neurological disorders part III

what is multiple sclerosis (MS)?

 Progressive demyelinating disease of the CNS

 PNS spared

 Most common cause of neurological disability in young adults

 Onset usually occurs between 20-40 yrs old

 Cycles of exacerbations/remissions over many yrs

 Involves different areas of the CNS

 Women>men

 Familial predisposition

 Human leukocyte antigen (HLA)-DR2 haplotype

what is the pathophysiology multiple sclerosis (MS)?

 Nerve fibers of brain, spinal cord, and optic nerve are affected

 Inflammation and scarring are usually present

 Scarring takes the form of plaques

 MS considered to be an autoimmune disorder

 ? Antibody mediated damage against myelin oligodendroglial protein

 Exact mechanism is unknown

what are the symptoms of MS?

 Depending on the location and extent of the lesions:

 Optic neuritis: visual disturbances like diminished acuity, dimness, loss of color perception.

 Usually, unilateral

 Diploplia

 Fatigue

 Muscle weakness: of limbs and face

 Swallowing difficulty

 Speech disturbance

 Spasticity: spontaneous and movement induced muscle spasms

 Cognitive dysfunction

 Bladder and bowel problems

 Sensory symptoms: Numbness, tingling, and/or pain

 Tremor

 Vertigo

 Ataxia

what is the treatment of MS?

• No cure

•  Treatments include:

•  Drugs used to treat acute symptoms

•  Corticosteroids (glucocorticoids like prednisone)

•  Drugs to modify the course of the disease and treat chronic symptoms (i.e. ↑time in remission)

•  Interferon-beta, immunosuppresants such as methotrexate, Baclofen

what is ALS?

 Lou Gehrig’s disease

 a neuromuscular disease

 Progressively affects motor function

 Onset between 40-60 yrs of age

 Men>women

 Mean survival 2-5 yrs

what is ALS etiology?

 Etiology is unknown

 Maybe genetic (10%)

 Linked to:

 Malfunctioning genes for glutamate transporter

excitotoxicity

 And/or malfunctioning genes for superoxide dismutase

what is ALS patophysiology?

 Mitochondrial dysfunction leading to apoptosis of the neurons

 ER dysfunction leading to misfolded proteins which become deposited in the neuronal cytoplasm:

 TAR DNA-binding protein of 43 Kda (TDP-43)

 SOD1

 Fused in sarcoma (FUS)

 Cause a “prion-like” propagation

 Pathophysiology:

 Destruction of upper motor neurons in the cerebral cortex and the lower motor neurons in the brain stem and spinal cord

 Spares cognitive function

what are the symptoms of ALS?

 Muscle weakness, twitching, and cramping

 Muscle atrophy

 Difficulty speaking

 Trouble chewing and swallowing

 ↑Risk of choking

 Trouble breathing

 will need a ventilator

 Bladder and bowel control are usually preserved in ALS

what is the treatment of ALS?

 No cure

 Respiratory/speech/physical therapy

 Riluzole: anti-glutamate drug

 Future treatments: stem cells?

what is parkinson’s disease?

 Progressive neurodegenerative disease

 Resulting from the destruction of DA neurons of the nigrostriatal pathway in the midbrain

 Affects ~1.5 million people in the US alone

 Considered to be a “hypo dopaminergic” disorder

 Onset of symptoms is ~ 60 yrs of age

 Although 10% of cases occur in people < 40 yrs old

 Incidence ↑age

 Mortality rate is 1.6 times higher than in the normal population

 Too much or too little DA

 problems and generates “jerky,” and/or unwanted muscle movements

what are the symptoms of parkison’s disease?

 Onset of symptoms is gradual

 Cardinal symptoms include:

1. Rigidity (cogwheel)

2. Bradykinesia

3. Resting tremor

4. Postural abnormalities

 cease with voluntary movement and during sleep

 Loss of sense of smell

 Insomnia

 Drooling and difficulty swallowing

 “Pill rolling” rhythmic tremor

 Difficulty initiating and stopping movements

 Stooped posture, and shuffling gait

 Dementia

 Lack of arm swing

 Occasional "freezing" episodes

 Mask –like face and seborrhea

 Micrographia, and microphasia

what is the etiology of parkinson’s disease?

 Unknown etiology

 A small % of PD cases are familial, resulting from a genetic mutation in the α-synuclein gene —> Protein misfolding and aggregation

 Idiopathic PD may be multi-factorial, with several intrinsic and extrinsic factors contributing to its development

what is the pathophysiology of parkinson’s disease?

 Alpha synuclein misfolding and aggregation

 Mitochondrial dysfunction

 Protein degradation dysfunction —> Impaired autophagy

 Microglial activation

 Lewy body formation

what is the treatment of parkinson’s disease?

 No cure

 Treatment only alleviates symptoms

 Treatment strategies:

 ↑DA levels

 Stimulate DA receptors

 ↓DA breakdown

 Inhibit activation of acetylcholine receptors

what is alzheimer’s disease?

 Progressive neurodegenerative disease

 causing dementia (loss of ordered neural function)

 Diagnosis >60 yrs of age, but early onset is possible

 Early onset has a genetic component (rare= 5%)

what is the pathophysiology of AD?

 Characterized by cortical atrophy, loss of neurons (esp. in the parietal and temporal lobes), and enlargement of the ventricles.

 Loss of cortical neurons results in a deficit in choline acetyltransferase which then results in a deficit in ACh

 Gyri shrink, and ventricles expand

what are neuritic (senile) plaques?

 Hallmark feature of AD

 Patches of degenerating nerve terminals surrounding a core of amyloid β peptide (Aβ)

 Aβ42 is particularly problematic

 Toxic —> may induce inflammatory responses, activation of microglia, and release of free radicals

what are the microscopic findings of AD?

 Microscopic findings:

 Neurofibrillary tangles:

 Bundles of filaments that encircle or displace the nucleus

 Made of hyperphosphorylated tau protein

 Aβ peptide can trigger tau hyperphosphorylation

what are the symptoms of AD disease?

 Early stages:

 Short term memory loss and inability to acquire new information

 PT may get loss

 Has trouble handling money and paying bills

 Daily tasks may take longer to complete

 As the disease progresses:

 Long term memory becomes compromised

 Changes in mood and personality

 Cognition is impaired

 dementia.

 Difficulty in performing learned motor tasks

 Psychosis

what is the etiology and diagnosis of AD?

 Etiology= unknown

 Diagnosis:

 Based on symptoms

 Definitive diagnosis= post-mortem histology of the brain

 MRI serves to exclude other disease states, and may show cortical atrophy

what are the risk factors of AD?

 Increased risk

 Diabetes

 HTN

 Hypercholesteronemia

 Smoking

 Decreased risk:

 Exercise

 Intellectual activities

 Healthy diet

what are the genetic risk factors of AD?

 Mutations in the genes Presenilin 1 and 2 (which encode for gamma secretase)

 Mutations in the gene for APP (amyloid precursor protein) which is in chromosome 21

 APO E4 allele

what is the treatment of AD?

 No cure

 Treatment only alleviates symptoms?

 Current treatment strategies:

 Cholinesterase inhibitors (ex: Aricept)

 NMDA receptor antagonist (Namenda)

what is huntington’s disease?

 Also called Huntington’s chorea

 Progressive neurodegenerative genetic disorder affecting 1/10,000 people

 Due to defect in gene encoding for the huntingtin protein

 polyglutamine (polyQ) expansion in the huntingtin protein and protein aggregation. CAG repeats >40

 Offspring of an affected pt has a 50/50 chance of developing the disease

 Causes constant involuntary writhing or dance-like movements

 Involving the extremities at first, then the entire body

 Gradual loss of cognitive function: —> dementia —> Onset 20-50 yrs old —> Fatal in ~15 yrs

what is hungton’s disease pathophysiology?

 Considered a “hyper dopaminergic” condition because less GABA is released in the striatum

 ↑DA release

 Massive neuronal loss in the caudate and putamen (= striatum)

 Also, secondary loss of neurons from the frontal cortex

what is the treatment huntington’s disease?

 No cure

 Treatments help with symptoms:

 Antipsychotics

 block DA receptors