DEGENERATIVE DISEASES Flashcards
Most of the degenerative diseases, as are characterized by the selective involvement of anatomically and physiologically related systems of neurons. Thus, these degenerative diseases had in the past been
called_______
SYStem atrophies .
MOST IMPT mechanism that lead to neuronal degeneration
APOPTOSIS
the rate of cerebral atrophy, specifically
of the ____________, is accelerated in the early stages of Alzheimer
disease, and
hippocampus and medial parts of the temporal
lobes
The survival of patients with Alzheimer disease
is reduced to______ the expected rate, mainly because of
respiratory and cardiovascular causes and inanition, but
also for other reasons that are not entirely clear
half
The failial occurrence of Alzheimer disease has been
well established.
In less than ________ of such cases there
is a dominant inheritance pattern with a high degree of
penetrance and appearance of disease at a younger age
1 percent
Major sx of AD
The gradual development of forgetfulness is the major
symptom.
remote memories are preserved and recent ones lost
(the Ribot law of memory),
presence of cognitive difficulties in one or all spheres that are not severe enough to interfere with daily life
MCI
5 early symptoms of AD
1. amnesia 2 dysnomia 3. Visuospatial disorientation 4. Paranoia and personality changes 5. Executive dysfunction
The early stages of Alzheimer disease are
usually dominated by a disproportionate failure of
______
episodic (autobiographical) memory
AD definition according to NINCDS and ARDA
(1) dementia defined by clinical examination, the \_\_\_\_\_\_\_ (see Table 21-6), the \_\_\_\_\_\_ or similar mental status examination;
(2) patient older than age ___
(3) deficits in 2 or more
areas of cognition and progressive worsening of memory
and other cognitive functions, such as language, perception,
and motor skills (praxis);
(4) absence of disturbed
consciousness; and
(5) exclusion of other brain diseases
Mini-Mental Scale, Blessed
Dementia Scale,
40 years;
Using NINCDS and ARDA,
the correct diagnosis is achieved in more than ____
percent of patients,
85
________, the most prominent finding
visible on MRI (mainly coronal images), is diagnostic in the proper clinical circumstances.
atrophy of the hippocampus
Microscopically, there is widespread loss of nerve
cells. Early in the disease this is most pronounced in
____________
Layer II of the entorhinal cortex.
Pathology:
______ (more than proliferation) is in evidence as a
compensatory or reparative process, most prominent in
layers III and V.
Astrocytic hypertrophy
3 microscopic changes give this disease
its distinctive character
- Alzheimer neurofibrillary changes or
“tangles” - neuritic plaques
- Granulovacuolar degeneration
Alzheimer neurofibrillary changes or
“tangles” are composed of a
hyperphosphorylated form of the microtubular protein,_____and appear as pairs of helical filaments when studied
ultrastructurally.
tau
Amyloid is also scattered throughout the cerebral
cortex in a nascent “diffuse” form, without organization or core formation and then is appreciated mainly by
immunohistochemical methods, as well as deposition
in the walls of small blood vessels near the plaques, so called
__________
congophilic angiopathy.
This last change is least important
in diagnosis but there is uncertainty regarding its nature;
it had been thought to be simply a reactive process but
recent studies suggest it reflects a defect in phagocytosis of degraded proteins
Granulovacuolar degeneration
favored sites of neuronal loss
CAl and CA2 zones
(of Lorente de N6) and the entorhinal cortex, subiculum,
and amygdala.
_____ percent of their Alzheimer patients showed
the pathologic (and clinical) changes of Parkinson disease,
a much higher incidence than can be attributed
to chance
25
Electrophoretically, tau moves with the /32-globulins and
is thought to function as a _______, that is it binds iron
and delivers it to the cell
transferrin
The AB protein is a small portion of a larger entity,
the _____
amyloid precursor protein (APP),
During normal cellular
metabolism, APP is cleaved by either _______. The
products of this reaction are then cleaved by the __________ isoform of the enzyme
alpha and beta secretase
gamma secretase
cleavage by ______results in
a 40-amino-acid product, AB40, and a longer 42-aminoacid form.
____ is critical to the neuronal toxicity of amyloid.
B and then Gamma
ratio of AB42 to AB40
the gene
coding for APP is located on _____
chromosome 21
TDP-43, the product of inadequate functioning of the
progranulin gene, is also deposited in neurons and may
play a substantial role in the ______
severity of expression of
Alzheimer disease
marked reduction in ________ in the hippocampus and neocortex of patients with Alzheimer disease
choline acetyltransferase (ChAT) and acetylcholine
Other kindreds with familial Alzheimer
disease have been linked to rare dorrtinant mutations of the presenilin genes on ____
chromosome 14
Of the
several isoforms of Apo E, the presence of _____ (and itscorresponding allele e4 on chromosome 19) is associated
with a tripling of the risk of developing sporadic Alzheimer disease
The e4 allele also modifies the _____ of some of the familial forms of the disease
E4
age of onset
In sporadic Alzheimer disease, the TREM2
polymorphism that is implicated in Alzheimer disease putatively causes inadequate _______
phagocytic clearance of
amyloid
Newer PET ligand
agents that bind to amyloid, such as the _________
and tau-ligands are more sensitive in identifying
and observing the course of Alzheimer disease
“Pittsburgh compound”
this drug has been approved for use in
late-stage Alzheimer disease and in conjunction with cholinergic drugs.
Memantine
the symptoms of dementia and parkinsonism
are related to neurofibrillary changes in the cerebral cortex
and substantia nigra, respectively; senile plaques and
Lewy bodies are unusual findings
Guamanian
Parkinson-dementia complex,
The finding of neurofibrillary tangles (and to a lesser extent of plaques) in boxers_____ is another interesting ramification
of the Alzheimer disease process in that trauma appears
to be able to elicit one of the core features of the disease
(“punch-drunk” syndrome, or demen tia p ugilistica)
Pathologic changes in lobar atrophty
Pick inclusion bodies,
neurofibrillary
tangles,
other inclusions, or with no characteristic
changes except for neuronal loss.
variants of FTD
behavioral variant and a language variant (semantic dementia, progressive nonfluent aphasia, and a logopenic variant,)
A form of motor neuron disease is also linked
to frontotemporal dementia in a small number of cases.
This is particularly the case in the Guamanian (now called western Pacific) variety and in the heredofamilial
frontotemporal atrophy linked to a mutation on chromosome
1 7.
Focal disturbances,
particularly aphasia and apraxia, occur early and prominently in certain patients with lobar degenerations,
indicating a lesion in the left frontal or temporal lobes
Primary Progressive Aphasias (PPA)
_______ is characterized by
early difficulty naming items, people, and words, followed
by verbal perseveration, but fluency is retained.
semantic dementia,
________,
that shares most aspects of nonfluent aphasia but in
which the meaning of words is retained.
logopen ic aphasia
The fundamental
feature is the progressive loss of the ability to
understand and use visual information.
The result is
progressive and ultimately severe visuospatial difficulty
with a relative preservation of memory.
Posterior Cortical Atrophy
The disease is defined by the diffuse involvement of
cortical neurons with Lewy-body inclusions and by an
absence or inconspicuous number of neurofibrillary
tangles and amyloid plaques
LBD
_____, main components of the Lewy body
ubiquitin
and synuclein
parkinsonian
features, dementia, and a tendency to episodic delirium,
especially nocturnally, and rapid eye movement (REM)
sleep behavior disorde
LBD
Diagnostic criteria have been offered by a working group,
requiring 2 of 3 of the following:
a parkinsonian syndrome
(usually symmetric),
fluctuations in behavior and cognition,
and recurrent hallucinations (McKeith et
Some patients with LBD also have orthostatic
hypotension corresponding to cell loss and Lewy bodies in the ______
intermediolateral cell column of the spinal cord or
in the sympathetic ganglia,
LBD
At least one randomized trial has described benefit
_________, in
reducing delusions, hallucinations, and anxiety in pts with LBD
from the anticholinesterase inhibitor, rivastigrnine
dominant
inheritance, choreoathetosis, and dementia,
HD
in HD
The usual age of onset is in the_______decades, but 3 to 5 percent begin before the fifteenth year
and some even in childhood, where it takes on special
form.
fourth and fifth
Huntington gene and localized to the short arm of _____
excessively long repeat
of the trinucleotide ____ within the Huntington gene
chromosome 4
CAG
Individuals
with 35 to 39 triplets may eventually manifest the disease
but it tends to be late in onset and mild in degree, or limited
to _____
“senile chorea”
Gross atrophy bilaterally o f the_________ is the characteristic abnormality,
usually accompanied by a moderate degree of gyral
atrophy in the frontal and temporal regions
head o f the caudate
nucleus and putamen
the _________ratio is
increased, which corroborates the clinical diagnosis in the
moderately advanced case.
bicaudate-to-cranial
The striatal degeneration in HD begins in the medial part ofthe caudate nucleus and spreads, tending to spare the
nucleus accumbens
The presence of more
_______ at the Huntington locus essentially
confirms the disease and gives some indication of the
expected time of onset;
than 39 CAG repeats
Other ddx of HD
DRPLA, propionic acidemia
In HD
____ in daily doses o f 2
to 10 mg, is effective partially in suppressing the movement
disorder
The dopamine antagonist haloperidol,
__________s make the
chorea worse and, in the rigid form of the disease, evoke
chorea.
Levodopa and other dopamine agost
Drugs that _________such as reserpine, clozapine, and particularly
tetrabenazine, which has been validated in a controlled
study (Huntington Study Group)-suppress the .chorea
to some degree,
deplete dopamine or block dopamine
receptors-
Preliminary studies
of the transplantation of ___________into
the striatum have achieved mixed results
fetal ganglionic tissue
Types of Acanthocytosis With Chorea
- one with a defect in the red cell lipid membrane
- second group that lacks a
lipid abnormality.
syndrome associated with defect in the red cell lipid membrane
[hypobetalipoproteinemia, acanthocytosis,
retinitis pigmentosa, and pallidal degeneration
What condition
1) onset in adolescence or
early adult life of generalized involuntary movements
2) mild to moderate mental deterioration with behavioral
disturbance in some but not all cases;
3) decreased or absent tendon reflexes and evidence of chronic axonal neuropathy and denervation atrophy of muscles; and
(4) the defining feature of acanthocytosis
Aca nthocytosis With Chorea
second group that lacks a
lipid abnormality.
________
is the result of an abnormal composition of covalently
(tightly) bound fatty acids in erythrocyte membrane
proteins (palmitic and docosahexanoic acids increased
and stearic acid decreased).
acanthocytosis
_________ another disorder with acanthocytosis and the gradual development of chorea in middle to
late life, is characterized by degeneration of the caudate
and putamen and a myopathy (elevated serum creatine
phosphokinase [CPK])
McLeod disease,
parkinsonism
and corticospinal degeneration are present in
various combinations.
CBGD
Progressive parkinsonism and dementia
are combined with upper or lower motor neuron disease
(ALS is also common among the Chamorro) leading to
death in 5 years. The
Guamanian Parkinson-dementia-ALS complex
families in
which several members developed a spastic paraparesis
and a gradual failure of intellectual function during the
middle adult years.
Mast syndrome
PAS-positive structures were composed of glucose polymers
(polyglucosans) and were readily demonstrated in
sural nerve biopsies
polyglucosan bodies
The dementia was relatively mild,
consisting of impairment of retentive memory, dysnomia,
dyscalculia, and sometimes nonfluent aphasia and deficits
of “visual integration”; this was overshadowed by rigidity
and spasticity of the limbs and the peripheral nerve
disorder
Ad u lt Polyg l u cosan Body Disease
The usual blink rate (12
to 20/min) is reduced in the parkinsonian patient to ________and with it there is a slight widening of the
palpebral fissures, creating a stare
5
to 10 /min,
speech disorder in PD characterized as
combined respiratory,
phonatory, and articulatory dysfunctions
hypokinetic dysarthria
A special problem of ________ occurs in some
Parkinson patients wherein an extreme forward flexion
of the spine and correspondingly severe stooping occur
camptocormia
Regarding elicitable neurologic signs, there is an
inability to inhibit blinking in response to a tap over the
bridge of the nose or glabella
(Myerson sign)
In PD
the mean period of time from
inception of the disease to a chairbound state is ___
7.5 years,
The typical case shows atrophy in one or more body parts, including at times the face, often since childhood,
and usually quite subtle. Signs of progressive parkinsonism
or dystonia begin in midlife on the atrophic
side and, for the most part, are responsive to L-dopa,
Hemiparkinson-Hemiatrophy Syndrome
The most constant and pertinent finding i n both idiopathic
and postencephalitic Parkinson disease is a loss
of pigmented cells in the substantia nigra and other pigmented
nuclei (_________
locus ceruleus, dorsal motor nucleus of the
vagus).
cells of the melanin contain
eosinophilic cytoplasmic inclusions, surrounded by
a faint halo, called Lelvy bodies
Lewy bodies
In PD
_____ the rate-limiting enzyme for the synthesis
of dopamine, diminishes correspondingly
Tyrosine-hydroxylase,
a neurotoxin _______produces
irreversible signs of parkinsonism and selective destruction
of cells in the substantia nigra
(known as MPTP
[1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine])
Numerous observations have implicated the nuclear
and synaptic protein ________, the main component
of Lewy bodies in both the sporadic and inherited forms
of Parkinson disease,
a-synuclein
Collectively, they can often be identified by
an extreme sensitivity to L-dopa, maintaining an almost
complete suppression of symptoms over decades with
only small doses of medication; also, they have a low
threshold for dyskinesias induced by L-dopa
A second feature has
been that most of these patients may enjoy a remarkable
restorative benefit from sleep,
Parkin mutation
One is a dominantly inherited mutation
in the gene _____whose normal function is to specify
the identity of doparninergic neurons.
Another is in
recessively inherited parkinsonism caused by defects in
the gene _____ a protein that is essential for the normal
neuronal response to oxidative stress
Nurrl,
DJ-1,
the most effective agent for the treatment of Parkinson
disease and the therapeutic results
L DOPA
T or F
In PD
The number of neurons in the striatum
is not diminished
T
Over time, however, the number of remaining nigral neurons becomes inadequate and the receptivity to dopamine
of the striatal target neurons becomes excessive, possibly
as a result of _________; this results in
both a reduced response to L-dopa and to paradoxical
and excessive movements (dyskinesias) with each dose.
denervation hypersensitivity
By combining L-dopa with a decarboxylase inhibitor
______ which is unable to
penetrate the central nervous system (CNS), decarboxylation of L-dopa to dopamine is greatly diminished in
peripheral tissues
(carb idopa or benserazide),
\_\_\_\_\_\_extends the plasma half-life and the duration of L-dopa effect by preventing its breakdown (as opposed to increasing its bioavailability, as in the case of carbidopa).
A class of catechol-0-methyltransferase (COMT) inhibitors, typified by entacapone,
_________are synthetic
ergot derivatives whose action in Parkinson disease is
explained by their direct stimulating effect on dopamine
(D2) receptors located on striate neurons
Bromocriptine and lisuride
The nonergot
dopamine agonists _________ have a
similar type and duration of effectiveness
ropinirole and pramipexole
_______ and the related drug cabergoline are no longer
used because of the risk of cardiac valvular damage, particularly
at higher dose levels
Pergolide
When the predominant manifestation is
tremor, very satisfactory results can be obtained in some
patients for up to several years with________
anticholinergic agents alone.
The antiviral agent _______ has mild
or moderate benefit for tremor, hypokinesia, and postural
symptoms. In some patients, it reduces L-dopa-induced
dyskinesias (see further on) .
Its mechanism of action is
unknown but antagonism of NMDA or release of stored
dopamine has been proposed.
amantadine (100 mg bid)
rasagiline trial
ADAGIO
_______ have
“neuroprotective” effects in Parkinson disease
ropinirole, pramipexole, and even L-dopa
the atypical
neuroleptics __________may be given in low doses for pts with psychosis
olanzapine, clozapine, risperidone, or
quetiapine
_____ has been said
to provide an additional benefit of suppressing dyskinesias
in advanced Parkinson disease,
clozapine
While
the _________s have been
useful in cases of apathetic depression, they may cause
slight worsening of parkinsonian symptoms.
selective serotonin reuptake inhibitor
a group of disorders characterized by neuronal degeneration
mainly in the substantia nigra, striatum, autonomic
nervous system, and cerebellum
MSA
The postmortem examinations of MSA disclosed extensiveloss of neurons in the zona compacta of the substantia
nigra, but notably, there were __________in the remaining cells
no Lewy bodies or neurofibrillary
tangles
More
than half of the patients with striatonigral degeneration
have______, which proves at autopsy to
be associated with loss of intermediolateral hom cells
and pigmented nuclei of the brainstem.
orthostatic hypotension
abnormal staining material in the
cytoplasm of astroglia and oligodendrocytes and in some
neurons as well of MSA pts
glial cytoplasmic inclusions
In the cerebellar form of MSA, a ________ sign has
been emphasized on MRI;
it reflects atrophy of the pontocerebellar
fibers that manifest high T2 signal intensity
in an atrophic pons
“hot cross bun”
The Multiple System
Atrophy Research Collaboration identified a mutation in
the _____e, coding for a protein involved in the synthesis
of coenzyme Ql O’ in both familial cases and a very
small proportion of sporadic ones.
COQ2 gene
earliest sign of PSP
The most common early complaint
is unsteadiness of gait and unexplained falling
without loss of consciousness
By MRl OF PSP one can, in advanced cases, appreciate atrophy
of the ________giving rise to a “mouse ears” configuration
dorsal mesencephalon (superior colliculi, red nuclei)
Pathology of PSP
bilateral loss of neurons and gliosis in the periaqueductal
gray matter, superior colliculus, subthalamic nucleus,red nucleus, pallidurn, dentate nucleus, and pretectal
and vestibular nuclei
Most common initial presentation of CBD
asymmetrical clumsiness of the limbs,
in half of the patients, with rigidity and, in one-fifth, with
tremor;
MC and impt gene in heritable dystonia
The most important of these is an abnormal
gene (DYT1, also known as TORlA) on chromosome 9q, which codes for the protein,torsin A
It
may function as a chaperone protein that shuttles other
proteins in and out of cells. A current speculation, shared
with other degenerative disease, is that the absence of
_______ renders neurons unduly sensitive to oxidative
stress
torsin A
The cardinal feature of these severe dystonic
muscle contractions is the ____
simultaneous contraction of
both agonists and antagonists at a joint
Early in the course of the illness, several
drugs including______ to be helpful, but only
in a few patients, and the benefit is not lasting
L-dopa, bromocriptine, carbamazepine,
diazepam, and tetrabenzine seem
________
is beneficial in some patients with segmental myoclonus.
Clonazepam
high dose of _____ may be given for pts with dystonia
the use of very high doses
up to 30 mg daily or more) of trihexyphenidyl (Artane
dystonia that is responsive to L-dopa, but most
cases also have features of parkinsonism
H e red ita ry Dysto n i a -Pa rki n s o n i s m
( S e g awa Sy n d ro m e , J u v e n i l e
D o p a - R es p o n s ive Dysto n i a )
SEGAWA
linkage to the
gene on chromosome 14q for the protein GTP cyclohydrolase
1 (GCH1 gene) that is implicated in the synthesis of
tetrahydrobiopterin, a cofactor for_____
tyrosine hydroxylase
feature of SEGAWA
A remarkable feature is the disappearance or marked
subsidence of the symptoms after a period of sleep and
worsening as the day progresses.
dose of Levodopa
10 mg/kg/ d
This i s the prototype o f all forms o f progressive spinocerebellar
ataxias and accounts for about half of all cases
F r i e d re i c h Atax i a
Friedrich
expansion of a ______ trinucleotide repeat within a gene
that codes for the protein ______
GAA
frataxin
function of frataxin
frataxin is a mitochondrial matrix protein
whose function is to prevent intrarnitochondrial iron
overloading.
foot deformity associated with Friedrich
The characteristic foot deformity takes
the form of a high plantar arch with retraction of the toes
at the metatarsophalangeal joints and flexion at the interphalangeal
joints (hammertoes).
PCOD of pts with FA
Many
of the patients die as a result of cardiac arrhythmia or
congestive heart failure.
characteristic gait
tabetocerebellar
in FA
Torsional and vertical nystagmus is rare but
_______are seen in the early stages of disease.
“square wave jerks”
T or F
The tendon reflexes are abolished in
nearly every case of FA
T
The _______
are all depleted of myelinated fibers, and there is a mild
gliosis that does not replace the bulk of the lost fibers
posterior
columns and the corticospinal and spinocerebellar tracts
The _______ of the disease are explained by
the degeneration of large cells in the dorsal root ganglia
and the large sensory fibers in nerves, dorsal roots, and
the columns of Goll and Burdach.
tabetic aspects
Cerebellar ataxia is attributable to a combined
degeneration of the______ and the ______
pathways but also the spinocerebellar tracts
superior vermis
dentatorubral
It is advisable to
assay serum______, as a rare but treatable inherited deficiency causes a spinocerebellar syndrome with
areflexia in children that resembles Friedreich disease
vitamin E levels
A double-blind
crossover study by Trouillas and associates found that the
administration of oral________ modified the
cerebellar symptoms of FA
5-hydroxytryptophan
In several
small trials,_______ an antioxidant (the short-chain analogue of coenzyme Q10), reduced the progression of
left ventricular hypertrophy, a risk factor for arrhythmias
and sudden death in these patients, but
idebenone,
Pred o m i n a ntly Cerebel l a r
________ Hered ita ry
a n d Spora d i c Ataxia
(Cortical, H o l m es Type)
This type o f developmental delay, caused b y an unstable
extended trinucleotide repeat sequence and breakage of
the X-chromosome
Fra g i l e X Trem o r-Ataxic Prem utatio n
Synd rome
Fragile X
The process affects carriers of a “premutation”
who have 50 to 200 _________ repeat sequences in the
FMRl gene.
CGG
A sporadically occurring disorder closely resembling the
Holmes type of cortical cerebellar degeneration but with
additional features of brainstem atrophy
olivopontocerebellar
atrophy (OPCA)/ MSA-C
OPCA with neuropathy and
slowed eye movements ____
(Wadia type)
The disorder is characterized by an autosomal dominant
pattern of inheritance and by a slowly progressive
ataxia beginning in adolescence or early adult life in
association with hyperreflexia, extrapyramidal features,
dystonia, bulbar signs, distal motor weakness, and ophthalmoplegia
Cerebel l a r Atrophy With Pro m i n e nt Basal
Gang l io n i c Featu res
M a c h a d o-J ose p h -Azo rea n D i sease ( S CA3
M a c h a d o-J ose p h -Azo rea n D i sease
unstable number of _____repeating
sequences in a gene,_______and named the disorder
spinocerebellar ataxia type 3 (SCA3
CAG
ataxin-3,
cerebellar ataxia are coupled with those of choreoathetosis
and dystonia and, in a few instances, parkinsonism,
myoclonus, epilepsy, or dementia
D e ntato r u b ro p a l l i d o l u ys i a n At ro p h y ( D R P LA)
In DRPLA
this disease
is inherited as an autosomal dominant trait and shows
an inverse correlation between the age of onset and the
size of the gene expansion otherwise known as
(anticipation).
