pathology: neurodegenerative disease and neuropathies

Most common cause of dementia in people > 50 years
cerebral cortex affected; dementia clinical manifestation

Pathological examination of brain tissue at autopsy needed for definitive diagnosis

Alzheimers

you see cortical atrophy and with significant atrophy you can have compensatory ventricular enlargment (hydrocephalus ex vacuo)

Alzheimers

accumulation of two proteins: tau and A-beta

you see A-beta aggregates (plaques) and aggregates of tau (tangles)

Fundamental problem : deposition of A-beta peptides, derived from processing of APP (amyloid precursor protein)

Alzheimers

with alzheimers disease, the number of ___ correlates better with the degree of dementia than the number of ___

tangles correlate better than neuritic plaques

Genetics: APP protein on chromosome 21

presenilin-1, presenilin-2

alzheimers

unlike ____, ____ is found in other neurodegenerative disorders, not just alzheimers

neuritic and diffuse plaques are alzheimers

the neurofibrillary tangles are found in other disease not just AD

alterations in personality, behavior, and language (aphasias) preceding memory loss

frontotemporal lobar degeneration

a subtype of FTLD-tau: severe atrophy of the frontal and temporal lobes (lobar atrophy), often with “knife-edge” atrophy of the gyri. Thin, wafer-like gyri

pick disease

Severe neuronal loss with intense gliosis in affected cortical regions

pick disease

An autopsy study is performed of patients who died from 55 to 80 years of age. A subset of these patients had cerebral atrophy and brain weights that were less than normal for age and body size. The brains showed hydrocephalus ex vacuo, but no focal lesions. Microscopic examination showed the presence of increased numbers of neurofibrillary tangles and neuritic plaques within the cerebral cortex. Which of the following was most likely present in those groups of patients?

A. symmetric muscle weakness
B. gait disturbances
C. grand mal seizures
D. progressive dementia
E. choreiform movements

D. progressive dementia

Neurodegenerative hypokinetic movement disorder caused by loss of dopaminergic neurons from substantia nigra

tremor, rigidity, and bradykinesia

parkinsons

with parkinson disease, the severity of motor yndrome is proportional to ____

dopamine deficiency

genetics: NCA, gene that encodes α-synuclein; Lewy body (diagnostic hallmark)

parkinsons

Neuronal loss in the substantia nigra accompanied by numerous pigment-laden macrophages and gliosis

parkinsons

A 70 year old man has had increasing difficulty with voluntary
movements because of muscular rigidity. On physical exam, he
has difficulty initiating movement, but he can keep moving if he
follows someone walking ahead of him. He has an expressionless
facies. When he is sitting, his hands have a resting, "pill-rolling"
tremor. What histopathological findings is most likely to be present in his brain?

Loss of pigmented neurons in the substantia nigra

Autosomal dominant, progressive movement disorder with dementia caused by degeneration of striatal neurons

mild cortical atrophy and severe atrophy of basal ganglia
Jerky, hyperkinetic, sometimes dystonic movements involving all parts of body
(chorea)

huntington disease

Prototype of polyglutamine trinucleotide repeat expansion

No sporadic form

CAG repeats he longer the repeats, the earlier the onset of disease

huntington disease

Loss of striatal neurons (usually dampen motor activity), causes increased motor output - choreoathetosis

Motor symptoms usually precede cognitive impairment

choreiform

huntington disease

A 50 year old man is brought to his doctor by family members who state that he has become more forgetful in the past few months. He is emotionally labile. His mother dies a few years after experiencing similar symptoms. On physical exam, he has some choreiform movements of his extremities. Which of the following findings is most likely present in this patient?

Increased trinucleotide CAG repeats

loss of upper motor neurons in cerebral cortex and lower motor neurons in spinal cord and brain stem

genetics: superoxide dismutase (SOD1)

Asymmetric weakness of hands, early – dropping of objects and difficulty with fine-motor tasks along with cramping and spasticity of arms and legs

Amyotrophic Lateral Sclerosis (ALS)

aggregation and intercellular spread of misfolded PrP;
may be sporadic, familial, transmitted

PrPc → PrPsc

prion diseases

A 53 year old female with a hx of corneal transplant 6 months ago, presents with loss
of balance, mood swings and memory loss. She had not noticed these symptoms
until her coworkers and family pointed it out to her. These symptoms presented 4
months ago, and began to interfere with her daily activities. Her ataxia has
progressed to the point that she is stumbling and falling.
Her family reports that over the past month her memory quickly deteriorated to the
point that she is unable to recognize friends, is unable to drive, is not able to work
and forgets if she has eaten. A CT scan of her brain is performed and shows no
abnormalities. What abnormal protein in the brain is associated with this condition?

PrPsc

Most common prion disease

rapidly progressive dementia

Uniformly fatal; average survival 7 months after onset of symptoms

little to no cerebral atrophy

Creutzfeldt-Jakob Disease

transmissible neurodegenerative disease first seen in Papua New Guinea (funerary cannibalism)

kuru

CMT1 - group of AD demyelinating neuropathies, collectively most common subtype of hereditary motor and sensory neuropathy

Peroneal muscular atrophy

Distal muscle weakness, atrophy of leg beneath knee, secondary orthopedic issues
(pes cavus)

Charcot-Marie Tooth Disease

"Onion bulb" formations: concentric layers of Schwann cell processes and collagen
around axons, caused by repetitive segmental demyelination and regeneration of myelin. May cause gross thickening of peripheral nerves (hypertrophic neuropathy) which can be clinically palpated

Charcot-Marie Tooth Disease

“stocking and glove” – decreased sensation in distal extremities; loss of pain
can lead to ulcers which heal poorly because of vascular injury

diabetic neuropathy

discontinuity between proximal and distal parts of nerve sheath/misalignment of nerve fascicles
If axons continue to grow, (distal segments not positioned correctly)- mass of tangled
axonal processes result: Traumatic or amputation neuroma

traumatic neuropathy

compression of median nerve at level of wrist within compartment delimited by transverse carpal ligament

include numbness and paresthesias of tips of thumb and first two digits

compression neuropathy: specifically carpal tunnel syndrome