one side of the body is called _
Sudden, wild flailing of one side of the body is called hemiballismus
* Caused by contralateral subthalamic nucleus lesion (lacunar stroke)
The goal of most parkinson drugs is to _
The goal of most parkinson drugs is to increase or enhance dopamine signaling
Levodopa works as [mechanism of action]
Levodopa works as a precursor of dopamine synthesis
* It does cross the blood brain barrier, which is good because we need dopamine in CNS
The issue with giving levodopa alone is that _ breaks it down in the periphery
The issue with giving levodopa alone is that DDC (DOPA decarboxylase) breaks it down in the periphery
* Side effect is dopamine in periphery = vasoconstriction
Carbidopa mechanism is _
Carbidopa mechanism is blockage of peripheral DDC
* It does not cross the BBB so it cannot block central DDC which is a good thing –> we want conversion to dopamine in CNS
_ is another drug which blocks peripheral degradation of levodopa by blocking COMT
Entacapone is another drug which blocks peripheral degradation of levodopa by blocking COMT
_ and _ are two dopamine agonists sometimes used to treat Parkinson disease
Pramipexole and Ropinirole are two dopamine agonists sometimes used to treat Parkinson disease
_ and _ are two drugs that can be used for Parkinson disease but also alternate treatments for restless leg syndrome
Pramipexole and Ropinirole are two drugs that can be used for Parkinson disease but also alternate treatments for restless leg syndrome
Toxicities of dopamine agonists like pramipexole and ropinirole:
Toxicities of dopamine agonists like pramipexole and ropinirole:
* Inhibits prolactin secretion
* Sleep attacks
* OCD/ICD
_ and _ are selective MAO-B inhibitors that slow the degradation of dopamine (and all other monoamine neurotransmitters)
Selegiline and Rasagiline are selective MAO-B inhibitors that slow the degradation of dopamine (and all other monoamine neurotransmitters)
* They also increase the release of dopamine
Selegiline and Rasagiline are _ type drugs
Selegiline and Rasagiline are MAO-B inhibitors and also increase release
An off-target toxicity of selegiline and rasagiline is _
An off-target toxicity of selegiline and rasagiline is inhibition of MAO-A in the gut –> hypertensive crisis
* This is rare because the drugs are selective for MAO-B
* However, tyramine containing foods can cause hypertensive crisis
Selegiline and rasagiline should not be combined with other [type drugs]
Selegiline and rasagiline should not be combined with other serotonergic drugs
* Can cause serotonin syndrome
All Parkinson drugs can have _ as a side effect due to enhanced signaling via the mesocortical and mesolimbic dopaminergic pathways
All Parkinson drugs can have hallucinations as a side effect due to enhanced signaling via the mesocortical and mesolimbic dopaminergic pathways
Amantadine can be used to treat Parkinson disease; it works by _
Amantadine can be used to treat Parkinson disease; it works by increasing dopamine release and inhibiting reuptake
Benztropine and trihexyphenidyl are two [category of drugs] that help Parkinson’s patients by _
Benztropine and trihexyphenidyl are two anti-cholinergics that help Parkinson’s patients by rebalancing Ach & DA in the basal ganglia
Benztropine and trihexyphenidyl act in the [location] and they only help to improve _ symptoms
Benztropine and trihexyphenidyl act in the striatum and they only help to improve tremor and rigidity
* Does not improve bradykinesia or gait instability
Benztropine and trihexyphenidyl have _ toxicities
Benztropine and trihexyphenidyl have anti-parasympathetic toxicities
“-Benazine” drugs are [drug type] that can be used for Huntington’s
“-Benazine” drugs are vMAT inhibitors that can be used for Huntington’s
* They deplete the DA from vesicles
* Ex: deutetrabenazine & tetrabenazine
_ , _ , and _ are three anti-psychotic drugs that treat Huntington’s by antagonizing dopamine receptors
Aripiprazole , Olanzapine , and Risperidone are three anti-psychotic drugs that treat Huntington’s by antagonizing dopamine receptors
_ , _ , and _ are three AchE inhibitors that improve Alzheimer disease by slowing the breakdown of Ach
Donepezil , Galantamine , and Rivastigmine are three AchE inhibitors that improve Alzheimer disease by slowing the breakdown of Ach
Donepezil , Galantamine , and Rivastigmine are AD drugs that have _ toxicities
Donepezil , Galantamine , and Rivastigmine are AD drugs that have parasympathetic toxicities
Abeta plaques in Alzheimer disease can affect the reuptake of _ , causing an increase in synaptic levels, spilling over into extrasynaptic receptors and causing excitotoxicity
Abeta plaques in Alzheimer disease can affect the reuptake of glutamate , causing an increase in synaptic levels, spilling over into extrasynaptic receptors and causing excitotoxicity
_ is an AD drug that inhibits NMDA receptors in the postsynaptic neuron to prevent glutamate excitotoxicity
Memantine is an AD drug that inhibits NMDA receptors in the postsynaptic neuron to prevent glutamate excitotoxicity
Lecanemab and Aducanumab are two AD drugs that work by _
Lecanemab and Aducanumab are two AD drugs that work by clearing amyloid beta plaques
* However, they do not improve neurofibrillary tangles
_ is an ALS drug that inhibits glutamate excitotoxicity and cell death
Riluzole is an ALS drug that inhibits glutamate excitotoxicity and cell death
Edaravone is an ALS drug with [MoA]
Edaravone is an ALS drug that scavenges O2-radicals
