Degenerative Neurological Diseases

The Basics
Degenerative Dx: Affects gray matter, neurons with associated 2 white matter changes
Pathogenesis usually involves protein aggregation
Neuronal loss is selective
No clear inciting event or previous deficits, diagnosis of exclusion
Locations of degenerative Dx
Cortex (Alzheimer, FTLD, Vascular Dementia)
Basal Ganglia (Parkinson, Huntington)
MNs (ALS, Werdnig Hoffman Dx)
I. Cortical Degenerative Diseases
1. Dementia: Degenerative cortical Sd characterized by higher cortical fxn without clouding of
consciousness
a. Caused by degenerative Dx, chronic infection, vitamin deficiency, toxins, diffuse injury, metabolic
disorders, mass lesions, genetic Dx
2. Alzheimer Dx (Senile Dementia of Alzheimers Type)/AD
a. Most common cause of elderly dementia, rarely symptomatic before 50
i) 1% of 60-65, 40% of 85-89
b. 5-10% cases are familial (early onset is AD)
c. Some Trisomy 21 patients have a form of AD (Ch 21 codes for cerebral amyloid)
d. Diagnose w/ clinical tests & radiographs (tissue examination is definitive)
e. Pathogenesis: Accumulation of abnormally cleaved (-secretase) A amyloid and hyperphosphorylated
Tau
f. Gross: Variable cortical atrophy in frontal, parietal, temporal lobes hydrocephalus ex vacuo
g. Micro: A amyloid plaques extracellularly, tau tangles intracellularly (extracellular after neuron death),
amyloid angiopathy (A40 amyloid deposited around vessels, can occur without Alzheimer)
i) Also found in elderly nondemented patients
ii) Tangles contain paired helices of Tau (dementia associated with synapses, tangles)
iii) Amyloid stains w/ Congo Red, shows apple-green birefringence under polarized light
iv) Granulovacuolar degeneration: Small, clear intraneuronal vacuoles (hippocampus, olfactory bulb)
that stain w/ silver stains
v) Hirano bodies: Glassy eosinophilic bodies (paracrystalline actin) in hippocampus pyramidal cells
h. Entorhinal cortical atrophy loss of spatial direction, hippocampal atrophy memory loss,
neocortical atrophy higher cortical fxn

3. Frontotemporal Lobar Degenerations/FTLD: Heterogeneous, focal degeneration

a. (personality, behavior, language) memory loss
b. Separated into FTLD-tau & FTLD-TDP based on cellular inclusions
c. FTLD-tau: Neuronal loss, reactive gliosis w/ tau-containing inclusions (tangles or Pick bodies)
i) Pick Dx: Severe gyral atrophy of anterior frontal, lower temporal lobes (also caudate & putamen)
(1) Usually sporadic (familial assoc. with tau mutations)
ii) Pick bodies (neurofilaments) stain w/ silver, do not persist after neuron death
4. Vascular Dementia
 a. Results from >1 small infarcts or cortical laminar necrosis (hTN) or diffuse white matter injury
(Binswanger Dx chronic HTN)
b. Resolving vasculitis clears up dementia
c. Also assoc. with strategic (embolic) infarcts in the hippocampus, DM thalamus, frontal cortex
d. Multiple infarcts over time multi-infarct dementia
II. Basal Ganglia Degenerative Dx
1. Parkinson Dx
a. Middle/late life
b. Most cases are sporadic but familial cases are AD
i) Familial cases involve mutated forms of genes for -synuclein (lipid binding, forms Lewy bodies),
Parkin (E3 ubiquitin ligase), UCH-L1 ((de)ubiquitination) accumulation from altered
degradation
c. Facial expression, stooped posture, slowed voluntary movement w/ accelerated steps, rigidity, pill-
rolling tumor
d. Pigmented neurons of SN synthesize dopamine, project to BG neuron death PD
e. Gross: Pallor of the substantia nigra, locus coeruleus
f. Micro: Catecholaminergic neurons in the SN & LC w/ gliosis, Lewy bodies in remaining neurons
i) Lewy bodies are cytoplasmic, eosinophilic inclusions w/ a dense core & pale halo
g. L-Dopa provides symptomatic relief but does not arrest/reverse pathogenesis
h. MPTP SN degeneration causes PD symptoms
i. Parkinsonism: Clinical Sd (caused by PD, multiple system atrophy, post(influenza)encephalitis, toxins
(pesticides) & Rx (MPTP)) related to damaged SN dopaminergic system
j. Dementia w/ Lewy Bodies (10-15% of patients): Can be AD, but other cases show many Lewy bodies
advanced PD
k. Atypical Parkinsonism: Clinical Parkinsonism without responsiveness to L-DOPA
i) Tauopathies (Progressive Supranuclear Palsy/PSP (abnormal eye movement) & Corticobasal
Degeneration/CBD (asymmetric movement)
ii) Synucleinopathies (multisystem atrophy (cerebellar ataxia)
2. Huntington Dx: Progressive movement disorder & dementia
a. Symptomatic @ 30-50y, fatal within several years
b. AD, mutation in Huntingtin protein (4p16.3) excessive number of CAG repeats (more repeats =
earlier onset), no sporadic cases
i) Normally have 6-35 CAG repeats
ii) Paternal transmission associated with anticipation (early onset, severity in next generation)
c. Loss of striatal input subthalamic n. inhibited dysregulation of motor activity & choreoathetosis
i) Loss of striatal neurons & fibrillary gliosis
ii) Later cortical loss, cognitive changes & dementia
III. Motor Neuron Degenerative Dx
1. Amyotrophic Lateral Sclerosis/ALS: Loss of anterior horn LMNs & CST UMNs (Betz cells)
a. Presents after 40y, 5-10% AD familial
b. Muscle wasting & spastic paralysis
c. Early asymmetric hand weakness w/ cramping & spasticity of arms/legs muscle strength/mass &
fasciculations affects respiratory muscles i.e. pneumonia
i) Death within 5-10 years
d. Gross: Degeneration of anterior roots
 e. Micro: Loss of CST myelin, atrophy of anterior nerve roots in spinal section
i) Skeletal muscle: Groups of small angulated fibers w/ space between fibers
2. Progressive Muscle Atrophy: Anterior horn cell degeneration flaccid paralysis & muscle wasting
3. Primary Lateral Sclerosis: CST degeneration dominant spasticity
4. Progressive Bulbar Palsy: Degeneration of lower brainstem cranial motor n. (V, VII, IX, XII)
5. Werdnig-Hoffman Dx
a. Infants w/ poor suck, weak cry, little limb movement
i) Usually symptomatic @ birth, death in several years
b. DDx is 1 muscle Dx
c. Some cases are sporadic, some are familial (AD or AR)
d. Pathology similar to adult MN Dx