Neurodegenerative disorders and Drugs for ALS

• -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

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

• 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

• 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

• Pathophysiology: deposition of Aβ peptides that result from the abnormal processing of the amyloid precursor protein (APP)
• -APP has an unknown function

inflammatory response to the aggregates of amyloid. may contribute to the abnormal tau phosphorylation and oxidative injury to neurons

• 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)

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

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

*mediam raphe (5-HT projection system) also affected)

• 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

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)

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

• 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)

• -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

• 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

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

• 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

• 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

• Disease specific therapy: Riluzole
• Spasticity: Baclofen (GABA_B receptor agonist) and Tizanidine (α2 receptor agonist)
• SKM spasms, cramps: Carbamazepine, Phenytoin
• Sialorrhea: Atropine, Botulinum toxin
• Pseudobulbar affect: Dextromethorphan + quinidine