neurodegenerative diseases Flashcards
Cerebral cortex
Frontal occipital and temporal , but theres the insula as well that is deep cortex- (basically the cingulate gyrus)
Internal structure of the cerebral cortes
primary and association cortex
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
structural organization of the basal ganglia
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)
common features of neurodegenerative diseases
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
misfolded/ aggregated proteins
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
sporadic and familial forms
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,
Neurodegenerative diseases etiology and cell mechanisms
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)
Free radical formation
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
Oxidative stress
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
Neurocognitive disorders DSM V
Delerium, major neurocognitive disorders (demntia), Monor neurocognitive disorder, mild cognitive imapairment)
Dementia
not made during the course of a delerium
Memory impairment +( Aphasia, apraxia, agnosia, disturbance in execuive functioning ) and Social or occupational function is impaired
Minor neurocognitive disorder
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
Alzheimers disease
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
Alzheimers cognitive domains
Memory (esp short), language, abstract thinking and judgment, visuospatial or perceptual skills, praxis, excutive function
Alzheimers disease Staging
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
Probably dementia vs definite dementia
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
alzheimers disease senile plaques
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
Cerebral amyloid angiopathy
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)
Neurofibrillary tangles (NFT)
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
Pathological diagnosis of AD
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
Inheritanc of alzheimers disease
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
Amyloid precursor protein
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
Gentic of AD
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)
Apo E protein APOE gene
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
Cholinergic signaling deficiency
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)
Acetylcholine
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
Acetylcholine esterase inhibitors
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
Memantine
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
Frontotemporal degeneration
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
Clinical subtypes of FTD
Behavioral Variant 50%- bifrontal lobe atrophy
Primary progressive Aphasia
Motor predominant- parkinsonism, motor neuron disease
Consensus criteria for behavioral variant of frontotemporal degeneration
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
Frontotemporal degeneration etiology
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)
Frontotemporal lobar degeneration pathology
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
Parkinsons disease aka the shaking palsy
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
Tremor of parkinsons
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
Parkinsons disease genetic
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
pd environmental toxins and pesticide
Manganese, CO, rural living (well water), paper mills, hydrocarbons (petroleums, plastics), residential use of pesticides (protective cigarette smoking and caffeine
PD pathology
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
Parkinsonism
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
Dementia with lewy body
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
Lewy bodies
in substantia nigra and cerebral cortex in DLB
Alpha synuclein
An owels eye
Parkinsons pharm
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
Basal ganglia cicuitry
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
Parkinsons basal ganglia
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
Dopamine
Tyrosine (tyrosine hydroxylase, also RLS))–> dopa–> AAdC-> Da
Dopamine is broken down by MAO (n and out the cell)
L dopa (levodopa)
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
Levodopa pharmokinetics
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
SE of dopamine
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)
Peripheral side effects
greatly reduced by carbidopa
GI nausea
CV- hypotension, arryhthmias and HTN
Drug interactions of Levodopa
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
neuroleptic malignant syndrome
Abrupt withdrawal of Levodopa or dopamine agonists, includes confusion, rigidity and hyperthermia
Dopamine receptor agonists
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
Adverse effects of direct DA agonists
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
MAO (a nightmare that is avoided)
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)
MAOB inhibitors
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)
COMT ihibitors
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
antimuscarinics
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
Amantadine
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
huntingtons diesease
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
huntington disease tests
MRI of brain shows caudate atrophy, HTT gene and CAG repeat xpansion >35
Huntington dissease mutations
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)
HD pathology
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
Treatment of huntington
just the treatment not the disease
Fluoxetine for depression, low dose antipsychotic for delusions and paranoid, tetrabenazine (inhibits) VMAT for movement control
ALS Amyotrophic lateral sclerosis
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
Familial ALS 5-10%
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)
Pharmacotherapy of ALS
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)
Symptomatic treatemnt of spasticity
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)
