DEGENERATIVE DISEASES OF BASAL GANGLIA AND BRAINSTEM

Question 1

Diseases affecting these regions of the brain are frequently associated with movement
disorders, includingrigidity, abnormal posturing, and chorea. In general, they can be
categorized as manifesting either a _____________

Answer 1

• reduction of voluntary movement
• or an abundance of involuntary movement.

Question 2

The basal ganglia, especially the ________-, play an

• *important role in the system of positive and negative regulatory synaptic pathways** that serve to
• *modulate feedback from the thalamus to the motor cortex.**

The most important disorders in this
group are those associated with parkinsonism and Huntington disease.

Answer 2

nigrostriatal pathway

Question 3

What is Parkinsonism?

Answer 3

It is a is a clinical syndrome characterized by:

• diminished facial expression,
• stooped posture,
• slowness of voluntary movement,
• festinating gait (progressively shortened,accelerated steps),
• rigidity,
• and a “pill-rolling” tremor.

This type of motor disturbance is seen in
a number of conditions that have in common damage to the nigrostriatal dopaminergic system.
Parkinsonism may also be induced by drugs that affect this system, particularly dopamine
antagonists and toxins.

Question 4

The principal diseases that involve the nigrostriatal system are as
follows:

Answer 4

• Parkinson disease (PD)
• Multiple system atrophy, commonly associated with parkinsonism as well as other
symptoms
• Postencephalitic parkinsonism, which was observed as a late consequence of the influenza pandemic of 1918
• Progressive supranuclear palsy and corticobasal degeneration, movement disorders
that may also show cognitive impairment (discussed above with the FTDs)

Question 5

How is the diagnosis is made in individuals with Parkinson Disease?

Answer 5

• with progressive L-DOPA-responsive signs of parkinsonism (tremor, rigidity, and bradykinesia) in the absence of a toxic or other known underlying etiology.
• Familial forms of PD with autosomal dominant or autosomal recessive inheritance exist.

Although these make up a limited number of cases, they have contributed to our understanding of the pathogenesis of the disease.

Question 6

What is the typical macroscopic findings in parkinson’s disease?

Answer 6

pallor of the substantia nigra
(compare Fig. 28-40A and B) and locus ceruleus.

Question 7

Answer 7

C, Lewy body in a substantia nigra
neuron, staining bright pink (arrow)

Question 8

What is the microscopic finding in** Parkinson’s Disease?**

Answer 8

On microscopic examination, there is:

• loss of the pigmented, catecholaminergic neurons in these regions,
• associated with gliosis.
• Lewybodies ( Fig. 28-40C ) may be found in some of the remaining neurons. These are single or
• multiple, cytoplasmic, eosinophilic, round to elongated inclusions that often have a dense core surrounded by a pale halo.

Note:

Ultrastructurally, Lewy bodies are composed of fine

filaments, densely packed in the core but loose at the rim; these filaments are composed of α-synuclein.

Lewy bodies may also be found in the cholinergic cells of the basal nucleus of Meynert, which is depleted of neurons (particularly in patients with abnormal mental function), as well as in other brainstem nuclei including the locus ceruleus and the dorsal motor nucleus of the vagus.

Question 9

More than a dozen genetic loci for PD have been identified through linkage studies.

The five genes currently known to be clearly associated with the disease point to a complex set of
possible disease mechanisms. [53,] [54]

Answer 9

• The first gene to be identified as a cause of autosomal dominant PD encodes α-synuclein,
• 2nd: LRRK2 (leucine-rich repeat kinase 2)
• 3rd: parkin
• 4th:** DJ-1, **
• 5th: PINK1

Question 10

What is α-synuclein?

Answer 10

It is an an abundant lipid-binding protein normally associated with** synapses that is also a major component of the Lewy body**.

Mutations in α-synuclein are rare; they take the form of point mutations and amplifications of the region of chromosome 4q21 that contains the gene.

The occurrence of disease caused by changes in gene copy number implies a gene dosage effect, similar to what has been observed with APP in AD, and suggests that polymorphisms in the α-synuclein promoter that alter its expression may influence the risk of PD.

Question 11

Mutations in the gene encoding __________-are a more common
cause of autosomal dominant PDand are found in somesporadic cases of the disease.

Answer 11

LRRK2 (leucine-rich repeat kinase 2)

Note: Several
of these pathogenic mutations increase the kinase activity of LRRK2, suggesting that gains in
LRRK2 function contribute to the development of PD

Question 12

A juvenile autosomal recessive form of PD is caused by loss of function mutations in the gene
encoding __________ an E3 ubiquitin ligase with a wide range of substrates.

Answer 12

parkin,

Question 13

The pathology of
parkin-linked PD is similar to that of α-synuclein–linked or sporadic PD except that__________
are absent in most cases.

Answer 13

Lewy bodies

Question 14

Other cases of autosomal recessive PD are the result of mutations in
the gene encoding ___________a protein involved in regulating redox responses to stress; or the gene
encoding the kinase _________, which appears to regulate normal mitochondrial function.

Answer 14

DJ-1,

PINK1

Question 15

What is the pathogenesis of PD?

Answer 15

No unifying pathogenic mechanism has emerged yet from these diverse genetic and
biochemical clues, and many possibilities have been suggested, including a misfolded
protein/stress response triggered by α-synuclein aggregation; defective proteosomal function
due to the loss of the E3 ubiquitin ligase parkin; and altered mitochondrial function caused by
the loss of DJ-1 and PINK1.

Intriguingly, other lines of evidence also point to a role for
mitochondrial dysfunction; for example, levels of mitochondrial complex I, a component of the
oxidative phosphorylation cascade, are reduced in the brains of patients with sporadic PD, and
some models of experimental PD are produced by the administration of mitochondrial inhibitors.

Question 16

The dopaminergic neurons of the substantia nigra project to the striatum, and their
degeneration in PD is associated with a reduction in the striatal dopamine content.

The severity
of the motor syndrome is proportional to the dopamine deficiency, which can, at least in part, be
corrected by replacement therapy with ____________ (the immediate precursor of dopa mine).

Treatment does not, however, reverse the morphologic changes or arrest the progress of the
disease; moreover, with progression, drug therapy tends to become less effective and
symptoms become more difficult to manage.

Answer 16

L-DOPA

Question 17

An acute parkinsonian syndrome and destruction
of neurons in the substantia nigra follows __________, discovered as a contaminant in the illicit synthesis of psychoactive
meperidine analogues.

The use of this toxin in experimental animals has proved highly useful in
studies of therapeutic interventions for PD, including transplantation.

Epidemiologic evidence
has also suggested pesticide exposure as a risk factor for PD, while caffeine and nicotine may
be protective.

Answer 17

exposure to MPTP (1-methyl-4-phenyl-1,2,3,6-
tetrahydropyridine)

Question 18

In addition to the signs of parkinsonism,___________ is common, as is some
impairment of cognitive function.

Parkinson disease is sometimes accompanied by a dementia,
either early in the course of the illness or as a late additional morbidity.

While L-DOPA therapy
is often extremely effective in symptomatic treatment, it does not significantly alter the
intrinsically progressive nature of the disease.

Over time, L-DOPA becomes less able to help
the patient through symptomatic reliefandbegins to lead to fluctuations in motor function on its
own.

Given the wellcharacterized biochemical defect in PD, it has been the focus of early
therapeutic trials for neural transplantation and gene therapy. [55] Other current neurosurgical
approaches to this disease include the strategic placement of lesions elsewhere in the
extrapyramidal system to compensate for the loss of nigrostriatal function and placement of
stimulating electrodes (deep brain stimulation).

Answer 18

autonomic dysfunction