4.4 Pathology

Question 1

Cerebral amyloid angiopathy (CAA) is a disease in which the same amyloidogenic peptides as those found in Alzheimer disease deposit in the walls of ________________.

The amyloid confers a ____________ appearance and stains with ___________.

Amyloid deposition weakens vessel walls and increases the risk for hemorrhages, which differ in distribution from those associated with hypertension.

CAA-associated hemorrhages often occur in the __________. In addition to these symptomatic hemorrhages, CAA also results in ___________________).

Answer 1

medium- and small-caliber meningeal and cortical vessels;

rigid, pipe-like;

Congo red;

lobes of the cerebral cortex (lobar hemorrhages);

small (<1 mm) cortical hemorrhages (microhemorrhages

Question 2

Prion diseases are a group of infectious diseases in which the causative agent is an _______________. These include sporadic, familial, iatrogenic, and variant forms of Creutzfeldt-Jakob disease (CJD), as well as animal diseases such as scrapie in sheep and ______________ in cattle (“mad cow disease”).

The causative protein, termed prion protein (PrP), may undergo a conformational change from its normal shape (PrP c ) to an abnormal conformation called PrP sc ( sc for scrapie ).

PrP normally is rich in ___________, but PrP sc has a high content of ____________, a characteristic that makes it resistant to ________.

More important, when PrP sc physically interacts with PrP molecules, it induces them to adopt the PrP sc conformation ), a property that accounts for the “infectious” nature of PrP sc . Over time, this self-amplifying process leads to the accumulation of a high burden of pathogenic PrP sc molecules in the brain. Certain mutations in the gene encoding PrP c (PRNP) accelerate the rate of spontaneous conformational change; these variants are associated with early-onset familial forms of prion disease (familial Creutzfeldt-Jakob disease [fCJD]). PrP c also may change its conformation spontaneously (but at an extremely low rate), accounting for _________________.

Accumulation of PrP sc in neural tissue seems to be the cause of cell injury, but the mechanisms underlying the cytopathic changes and eventual neuronal death are still unknown.

Answer 2

abnormal form of a cellular protein;

bovine spongiform encephalopathy;

α-helices;

β-sheets;

proteolysis (hence an alternative term for the pathogenic form, PrP res —i.e., protease-resistant)

sporadic cases of prion disease (sporadic Creutzfeldt-Jakob disease [sCJD]

Question 3

CJD is a rapidly progressive dementing illness, with a typical duration from first onset of subtle changes in memory and behavior to death in only 7 months. It is ___________ in approximately 85% of cases and has a worldwide annual incidence of about 1 per million. While commonly affecting____________, familial forms caused by mutations in PRNP may present in younger individuals. In keeping with the infectious nature of PrP sc , there are well-established cases of iatrogenic transmission by contaminated ___________________

Answer 3

sporadic;

individuals older than 70 years of age;

deep implantation electrodes and human growth hormone preparations.

Question 4

MORPHOLOGY
The progression to death in CJD usually is so rapid that there is little, if any, macroscopic evidence of brain atrophy. On microscopic examination, the pathognomonic finding is a ___________________; this multifocal process results in the uneven formation of small, apparently empty, microscopic vacuoles of varying sizes within the neuropil (_______________ and sometimes in the perikaryon of neurons . In advanced cases, there is severe _____, ________, and sometimes expansion of the vacuolated areas into cystlike spaces (“status spongiosus”).

No inflammatory infiltrate is present. Immunohistochemical staining demonstrates the presence of proteinase K–resistant PrP sc in tissue, while _____________ of tissue extracts after partial protease digestion allows detection of diagnostic PrP sc .

Answer 4

spongiform transformation of the cerebral cortex and deep gray matter structures (caudate, putamen);

the eosinophilic regions in grey matter that contain dendrites, axons, and synapses);

neuronal loss, reactive gliosis

western blotting

Question 5

Variant Creutzfeldt-Jakob Disease
Starting in 1995, cases of a CJD-like illness appeared in the United Kingdom. The neuropathologic findings and molecular features of these new cases were similar to those of CJD, suggesting a close relationship between the two illnesses, yet this new disorder differed from typical CJD in several important respects: the disease affected young adults; _____________ figured prominently in early disease stages; and the neurologic syndrome progressed somewhat more slowly than typical CJD. Multiple lines of evidence indicate that this new disease, termed variant Creutzfeldt-Jakob disease (vCJD) is a consequence of __________________. Also, there is now documentation of transmission by ________________. This variant form has a similar pathologic appearance to that in other types of CJD, with spongiform change and absence of inflammation. In vCJD, however, there are abundant __________________, surrounded by the spongiform change

Answer 5

behavioral disorders;

exposure to the prion disease of cattle, called bovine spongiform encephalopathy;

blood transfusion;

cortical amyloid plaques

Question 6

[Multiple sclerosis: Pathogenesis]
The lesions of MS are caused by an autoimmune response directed against components of the myelin sheath. As in other autoimmune diseases, the development of MS is related to genetic susceptibility and largely undefined environmental triggers. The incidence of MS is 15-fold higher when the disease is present in a first-degree relative and roughly 150-fold higher with an affected monozygotic twin. Only a portion of the genetic basis of the disease has been explained, and many of the identified loci are associated with other autoimmune diseases.

There is a strong effect of the major histocompatibility complex; each copy of the _______________ allele an individual inherits brings with it a roughly 3-fold increase in the risk for MS. Other genetic loci that are associated with MS include the ____________ receptor genes and other genes encoding proteins involved in immune responses.

Immune mechanisms that underlie the destruction of myelin are the focus of much investigation. The available evidence indicates that the disease is initiated by T H 1 and T H 17 T cells that react against myelin antigens and secrete cytokines. Experimental autoimmune encephalomyelitis, an animal model of MS in which demyelination and inflammation occur after immunization of animals with myelin proteins, can be passively transferred to unimmunized animals with T H 1 and T H 17 cells that recognize myelin antigens. T H 1 cells secrete _________, which activates ____________, and T H 17 cells promote the __________________. The demyelination is caused by activated leukocytes and their injurious products. The infiltrate in plaques and surrounding regions of the brain consists of T cells (mainly CD4+, some CD8+) and macrophages. B lymphocytes and antibodies also play an important, but poorly defined, role in the disease, as indicated by the surprising success of B cell depleting therapies.

Answer 6

HLA-DRB1*1501;

IL-2 and IL-7;

IFN-γ;

macrophages;

recruitment of leukocytes

Question 7

[Multiple sclerosis: Morphology]
MS is primarily a multifocal white matter disease. Grossly, the characteristic lesions, termed plaques , are discrete, slightly depressed,_____________-appearing, and _____________ in color. Plaques are common near the ventricles and also frequently occur in the optic nerves and chiasm, brain stem, ascending and descending fiber tracts, cerebellum, and spinal cord. The lesions have __________________ at the microscopic level.

Active plaques contain ________________, evidence of ongoing myelin breakdown. Lymphocytes also are present, mostly as _______________. Small active lesions often are centered on small veins. Axons are relatively preserved but may be reduced in number. When plaques become quiescent (inactive plaques), the inflammation mostly disappears, leaving behind little to no myelin, astrocytic proliferation, and gliosis.

Answer 7

glassy;

gray-tan;

sharply defined borders;

abundant macrophages stuffed with myelin debris;

perivascular cuffs

Question 8

[Multiple Sclerosis: Clinical features]
The course of MS is variable, but commonly there are multiple relapses followed by episodes of remission; typically, recovery during remissions is not complete. As a consequence, over time there is usually a gradual, often stepwise, accumulation of neurologic deficits. Imaging studies have demonstrated that there are often more lesions in the brains of patients with MS than might be expected from the clinical examination, and that lesions can come and go much more often than was previously suspected. Changes in cognitive function can be present, but are often much milder than the other deficits. In any individual patient, it is difficult to predict when the next relapse will occur; most current treatments, which are intended to control the immune response, aim at decreasing the rate and severity of relapses rather than recovering lost function.

The CSF in patients with MS shows a ____________________; in one-third of cases, there is moderate pleocytosis. When the immunoglobulin is examined further, ___________________ usually are identified. These antibodies are directed against a variety of antigenic targets and can be used as markers of disease activity. The contribution of these antibodies to the disease process is unclear.

Answer 8

mildly elevated protein level with an increased proportion of immunoglobulin;

oligoclonal bands

Question 9

Neurodegenerative diseases are characterized by the progressive loss of neurons, typically affecting groups of neurons with functional interconnections. Different diseases tend to involve particular neural systems and therefore have relatively stereotypic presenting signs and symptoms ( Table 23.3 ):

Diseases that involve the hippocampus and associated cortices present with ______________________. With time these progress to dementia, as occurs with Alzheimer disease.

Diseases that affect the basal ganglia manifest as movement disorders; these may be hypokinetic, as with __________________, or hyperkinetic, as with ________________.

Diseases that affect the cerebellum or its input and output circuitry result in _________________.

When the motor system bears the burden, ___________________ are often seen first, as with amyotrophic lateral sclerosis.

Answer 9

cognitive changes, often including disturbances of memory, behavior, and language;

Parkinson disease;

Huntington disease;

ataxia, as seen in the spinocerebellar ataxias;

weakness and difficulty with swallowing and respiration

Question 10

what are the protein inclusions in alzheimer disease? what is the clinical pattern?

Answer 10

Dementia;

Aβ (plaques)
Tau (tangles)

Question 11

what are the protein inclusions in Frontotemporal lobar degeneration (FTLD)? what is the clinical pattern?

Answer 11

Behavioral changes, language disturbance;

TDP43;
Tau

Question 12

what are the protein inclusions in Parkinson disease (PD)? what is the clinical pattern?

Answer 12

Hypokinetic movement disorder;

a-synuclein & tau

Question 13

what are the protein inclusions in Huntington disease (HD)? what is the clinical pattern?

Answer 13

Hyperkinetic movement disorder

Huntingtin (polyglutamine repeat expansions)

Question 14

what are the protein inclusions in Spinocerebellar ataxias? what is the clinical pattern?

Answer 14

Cerebellar ataxia

Various proteins (polyglutamine repeat expansions)

Question 15

what are the protein inclusions in Amyotrophic lateral sclerosis (ALS)? what is the clinical pattern?

Answer 15

Weakness with upper and lower motor neurons signs

SOD1, TDP43

Question 16

Alzheimer disease (AD) is the most common cause of dementia in older adults, with an increasing incidence as a function of age. The incidence is about 3% in individuals 65 to 74 years of age, 19% in those 75 to 84 years of age, and 47% in those older than 84 years of age. Most cases of AD are sporadic, but at least 5% to 10% are familial. Sporadic cases rarely present before 50 years of age, but early onset is seen with some heritable forms.

The disease usually manifests with the insidious onset of _________________, _____________, and altered __________. Over time, disorientation and aphasia, findings indicative of severe cortical dysfunction, often develop; those in the final phases of AD are profoundly disabled, often mute and immobile. Death usually occurs from _______________.

Answer 16

impaired higher intellectual function;

memory impairment;

mood and behavior;

intercurrent pneumonia or other infections

Question 17

[Alzheimer disease (AD): Pathogenesis]
The fundamental abnormality in AD is the accumulation of two proteins (Aβ and tau) in specific brain regions, in the forms of plaques and tangles, respectively; these changes result in secondary effects including ______, _______, _____.

Plaques are ___________________, while tangles are ___________________, which develop intracellularly and then persist extracellularly after neuronal death. Both plaques and tangles appear to contribute to neural dysfunction. The details of the interplay between the processes that lead to the accumulation of these abnormal aggregates are a critical aspect of AD pathogenesis that has yet to be unraveled.

Clinical and experimental evidence strongly suggests that Aβ generation is the critical initiating event for the development of AD. Notably, mutations or alterations in copy number of the gene encoding the precursor protein for Aβ are associated with an elevated risk of AD, whereas mutations in the gene for tau do not give rise to AD but rather cause _________________. Overexpression of Aβ can replicate the disease in animal models.

Answer 17

neuronal dysfunction, neuronal death, and inflammatory reactions;

deposits of aggregated Aβ peptides in the neuropil;

aggregates of the microtubule binding protein tau;

frontotemporal lobar degenerations

Question 18

[Alzheimer disease (AD): Pathogenesis]

Role of Aβ.

Aβ is created when the transmembrane protein amyloid precursor protein (APP) is sequentially cleaved by the enzymes _______________.

APP also can be cleaved by _______________, liberating a different peptide that is nonpathogenic.

Mutations in APP or in components of γ-secretase (encoded by the ____________) lead to familial AD by increasing the rate at which Aβ, particularly its most aggregation-prone form, is generated.

The APP gene is located on chromosome 21, and the risk for AD also is higher in those with an extra copy of the APP gene, such as patients with trisomy 21 (Down syndrome) and individuals with small interstitial duplications of APP, presumably because this too leads to greater Aβ generation.

Once generated, Aβ is highly prone to aggregation; it first forms ______________, and these eventually propagate into large aggregates and fibrils. It is these aggregates that deposit in the brain and are visible as plaques. There is evidence that these oligomers decrease the number of synapses present and alter the function of those that remain so that the cellular processes felt to underlie learning and memory are disrupted

Answer 18

β-amyloid–converting enzyme (BACE) and γ-secretase;

α-secretase and γ-secretase;

presenilin-1 or presenilin-2 gene;

small oligomers

Question 19

[Alzheimer disease (AD): Pathogenesis]
Role of tau.
Because neurofibrillary tangles contain the tau protein, there has been much interest in the role of this protein in AD. Tau is a microtubule-associated protein present in axons in association with the microtubular network. With the development of tangles in AD, tau shifts to a ____________, becomes _____________, and loses the ability to bind to microtubules. The formation of tangles is an important component of AD, but the mechanism of tangle injury to neurons remains poorly understood. Two pathways have been suggested; 1) aggregates of tau protein elicit a stress response, which persists and eventually leads to cell death; and 2), the microtubule stabilizing function of tau protein is lost, leading to neuronal toxicity and death. It has been shown that tau aggregates can be passed across synapses from one neuron to the next; this may underlie some of the spread of lesions across the brain.

Answer 19

somatic-dendritic distribution;

hyperphosphorylated;

Question 20

[Alzheimer disease (AD): Pathogenesis]

Other genetic risk factors.

The genetic locus on chromosome 19 that encodes apolipoprotein E (ApoE) has a strong influence on the risk for developing AD. Three alleles have been identified (______________) based on two amino acid polymorphisms. The dosage of the ε4 allele increases the risk for AD. This ApoE isoform promotes _________________, although the mechanisms have not been established. Overall, this locus has been estimated to convey about one fourth of the risk for development of late-onset AD. Genome-wide association studies have identified multiple other loci that contribute to the risk for AD, but the roles of the encoded proteins in disease pathogenesis are not established.

Answer 20

ε2, ε3, and ε4l

Aβ generation and deposition

Question 21

[Alzheimer disease (AD): Pathogenesis]

Role of inflammation. Both genetic and histologic studies have indicated that the innate immune system responds to Aβ and tau. Deposits of Aβ elicit an inflammatory response from _______________. This response probably assists in the clearance of the aggregated peptide, but also may stimulate the secretion of mediators that cause neuronal injury over time.

Answer 21

microglia and astrocytes

Question 22

[Alzheimer disease (AD): Pathogenesis]

Basis for cognitive impairment. Deposits of Aβ and tangles begin to appear in the brain well in advance of cognitive impairment. While there remains disagreement regarding the best correlate of dementia in individuals with AD, the presence of a large burden of plaques and tangles is strongly associated with severe cognitive dysfunction. The number of ____________________correlates better with the degree of dementia than does the number of neuritic plaques. Biochemical markers that have been correlated with the degree of dementia include amyloid burden.

Answer 22

neurofibrillary tangles

Question 23

[Alzheimer disease (AD): Morphology]

Brains involved by AD show a variable degree of cortical atrophy, resulting in a widening of the cerebral sulci that is most pronounced in the ________________. The atrophy produces a compensatory ___________________. At the microscopic level, AD is diagnosed by the presence of neuritic plaques (an extracellular lesion) and neurofibrillary tangles (an intracellular lesion).

Answer 23

frontal, temporal, and parietal lobes;

ventricular enlargement (hydrocephalus ex vacuo)

Question 24

[Alzheimer disease (AD): Morphology]

Neuritic plaques are focal, spherical collections of dilated, tortuous, processes derived from _______________, often around a _________________ (see Fig. 23.25A ). Neuritic plaques range in size from 20 to 200 µm in diameter; microglial cells and reactive astrocytes are present at their periphery. Plaques can be found in the_____________________, although there is relative sparing of primary motor and sensory cortices until late in the disease course. The amyloid core contains Aβ ].

Aβ deposits also can be found that lack the surrounding neuritic reaction, termed ______________; these are found in the superficial cerebral cortex, the basal ganglia, and the cerebellar cortex and may represent an early stage of plaque development.

Answer 24

dystrophic neurites;

central amyloid core;

hippocampus and amygdala as well as in the neocortex;

diffuse plaques

Question 25

[Alzheimer disease (AD): Morphology]

Neurofibrillary tangles are _________________ visible as basophilic fibrillary structures in the cytoplasm of the neurons that displace or encircle the nucleus; tangles can persist after neurons die, becoming a form of extracellular pathology. They are commonly found in cortical neurons, especially in the _______________, as well as in the pyramidal cells of the hippocampus, the amygdala, the basal forebrain, and the raphe nuclei. A major component of paired helical filaments is _______________.

Answer 25

bundles of paired helical filaments;

entorhinal cortex;

hyperphosphorylated tau

Question 26

[Alzheimer disease (AD): Morphology]

In individuals harboring autosomal dominant mutations that cause AD, deposition of Aβ and the formation of tangles precede the emergence of cognitive impairment by as much as 15 to 20 years. For this reason, the current diagnostic criteria consider the burden and distribution of ___________________—a constellation known as Alzheimer disease neuropathologic changes. The staging of each of these processes, which has a fairly consistent pattern across individuals, is then used to assess the likelihood that the observed lesions resulted in cognitive impairment.

Answer 26

amyloid deposits, tangles, and neuritic plaques

Question 27

Parkinson disease (PD) is a neurodegenerative disease marked by a __________________. Parkinsonism is a clinical syndrome characterized by __________________. These types of motor disturbances may be seen in a range of diseases that damage dopaminergic neurons, which project from the substantia nigra to the striatum and are involved in control of motor activity. Parkinsonism can be induced by drugs such as dopamine antagonists or toxins that selectively injure dopaminergic neurons. Among the neurodegenerative diseases, most cases of parkinsonism are caused by PD, which is associated with characteristic _________________.

Answer 27

hypokinetic movement disorder that is caused by loss of dopaminergic neurons from the substantia nigra;

tremor, rigidity, bradykinesia, and instability;

neuronal inclusions containing α-synuclein

Question 28

[Parkinson disease: morphology]
A typical gross finding at autopsy is ________________. Microscopic features include loss of the pigmented, catecholaminergic neurons in these regions associated with gliosis.

Lewy bodies may be found in those neurons that remain. These are single or multiple, cytoplasmic, eosinophilic, round to elongated inclusions. On ultrastructural examination, Lewy bodies consist of fine filaments, composed of ________________. The other major histologic finding is the presence of Lewy neurites, dystrophic neurites that also contain aggregated α-synuclein. Immunohistochemical staining for α-synuclein highlights more subtle Lewy bodies and Lewy neurites in many brain regions outside of the substantia nigra and in non-dopaminergic neurons, including regions of the medulla, the pons, the amygdala, and the cerebral cortex. Eventually they appear in the subcortical areas and the cerebral cortex. With involvement of the cerebral cortex, there is typically ____________________

Answer 28

pallor of the substantia and locus ceruleus;

α-synuclein and other proteins, including neurofilaments and ubiquitin;

dementia present in addition to the movement disorder.

Question 29

[Parkinson disease: clinical features ]
PD commonly manifests as a movement disorder in the absence of a toxic exposure or other known underlying etiology. The disease usually progresses over 10 to 15 years, eventually producing severe motor slowing to the point of near immobility. Death usually is the result of _____________________.

Movement symptoms of PD initially respond to___________________, but this treatment does not slow disease progression. Over time, l -DOPA becomes less effective and begins to cause problematic fluctuations in motor function. Another treatment for the motor symptoms of PD is deep brain stimulation, in which electrodes are implanted in the _____________________ to modulate basal ganglia circuitry, often allowing a significant reduction in l -DOPA dose.

While the movement disorder associated with loss of the nigrostriatal dopaminergic pathway is an important feature of PD, it is clear that the disease has more extensive clinical and pathologic manifestations. Lesions in the brain stem (in the ____________________), in advance of nigral involvement, can give rise to behavioral sleep disorder often before the motor problems. Dementia, typically with a mildly fluctuating course and hallucinations, emerges in many individuals with PD and is attributable to involvement of the cerebral cortex. When dementia arises within 1 year of the onset of motor symptoms, it is referred to __________________

Answer 29

aspiration pneumonia or trauma from falls caused by postural instability;

l -dihydroxyphenylalanine ( l -DOPA);

globus pallidus or subthalamic nucleus;

dorsal motor nucleus of the vagus and in the reticular formation;

Lewy body dementia (LBD).

Question 30

Amyotrophic lateral sclerosis (ALS) results from the____________________ The loss of lower motor neurons results in denervation of muscles, muscular atrophy (the “amyotrophy” of the condition), weakness, and fasciculations, while the loss of upper motor neurons results in paresis, hyperreflexia, and spasticity, along with a Babinski sign. An additional consequence of upper motor neuron loss is degeneration of the __________________ (“lateral sclerosis”). Sensation usually is unaffected, but cognitive impairment is not infrequent.

The disease affects men slightly more frequently than women and becomes clinically manifest in the fifth decade or later. It usually begins with ___________________. As the disease progresses, muscle strength and bulk diminish, and involuntary contractions of individual motor units, termed fasciculations, occur. The disease eventually involves the______________, which is the usual cause of death. The balance between upper and lower motor neuron involvement can vary, although most patients exhibit involvement of both. In some patients, degeneration of the lower brain stem cranial motor nuclei occurs early and progresses rapidly, a pattern of disease referred to as ________________. With this disease pattern, abnormalities of swallowing and speaking dominate.

Answer 30

death of lower motor neurons in the spinal cord and brain stem as well as upper motor neurons (Betz cells) in the motor cortex.];

corticospinal tracts in the lateral portion of the spinal cord;

subtle asymmetric distal extremity weakness;

respiratory muscles, leading to recurrent bouts of pulmonary infection;

bulbar amyotrophic lateral sclerosis

Question 31

[ALS: Pathogenesis]

While most cases are sporadic, about 10% are familial, mostly with autosomal dominant inheritance. Familial disease begins earlier in life than sporadic disease, but once symptoms appear, the clinical course is similar in both forms. Mutations in the __________________ were the first identified genetic cause of ALS and account for about 20% of the familial forms. These mutations are thought to generate abnormal misfolded forms of the SOD1 protein, which may trigger the unfolded protein response and cause apoptotic death of neurons.

A number of other genetic loci have been identified as associated with ALS. The most common cause of familial ALS is ___________________ in a gene with the rather cumbersome name C9orf72 , which is also frequently expanded in frontotemporal lobar degeneration. The protein encoded by C9orf72 associates with _________________; notably, two other genes that when mutated may cause ALS, TDP43 (also associated with FTLD) and FUS, encode RNA binding proteins. This convergence suggests that an abnormality of RNA processing directly or indirectly contributes to the pathogenesis of ALS, but it is uncertain how mutations in SOD1 fit into this picture, and much remains to be discovered. As expected from the genetic overlap, there is some clinical overlap between ALS and FTLD, such as cognitive impairment.

Answer 31

superoxide dismutase gene, SOD1, on chromosome 21;

hexanucleotide repeat expansion;

RNA binding proteins

Question 32

[ALS: Morphology]
The most striking gross changes are found in ________________. In especially severe cases, the ________________ is mildly atrophic due to the death of upper motor neurons. Microscopic examination demonstrates a reduction in the number of anterior horn cell neurons throughout the spinal cord associated with reactive gliosis and loss of anterior root myelinated fibers. Similar findings are found with involvement of motor cranial nerve nuclei except those supplying the extraocular muscles, which are spared in all but a few long term survivors. Cytoplasmic inclusions that contain TDP43 may be seen in a subset of cases. With the loss of innervation from the death of anterior horn cells, skeletal muscles show neurogenic atrophy.

Answer 32

anterior roots of the spinal cord, which are thin and gray;

precentral gyrus (motor cortex)