Neuro2: Neuropathology Of Movement Disorders

Front 1

Components to Motor Control

Back 1

Motor cortex, motor pathway, anterior (ventral) horn cell/motor unit, peripheral nerve and muscle, basal ganglia-based (extrapyramidal) system

Front 2

ALS Pathophysiology, epidemiology, Clinical Findings, inheritance, Gross Pathology, Microscopic Pathology

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Amyotrophic Lateral Sclerosis

Pathophysiology: Loss of LMNs in the spinal cord and brainstem, loss of UMNs that project to the corticospinal tract

Epidemiology: 5th decade or later, RARE, Male slightly more

Clinical Findings: Initially MUSCULAR WEAKNESS IN HANDS. that progresses to overall muscle bulk decreases leading to recurrent pulmonary infections and fasciculations

Inheritance: sporadic, 5% are familial (AD inheritance, 25% due to superoxide dismutace c21 mutation)

Gross Pathology: Anterior nerve roots of spinal cord thinned, Atrophy of PRECENTRAL GYRUS

Microscopic Pathology: Loss of UMNs in cortex, loss of LMNs in brainstem and cord (ventral horn), Bunina bodies (pathologic intraneuronal cytoplasmic inclusions)

Front 3

Chronic ALS signs

Back 3

Overall muscle bulk decreases
Recurrent pulmonary infections
Fasciculations
Degeneration of lower brainstem CN motor nuclei in Bulbar ALS leading to impaired swallowing and phonation

Front 4

Initial clinical finding in ALS

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MUSCULAR WEAKNESS IN HANDS

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Bulbar ALS

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degeneration of lower brainstem CN motor nuclei leading to impaired swallowing and phonation

Front 6

Gene mutation in familial ALS

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25% have AD superoxide dismutase mutation

VAST MAJORITY OF ALS CASES ARE SPORADIC

Front 7

a) Bunina bodies

b) Ubiquitinated Neuronal Intranuclear inclusions

c) Lewy bodies in cytoplasm of neurons

d) hyperphosphorylated four repeat (4R) tau protein in neurons and glia

Back 7

a) Pathologic intraneuronal cytoplasmic inclusions in ALS

b) Huntington's Disease

c) Parkinson's (a-synuclein filaments)

d) Progressive Supranuclear Palsy (PSP)

Front 8

Globus pallidus parts

Back 8

External segment (GPe) - synonymous with lateral globus pallidus (LGP)

Internal segment (GPi)- synonymous with medial globus pallidus (MGP)

Front 9

Globus pallidus inputs and outputs

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Inputs - Glutamate from cortex (excitatory), D1 from SNc (DA, excitatory), D2 from SNc (DA, inhibitory)

D1 globus activation to SNr is GABAergic. SNr is GABA to thalamus SO inhibition of inhibitor leads to more active thalamus and more movment (direct pathway)

D1 striatum is GABAergic on MGP (inhibitory) which normally is GABA on thalamus. So reduces MGP inhibition of thalamus to increase movement overall

D2 is inhibitory of GABAergic on LGP which is GABA ergic on STN. This leads to higher STN activity. STN acts on SNr and MGP via glutamate. SNr and MGP HIGH are GABA to VL (less activation on cortex) so LESS MOVEMENT overall

Front 10

Huntington's Disease Manifestations, Onset, Inheritance, Gross Pathology, Pathogenesis, Microscopic Findings

Back 10

Clinical Manifestations: Chorea, Psychiatric symptoms, Dementia, Cachexia

Onset: 40 years old

Inheritance: "anticipation" affected children have earlier onset than parent with disease especially if parent transmits to them

AD due to CAG repeats in huntingtin gene on C4p

Gross pathology: neuronal degeneration in the striatum (MOSTLY CAUDATE NUCLEI)

Pathogenesis: Loss of medium spiny striatal neurons (normally fxn to dampen motor activity), dysregulation of basal ganglia circuitry modulating motor output, Development of pathologic changes (Medial to lateral direction in the caudate and dorsal to ventral in the putamen). ALL lead to LESS inhbition of the THALAMUS and GREATER activation on the cortex

Microscopic Findings: neuronal loss, gliosis, abnormal collections of huntingtin in neurons, UBIQUITINATED NUCLEAR INCLUSIONS, ABNORMAL CORTICAL NEURITES

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Development of pathologic changes in HD directionally

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Medial to lateral direction in the caudate

Dorsal to ventral in the putamen

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Hemiballismus Presentation and Lesion

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Flailing movements of one arm and leg due to responsible lesion in the contralateral subthalamic nucleus (STN)

STN has outputs to GPe, GPi and SNr

Front 13

Dystonia Primary vs Secondary; Early onset and late onset signs

Gross vs microscopic

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Primary - NO gross signs, early onset has microscopic neuronal inclusions for torsion dystonia (torsin A, ubiquitin in brainstem), Late onset no signs

Secondary due to trauma,. birth anoxia, neurodegenerative, others that impair the basal ganglia output with variable microscopic signs

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Essential Tremor Overview

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Relatively common condition (12% of people over 70) with a benign clinical course and no specific pathology

Front 15

Parkinson's Disease Presenting Symptoms if looking at pt, pathophysiologic cause, Microscopic signs

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Most common disease of basal ganglia

Hypokinetic disorder with:

Rigidity
Bradykinesia
Stooped posture
Resting tremor "pill rolling"

Pathophysiologic Cause: LOSS of Dopamine from SNr. Uninhibited striatum LGP inhibition (D2 normally blocks), so LGP no longer inhibits STN anymore. HIGH STN excitatory output to MGP and SNr which both are GABAergic to thalamus. Thalamus no longer is activating cortex as much

Microscopic - Lewy bodies of alpha synuclein in neurons of substantia nigra, locus ceruleus and dorsal motor nucleus of vagus

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Most common disease of the basal ganglia

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Parkinson's disease

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MPTP and effect

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Contaminatn in illicit synthesis of meperidine analogues

Causes AQUIRED ACUTE PARKINSONIAN SYNDROME due to neuronal loss in substantia nigra

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Progressive Supranuclear Palsy (PSP) Onset, Neuropathology, Clinical Features, Neuronal losses, microscopic features, molecular features

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Onset: 5th - 7th decades, Men 2x >, fatal at 5-7 yrs

Neuropathology - accumulation of hyperphosphorylated four repeat (4R) tau proteins in neurons and glia

Clinical: Truncal rigidity, dysequilibrium, nuchal dystonia, pseudobulbar palsy, abnormal speech, VERTICAL GAZE PALSY, mild progressive dementia

Neuronal losses:

Subthalamic nucleus, globus pallidus, substantia nigra, colliculi, periaqueductal gray, dendate nucleus

Microscopic features: globose neurofibrillary tangles, tufted astrocytes

Molecular features: filaments of 4R tau via immunohistochemistry or ultrastructural (electron microscopic) analysis

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Disease with globose neurofibrillary tangles and tufted astrocytes

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Progressive supranuclear palsy