DEGENERATIVE DISEASES OF BASAL GANGLIA AND BRAINSTEM-Multiple System Atrophy

Question 1

What is multiple system atrophy (MSA) ?

Answer 1

describes a group of disorders characterized
by the presence of glial cytoplasmic inclusions, typically within thecytoplasm of
oligodendrocytes, that can havedifferent patterns of clinical presentation. [60]

Question 2

What are the dominant symptoms of MSA?

Answer 2

It can be:

• parkinsonism (MSA-P, historically known as striatonigral degeneration), or
• cerebellar dysfunction (MSA-C, previously known as olivopontocerebellar atrophy), or
• autonomic dysfunction (MSA-A, once known as Shy-Drager syndrome).

Question 3

Of these MSA, _________ is the** least frequently observed** pure syndrome.

These variants appear to stem from a single disease
mechanism, and many affected individuals develop symptoms during the course of the illness
that fall into more than one clinical pattern.

Answer 3

MSA-C

Question 4

What is the morphology of MSA?

Answer 4

The gross pathology matches the clinical presentation.

In cerebellar forms
there is typically atrophy of the cerebellum, including the cerebellar peduncles, pons
(especially the basis pontis), andmedulla (especially the inferior olive), while in parkinsonian
forms the atrophy involves both the substantia nigra and striatum (especially putamen).

Since autonomic symptoms are related to cell loss from the catecholaminergic nuclei of the
medulla and the intermediolateral cell column of the spinal cord, there are usually no specific
gross findings.

Atrophic brain regions show evidence of neuronal loss as well as variable numbers of neuronal cytoplasmic and nuclear inclusions.

Question 5

What is the diagnostic finding in MSA?

Answer 5

The diagnostic glial cytoplasmic inclusions were originally demonstrated in oligodendrocytes
with silver impregnation methods and contain α-synuclein as well as ubiquitin and αBcrystallin.
The inclusions are ultrastructurally distinct from those found in other neurodegenerative diseases and are composed primarily of 20- to 40-nm tubules

. Similar inclusions may also be found in the cytoplasm of neurons, sometimes in neuronal and glial
nuclei, and in axons.

Question 6

What is the major component in the inclusion of MSA?

Answer 6

As in PD, α-synuclein is the major component of the inclusions, but unlike PD, no mutations in
the gene encoding this protein have been found in patients with MSA.

Furthermore, unlike in PD, α-synuclein–containing inclusions are found in glial cells, notably oligodendrocytes.

The
relationship between glial cytoplasmic inclusions and disease is supported by the observation that the inclusions are present in low numbers at earliest stages of MSA and increase in abundance as the disease progresses, although they eventually disappear as cells die in the
final stages.

It appears that glial cytoplasmic inclusions can occur in the absence of neuronal loss, suggesting that they may represent a primary pathologic event; for example, glial
cytoplasmic inclusions are consistently observed in the white matter projecting to and from the
motor cortex.

The origin of the α-synuclein in oligodendrocytes remains perplexing, since this is
a neuronal protein associated with synaptic vesicles. Several studies have shown that there is no up-regulation of α-synuclein expression in white matter or in oligodendrocytes in MSA, suggesting that the protein may be acquired secondarily by oligodendrocytes from injured or
dying neurons.

It may be that the less conspicuous neuronal inclusions of α-synuclein, which
are also present in MSA, are more closely linked to the disease process