MBB II. WEEK 5-6.

READING: NERODEGENERATIVE DISORDERS

Neurocognitive Degeneration
Introduction
Dementia is defined by a loss of cognitive function and memory impairment that exceeds
those of normal cognitive aging. The reason for both dementia and normal cognitive aging
is a loss of neurons. As humans age, neurons are lost. All patients will experience cognitive
decline and impaired memory. That loss of neurons can be stifled—the more that synapses
reinforce pathways, the more an individual engages their brain, the slower that loss will
occur. A human can also engage in behaviors, such as heavy alcohol consumption, or
experience disease, such as stroke or seizure, that lead to more abrupt cognitive decline.
But in some genetically susceptible people, cognitive decline is accelerated by the
accumulation of protein aggregates and the apoptotic loss of neurons—
neurodegenerative disease.

Neurodegenerative diseases are characterized by the progressive loss of neurons and

typically affect groups of neurons of a common tract, even if they are not immediately
adjacent to each other. Each neurocognitive disease tends to have a predilection for a
particular neural system and, therefore, has a stereotypical presentation that is fairly non-
overlapping with others. However, all of them, if given enough time, will progress to
widespread neuronal loss. The symptoms that each disease causes are based on where it
starts.

Although these diseases can be separated by their clinical manifestations and stereotypical
findings on brain imaging, they are, in fact, NOT linked by dementia but by infectious
protein aggregates. These protein aggregates accumulate in neurons, inducing their
apoptosis. Neuronal death results in the spilling of these aggregates. This isn’t just in the
cell body, these protein aggregates can be found in axons; therefore, the entire tract is
vulnerable to infection. Neighboring neurons take up these protein aggregates,
accumulating ever more. This feeds the disease forward, with more aggregates made and
more released as neurons subsequently die off. By the time symptoms are present, every
neuron everywhere has some amount of protein aggregates. The ones that reach a critical
concentration first, die off first.

The protein that aggregates varies by disease. The syndromes are not defined by which
aggregate accumulates, but rather where the aggregates accumulate the most, where
the neuron loss starts. In every disease, if the patient survives long enough, the aggregates
will claim all neurons.
 MBB II. WEEK 5-6. READING: NERODEGENERATIVE DISORDERS

QESTIONS FOR PRACTICE:

1. The common reason for both dementia and normal cognitive aging is:
_____________________________________________________________

2. The cognitive decline can be genetically accelerated by:

_____________________________________________________________

3. The protein aggregates may accumulate not only in neuron cell bodies but also in:
__________.

4. The neurodegenerative symptoms and syndromes depend on:

a. Type of the protein aggregates
b. Location, where the aggregates accumulate the most

Prion Disease
Prion disease isn’t an important disease process in and of itself because it is so rare.
However, it is the most severe, fastest-acting disease caused by protein aggregate
accumulation and lays the foundation for comprehending the other neurodegenerative
disorders.

There are multiple subtypes of prion disease, but they all come down to one protein—PrP.
PrP is a cell-surface glycoprotein that is normally found in all neurons. When it undergoes
c

a spontaneous conformational change to the evil PrP (Sc is for scrapie, the same disease
Sc

process as seen in goats), it becomes resistant to proteases. PrP , independent of how it

Sc

originates, then facilitates the conversion of other PrP proteins to PrP . It is this propagation
c Sc

of PrP that accounts for the transmissible nature of prion diseases.

Sc

Figure 1: Mechanism of Prion Disease

When a normal protein (PrP ) spontaneously converts to PrP , it not only instigates the conversion
C Sc

of more PrP to PrP in the affected neuron, but as the neuron undergoes apoptosis, it releases the
C Sc
 MBB II. WEEK 5-6. READING: NERODEGENERATIVE DISORDERS

PrP , which neighboring neurons uptake, repeating the process. Thus, neurons rapidly undergo
Sc

apoptosis, resulting in the death of a patient within 6 months.

This capacity for a protein in an abnormal conformation to induce a similar structural

change in other molecules as a self-propagating process has recently been demonstrated in
each of the diseases discussed in this lesson. Prion disease is just much faster than the
others that follow. From the time of symptom onset to death is less than 6
months. Creutzfeldt-Jakob Disease (CJD) is the most common prion disease, occurring in
1 per 1,000,000 people. You will never see a case of CJD. The most common ways
of acquiring CJD were from transplanting neural tissue (corneal transplant), ingesting
neural tissue (cannibalism caused Kuru), and sticking things into neural tissue (deep brain
electrodes). We are more careful now, so the most likely mechanism will be a sporadic
mutation in the PRNP gene. The incidence is highest in the seventh and eighth decades of
life. There is a rapid decline in memory, behavior, and motor function, with severe cognitive
defects, memory impairment, and spastic contractions of the extremities.

Vacuolization of neurons is seen universally in prion disease, but the mechanism by which
it happens is unclear. The protein spreads rapidly and involves the cerebellum, striatum,
and most of the cortex.

The importance of this disease is that it demonstrates the infectious protein process. Proteins
accumulate and neurons die off, releasing the protein to neurons around them, even at
synapses. The protein is taken up by other neurons, which suffer the same fate and
accelerate the disease process by having more protein converted within them, leading to the
accumulation of more and more protein aggregates.

QESTIONS FOR PRACTICE:

1. The cell-surface glycoprotein that is normally found in all neurons an is affected in

prion disease known as: _______________

2. The pathological confirmation of this glycoprotein is _____________

3. Regarding the speed of the neurodegenerative diseases associated with pathological

protein aggregates, a prion disease is:
a. much faster than the others that follow
b. much slower than the others that follow

4. The most common prion disease is _____________________________

5. Please, shortly describe how infectious protein spreads around:
_____________________________________________________________
_____________________________________________________________
 MBB II. WEEK 5-6. READING: NERODEGENERATIVE DISORDERS

PRIMARY PRIMARY
DISEASE INCLUSIONS
DYSFUNCTION LOCATION

Aβ (plaques,
Alzheimer’s disease
Dementia, memory Hippocampus causative)
(AD)
τ (tangles, present)

Frontal lobe
τ
Hippocampus
Behavioral changes,
Frontotemporal lobar language disturbance
degeneration (FTLD) TDP-43
Loss of inhibition
FUS

Parkinson’s disease
Bradykinetic movement Substantia nigra α-synuclein
(PD)

Huntington’s disease Hyperkinetic movement Huntingtin

Striatum
(HD) disorder (polyglutamine)

Weakness with upper and intracellular superoxide

Amyotrophic lateral
lower motor neurons Motor neurons dismutase aggregates
sclerosis (ALS)
signs
Table 1: Neurocognitive Degeneration

Alzheimer’s
Alzheimer’s disease is the most common cause of dementia in the United States. The
clinical features are a loss of memory and impaired attention. Personality, motor, and
sensation remain intact. The area of most atrophy or the first area to experience atrophy is
the hippocampus of the temporal lobe. The pathogenesis is not completely understood at
this time. We do know that there are two abnormal proteins—amyloid β (Aβ) and tau (τ).
However, as we postulate in this section, τ is likely a symptom rather than a cause.

Aβ generation is the critical initiation event for the development of the neurodegenerative
disorder with the phenotype of Alzheimer’s disease. To support this claim, there are
diseases in which τ deposits appear, such as frontotemporal lobar degeneration, progressive
supranuclear palsy, and corticobasal degeneration, but neither Aβ deposits nor the
symptoms of Alzheimer’s disease develop. And there is good evidence based on familiar
forms or causes of early-onset disease—ApoE (APOE), trisomy 21, and presenilin-1
(PSEN1).

In Trisomy 21 (Down’s syndrome), there is an extra copy of chromosome 21. A

transmembrane protein found in neurons and glial cells alike, amyloid precursor protein
(APP), is encoded by the APP gene. It is constitutively expressed by neurons and glial cells
as it is a regular part of the plasma membrane. Therefore, having three copies of the gene
 MBB II. WEEK 5-6. READING: NERODEGENERATIVE DISORDERS

will produce about 50% more APP than normal. Patients with trisomy 21 have cognitive
impairments—intellectual disability—with varying degrees of severity. However, even
those with only mild impairments experience cognitive decline and impaired memory as
early as their 20s or 30s (normal onset is 60s and 70s). The accelerated onset of Alzheimer’s
disease isn’t the same in all patients with trisomy 21; thus, it isn’t causal, but APP
production is strongly indicated to be a risk factor.

The causal link between apolipoprotein E (ApoE) and Alzheimer’s isn’t established, but it
certainly plays a role. There are three possible APOE alleles—2, 3, and 4—based on two
amino acid isoforms. The gene dosage of ApoE is correlated to increased risk. Having one
4

copy of APOE4 is bad, having two copies is worse. Conversely, ApoE is protective from
2

Alzheimer’s disease, likewise in a gene dosage-dependent fashion.

Aβ is a cleavage product of APP. Periodically, as part of normal plasma membrane

remodeling, APP is recycled. Follow along with Figure 2, below. APP is recycled via both
extracellular and intracellular cleavage. The final step is always carried out by γ-
secretase, the intracellular cleavage protein. When things go well, the first cut is made by α-
secretase. This removes an extracellular APPsα (a soluble extracellular protein) from APP,
leaving behind αAPP in the membrane. When γ-secretase makes its cut, healthy, soluble
p3 peptide is released into the extracellular environment. What happens intracellularly
doesn’t matter. But if β-secretase makes that first cut, a shorter APPsβ (also soluble, so not
the problem protein) is released, leaving behind βAPP in the membrane. When γ-secretase
cleaves βAPP, it releases insoluble Aβ protein instead of the usual soluble p3 into the
extracellular space. Astrocytes and neurons can’t process the Aβ proteins, so they
accumulate. Then, they form Aβ protein aggregates, forming Aβ plaques. The neurons
don’t like plaques, and the astrocytes don’t either. But neither are equipped to deal with the
plaques. We’re going to come back to what “don’t like plaques” means.

Figure 2: Aβ Pathogenesis
When the sequence is α-secretase then γ-secretase, the result is two soluble molecules. When the
sequence is β-secretase then γ-secretase, the result is an insoluble Aβ protein that accumulates
outside the affected neuron, forming the Aβ plaque.
 MBB II. WEEK 5-6. READING: NERODEGENERATIVE DISORDERS

τ is a microtubule-associated protein (MAP) that supports and maintains the axon

microtubules. When τ is phosphorylated, it is more likely to dissociate from the
microtubule it was bound to. Neurofibrillary tangles are a histological hallmark of
Alzheimer’s, but they are also found in other neurocognitive diseases. Neurofibrillary
tangles are made of hyperphosphorylated τ protein aggregates. These neurofibrillary
tangles are found in the axons and cell bodies that encounter an Aβ plaque. Aggregated τ is
also present in dystrophic neurites that form the outer portions of neuritic plaques and axons
coursing through the affected gray matter. Wherever there are plaques outside the
cell, tangles develop inside the cell and only at that spot.

This next sentence is our inference, not something that has been proven. It really seems that
certain neurons express more APP than other neurons, and those are the ones that make the
plaques. The neuron that makes the plaque doesn’t like the plaque, as evidenced by the
changes in the plasma membrane of the neuron near the plaque, the same location that
the τ tangles form in the cell body. Other neurons don’t like the plaque, as evidenced by
histology; wherever a plaque is, the part of another cell in contact with the plaque—be it
axon, dendrite, cell body, whatever—will develop τ tangles. It seems like the plaques cause
the neurons to freak out whenever they’re touched by one. “Freaking out near a plaque”
leads to something that medical science has not yet elucidated that changes the
phosphorylation of cytoplasmic molecules at that spot. τ is likely phosphorylated
secondarily, a result of locally upregulated kinases. It just so happens that τ is really
vulnerable to phosphorylation, and phosphorylation causes τ to release its microtubule. And
because they are only hyperphosphorylated at that spot, more and more τ molecules try to
pass through that spot only to be phosphorylated and dissociate. The dissociation
of τ proteins over time results in the tangle.

The typical Alzheimer’s patient is one with progressive memory loss. The neurons that
are affected first and in greatest severity are in the hippocampus, the memory storage part
of the brain. The patient first loses the ability to form new memories. Short-term memory
and attention may be retained early in the disease. Then, short-term memory is lost
altogether, followed by the subsequent loss of long-term memory (retrograde amnesia). The
person will not recall recent events, some patients in no more than a 10-second loop, and
will often become disoriented, not remembering their own house or spouse. With the
degeneration of cortical mass, the remaining space is filled with CSF. There will be overall
atrophy, most pronounced in the hippocampus.

Figure 3: Alzheimer’s Disease

 MBB II. WEEK 5-6. READING: NERODEGENERATIVE DISORDERS

(a) Neurofibrillary tangles of hyperphosphorylated τ protein. (b) Two plaques are visible, and only
the top plaque demonstrates a neuron. At this magnification, neurites are not visible. (c) Coronal
T1-weighted MRI from a patient with Alzheimer’s disease for comparison with (d), a normal coronal
section from approximately the same location. Notice the disproportionate temporal atrophy in
addition to hydrocephalus and superior atrophy. Panels (e) and (f) show sagittal views from the
same patients as in (c) and (d), respectively, demonstrating severe degeneration of the temporal
lobe in the patient with Alzheimer’s disease.

NOTE: CSF ex vacuo is a proposed designation for abnormal collections of CSF replacing brain tissue
which is absent or has disappeared as a result of maldevelopment, injury, infection, vascular
disturbances, brain atrophy, etc.

Although histologically, the disease burden (i.e., the severity of memory and cognitive
impairment) is better correlated to the number of τ tangles than the number of Aβ plaques,
Alzheimer’s disease is not based on brain biopsy. And, consistent with our theory, more
tangles indicates more severe disease burden, the two symptoms—τ tangles and impaired
cognition—advancing together. Medical science possesses the ability to perform functional
MRI, evaluate the current Aβ plaque burden, and reliably deduce when dementia will set
in. This isn’t helpful yet, as there are no Aβ plaque-removing medications. Future
treatments could facilitate Aβ plaque removal or target β-secretase to prevent more
Aβ from being released.

Nothing has been found to slow the disease progression. Acetylcholine and glutamate are
excitatory neurotransmitters. There have been trials that demonstrate that glutamate
antagonists (such as memantine) and acetylcholinesterase inhibitors (donepezil)
improve quality of life. The benefit derived is empirical, so the mechanism need not be
explored. Once symptomatic, the average lifespan is 5–10 years with a progressive decline
in cognitive and, eventually, motor function. Death is often secondary to infection. Like the
other neurodegenerative diseases, the medications improve symptoms but do not affect the
progression of the disease.

QESTIONS FOR PRACTICE:

1. What are the most typical symptoms of Alzheimer’s disease:

a. Significant changes in personality,
b. Sensation disturbances
c. Loss of memory and impaired attention
d. Hypokinetic movement disorders
2. The area of most atrophy or the first area to experience atrophy in Alzheimer’s
disease is:
a. The hippocampus of the temporal lobe
b. Thalamus and hypothalamus
c. Substantia nigra and subthalamic nucleus
d. Prefrontal cortex
3. There are two abnormal proteins in Alzheimer’s disease: ________ and __________.
 MBB II. WEEK 5-6. READING: NERODEGENERATIVE DISORDERS

4. In Alzheimer’s disease:
a. Aβ protein accumulates outside the affected neuron
b. Aβ protein accumulates inside the affected neuron
c. Aβ protein accumulates in microtubules
d. Aβ protein accumulates inside the astrocytes

5. The difference between Aβ plaques and neurofibrillary tangles (that are made
of hyperphosphorylated τ protein aggregates) is:
a. Aβ plaques develop inside the cell, and tangles develop outside the cell
b. Aβ plaques develop outside the cell, and tangles develop inside the cell

6. What is happening to the space around the degenerated cortical areas?

_____________________________________________________________
7. Describe the main memory loss symptoms in Alzheimer’s disease:
______________________________________________________________
______________________________________________________________
______________________________________________________________
______________________________________________________________

Frontotemporal Lobar Degenerations (FTLDs)

FTLDs are a heterogeneous set of disorders (plural) that share a common phenotype—
disinhibition, loss of social grace, personality changes, and memory loss. They affect
the frontal lobes first and more severely than the temporal lobes. Given long enough, just
as in any of the protein-aggregate diseases, all neurons will be claimed. The description of
these disorders often confuses learners as they are also studying Alzheimer’s. The opening
sentence was written deliberately. FTLDs don’t affect the frontal lobes and temporal lobes,
just as Alzheimer’s doesn’t affect the frontal lobes and temporal lobes—that would being
saying they are identical. Alzheimer’s takes the temporal lobes first and foremost, and late
in the disease, the frontal lobe is the next vulnerable area taken, followed by the disease
spreading elsewhere. In a similar vein, FTLDs take the frontal lobe first, then late in the
disease, the temporal lobe is the next vulnerable area taken, followed by the disease
spreading to the rest of cortex.

Formerly known as frontopolar dementia and by its eponym “Pick’s disease,” FTLDs are
yet another example of aggregate protein deposition causing neuronal apoptosis. The
term FTLD is now preferred because it accurately depicts the lobes that are most affected,
even listing them in the order that they are most affected. In all FTLDs, loss of the frontal
lobe results in personality and behavior changes. Patients with FTLDs are compulsive,
demonstrate a loss of social restraint, and sometimes loss of empathy. That is because the
back of the frontal cortex is dedicated to movement, but the front of the frontal cortex is
where personality, behavior, mood, and cognition interact with the subcortical tracts (down
to the basal ganglia). The disease progresses posteriorly through the frontal lobe, and at end
 MBB II. WEEK 5-6. READING: NERODEGENERATIVE DISORDERS

stage, there may be a loss of movement (premotor and motor cortex) or the inability to
speak (Broca’s area).

Figure 4: Frontotemporal Lobar Degeneration

(a) Comparison between a patient with FTLD (top) and a healthy patient (bottom) using axial FLAIR
MRI. The hydrocephalus ex vacuo in the frontal lobe isn’t as impressive as that seen in the
following scan (both from the same patients as in (a). The absence of lateral tissue (temporal) and
the diminished shape of the frontal lobes shows overt atrophy. (b) Coronal T1-weighted MRI
showing overt hydrocephalus ex vacuo of the frontal and temporal lobes, with resultant
enlargement of the ventricles. The patient’s left lobe (right side of image) appears to be less
affected than the right lobe (left side of image). (c) High-powered light microscopy reveals Pick
cells containing Pick bodies—round, intracytoplasmic inclusions. The dark circles within the purple
cells are nuclei. The smaller, paler-staining structures are the Pick bodies. τ Tangles are not visible
in either image.

The frontal and temporal lobes atrophy to a variable extent and with variable severity. It is
asymmetrical, although the disease progression occurs comparably. The atrophic cortical
regions are marked by neuronal loss and the presence of hyperphosphorylated τ-
containing neurofibrillary tangles. Although Alzheimer’s disease is characterized by the
combination of Aβ and τ deposition, FTLD-τ shows only τ aggregation and
accumulation. In some cases, FTLD-τ will also show smooth-contoured
intracytoplasmic inclusions (Pick bodies within Pick cells). Pick bodies and Pick
cells are the definitive means to differentiate FTLD from Alzheimer’s, which you only do
on autopsy. Like the other disorders of protein aggregation, there is no treatment. And for
FTLD, there aren’t any known medications to improve symptomology.
 MBB II. WEEK 5-6. READING: NERODEGENERATIVE DISORDERS

QESTIONS FOR PRACTICE:

1. In terms of the affected cortical areas, the differences between FTLDs and
Alzheimer’s disease (AD) is:
a. FTLDs affects the frontal lobe first, and the temporal lobe later while in AD
the temporal lobe is affected first and the frontal one later
b. FTLDs affects the temporal lobe first, and the frontal lobe later while in AD
the frontal lobe is affected first and the temporal one later
c. There is no difference in the sequence of the degeneration in cortical regions

2. The typical symptoms of FTLDs are:

3. In terms of the protein aggregations, the differences between FTLDs and

Alzheimer’s disease (AD) is:
a. Alzheimer’s disease is characterized by the combination of
Aβ and τ deposition, FTLD-τ shows only τ aggregation and accumulation.
b. Alzheimer’s disease is characterized by the Aβ plaques deposition only, while
FTLD-τ shows τ aggregation and Aβ plaques accumulation.
c. Both diseases are characterized by the combination of Aβ and τ deposition.

Parkinson’s Disease and Lewy Body Dementia

We discussed Parkinson’s disease in Cortex: Basal Ganglia. It is caused by the
accumulation of α-synuclein. When motor symptoms predominate, it is Parkinson’s
disease. The same α-synuclein aggregates also cause Lewy body dementia. When
cognitive and memory impairments predominate over the parkinsonian symptoms, the
disease is called Lewy body dementia. Both Parkinson’s with dementia (the movement
disorder predominates/develops sooner than dementia) and Lewy body dementia with
parkinsonism (dementia predominates/develops sooner than the movement disorder)
represent two outcomes of the same pathological process, which is caused by the
aggregation of α-synuclein into Lewy bodies. These intracytoplasmic inclusions induce
apoptosis in neurons. These aggregates have a predilection for, or at least form earliest and
most severely in, the substantia nigra of the basal ganglia. The loss of dopaminergic
neurons results in the inability to initiate movement. Thus, the motor symptoms are a mask-
like face (diminished expression), slowed movement, cogwheel rigidity, short shuffling
steps, and a pill-rolling tremor.
 MBB II. WEEK 5-6. READING: NERODEGENERATIVE DISORDERS

Figure 5: Lewy Bodies

The small, smooth, darker colored circles in each of these cells represent Lewy bodies. τ Tangles
(middle image left, right image bottom right) may be present, but it is the Lewy Bodies that make
this diagnosis.

Consistent with the protein aggregate theme, Lewy bodies can be released from one neuron
and taken up by another, suggesting a capacity for prion-like dissemination within the brain.
The progressive pattern of worsening movement disorder, worsening dementia, and
eventually, symptoms of other dopaminergic pathways supports this hypothesis. α-
Synuclein aggregates first appear in the medulla and then in contiguous areas of the brain,
ascending through the brainstem and extending into limbic structures and, finally, the
neocortex. There are links to mutations in both the α-synuclein gene (SNCA), leading to
the overexpression of α-synuclein, and the parkin gene (PRKN), leading to mitochondrial
dysfunction.

No therapy prevents the progression of neural degeneration. Parkinsonism, the movement

disorder, can be treated with dopamine, as discussed in Cortex: Basal Ganglia. Although
those medications treat the symptoms, they eventually stop working as the brain atrophy
progresses. Unlike the other neurocognitive degeneration disorders, parkinsonism has no
characteristic radiological findings, no detectable changes in the substantia nigra on MRI.

QESTIONS FOR PRACTICE:

1. Please describe shortly the difference between Parkinson’s Disease and Lewy Body Dementia:
___________________________________________________________________________
___________________________________________________________________________
___________________________________________________________________________
___________________________________________________________________________
___________________________________________________________________________
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Huntington’s
Huntington’s disease is a neurodegenerative disorder that results in abnormal movement
and, eventually, dementia. The protein huntingtin is encoded by the HTT gene located
on chromosome 4. The accumulation of huntingtin aggregates can eventually claim the
entire cortex, but like Parkinson’s disease, the most affected area (or, more likely, the first
area that demonstrates symptoms) is the basal ganglia. Whereas Parkinson’s claims the
substantia nigra first, Huntington’s claims the striatum.

We left the striatum as “the striatum” in Cortex: Basal Ganglia. In truth, “the striatum”
comprises the caudate nucleus, putamen, and globus pallidus. The putamen and globus
pallidus together make the lentiform nucleus. All the different ways of naming nuclei or
combinations of nuclei make this subject really annoying for new learners. And so, back to
the cables of light we go. You are the cortex, standing on the striatum, with the globus
pallidus externa (GP ) and globus pallidus interna (GP ) to your left, substantia nigra off
ext int

to the right, the subthalamus between you and the thalamus. A red cable runs from the
substantia nigra and the GP , the default state, the thalamus silent. Green cables run from
int

the subthalamus to the substantia nigra and GP , stimulating their inhibitory signal. The
int

striatum has a glowing red cable to the GP and a non-glowing black cable to the substantia
ext

nigra. Finally, a non-glowing black cable extends from the GP to the subthalamus.
ext

In Huntington’s disease, there is atrophy of the striatum. This changes the default state in
a big way. With the loss of the striatum, there is a loss of that glowing red cable to the left,
from the striatum to the GP . The GP is disinhibited, and its black non-glowing cable to
ext ext

the subthalamus is now, by default, a glowing red cable that inhibits the subthalamus. This
physiologically occurs when the cortex “dumps the bucket of dopamine” to get a movement
started. The inhibition of the subthalamus turns off the glowing green cables to the GP and
int

substantia nigra. Without that signal, the GP and substantia nigra’s glowing red cables go
int

dark. There is no inhibition of the thalamus. In the real disease, there isn’t a total loss of
the striatum, but the more striatum that is compromised, the less thalamic inhibition there
will be, and so, a disinhibited thalamus causes more movement.
 MBB II. WEEK 5-6. READING: NERODEGENERATIVE DISORDERS

Figure 6: Cables of Light In Huntington’s Disease

In keeping with our safely-not-a-trademark-violation theme of the basal ganglia, here is the
“straight to DVD” episode, the search for Gar Gar Pinks. It doesn’t get an episode because it breaks
canon altogether. In Huntington’s disease, the damage to the striatum (caudate nucleus) causes
the indirect path to fail. No matter how hard or how many times cortex pushes on the controller
(which should maintain the inhibition of movement), there is no effect. The result is the ABSENCE
of INHIBITION of the globus pallidus externa, and so, the default state is always to move. The
indirect pathway is lost, and so the default state of inhibition is lost.

Huntingtin aggregates are found in every area of the cortex on autopsy. The aggregates
(and, therefore, the apoptosis and neuronal loss) are worst in the striatum—specifically the
caudate nucleus. And like prion proteins and Parkinson’s Lewy bodies, neurons
demonstrate the ability to uptake the aggregates, leading to the gradual worsening of disease
as more aggregates develop within neurons and become available to infect other neurons.
Because this process is apoptotic, like the other disease processes discussed so far, there is
no inflammation, and no inflammatory cells would be seen if a biopsy were performed. As
neurons die off, both the grey matter and white matter atrophy with resultant hydrocephalus
ex vacuo.

Huntington’s disease is the prototypical disease that so well-characterizes genetic

anticipation—progressive worsening of the disease burden with successive
generations. The genetic defect is caused by excess CAG trinucleotide
repeats in HTT exon 1. Normal HTT alleles have 6–35 CAG repeats. There is an inverse
relationship between the repeat number and age of onset, meaning that more repeats tend
 MBB II. WEEK 5-6. READING: NERODEGENERATIVE DISORDERS

to be associated with earlier onset. Repeat expansions occur during spermatogenesis (not
gametogenesis, it seems, only spermatogenesis) such that paternal transmission is
associated with early onset in the next generation as the trinucleotide repeat expands (more
CAG repeats added to HTT in the spermatocyte from which his offspring develops).
Huntington’s has an autosomal dominant inheritance pattern—even if one allele is
normal, the presence of excess repeats on the other allele translates to bad proteins, leading
to aggregates.

Figure 7: Huntington’s Disease

(a) Axial T1-weighted MRI demonstrating severe atrophy of the caudate nucleus and hydrocephalus ex vacuo of
the Huntington’s-affected area (top) versus normal (bottom). (b) Coronal T1-weighted MRI of the same patients,
again demonstrating severe atrophy of the caudate nucleus with global atrophy and hydrocephalus ex vacuo. (c)
Representative gross samples with (top) and without (bottom) Huntington’s showing a significant difference in
caudate nucleus volume and hydrocephalus ex vacuo.

Onset is most common in the fourth and fifth decades of life but can occur at any age due
to the association between symptom onset and the number of trinucleotide repeats. Motor
symptoms often precede cognitive impairment. The motor dysfunction is choreiform, with
increased and involuntary jerky movements of all parts of the body,
and writhing movements of the extremities are typical. There is a genetic screen, but no
treatment. Death usually occurs due to either infection or suicide, the movement disorder
and cognitive decline progressing over 10–15 years.

QESTIONS FOR PRACTICE:

1. The Huntington’s disease is associated with

a. The abnormal protein called: __________________

b. This abnormal protein is encoded by the _______ gene located

on chromosome ____.
c. The most affected area is: ____________________.
 MBB II. WEEK 5-6. READING: NERODEGENERATIVE DISORDERS

Citations
Figure 3a: Image by Patho, distributed under a CC-BY-SA-3.0
license creativecommons.org/licenses/by-sa/3.0.
Figure 3b: Image by KGH, distributed under a GFDL-self
license creativecommons.org/licenses/by-sa/3.0.
Figures 3c, 3d, 3e, 3f: Case courtesy of Dr Bruno Di Muzio, Radiopaedia.org, rID: 57097.
Figures 4a, 4b: Case courtesy of Assoc Prof Frank Gaillard, Radiopaedia.org, rID: 14321.
Figures 4c, 4d, 5: Originating from the University of Alabama at Birmingham, Department
of Pathology PEIR Digital Library at http://peir.net pursuant to a license grant by the UAB
Research Foundation.
Figure 7a, 7b (normal): Case courtesy of Dr Bruno Di Muzio, Radiopaedia.org, rID: 39310.
Figures 7a, 7b (atrophy): Case courtesy of Dr Bruno Di Muzio, Radiopaedia.org, rID:
38264.