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1. neuro > neurodegenerative diseases > Flashcards

neurodegenerative diseases Flashcards

1
Q

Cerebral cortex

A

Frontal occipital and temporal , but theres the insula as well that is deep cortex- (basically the cingulate gyrus)

Internal structure of the cerebral cortes

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2
Q

primary and association cortex

A

Primary cortices- somatosensory, motor, visual, and auditory

Association cortices:
Unimodal- concerned with integration of function from a single area
heteromodal- higher order information processing- integration of function from multiple sensory and or motor modalities

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3
Q

structural organization of the basal ganglia

A

caudate- on the edge of the latereal ventricles
Putamen - the lateral bar
Glbus pallidus external and internal are the 2 smaller bars

Putamen+ globus pallidus= lentiform/ lenticular nuclei
Caudate + Putamne= Striatum/ neostriatum
Caudate + GP + Putamen= Corpus striatum

Subthalamic nucleus (luys)- deep to globus pallidus
Substantia nigra- under the subthalamic nuclei: Pars compacta- (SNc- dopaminergic), Pars reticulata ( SNr- Gabaergic)
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4
Q

common features of neurodegenerative diseases

A

Selective vulnerability of specific neurons and systems:
Gray matter diseases- progressive loss of neurons, groups of neurons, associated fiber tracts, usually functionally related (rather than physically contiguous and relatively symmetric
Leading to pregressive decline in nervous system function
Parkinsons disease- extrapyrimidal system, Alzheimers- cerebral cortex (higher order association cortices and limbic system), huntingtons- extrapyrimidal system, amyotrophic lateral sclerosis- pyramidal system

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5
Q

misfolded/ aggregated proteins

A

Common cellular hallmark in many degenerative diseases
Resitistant to normal degradation processes (ubiquitin-proteosome system), often form inclusions- traditionally used to diagnose disease at autopsy
Cytotoxic to neuron wi/o marker of disease presence, distribution of the aggregated protein in brain determines the clinical phenotype
Alheimers disease- amyloid B and tau, Parkinsons disease- alpha synuclein, frontotemporal lobar degeneration- tau, ubiquitin, TDP43, Huntingtons disease- polyglutamine

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6
Q

sporadic and familial forms

A

in many neurodegenerative disesases sporadic forms are more common than familial

Alzheimers disease, parkinsons disease, amyotrophic lateral sclerosis

Exception is huntingtons disease (only an autosomal form is known)
Familial forms of disease: genetic linkage studies,

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7
Q

Neurodegenerative diseases etiology and cell mechanisms

A

Etiology- genetic mutations, genetic polymorphisms (risk factors), aging, environmental toxins

Cellular mechanisms- Oxidative stress and generation of reactive oxygen species, inflammation, activation of innate immune system, disruption of axonal transport and synaptic function, dysfunctional waste clearance, inhibition of Ub-proteosome system and autophag, mitorchondrial dysfunction, programmed cell death (apoptosis)

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8
Q

Free radical formation

A

Can arise from dysfunctional mitochondria, toxins aging lead to loss of mitochondrial function, inefficient mitochondrial electron transport (leaks out) electrons–> oxygen radicals

In particular, complex 1 is vulnerable to injury in response to free radicals
free radicals cause lipid peroxidatio–> loss of membrane integrity

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9
Q

Oxidative stress

A

Hydrogen peroxide and superoxide
Oxygen is easily converted to these reactive molecules by the same enzymes that utilize oxygen as fuel, leaky inefficient

A precipitating factor for both excitotoxicity and mitochondrial dysfunction, also results from both excitotoxicity and mitochondrial dysfunction

Superoxides and excessive glutamate–> persistent activation of NMDA receptors–> Excess intracellular calcium–> ATP depletion and cell death–> excessive glutamate–> loops again

Cells have mechanisms to deal with oxyradicals- Ascorbate, glutathione, superoxide dismutase, catalase (inactivates hydrogen peroxide)

Degenration occurs when the cells either produce too many radicals or lose the ability to detoxify them

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10
Q

Neurocognitive disorders DSM V

A

Delerium, major neurocognitive disorders (demntia), Monor neurocognitive disorder, mild cognitive imapairment)

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11
Q

Dementia

A

not made during the course of a delerium
Memory impairment +( Aphasia, apraxia, agnosia, disturbance in execuive functioning ) and Social or occupational function is impaired

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12
Q

Minor neurocognitive disorder

A

Evidence of modest cognitive decline in one or more domains- Hisory ot cognitive measure

Mild cognitive defects, But no decline in function- common label- mild cognitive impairment MCI

Everyone experieces slight cognitive changes during aging

Preclinical- silent brain changes without measurable symptoms, individual may notice changes but not detectable on tests, a stage where the pt knows but the doctor doesnt

MCI- Cognitive changes are of concern to individual and or family, one or more cognitive domains impaired significantly, preserved activities of daily living

Demenia- Severe enough to interfere with everyday abilities

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13
Q

Alzheimers disease

A

Gradual and progressive decline in cognitive function with impairments in recent memory and one additional cognitive domain that is not due to other medical or psychiatric illness, and results in a functional impairment socially or occupationally

The most common neurodegenerative disease, doubling every 5 years after 65
85yos 50% of people have it, disease duration varies 2-20 yrs

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14
Q

Alzheimers cognitive domains

A

Memory (esp short), language, abstract thinking and judgment, visuospatial or perceptual skills, praxis, excutive function

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15
Q

Alzheimers disease Staging

A 
Stage 1 (years 1-3) Memory- (new learning defective, remote recall midly impaired), Visuospatial skills (topographic disorientation, poor complex construction), language - poor wordlist generation, anomia 
Psychiatric- depression and delusions

Stage 2- years 2-10 (memory recent and remote recall more severly impaired), visuspatial skills poor construction spatial disorientation, calculation acalculia, psychiatric features- delusiosn

Stage 3- intellctual functiona severly impaired, sphinter control (urinary incontinence, motor - limb rigidity and flexion posture

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16
Q

Probably dementia vs definite dementia

A

Clinnically is probable
Definite is alzheimers dementia + biomarkers (AD pathophysiological process)- biomarkers markers increase the certainty that the basis of the clinical dementia syndrome is the AD pathophysiological process
However- the core clinical criteria provide very good diagnostic accuracy
Limited standardization of biomarkers, more research needs to be done, limited access to biomarkers

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17
Q

alzheimers disease senile plaques

A

diffuse plaque- extracellular accumulation of A B protein , normal protein whose function is not yet completely known, comes from amyloid precursor protein
Neuritic plaque- extracellular accumulation of A B protein and tau contianing neurites, More closely associated with cognitive decline than the diffuse plaque, neurites are axons or dendrites

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18
Q

Cerebral amyloid angiopathy

A

Almost always found in alzheimers, occurs in absence of AD also (associated with lobar hemorrhages in ederly)
Congo red stain (stains all types of amyloid)

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19
Q

Neurofibrillary tangles (NFT)

A

Intraneuronal accumulation of an abnormally phosphorylated form of tau, a normal microtubule associated protein, NFTs are not unique to AD also found in other degenerative diseases no evidence of mutation of Tau gene in AD

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20
Q

Pathological diagnosis of AD

A

current criteria utilize (density or neuritic plaques, staging scheme for neurofibrillary tangles), Relationship between NP and NFT not understood

relationship between aging and AD still under investigation, Ag is the the biggest risk factor for AD, Are AD like changes in brain a sign of age or an early manifestation of AD

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21
Q

Inheritanc of alzheimers disease

A

3 patterns
75% are sporadic, 20-25% have a history of affected relatives who develop disease randomly
1-5% prominent family history, usually consistent with autosomal dominant inheritance patter (FAD= familial Ad

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22
Q

Amyloid precursor protein

A

APP is a transmembrane glycoprotein, gene on chromosome 21, normal functions not fully understood, B amyloid, A B, in senile plaques derived from APP

Older individuals with downs syndrome (trisomy 21) develop AD in Late 30s

You dont want just a b, you want a b and y

a secretase cleaves within AB sequence- no AB produced
Cleavage at B and y sites of APP- A B produced, B secretase enzyme, y secretase enzyme unknwon (presenilin proteins

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23
Q

Gentic of AD

A

Presenilin 1 (PSEN1 gene) on chromosome 14, most commonly occurring genetic mutation, explains 50% of familial AD, transmembrane protein (ER and golgi), normal function not definitively known

Amyloid precursor protein APP gene on chromosome 14- rare

Presenilin 2 (PSEN2 gene) on chromosome 1 very rare

Mutations in each of the 3 genes: autosomal dominant inheritance, result in increased depositiion of Ab amyloid protein, result in early AD (<65 yrs age)

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24
Q

Apo E protein APOE gene

A

Established genetic risk factor for late onset AD

3 alleles at gene locus on chr 19: e2,e3, and e4
Code 3 protein isoforms E2 E3 E4, apoE protein involved in cholesterol transport, metabolism and storage, no associated mutations in gene

Presence of e4 modifies genetic risk, dose dependent ( people with one e4 allele have 3x increased risk of AD, 3 e4 allels have approx 15x increased risk of AD, association robus but not specific, presence of e4 not necessary nor sufficient

No consensus about mechanism by which effect occurs, increased AB deposition

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25
Q

Cholinergic signaling deficiency

A

involved in alzheimers disease, dementia with lewy bodies, vascular dementia

Due to atrophy and degeneration of subcortical cholinergic neurons

Anticholinergics can cause confusion

(glutamate, serotonin, neuropeptides also cause issues)

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26
Q

Acetylcholine

A

synthesized from choline and acetyl CoA via choline acyetyltransferase (ChAT), choline uptake is the rate limiting step

Metabolized by acetylcholine esterase (AChE), a very efficient enzyme especially at the neuromuscular junction

Choline is taken back into the synthesizing neuron RLS

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27
Q

Acetylcholine esterase inhibitors

A

3 potent central acting cholinesterase inhibitors are used to treat AD, Donepezil, Rivastigmine, Galantamine

Reversible inhibitors of acetylcholinesterase

Modest improvement, prolongs disease progression

Usually well tolerated but can cause Gi problems, muscle cramping and abnormal dreams

28
Q

Memantine

A

AD like all neurodegeneratice disorders, includes excitotoxicity, oxidative stress an dneuroinflammation

Memantine is an NMDA channel blocker (inhibits the action of glutamate and slows disease progression

29
Q

Frontotemporal degeneration

A

FTD refers to the clinical frontotemporal dementia syndrome

Second most common form of early dementia after AD

causes focal degeneration in the frontal and anterior tporal lobes, frontotemporal degeneration (FTLD) refers to the pathologic entity

30
Q

Clinical subtypes of FTD

A

Behavioral Variant 50%- bifrontal lobe atrophy

Primary progressive Aphasia

Motor predominant- parkinsonism, motor neuron disease

31
Q

Consensus criteria for behavioral variant of frontotemporal degeneration

A

Core diagnostic features- insidious onset and gradual progression, early decline in social interpersonal conduct, early impairment in regulation of personal conduct, early loss of insight

32
Q

Frontotemporal degeneration etiology

A

sporadic- approximately 50%
Familial cases-
Mutations:
Inherited as autosomal dominant, Tau gene (MAPT) results in accumulation of tau (FTLD-tau)
Progranulin (GRN)- results in accumulation of TDP- 43 protein (FTLD-TDP-43)
C9orf72- results in accumulation of TDP43 protein (FTLD TCP 43)

33
Q

Frontotemporal lobar degeneration pathology

A

Gross- frontal and temporal atrophy
Microscopy findings vary by subtype
Tauopathies- accumulation of tau protein (Picks disease- atrophy of fronal and temporal lobes, severe neuronal loss in frontal and temp cortex), pick bodies- round cytoplasmic inclusion in neurons, contain abnormal tau filaments

FTLD-TDP 43- cytoplasmic protein accumulation in frontal/temporal lobes

34
Q

Parkinsons disease aka the shaking palsy

A

Parkinsons disease is the second most common neurodegenerative disorder after AD
Typically PD develops in the fifth and sixth decades, the disease affects 1% of persons over the age of 60 up to 60000 new cases are diagnosed each year, 1 in 40 lifetime risk of having PD

Slight male predominance, age is the strongest factor, positive family history in 6-16% of PD cases

Clinical features- resting tremor, rigidity, bradykinesia (slowness), gait/balance

35
Q

Tremor of parkinsons

A

the most common symptom (present in 70% of pt with parkinsons, its asymmetric and low frequency, pill- rolling type of movements, most often affects the distal upper extremities, chin tremor specific for PD

Supportive criteria: unilateral onset, resting tremor present, progressive disorder, persistent asymmetry, clear and definite response to levodopa, severe levodopa induced chorea, levo dopa response for 5 yrs or more, clinical course of 10 yrs

36
Q

Parkinsons disease genetic

A

Predominantyl sporadic
Familial cases- mutations in 5 genes, involved synaptic function, protein degradation, and mitochondrial function

Parkin gene- chromosome 6, younger onset, 6% of all families screened had mutations

a-synuclein gene- Very rare mutations present in families with auto dom familial PD, a-synuclein subsequently discovered to be a major component of lewy bodies, sporadic PD- no mutation in a-synuclein gene
Linkage between a-synuclein and disease pathogenesis not understood

37
Q

pd environmental toxins and pesticide

A

Manganese, CO, rural living (well water), paper mills, hydrocarbons (petroleums, plastics), residential use of pesticides (protective cigarette smoking and caffeine

38
Q

PD pathology

A

Pallor of substantia nigra
Neuronal loss and Lewy bodies in subtantia nigra
Lewy bodies- eosinophilic cytoplasmic neuronal inclusions, contain alpha- synuclein

red halo and dark spots on the side

39
Q

Parkinsonism

A

Clinical syndrome- rigidity, bradykinesia (slowed movemnts), tremor (usually resting), mask facies, stooped posture, festinating gait (progressively shortened accelerated steps)

Clinical differential diagnosis- Idiopathic parkinsons disease, multiple system atrophy, progressively supranuclear palsy, corticobasal degeneration, intoxication with MPTP, post encephalitic parkinsons disease, dementia with lewy bodies

40
Q

Dementia with lewy body

A

DLB is charachterized by demnetia PLUS Fluctuating cognition of level of consciousness, visueal hallucinations, Parkinsonian motor signs, rem sleep behavior disorder RBD which may precede cognitive decline

41
Q

Lewy bodies

A

in substantia nigra and cerebral cortex in DLB

Alpha synuclein

An owels eye

42
Q

Parkinsons pharm

A

Primarily targeted to restoring the neurotransmission in the circuit that regulates the extrapyramidal system

Among neurogenerative diseases - PD is the most drug responsive, PD is responsive to DBS

43
Q

Basal ganglia cicuitry

A

Subtantia nigra pars compacta- gives off dopamine which to Striatum and that inhibits the Substania nigra pars reticulata and Globus palluidus interna via the direct pathway

SNpr/GPi inhibit the Thalamus (which controls movement via the cerebral cortex)

Indirect pathway is thru the SNpc inhibiting the GPe which inhibits the STN which activates the inhibitor SNpr/GPi

Indirect pathway activates the inhibitor of movement
Direct pathway inhibits the inhibitor –> movment

44
Q

Parkinsons basal ganglia

A

no dopamine coming off the SNpc so you cant inhibit the inhibitor (direct path, movement

And you cant inhibit the activator STN-

Turn off the thalamus and turns off fine movement

45
Q

Dopamine

A

Tyrosine (tyrosine hydroxylase, also RLS))–> dopa–> AAdC-> Da

Dopamine is broken down by MAO (n and out the cell)

46
Q

L dopa (levodopa)

A

Rationale- Restore levels of DA in the basal ganglia,
MOA- uses amino acid transporters to enter the brain, decarboxylated to DA in DA cells, other neurons that express L aromatic amino acid decarboxylase AADC)

At ,most 2% of an oral dose of levodopa gets into the brain, most levodopa is metabolized to dopamine by peripheral AADC in the liver, this is a problem 2 reasons lots of dopamine where you dont want leads to side effects, not enough gets into the brain

The solution–> levodopa is almost always coadministered with carbidopa, an inhibitor of AADC that does not cross the BBB, results in increased dose in the CNS decreased peripheral side effects, levodopa is also increasingly co adminstered with entacapone a COMT inhibitor, COMT is present in the intestine and converts levodopa to 3- O mDOPA

47
Q

Levodopa pharmokinetics

A

half life of levodopa is very short (1-3 hours)
absorption is dependnet upon GI contnets, its taken up by amino acid transporters that can be saturated after a high protein meal

So absorption is delayed by a high protein meal , generally taken several hours prior to eating, entry in the brain is dependnent upon amino acid transporters

Very effective against all of the symtpoms esp bradykinesia,

Early disease beneficial effects outlast half life which suggests that the DA vesicles are filled, effects are sustained and smooth, this buffering capacity is lost as the disease progresses, resulting in wearing off and increasingly brief periods of therapeutic benefit, 2 forms reduce wearing off a sustained release, oral formulation and gel administered thru a gastrostomytume

48
Q

SE of dopamine

A

due to conversion to DA
too much dopa (very tricky to get it just right)

CNS side effects not alleviated by co0administration with carbidopa, dyskinesias- too much movement, dementia, confusion, treat with atypical antipsychotics (clozapine and quetiapine) impulse control disorders (gambling, hypersexuality, compulsive behaviors), need to watch for suicidal thoughts, depression (esp in the elderly)

49
Q

Peripheral side effects

A

greatly reduced by carbidopa
GI nausea
CV- hypotension, arryhthmias and HTN

50
Q

Drug interactions of Levodopa

A

Pyrodoxine (vit B6- increases metabolism of DA in periphery)

Non selective MAO inhibitors (can cause life threatening HTN and Hyperpyrexia, should be discontinued 14 days before starting levo dopa), antipsychotics that are DA receptor antagonists

Contraindications- Glaucoma, psychosis, cardiac disease, malignant melanoma

51
Q

neuroleptic malignant syndrome

A

Abrupt withdrawal of Levodopa or dopamine agonists, includes confusion, rigidity and hyperthermia

52
Q

Dopamine receptor agonists

A

Rational mimic dopamine without need for intact nerve terminals
MOA- agonists of DA receptors in striatum
Advantages ove L- DOPA: no enzymatic conversion is needed, selectivity for receptor subtypes, longer half life, less DA- dependent oxidative stress

Pramipexole and roniperole- selective D2 receptor agonist (D2 and D3 receptors) most commonly used currently
they restore activity in the indirect pathway
Rotigotine- transdermal, less selective (D1 as well as D2)

Apomorphine- high affinity D4 agonist, moderate affinity for D2 3 and 5, used by SubQ for immediate therapy of an off episode

53
Q

Adverse effects of direct DA agonists

A

Nausea and orthostatic hypotension (esp apomorphine, requires Rx but not ondansetron), fatigue and somnolence (problematic for driving)

CNS toxicity- confusion can be worse than levodopa (hence the avoidance of use in elderly pts), dyskinesia is not as bad as L DOPA, impulse control disorders, Gambling, hypersexuality, compulsive behaviors
Need to watch for suicidal thoughts, depression

Apomorphine can cause increase QT prolongation and injection site reaction, abuse liability

54
Q

MAO (a nightmare that is avoided)

A

MAO-B is in the brain

Rationale- MAO inhibition will prolong the action of dopamine
Mechanism- Selective, irreverxible inhibition of MAO-B Drugs - Selegiline, Rasagiline

Can be perscribed early, beneifit is modest, rasagiline in particular is used togeth with levodopa to prolong its effective half life

Antidepressants (increase NE)

55
Q

MAOB inhibitors

A

generally well tolerated in early disease, when coadminstered with levodopa, can exacerbate the adverse effects of levodopa in advanced disease

Selegiline is metabolized to amphetamine and methamphetamine- can cause anxiety and insomnia, reduced when administered as an orally-disintegrating tablet or as a patch (these avoid first pass metabolism)

56
Q

COMT ihibitors

A

Rationale- ComT metabolizes dopamine so its inhibition will prolong the action of dopamine, COMT inhibition also decreases L DOPA metabolism to non-dopamine metabolites

Mechanism- Enzymes inhibitors-
Drugs- Tolcapone- Causes significant hepatotoxicity, limits usefulness), Entacapone

Tolcapone longer half life

57
Q

antimuscarinics

A

Rationale- cholinergic interneurons in the striatum are normally inhibited by dopamine, the loss of dopamine results in overactivity of these excitatory neurons, this is blunted by the anticholinergics

MOA- antagonists of striatal muscarinic receptors - Drugs (triexyphenidyl, benztropine, diphenhydramine antihistamine with anti muscarinic side effects)

Good for tremor, sedation

58
Q

Amantadine

A

Antiviral, increases dopamin release, mild anticholinergic, blocks NMDA receptors

Less effective, short lived benefits
Often given with levodopa or anticholinergics, not useful when levodopa is ineffective

59
Q

huntingtons diesease

A

autosomal dominant, progressive motor, cognitive and behavioral domains
prevalence 4 to 8 per 100000person
symptoms present in the 4th to 5th decade

relentless progression 10-20 yrs

neuropsychiatric symptoms are exhibited in 98% of pts
dysphoria, apathy, irritability, agitation, anxiety most common
over10% of pts with HD have attempted suicide, often misdiagnosis as mental health

60
Q

huntington disease tests

A

MRI of brain shows caudate atrophy, HTT gene and CAG repeat xpansion >35

61
Q

Huntington dissease mutations

A

mutation on huntingtin gene on ch4, expanded trinucleotide repeat in gene (cag) causes structural abnormalities in huntingtin protein. Higher number of repeat associated with early age of onset, Anticipation- earlier age of onset in subsequent generation found when mutated gene passed to offspring from father

Function of huntingtin protein is unknown, hypothesized that gene expansion causes a toxic gain of function in the huntingtin protein, mutation cuases protein aggregation (formation of intranuclear inclusions in basal ganglia, direct pathway to cellular injury is not understood)

62
Q

HD pathology

A

Loss of medium striatal neurons in the caudate and putamen (these modulate motor activity), loss results in increased motor output chorea, neuronal loss in cerebral cortex- cognitive changes
No inhibition of the thalamus

63
Q

Treatment of huntington

A

just the treatment not the disease
Fluoxetine for depression, low dose antipsychotic for delusions and paranoid, tetrabenazine (inhibits) VMAT for movement control

64
Q

ALS Amyotrophic lateral sclerosis

A

Amyotrophic- Muscle atrophy, weakness and fasciculations that signify disease of the LMN
Lateral sclerosis- hardness to palpation of the lateral columns of the spinal cord at autopsy from gliosis of degeneration or the Corticospinal tracts (UMN)

ALS goes everywehre even in head and necks- 3-5 yer survival

MALE 55 almost 90% is sporadic, fTD is a common

65
Q

Familial ALS 5-10%

A

14 genes, AD, SOD 1 gene mutation
TDP 43 accumulations and gene muations are also found in a subset of ALS

Pathology- Anterior motor roots of spinal cord are atrophic, primary motor cortex (CEREBRUM) may show atrophy, reduced numbers of anterior horns cells, loss of corticospinal tract axons and myelin, brainstem motor cranial nerves may be affected (hypoglossal, motor trigeminal)

66
Q

Pharmacotherapy of ALS

A

Riluzole- MOA- inhibitor of NMDA and kainate glutamate receptors, inhibits glutamate release, inhibits sodium channels
Has modest but genuine effects on ALS, increases life span 2-3 months

Edaravone- slows of functional decline (2 weeks on and off)

67
Q

Symptomatic treatemnt of spasticity

A

Baclofen- GABAb receptor agonis, can be administered orally, also can be andministered directly into the intrathecal space with a pump and cathetere- –sedation, but has the risk of producing life threatening CNS depression

TIzanidine- Alpha 2 receptor agonist, likely acts by increasing presynaptic inhibition motor neurons, can cause drowsiness, asthenia, dizziness, Dantrolene is not used (causes weakness)

1. neuro (18 decks)

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