Neurodegenerative Disease

Neurodegenerative Spinal Weakness

Amylotrophic Lateral Sclerosis (ALS) (aka in Britain as Motorneurone Disease)

A progressive and fatal disorder characterized by upper and lower motor neuron degeneration of brain and spinal cord.

Pathology

Bunina bodies = very small, eosinophilic cytoplasmic bodies found in surviving anterior horn cells in ¾ of patients. Hallmark of ALS

Like most neurodegenerative diseases, the relative risk of having this disease increases with age.

Large motor neuron anterior horn cells which project to muscle degenerate and cause the muscle atrophy.

Glial reaction occurs but is not as dramatic as seen in infarct. Myelin staining shows ß horn cells and Ý glial cells.

When neuron breaks down – so do the motor roots of spinal cord which grossly looks dark and shrunken (sensory don’t).

Appearance is do to demyelination secondary to axonal degeneration (as opposed to primary demyelinating disease.)

Break down of axons leads to muscle atrophy in tongue, axial or extremity muscles. (oculomotor and parasympathetic spared)

Motor cortex neurons degenerate but grossly are not very noticeable because they are surrounded by a lot of other stuff.

Lateral Cortical Spinal Tracts become Sclerotic due to reactive astrocytosis caused by death of these neurons.

An increased number of macrophages are seen. ALS can be distinguished from MS (an autoimmune disease) by:

(1) perivascular lymphocytes in MS that are not seen in ALS
(2) Macrophage infiltration and astrocytosis are severe (inflammatory response) in MS, not as bad in ALS
(3) In ALS there is anatomical restriction of myelin loss to only the cortico-spinal tract (bilateral damage), not in MS

Epidemiology: global incidence 1-2/10⁵; prevalence 3-4/10⁵; peaks 50-70 yo.; M/F-1.5/1; 4-6yr course; 5%genetic-AD

Basal Ganglia and Movement Disorders

Huntington’s Disease (HD) – Hyperkinetic

Characterized by cognitive and affective abnormalities with choreoathetoid movement disorder.

Epidemiology: Always genetic: autosomal dominant with full penetrance and anticipation (Clinical manifestation of triple repeat disease).

11-31 CAG repeats on short arm of Chrm 4 are normal; >38 repeat = HD

Global prevalence 5.1/10⁵; onset varies from 1^st to 8^th decade; mean onset age = 39; survival 10-25 yrs;

Pathology – IgG and CSF are increased

On CT you the basil ganglion, which normally bulge into the lateral ventricle, are flat or concave due to atrophy

This atrophy accounts for the hyperkinetic component of HD
Cortex also shows damage which accounts for the cognitive and affect components of this disorder.

In HD the GABA/Enkephalin neurons of the Striatum degenerate which reduces inhibitory inputs to the external GP which ultimately disinhibits VA/VL which then more effectively excites the premotor cortex leading to hyper kinetic movements.
HD has a predictable pattern of neuronal loss, staring with Caudate then Putamen. Degree of neuronal loss and disability are so closely linked that HD can be Graded based on Caudate Profile /and Neurologic Disability as follows:

(1) Normal/Assisted ambulation

(2) Less convex/minimal ambulation

(3) Flat/wheel chair bound

(4) Concave/Bed-ridden

Parkinson’s Disease (PD) – Hypokinetic

Characterized by resting tremor, bent trunk, ß muscle power of inactive parts, bradykinesia, eventual dementia

Epidemiology: Prevalence 75/10⁵; symptomatic during 6^th-7^th decade; progressively incapacitating until death in ~ 10years.

Pathology: Main abnormality: degeneration of pigmented Substantia niagra neurons, the pars compacta (dopamine is pigment).

Other areas are affected including the Locus Ceruleus.

Cytologic hallmark is the Lewy Body = eosinophilic spherical inclusion, usually with halo or lamination within surviving neurons in the brainstem pigmented nuclei as well as elsewhere in the nervous system.

Consist of neurofilaments which have undergone phosphorylation, ubiquination, proteolysis and cross-linking.

Synuclein is the major protein in Lewy Bodies. Associated with turn over of synaptic membranes.

Microscopically you see a few pigmented cells, an increase in glial cells and clusters of macrophages full of pigment.

Only patients with PD respond to dopamine replacement therapy.

Caudate/Putamen are the Striatum which receives dopaminergic neurons from the Substantia Niagra. The striatum has two types of inhibitory neurons w distinct dopamine receptors: D₂ is on neurons projecting to external GP and is inhibitory to its own cell when bound; D₁ is on neurons projecting to Internal GP and is excitatory to its cell when bound.

removal of dopamine from the D₁ and D₂ receptors will serve to directly reduce the inhibitory influence of the D₁ neurons increase the excitatory influence from the Subthalamus on the Internal GP. This in turn increases the Internal GP inhibition of the VA/VL complex which then less effectively excites premotor cortex, leading to hypokinetic movements.

One form of therapy for PD has been to lesion the Globus Palidus to balance its hyper active state in PD. This improves cortico-motor symptoms but not brain stem associated symptoms. Therefore an alternative therapy has been to lesion the Sub thalamic nucleus which also improves the brain stem symptoms. This is risky because you have to cross the internal capsule which you don’t want to damage. High frequency stimulation implants work w less risk than lesion.

Treatment – intracerebral neuronal grafting

Differential Diagnosis: Other Hypokinetic disorders that involve the nigrostriatal system.

Multiple System Atrophy (MSA)

Other known form of Synucleinopathy that includes: Shy-Dragar syndrome and olivopontocerebellar atrophy.
Characterized by depigmentation and presence of glial cytoplasmic inclusions, typically within oligodendrocytes.
These inclusions are distinct and may represent the primary pathological event. Does not have Lewy bodies

The pathologic process involves central somatic and autonomic motor systems

Progressive Super Nuclear Palsy (PSP)

Widespread neuronal loss in GP, sub thalamic nuclei, substantia niagra, colliculi, periaqueductal gray matter and dentate
Neurofibrillary tangles full of Tau protein are found in these areas. Some of the isoforms of Tau are same as in AD
Mimics PD; Clinically recognized by (1) Vertical gaze palsy and (2) Precipitate falls – knees buckle.
Onset between 5^th and 7^th decade with death in 7yrs. Mild progressive dementia in most patients.

Cortical Basal Degeneration (CBGD)

Asymmetric cerebral cortical degeneration leading to unilateral findings.
Extrapyramidal rigidity, asymmetric motor disturbance ("alien hand" as in Dr. Strangelove), sensory and cortical dysfunction

Tau is found in astrocytes, basal ganglion neurons and variably in cortical neurons.
Loss of pigmented neurons in substantia niagra and locus ceruleus.
Cortex shows sever loss of neurons, gliosis and ballooned neurons (neuronal achromasia)

Cortical Dementia

Alzheimer’s Disease

this is a disease with both Amyloid and Tau protein.
Cerebral atrophy is observed but not unique to this disorder or over laps with normal atrophic variation.

Senile plaques: core of amyloid surrounded by Neurofibrillary Tangles.

Neurofibrillary Tangles: perinuclear intraneuronal accumulations of paired helical filaments with an abnormally phosphorylated Tau protein core surrounded by ubiquitin reactive filaments.

Neuronal threads: The equivalent of tangles in dendrite and neuropil. Contain Tau and precede tangles

Amyloid is necessary but not sufficient

Pathological progression: evolution of bilateral damage centering around the limbic system. Bilateral entorhinal cortex damage impairs transmission of info from neocortext to hipoccampus preventing many declarative memory functions (D3J Neuro-541). Further limbic destruction leads to personality changes and cognitive decline. By the time Neocortex is involved, disease is particularly symptomatic. Hypertonic/hypokinetic syndrome due to striatum and substantia niagra involvement.

Pick Disease

AD like with frontal lobe (personality changes) and temporal lobe (language disturbances) symptomatology.
Asymmetric atrophy of the frontal and temporal lobes which can get wafer thin giving "Knife edge" appearance.

Lobar atrophy is grossly distinguishable from AD. Often has bilateral striatum atrophy also.

Pick cells contain Pick bodies similar to the tangles found in AD but do not remain after death as markers.

Vascular Dementia

Caused by multifocal vascular disease consisting of:

(1) cerebral atherosclerosis
(2) thrombosis or embolism from carotid or the heart
(3) cerebral arteriolar sclerosis from hypertension.

Multiple bilateral gray and white matter infarcts over months and years result in dementia, gait abnormalities, and pseudo-bulbar signs, often with superimposed focal neurological deficits.

Lewy Body Dementia – Idiopathic Parkinsons – 2^nd most common dementing disease in U.S.