Neurodegenerative disorders and Drugs for ALS

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  1. Neurodegenerative disorders
    general principles
    • -Diffuse; but not always symmetric (Parkinsonism, ALS)
    • -Chronic (progressive) over many years; onset is typically insidious... occurs after long period of normal nervous system function. Latent period, degeneration is occuring without symptoms
    • -Irreversible degeneration
    • -No treatments that slow or reverse the progression of the disease
    • -Little cellular response or tissue reaction (gliosis)
    • -CSF is typically normal
    • -leads to cell death (apoptosis, aggregations of nl or abnormal proteins) and loss of tissue, which can lead to atrophy
    • -...
    • -Some are from unstable nucleotide repeats
    • -Threshold that leads to an impairment of gene function and the clinical disorder
    • -anticipation (earlier onset in affected offspring)
    • -Potentiation (worsening of disease in affected offspring
    • -coding region repeat (Huntington's disease) tend to have neurodegenerative disorder that starts midlife; polyglutamine expansion leads to toxic gain of function
    • -Noncoding regions (myotonic dystrophy and fragile X syndrome) result in decreased protein synthesis and a loss of function; typically involve multiple systems
    • -...
    • -Hereditary degenerative polyneuropathies
    • onset and progression varry
  2. Alzheimer's disease
    presentation, epidemiology
    Gradually worsening dementia over years, with preservation of sensory and motor function

    Onset: insidious, slow progression

    • Presentation: Most pts begin with the basic amnesia syndrome which can progress to anomia, impairment of visuospatial skills, and executive dysfunction.
    • -Neuropsychiatric features include depression, delusions, hallucinations
    • -Mortality is most often due to medical illness (average is 8.5 years post onset of forgetfullness)
    • -Common disorder; atypical presentations are often seen

    • Epidemiology: Age is the only major risk factor
    • -1% of 65 year olds; Incidence doubles every 5 years thereafter!
    • -32% of 90 year olds have Alzheimer's

    • *Risk factor within age groups:
    • Apolipoprotein E genotype modifies the likelihood of older individual developing Alzheimer's
    • -more ε4 alleles increase a persons risk; ε2 is protective
    • -Head trauma, female sex, low education
    • -All pts with Down's syndrome will develop Alzheimer's during 40s-50s

    There is atosomal dominant Alzheimer's (early onset); but less than 1% of pts wtih Alzheimer's have this form
  3. Alzheimer's
    • Pathology: required for dx: shows gross atrophy that is most severe in the cerebral higher cortex (especially medial temporal lobe structures important for memory)
    • -Microscopic: neuronal loss, gliosis, abnormal neuritic plaques and neurofibrillary tangles

    • 1. Cerebral atrophy: narrowing of gyri, enlargement of sulci
    • -"hydrocephalus" ex vacuo

    2. Neuronal loss and gliosis are present

    • 3. Neuritic plaques: focal, spherical collections of dystrophic neuritic processes often surrounding a central core of amyloid
    • -Proteins of amyloid core are Aβ40 and Aβ42
    • - Plaques seen first in the association neocortex and later are found in the hippocampus
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    • 4. Neurofibrillary tangles: bundles of filaments in the cytoplasm of the neurons that displace or encircle the nucleus. "flame shaped", easy to see in silver stain
    • -Tangles are seen first in the entorhinal cortex, then in the hippocampus, then in the temporal and other neocortex; amygdala, basal forebrain, median raphe nuclei
    • -tangles contain paired helical filaments
    • -abnormally hyperphosphorylated forms of the protein tau
    • -Filaments also contain the microtubule associated protein MAP2 and ubiquitin

    Tangles are not specific for Alzheimer's disease
  4. Alzheimer's
    • Pathophysiology: deposition of Aβ peptides that result from the abnormal processing of the amyloid precursor protein (APP)
    • -APP has an unknown function

    Image Upload

    inflammatory response to the aggregates of amyloid. may contribute to the abnormal tau phosphorylation and oxidative injury to neurons
  5. Alzheimer's
    evaluation and treatment
    • Evaluation: Dx is made on history and exam
    • -neuroimaging may not show atrophy
    • -some lab tests may be ordered to r/o other conditions
    • -No good biomarkers

    • Treatment:
    • Non-pharmacologic therapy remains the mainstay of therapy
    • -education, continue activity for as long as possible, outpatient care for as long as possible, stop driving

    • Pharmacologic therapy: not very effective
    • -Cholinesterase inhibitors - efficacy is equal
    • 1. Donepezil - also approved for severe Alzheimer's (not just mild-moderate...)
    • 2. Galantamine
    • 3. Rivastigmine (patch available)

    AEs: nausea, diarrhea

    -Memantine  - low affinity NMDA receptor antagonist (approved for moderate to severe Alzheimer's disease)
  6. Fronto-temporal lobar degenerations
    Heterogeneous group of neurodegenerative disorders

    Onset: 40s-50s (younger than those with Alzheimer's); chronic, progressive abnormalities of "frontal lobe syndrome"

    -Some progressive behavioral disorder, or progressive aphasia

    • Pick's disease: well defined form of fronto-temporal lobar degeneration
    • -typically asymmetrical cortical atrophy in the frontal and anterior portions of the temporal lobe

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  7. Parkinson's disease
    idiopathic Parkinson's disease 

    Presentation, epidemiology, pathology
    Gradually worsening motor dysfunction, often with additional autonomic, cognitive neuropsychiatric or additional abnormalities

    • Presentation:
    • 1. Onset: 45 to 70 years (peak in the 60s)

    2. Motor dysfunction (asymmetric) that includes hyper- (tremor) and hypokinetic (bradykinesia, akinesia, rigidity, postural instability and decreased associated movements)

    • 3. Initial symptoms:
    • -Tremor 70%
    • -Gait disturbance 11%
    • -Stiffness 10%
    • -Slowness 10%
    • -Muscle aches 8%
    • ...
    • -Depression, nervousness, other psych disturbances 4%

    4. Autonomic dysfunction: constipation, seborrhea, excessive sweating, orthostatic hypotension

    5. Cognitive and neuropsychiatric dysfunction and depression. Dementia may be present in ~15% of patients, but increases with age

    6. REM sleep behavior disorder may occur before the motor manifestations

    7. Variable course - most have significant motor disability within 10 years

    • Epidemiology:
    • -1% of 65 year olds; 3% of 85 year olds (not exponential like Alzheimer's)
    • -Whites > Asians, blacks
    • -Familial Parkinson's disease is rare
    • -Almost always sporadic
    • -Environmental risk factors: pesticides
    • -Nicotine and caffeine may offer a very small degree of protection

    • Pathology:
    • -Pallor of the substantia nigra and of the locus ceruleus (locus ceruleus is in the ponto-midbrain junction; NE projection system)
    • -Surviving pigmented neurons may contain  Lewy bodies (eosinophilic core with clear halo)
    • alpha-synuclein

    Image Upload

    *mediam raphe (5-HT projection system) also affected)
  8. Parkinson's disease

    Pathophysiology, evaluation, and treatment
    • Pathophysiology:
    • 1. Loss of dopaminergic projections ..."too few movements"
    • -Depression in Parkinson's disease is most likely due to degeneration of the locus ceruleus (source of noradrenergic projections) and median raphe (source of serotonergic projections).

    2. Decrease in # of cells in substantia nigra; 30% or less of aged matched controls

    • 3. α-synuclein appears to play a role in the neural degeneration in Parkinson's disease; major component of Lewy bodies
    • -normal component of the synapse... instability or misfolding may lead to PD

    4. Pt treated with graft of fetal substantia nigra... 10 years later, the graft will have Parkinson's disease 

    • Evaluation: Dx is based on history and exam
    • -asymmetric
    • -good response to DA replacement
    • -no labs to support the dx; no biomarkers

    • Therapy:
    • -management of various features (orthostatic hypotension, neurogenic bladder, constipation, drooling)
    • -Delerium is typically transient
    • -Depression is treated in the usual manner
    • -REM sleep behavior disorders are treated with  meds that suppress REM sleep

    • Non-pharmacologic therapy:
    • -various therapy (occupational, physical...)
    • -Deep brain stimulation: adjustable, reversible, 'destructive' lesion of the subthalamic nucleus
    •       - Just as effective as Rx, but can be set at continual level (Rx tend to fluctuate in efficacy based on dose, which cycles up and down)

    • Pharmacologic therapy: Purely symptomatic
    • -Carbidopa/levodopa +/- COMT inhibitor (entacapone)
    • -Dopamine agonist (ropinirole)
    • -Muscarinic acetylcholine receptor antagonists (trihexyphenidyl, particularly effective for tremor)
    • -amantadine (NMDA glutamate receptor antagonist ... might not be mechanism of action in treating PD)
    • -monoamine oxidase B inhibitors (selegiline)

    *as disease progresses, pt becomes less responsive to drugs; drugs more likely to be used in combination
  9. Dementia with Lewy bodies
    Clinical overlap with both Alzheimer's and Parkinson's disease; pathologically is more similar to Parkinson's disease

    • Pathology: Lewy bodies in the cortex (diffuse)
    • -less distinct (not as eosinophilic); lack the halo
    • -contain predominantly α-synuclein

    Pathophysiology: unknown

    • Presentation:
    • -Parkinsonism, dementia, fluctuations in alertness and attention, and hallucination within the same year.
    • -Second most common form of progressive dementia seen in elderly
    • -Death on average 8 years post onset of symptoms
    • -Tx is difficult: pts are prone to have hallucinations... balance DA therapy (too much leads to hallucination, too little leads to parkinsonism)
  10. Huntington's disease
    Prototypical polyglutamine trinucleotide repeat expansion disorder

    • Autosomal dominant gene codes for protein huntingtin. Threshold is 35 repeats
    • -more repeats: earlier onset
    • -Paternal transmission is associated with anticipation and potentiation.
    • -function of normal gene is not known
    • -Gain of toxic function... selective regions are vulnerable to this toxicity (caudate> putamen)

    • Pathology: 
    • -Atrophy of caudate more than the putamen (apparent grossly and on neuroimaging)
    • -nucleus accumbens (third part of the striatum) is preserved
    • -loss of neurons, particularly of the medium spiny neurons, which give rise to direct and indirect pathways of the basal ganglia circuit
    • -protein aggregates containing huntingtin are found on surviving neurons

    • Clinical: 4-5 per million
    • -Autosomal dominant, complete penetrance
    • -Age of onset is 30s to 40s
    • -gradually worsening loss of sccadic eye movements, chorea, frontal syndrome and other neuropsychiatric dysfunction that may include depression and suicide
    • -clinical onset to death, ~15 years
    • -earlier onset can present with hypokinetic movement disorder > chorea

    • Tx: symptomatic and supportive
    • -DA depeleters (tetrabenazine) to suppress choria
  11. Amyotrophic lateral sclerosis (ALS)
    Lou Gehrig's disease

    • Clinical: gradual progressive asymmetrical lower and upper motor neuron dysfunction in an older patient
    • -Asymmetrical atrophy and weakness of the hands is a common presentation
    • -50% die in 3 years
    • -90% die within 6 years

    • Epidemiology: ~1 per 100,000
    • -Men > women  (2:1)
    • -onset is normally >45 years, incidence increases with age
    • -Most is sporadic; 5 to 10% have familial form of ALS

    • Pathology
    • -Anterior roots of the spinal cord and precentral gyrus appears atrophic (motor)
    • Image Upload

    • -microscopically, reduction in # of anterior horn cells. reactive gliosis
    • -surviving motor neurons often contain PAS-positive cytoplasmic inclusions called Bunina bodies
    • -stained sections of cord show loss of myelinated axons in the lateral cortical spinal tract.
    • -Muscles show neurogenic atrophy

    • Pathophysiology: not known for the sporadic ALS
    • -several genes identified in the familial ALS; most with autosomal dominant trait: copper-zinc superoxide dismutase (SOD1)

    • Evaluation: Clinical; based on history and exam
    • -EMG can confirm suspicion of widespread LMN dysfunction, though not found early in course
    • -MRI, labs to rule out other causes...

    • Tx: symptomatic and supportive
    • -antimuscarinics for drooling
    • -baclofen (GABA B agonist) for spasticity
    • -dextromethorphan for Pseudobulbar affect (inappropriate response to social situation)
    • -dietary fiber, fluids for constipation
    • -Ventilator
    • -Feeding tubes

    • -Riluzole: only FDA approved drug that slows the course of ALS; extends trach-free survival by 2 to 3 months...
    • -mechanism not known; AEs include nausea,,, abdominal discomfort, hepatotoxicity
  12. Spinal Muscular Atrophy
    • Clinical: autosomal recessive
    • -onset is infantile: birth, or within months
    • -One in every 20,000 live births: 2nd most frequent cause of death from an autosomal recessive disorder
    • -babies become weak and "floppy"; LMN disorder worsens and child typically dies before the age of one year

    • Cause:
    • -homozygous mutations of the survival motor neuron 1 (SMN1) gene.
    • -Clinical severity is inversely related to the number of copies of SMN2, highly homologous nearby gene. Lots of SMN2 means less severe disease and later onset
    • -SMN protein may be important for axonal transport, but appears to promote survival of motor neurons

    • Pathology: loss of the anterior horn cells and brain stem motor neuron nerve cell bodies
    • -associated reactive gliosis
    • -Motor roots atrophy
    • -Muscle pathology: atrophic fibers and scattered abnormally large muscle fibers

    • Image Upload
  13. Charcot Marie Tooth "disorder"
    Group of hereditary motor and sensory degenerative polyneuropathies

    • CMT type 1:
    • -Autosomal dominant inheritance 
    • -demyelinating

    • CMT1A (letter indicates mutation subtype)
    • -duplication of region that codes for Peripheral myelin protein 22 (PMP22) which is expressed in compact myelin and is involved in the myelin compaction process in the PNS.

    • Pathology: peripheral nerves show repetitive demyelination and remyelination with multiple onion bulbs that are most prominent distally
    • -segmental demyelination can be seen

    • Clinical: 1 in 2,500 individuals have CMT, majority is CMT1
    • -Sx start by age 30, but progression is slow
    • -symmetrical, predominantly motor, distal polyneuropathy
    • -lower extremity atrophy ("stork leg" appearance) and weakness, very high arched feet, and "hammer toes"
    • -Peripheral nerves may be enlarged to palpation (onion bulb process)
    • -Can be mild; many people with CMT never come to medical attention

    -Pts live normal lifespan, treatment is supportive, dx is based on history, PE, and genetic testing to confirm
  14. Myotonic dystrophy
    • Pathophysiology: Abnormal CTG trinucleotide repeat expansion on chromosome 19 that affects the mRNA for the "dystrophia myotonia protein kinase"
    • -Most common muscular dystrophy in adults

    • Normal people have <30 repeats; severe myotonic dystrophy pts can have thousands of repeats
    • -Anticipation occurs
    • -repeat expansion is in a non-coding region results in decreased protein synthesis and loss of function

    • Clinical: multisystem disorder affecting 13.5 per 100,000 live births
    • -Autosomal dominant with variable (but high) penetrance
    • -Onset: any age, most often in young adults
    • -progressive weakness and myotonia that often affects levator palpebrae, muscles of mastication and facial expression, sternocleidomastoid muscle
    • *characteristic appearance

    • -weakness is often distal
    • -Myotonia - delayed relaxation of a muscle following vigorous contraction

    -frontal baldness, cataracts, gonadal atrophy, cardiomyopathy, abnormal glucose tolerance, sleep apnea, lower IQ

    Tx: supportive, genetic counseling

    • Pathology: Skeletal muscle shows variation in fiber size, and may have internal nuclei
    • -Ring fiber - a subsarcolemmal band of cytoplasm that appears distinct from the center of the fiber
  15. Duchenne's muscular dystrophy
    • Pathophysiology: loss of the protein dystrophin due to many different mutations
    • -Dystrophin is one of the largest genes; high rate of mutation
    • -Most mutations are deletions, the rest are frameshift or point
    • -Cytoplasmic protein that is located adjacent to the cell membrane of the muscle: it forms (with an associated complex) a link between the contractile apparatus within the muscle cell and the connective tissue of the ECM
    • -role in transferring force of muscle contraction to surrounding tissue
    • -loss of this protein leads to degeneration of the muscle

    • Pathology:  variation in muscle fiber size, increased number of internal nuclei; degeneration, necrosis, phagocytosis of muscle fibers
    • -regeneration also apparent (but not enough to keep up with the degeneration)
    • -proliferation of endomysial connective tissue
    • -muscle is replaced by fat and connective tissue

    • Clinical: most common form of muscular dystrophy; 1 per 3,500 live male births
    • -2/3rds are X-linked recessive, males affected, females asymptomatic carriers
    • -1/3 are new mutations
    • -onset: <3 years; always by age of 6 years
    • -symmetrical and proximal > distal weakness; progressive
    • -Pseudohypertrophy of calf muscle (initial hypertrophy of muscle, subsequently replaced with fat)
    • -death occurs between adolescence and mid-20s

    • Evaluation/Tx: Dx is suspected by history and exam
    • -CK is markedly elevated
    • -Genetic testing confirms, though not all can be detected
    • -muscle bx reveals an absence of dystrophin
    • -Tx: supportive, genetic counseling
    • -Glucocorticoids may delay progression of weakness (keep them walking), but significant adverse effects
  16. Drugs for ALS
    • Disease specific therapy: Riluzole
    • Spasticity: Baclofen (GABAreceptor agonist) and Tizanidine (α2 receptor agonist)
    • SKM spasms, cramps: Carbamazepine, Phenytoin
    • Sialorrhea: Atropine, Botulinum toxin
    • Pseudobulbar affect: Dextromethorphan + quinidine
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Neurodegenerative disorders and Drugs for ALS
2013-01-29 06:28:25

Degenerative neuro, ALS drugs
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