Degenerative Diseases of Brain

Degenerative Diseases Spontaneous, progressive degeneration of neurons Sporadic, Familial Overlapping features

Degenerative Diseases Spontaneous, progressive degeneration of neurons Sporadic, Familial Overlapping features –Alzheimer disease –Parkinsonism –Huntington Disease

Alzheimer Disease Dementia, memory impairment, recent memory loss Most common cause of dementia in elderly >50 years (Down syndrome at 40y) 10% familial

Alzheimer Disease Clinical –Progressive memory and cognitive loss –Over 5-15 years –Starts with recent memory loss, missing words –Progress to language difficulties and loss of higher cortical function –Some: have parkinsonism like features –Death is due to pneumonia and other infections

Alzheimer Disease Pathogenesis: –Genetic factors Amyloid precursor protein (APP) –Ch 21 –Deposition of beta-amyloid (senile plaques) –Mutation in APP –Toxic to neurons Presenilin 1 Presenilin 2

Alzheimer Disease Pathogenesis: –Hyperphosphorylation of tau protein Deposition of tau protein –Expression of ApoProtein E Binds to APP

Alzheimer Disease Morphology: –Brain atrophy Frontal, temporal, parietal lobes (small gyri, wide sulci) Dilated ventricles –Micro: Neurofibrillary tangles –Contain tau protein Senile plaques –Contains amyloid beta Amyloid angiopathy Lewy bodies

Parkinsonism Degenerative disease Affect motor function Rigidity, mask face, gait disturbance, slow voluntary movement, tremor Progress over years (10y) Dementia Death from infections or trauma (fall)

Parkinsonism Pathogenesis –Disturbance of dopaminergic pathway in substantia nigra in the basal ganglia –Can be due to Parkinson disease or due to trauma, toxins, vascular insult, encephalitis. –Parkinson disease Genetic/environmental Mutation in alpha-synuclein Degeneration of substantia nigra and locus ceruleus Sixth decade of life

Parkinsonism Morphology: –Depigmentation of substantia nigra and locus ceruleus –Micro: Gliosis Loss of neurons Lewy bodies (intracytoplasmic inclusions contain alpha-synuclein and ubiquitin)

Huntington Disease Hereditary progressive fatal disorder Involve extra pyramidal motor system Involuntary movements (chorea) Dementia Autosomal dominant Appear in adulthood

Huntington Disease Gene: Huntingtin protein (ch 4) –Unknown function Trinucleotide repeat mutation –Normal: CAG: 6-34 repeat –Huntington diseas: CAG: repeat –Early onset disease: CAG: 70 repeat

Huntington Disease Morphology: –Brain atrophy <1100g –Atrophy of caudate nucleus, and putamen –In advanced cases atrophy of globus pallidus –Dilated ventricles –Micro: Loss of neurons gliosis

Huntington Disease Clinical –4 th -5 th decade –Anticipation phenomenon –Chorea –Seizure –Rigidity –Depression, cognitive impairment –Death: suicide, infections

Primary Disease of Myelin

Multiple Sclerosis Young adults 18-40y Attack of neurological abnormalities in different regions of the body Autoimmune disease –T cell mediated injury –Antibody mediated injury –Dystruction of myelin and oligodendrocytes Genetic: HLA-DR2 Environmental: regional risk

Multiple Sclerosis Morphology –Multiple plaques in brain, spinal cord –Common sites: peri-ventricular white matter, optic nerve, white matter of spinal cord –Micro: Areas of demyelination Lymphocytic infiltrate Shadow plaques: axons with thin myelin (re myelination)

Multiple Sclerosis Clinical –Visual disturbances, paresthesia, speech disturbance, gait abnormalities –Cognitive impairment (not severe) –CSF: high protein, lymphocytes, gamma globulin (oligoclonal band) –Some rapidly progress- death –Others have normal life span

Other Myelin diseases: Acute disseminated encephalomyelitis Central pontine myelinolysis Leukodystrophies

Metabolic diseases Thiamine deficiency –Chronic alcoholics –Wernicke-Korsakoff syndrome –Peripheral neuropathy –Wernick encephalopathy: confusion, paralysis, ataxia –Korsakoff psychosis: memory loss –Findings: Mamillary body hemorrhage

Metabolic diseases Hepatic encephalopathy –Confusion –Flabbing tremor –Large astrocytes (Alzheimer type II)

Peripheral Neuropathy

Axonal Degeneration Segmental Demyelination

Peripheral Neuropathy Axonal Degeneration –Wallerian degeneration Injury to proximal part with degeneration of the distal segment Followed by regeneration (incomplete) eg. Localized cut of nerve, vasculitis –Distal axonal degeneration eg. Generalized injury of cell bodies, thiamine deficiency, toxic: lead, arsenic Degeneration distally and extends proximally in continuous fashion Regeneration (incomplete)

Peripheral Neurophathy Segmental Demyelination: –Injury to myelin sheath (segmental) –Preservation of axons – poor conduction –New myelin sheath (remyelination) –“onion bulb” formation –Secondary axonal degeneration – eg. Hereditary neuropathy, Guillain-Barre syndrome, Leukodystrophies

Peripheral Neurophathy Clinical –Defect in motor, sensory or autonomic nerve –“Glove-and-stocking” distribution seen in distal axonal degeneration –Motor: muscle weakness, atrophy –Loss of deep tendon reflexes –Postural hypotension, constipation

Guillain-Barre Syndrome Etiology: unknown Follow viral infection, Mycoplasma, allergies, surgery ? Immune defect Rapid, progressive ascending motor weakness Minimal sensory loss Death from involvement of respiratory muscle Path: segmental demyelination with inflammatory infiltrate

Neoplasm of Peripheral Nerve Schwannoma Neurofibroma Malignant peripheral nerve sheath tumor

Schwannoma Well-circumscribed, encapsulated tumor At the edge of peripheral nerve Common in 8 th cranial nerve (acoustic neuroma) Micro –Antoni A, Antoni B –Verocay bodies

Neurofibroma Solitary or multiple (neurofibromatosis) Mixture of schwann cells and fibroblasts Malignant peripheral nerve sheath tumor