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: 40-55 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– 4th-5th 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

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 8th 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