neurodegenerative diseases

Question 1

Cerebral cortex

Answer 1

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

Internal structure of the cerebral cortes

Question 2

primary and association cortex

Answer 2

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

Question 3

structural organization of the basal ganglia

Answer 3

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)

Question 4

common features of neurodegenerative diseases

Answer 4

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

Question 5

misfolded/ aggregated proteins

Answer 5

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

Question 6

sporadic and familial forms

Answer 6

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,

Question 7

Neurodegenerative diseases etiology and cell mechanisms

Answer 7

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)

Question 8

Free radical formation

Answer 8

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

Question 9

Oxidative stress

Answer 9

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

Question 10

Neurocognitive disorders DSM V

Answer 10

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

Question 11

Dementia

Answer 11

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

Question 12

Minor neurocognitive disorder

Answer 12

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

Question 13

Alzheimers disease

Answer 13

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

Question 14

Alzheimers cognitive domains

Answer 14

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

Question 15

Alzheimers disease Staging

Answer 15

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

Question 16

Probably dementia vs definite dementia

Answer 16

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

Question 17

alzheimers disease senile plaques

Answer 17

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

Question 18

Cerebral amyloid angiopathy

Answer 18

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)

Question 19

Neurofibrillary tangles (NFT)

Answer 19

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

Question 20

Pathological diagnosis of AD

Answer 20

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

Question 21

Inheritanc of alzheimers disease

Answer 21

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

Question 22

Amyloid precursor protein

Answer 22

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

Question 23

Gentic of AD

Answer 23

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)

Question 24

Apo E protein APOE gene

Answer 24

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

Question 25

Cholinergic signaling deficiency

Answer 25

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)

Question 26

Acetylcholine

Answer 26

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

Question 27

Acetylcholine esterase inhibitors

Answer 27

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

Question 28

Memantine

Answer 28

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

Question 29

Frontotemporal degeneration

Answer 29

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

Question 30

Clinical subtypes of FTD

Answer 30

Behavioral Variant 50%- bifrontal lobe atrophy Primary progressive Aphasia Motor predominant- parkinsonism, motor neuron disease

Question 31

Consensus criteria for behavioral variant of frontotemporal degeneration

Answer 31

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

Question 32

Frontotemporal degeneration etiology

Answer 32

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)

Question 33

Frontotemporal lobar degeneration pathology

Answer 33

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

Question 34

Parkinsons disease aka the shaking palsy

Answer 34

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

Question 35

Tremor of parkinsons

Answer 35

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

Question 36

Parkinsons disease genetic

Answer 36

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

Question 37

pd environmental toxins and pesticide

Answer 37

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

Question 38

PD pathology

Answer 38

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

Question 39

Parkinsonism

Answer 39

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

Question 40

Dementia with lewy body

Answer 40

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

Question 41

Lewy bodies

Answer 41

in substantia nigra and cerebral cortex in DLB Alpha synuclein An owels eye

Question 42

Parkinsons pharm

Answer 42

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

Question 43

Basal ganglia cicuitry

Answer 43

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

Question 44

Parkinsons basal ganglia

Answer 44

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

Question 45

Dopamine

Answer 45

Tyrosine (tyrosine hydroxylase, also RLS))--> dopa--> AAdC-> Da Dopamine is broken down by MAO (n and out the cell)

Question 46

L dopa (levodopa)

Answer 46

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

Question 47

Levodopa pharmokinetics

Answer 47

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

Question 48

SE of dopamine

Answer 48

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)

Question 49

Peripheral side effects

Answer 49

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

Question 50

Drug interactions of Levodopa

Answer 50

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

Question 51

neuroleptic malignant syndrome

Answer 51

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

Question 52

Dopamine receptor agonists

Answer 52

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

Question 53

Adverse effects of direct DA agonists

Answer 53

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

Question 54

MAO (a nightmare that is avoided)

Answer 54

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)

Question 55

MAOB inhibitors

Answer 55

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)

Question 56

COMT ihibitors

Answer 56

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

Question 57

antimuscarinics

Answer 57

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

Question 58

Amantadine

Answer 58

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

Question 59

huntingtons diesease

Answer 59

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

Question 60

huntington disease tests

Answer 60

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

Question 61

Huntington dissease mutations

Answer 61

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)

Question 62

HD pathology

Answer 62

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

Question 63

Treatment of huntington

Answer 63

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

Question 64

ALS Amyotrophic lateral sclerosis

Answer 64

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

Question 65

Familial ALS 5-10%

Answer 65

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)

Question 66

Pharmacotherapy of ALS

Answer 66

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)

Question 67

Symptomatic treatemnt of spasticity

Answer 67

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)