AD, Huntington's disease and MD (CH. 6, 15)

Alzheimer's disease

Progressive degeneration of the brain that ultimately results in dementia.

AD symptoms

-dementia-progressive mental deterioration -memory loss-loss of visual-spatial orientation

AD risk factors

Greater age-family history-lower educational level-female gender

cause of AD

-loss of cholinergic neurons in brain areas-formation of beta amyloid plaques-formation of neurofibrillary tangles in neurons (due to disrupted Tau)

To slow progression of AD

-nonsteroidal anti-inflammatory drugs-HMG-CoA reduction inhibitors (statins)-moderate ethanol intake-strong social support (slows progression)-no cure

Early AD diagnostic clues

-progressive impairment of intellectual function-short term memory loss-aphasia, apraxia, agnosia or disturbance in executive functioning -memory and visuospatial abilities

end stage AD symptoms

near mutism; inability to sit up, hold up head, or track objects with eyes-difficulty swallowing and eating-weight loss, incontinencerecurrent respiratory and UTIs

Familial or early onset AD

-Early onset before age of 60/65-autosomal dominant -very rare (x < 5%)-type 1; APP mutationtype 3; PSEN1 mutationtype4: PSEN2 mutation

Late onset or sporadic AD

-majority of cases-APOE gene on chrom 19-35-50% of people have one copy of APOE e4 mutation

APOE gene for late onset AD

APOE makes proteins that help carry cholesterol in blood stream -may be involved in determining structure and function of fatty membrane surrounding cell

AD testing

examine brain structure for plaques and tangles-clinical eval; family history, medical history, lab tests, mini mental status exam, neuro imaging

AD treatment (mild-moderate)

-AD associated with loss of cholinergic neurons-Use of acetylcholinesterase inhibitors; donepezil, galantamine, rivastigmine-increase AcH available for brain-Block AcH destruction by acetylcholinesterase-for mild-moderate AD

AD treatment (moderate-severe)

memantine; NMDA receptor antagonist-too much glutamate leads to nerve degeneration and progresses AD-memantine blocks NMDA glutamate receptor, decrease stimulatory effect-can be combined with acetylcholinesterase inhibitors

Huntington's disease

characterized by uncontrollable body movements and degeneration of the nervous system-autosomal dominant-not reversible-excessive excitability leading to cell death

Huntingtons disease association

-neurodegenerative disease-involuntary movement of all parts of body-deterioration of cognitive function-severe emotional disturbance-microscopic deposits of amyloid related protein in basal ganglia

HD; chorea

quick, jerky, involuntary movements.-ceaseless rapid complex body movements

aphasia (AD)

loss of ability to understand or express speech

apraxia (AD)

difficulty with skilled movements

agnosia (AD)

loss of ability to identify objects, people, smells, shapes, sounds

HD genetics

-primarily affects Caucasians-mutation in HD gene on chromosome 4-only human disorder of complete dominance -mutation; expanded and unstable trinucleotide CAG repeat-earlier progression if disease obtained from affected father-remains latent 3-5 decades then manifests in progressive neuronal dysfunction

HD initial symptoms

abnormal movement or intellectual changes-between 30-50 onset-behavioral changes; irritability, moodiness, antisocial behavior, psychiatric disturbance-involuntary facial movement

HD late symptoms

Dementia-dyskinesia; difficulty in performing voluntary movements-progressive rigidity and akinesia-severe balance/coordination problems -difficulty swallowing-hesitant, halting or slurred speech -wide, prancing gait-unable to shift gaze without moving head

HD diagnostic testing

-Family and medical history-computerized tomography; screen for cerebral atrophy and atrophy of caudate nucleus-MRI and PET show reduced glucose utilization in caudate nucleus

HD treatment mechanism

-no cure-aims at known biochemical changes showing underactivity of neurons containing GABA, AcH or overactivity of dopaminergic neurons

HD treatment

-drugs blocking dopamine receptors--phenothiazines--haloperidol--control dyskinesia and behavioral disturbances---sedation is side effect-speech and occupational therapy

AD and cardio health

-nongenetic; higher risk associated if you have CVD-poor blood supply to brain -increased inflammation

Muscular dystrophy

-noninflammatory diseases characterized by progressive muscle wasting or atrophy-gene mutation affects production of muscle proteins to build healthy muscle tissue -affect muscles with fiber degeneration, without creating central or peripheral nerve abnormalities

AD and diabetes

-diabetes can have impact on vascular health-Too much sugar impact vessel cell health -damage to vessels in brain-

Duchenne MD

male diagnosed-onset of muscle weakness in early childhood-rapid progression

Becker MD

less severityprogress slower

Duchenne MD genetics

-X linked recessive-males receive defective gene from carrier mother-males 50% acquiring if mother has defective gene-daughters 50% of becoming carrier and have risk of acquiring cardiomyopathy

dystrophin

-muscle cell maintenance -protect muscle cells

Initial symptoms of duchenne MD

-waddling gait-pain/stiff muscles-difficulty running + jumping-learning disabilities-pseudohypertrophy of calf muscles

pseudohypertrophy (MD)

increase in size of organ or part thats not due to increase in size or number of specific functional elements

late signs of duchenne MD

inability to walk-shortening of muscles and tendons-breathing problems-abnormal curvature of spine-cardiac problems-difficulty swallowing; can lead to aspiration pneumonia

gowers sign in children with MD

classical sign; child has proximal muscle weakness-requires use of walking up his legs with his hands to maintain upright posture

creatine kinase (MD)

-protein needed for chemical reactions that produce energy for muscle contractions-high levels in blood indicate muscle damage-damaged muscles produce CK

diagnostic criteria MD

high CK-high levels of myoglobin (indicating breakdown of skeletal/cardiac muscle tissue)-children show muscle weakness 2-3 years of age and ck 10-20 x normal

electromyography (MD)

invasive-needle placed in heart to measure electrical activity

biopsy with western blot (MD)

most definitive way to testportion of muscle removed and examined-dystrophin analysis

DMD diagnosis

most common-symptoms before age 3-children wheelchair bound by 12-death via respiratory failure mid 20smost common among males

becker MD

later onset and slower progression than DMD-death mid 40s-most common among males

Emergy-Dreifuss Muscular Dystrophy

-Joint contractures in early childhood-slowly progressive muscle wasting and weakness-cardiac involvement; palpitations, presyncope, syncope, CHF-reduced penetrance

genetic testing MD

-increased CK levels-amniocentesis or CVS-dystrophin, skeletal muscle Dp427-may be incomplete penetrance

MD management and treatment

-no cure-corticosteroids; assist in muscle strength -cardiac meds; ACE inhibitors, beta blockers-anticonvulsants-immunosuppressants -antibiotics -physical and speech therapy-respiratory devices

genomic imprinting (HD)

-epigenetic changes-methylation on genes that control if they have activity-add methyl group to mol to create steric hinderance-blocks progression of machinery to turn transcription on-can keep gene from being activated

pathogenesis mechanism of HD; (1) aggregate formation

mutant huntintin with polyglutamine expansion is cleaved in toxic fragments-toxicity may arise from oligomeric soluble species or from insoluble inclusion that sequester essential proteins

pathogenesis mechanism of HD (2) transcriptional dysregulation

altered transcription of essential genes like BDNF-chromatin modifications

pathogenesis mechanism of HD (3) altered protein homeostasis

-proteasome dysfunction as mechanism of HD-autophagic degradation affected due to cargo sequestration or autophagosome transport

pathogenesis mechanism of HD (4) mitochondrial dysfunction

defective Ca homeostasis-altered mito. protein import-impaired mito. dynamics (increased fragmentation)-aberrant ROS production-decreased ATP production

pathogenesis mechanism of HD (5) altered synaptic plasticity

-excitotoxicity due to altered postsynaptic NMDAR, glutamate uptake-deficient delivery of synaptic vesicles and postsynaptic receptors

pathogenesis mechanism of HD (6) axonal transport defect

impaired organelles transport; mito., autophagosomes, synaptic vesicles-impaired synaptic transmission-failed trafficking of receptors and mediators to synapse

pathogenesis mechanism of HD (7) neuroglia dysfunction

-microglia secrete pro-inflammatory cytokines and chemokines-impaired glutamate uptake by astrocytes

axonal transport dysfunction (HD)

failed delivery of receptors like GABA inhibits synaptic excitability-striatal neurons in HD harmed by excessive neurotransmission, through glutamate stimulation of NMDA-leads to neuronal cell death via excitotoxicity

HD pathology

-Neuronal cell deaths (striatum)-overall shrinkage of brain (lead to dementia)-dementia-overproduction of vasopressin (puts stress on heart)-weight loss-skeletal muscle wasting-cardiac failure

HD treatment

-symptom management-interprofessional team needed for various symptoms associated

aducanumab (alzheimers)

-AB monoclonal antibody-acts as immune modifier -cost prohibitive-phase 3 trial showed;decrease in amyloid plaques-decrease in elevated CSF of phosphorylated tau protein-reduction of brain Tau PET signals-mixed outcomes on cognitive testing

insoluble inclusions

caused by mutant huntington protein-trinucleotide CAG repeat-aggregate of huntingtin protein