DEGENERATIVE DISEASES AFFECTING THE CEREBRAL CORTEX-Alzheimer Disease

Question 1

The major cortical degenerative disease is________

Answer 1

Alzheimer disease,

Question 2

What is the principal clinical
manifestation of alzeimer’s disease?

Answer 2

dementia, that is, progressive loss of cognitive function independent of the state of attention.

Question 3

There are many other causes of dementia, including the various forms of
___________

These diseases also involve subcortical structures, but many of the clinical symptoms are related to the changes in the cerebral cortex.

Answer 3

• frontotemporal dementia,
• vascular disease,
• dementia with Lewy bodies (considered later in the context of Parkinson disease,
• the other Lewy body disorder),
• CJD, and neurosyphilis (both considered earlier).

Question 4

• *Regardless of etiology**, dementia is
• *not part of normal aging** and always represents a pathologic process.

Question 5

____________) is the most common cause of dementia in the elderly.

Answer 5

Alzheimer disease (AD)

Question 6

When does AD becomes clinically apparent?

Answer 6

The disease
usually becomes clinically apparent as insidious impairment of higher intellectual function, with
alterations in mood and behavior.

Later, progressive disorientation, memory loss, and aphasia
become manifest, indicatingsevere cortical dysfunction.

Eventually, in 5 to 10 years, the
affected individual becomes profoundly disabled, mute, and immobile.

Question 7

AD Patients rarely become

• *symptomatic before 50 years of age, but the incidence of the disease rises with age,** and the
• *prevalence** roughly doubles every 5 years, starting from a level of_____________

Answer 7

1% for the 60- to 64-year-old
population

and reaching **40% or more for the 85- to 89-year-old cohort. **

Question 8

This progressive
increase in the incidence of the AD with age has given rise to major medical, social, and
economic problemsin countries with a growing number of elderly individuals.

Most cases are
__________, and although 5% to 10% are familial, the study of such familial cases has provided
important insight into the pathogenesis of the more common sporadic form.

Answer 8

sporadic

Question 9

What is the definitive diagnosis of AD?

Answer 9

While pathologic
examination of brain tissueremainsnecessary for the definitive diagnosis of Alzheimer disease,
the combination of clinical assessment and modern radiologic methods allows accurate diagnosis in 80% to 90% of cases.

Question 10

What is the gross appearance of AD?

Answer 10

Grossly, the brain shows a variable degree of cortical atrophy marked by
widening of the cerebral sulci that is most pronounced in the frontal, temporal, and parietal
lobes( Fig. 28-36 ).

With significant atrophy, there is compensatory ventricular enlargement
(hydrocephalus ex vacuo)secondary to loss of parenchymaand reduced brain volume.

Structures of the medial temporal lobe, including hippocampus, entorhinal cortex and
amygdala,areinvolved early in the courseand are usuallyseverely atrophied in the later
stages.

Question 11

What is the major microscopic abnormalitiy in AD which also forms the basic histologic diagnosis?

Answer 11

** neuritic (senile) plaque**s and neurofibrillary tangles.

There is progressive
and eventually severe neuronal loss and reactive gliosis in the same regions that bear the
burden of plaques and tangles.

Question 12

What are neuritic plaques in AD?

Answer 12

Neuritic plaques are focal, spherical collections of dilated, tortuous, neuritic processes
(dystrophic neurites)often around a central amyloid core,whichmay be surrounded by clear
halo ( Fig. 28-37A ).

Neuritic plaques range in size from 20 to 200 μm in diameter; microglial cells and reactive astrocytes are present at their periphery.

Question 13

In AD where can you find the Plaques ?

Answer 13

• hippocampus,
• amygdala,
• and neocortex,
• although there is usually relative sparing of primary motor and sensory cortices (this also applies to neurofibrillary tangles).

Question 14

In AD the amyloid core, which can be stained by Congo Red, contains several abnormal proteins. The dominant component of the amyloid plaque core is ________, a peptide derived through specific processing
events from a larger molecule, amyloid precursor protein (APP) ( Figs. 28-37 and 28-38 ).

Answer 14

Aβ

Question 15

The two dominant species of Aβ, called _____and ____________, share an Nterminus and differ in
length by two amino acids at the C-terminus.

Other proteins are present in plaques in lesser
abundance, including components of the complement cascade, pro-inflammatory cytokines,
α1-antichymotrypsin, and apolipoproteins.

Answer 15

Aβ40 and Aβ42

Question 16

What are diffuse plaques in AD?

Answer 16

In some cases, there is deposition of Aβ peptides
with** staining characteristics of amyloid** in the absence of the surrounding neuritic reaction.
These lesions, termed diffuse plaques, are found in **superficial portions of cerebral cortex **as well as in **basal ganglia and cerebellar cortex. **

Question 17

What appears to represent an early stage of plaque dev in AD?

Answer 17

• *Diffuse plaques** appear to represent an
• *early stage of plaque development.**

This conclusion is based primarily on studies of brains
from individuals with trisomy 21.

Recall that in patients with trisomy 21 (Down syndrome), early
onset of Alzheimer disease is common ( Chapter 5 )

. In some brain regions (cerebellar cortex
and striatum) these diffuse plaques represent a major manifestation of the disease, with other
clear-cut findings of Alzheimer disease, or in isolation.

Question 18

In some brain regions (cerebellar cortex
and striatum) these diffuse plaques represent a major manifestation of the disease, with other
clear-cut findings of Alzheimer disease,or in isolation.

While neuritic plaques contain both A
β40 and Aβ42,diffuse plaques are predominantly made up of ________

Answer 18

Aβ42.

Question 19

What are Neurofibrillary tangles?

Answer 19

These are bundles of filaments in the cytoplasm of the neurons that
displace or encircle the nucleus.

Question 20

How are AD neurofibillary tangles in pyramidal neurons?

Answer 20

In pyramidal neurons, they often have an elongated “flame”
shape; in rounder cells, the basket weave of fibers around the nucleus takes on a rounded
contour (“globose” tangles). Neurofibrillary tangles are visible as basophilic fibrillary structures with H&E staining ( Fig. 28-37C ) but are dramatically demonstrated by silver
(Bielschowsky) staining ( Fig. 28-37D ).

C, Neurofibrillary tangle is present within one neuron, and several
extracellular tangles are also present (arrows). D, Silver stain showing a neurofibrillary
tangle within the neuronal cytoplasm.

Question 21

Where can you commonly find neurofibrillary tangles?

Answer 21

They are commonly found in cortical neurons,
especially in the entorhinal cortex, as well as in other sites such as pyramidal cells of the
hippocampus, the amygdala, the basal forebrain, and the raphe nuclei.

Question 22

Neurofibrillary tangles
are insoluble and apparently resistant to clearance in vivo, thus remaining visible in tissue
sections as______________tangles long after the death of the parent neuron.

Answer 22

“ghost” or “tombstone”

Question 23

Ultrastructurally, neurofibrillary tangles are composed predominantly of ____________

Answer 23

paired helical **filamentsalong withsome straight filaments that appear to have a comparable composition.**

Question 24

What is the major compone​nt of paired helical filaments?

Answer 24

A major component of paired helical filaments is abnormally hyperphosphorylated forms of the protein tau,

Question 25

What is a protein tau?

Answer 25

an axonal microtubule-associated protein that enhances microtubule assembly (Fig. 28-37E )

Question 26

The other components of neurofibrillary tangles are:

Answer 26

Other components include **MAP2 (another microtubule-associated protein)** and **ubiquitin.** **Paired helical filaments** are also found in the dystrophic neurites that form the outer portions of neuritic plaques and in axons coursing through the affected gray matter as **_neuropil threads._** **Tangles are not specific to AD**, being found in other diseases as well.

Question 27

In addition to the diagnostic features of plaques and tangles, several other pathologic findings: are seen in the setting of AD. \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ is an **almost invariable accompaniment of Alzheimer disease**; however**, it can also be found in brains of individuals without AD** (see Fig. 28-18B )

Answer 27

Cerebral amyloid angiopathy (CAA).

Question 28

What is **Granulovacuolar degeneration?**

Answer 28

It is the **formation of small (∼5 μm in diameter),****clear intraneuronal cytoplasmic****vacuoles, each of which contains an argyrophilic granule.** While i**t occurs with normal aging**, it is **most commonly found in great abundance in hippocampus and olfactory bulb in AD.**

Question 29

What are Hirano bodies?

Answer 29

* They are found especially in AD, * ** elongated, glassy, eosinophilic bodies** * consisting of **paracrystalline arrays** of beaded filaments, * with actin as their major component. * They are found **most commonly within hippocampal pyramidal cells.**

Question 30

Since both plaques and tangles may be present in low abundance in nondemented individuals, the **diagnosis of Alzheimer disease** is based on a \_\_\_\_\_\_\_\_\_\_\_\_\_\_

Answer 30

combination of clinical and pathologic features. Note: The progression of changes is fairly constant.

Question 31

in the pathologic changes of AD what are the evident **earliest in the entorhinal cortex**, then **spread through the hippocampal formation** and **isocortex,** and then **extend into the neocortex.**

Answer 31

(specifically plaques, tangles, and the associated neuronal loss and glial reaction)

Question 32

How are plaques are assessed?

Answer 32

* semiquantitatively (absent, sparse, moderate, abundant) in each cortical area

Question 33

While tangles are assessed based on?

Answer 33

on **how widespread they are in the brain.** [38,] [39] These assessments are combined in the **current NIA-Reagan** **criteria** to provide an estimate of the likelihood that **AD pathology** **caused a particular patient's dementia**

Question 34

The fundamental abnormality in AD is the deposition of\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ ( Fig. 28-38 ).

Answer 34

A β peptides, which are derived through processing of APP

Question 35

What is an APP ?

Answer 35

It is a cell surface protein with a **single transmembrane domain**that may function as a**receptor**, although ligands have remained elusive. The Aβ portion of the protein extends from the extracellular region into the transmembrane domain. **Processing of APP begins with cleavage** in the extracellular domain, followed by an intramembranous cleavage.

Question 36

There are two potential pathways, determined by the type of initial proteolytic event.

Answer 36

1. nonamyloidogenic pathway 2. amyloidogenic pathway

Question 37

What is the nonamyloidogenic pathway?

Answer 37

If the **first cu**t occurs at the **α-secretase site** within the **Aβ sequence**, then Aβ is **not generated** (the nonamyloidogenic pathway).

Question 38

Where is the nonamyloidogenic commonly occurs?

Answer 38

This mostly occurs at the **cell surface,** since the various enzymes with **α-secretase activit**y are involved in the **shedding of surface proteins.**

Question 39

What is the amyloidogenic pathway?

Answer 39

Surface APP can also be endocytosed and may undergo cleavage by β-secretase, which cuts at the N-terminal region of the Aβ sequence (the amyloidogenic pathway).

Question 40

Following cleavage of APP at either of these sites, the γ-secretase complex performs an **intramembranous cleavage.** When paired with a first cut by α-secretase, it will produce a **soluble fragment,** but when paired with **β-secretase cleavage,** it generates\_\_\_\_\_\_\_\_\_\_\_\_ T

Answer 40

Aβ.

Question 41

The variation in peptide length (Aβ40 vs Aβ42) arises from **alterations in the exact location of the γ-secretase cleavage.** The **γ-secretase** **complex**—containing **presenilin**, **nicastrin,** **pen-2, and aph-1—**is also **responsible for processing** of **Notch,** a c**ell fate-determining molecule**, as well as many other membrane proteins. [42] \*\*\*\*\*Once generated, **Aβ is highly prone to aggregation—first into small oligomer**s (which may be the **toxic form responsible for neuronal dysfunction)**, and eventually into l**arge aggregates and fibrils.**,

Question 42

**Familial forms of AD** have provided support for the c**entral role** of _________ as a **critical step for at least initiation of AD pathogenesis**

Answer 42

Aβ generation

Question 43

. The gene encoding APP, on chromosome \_\_\_\_\_\_\_\_\_, lies in the Down syndrome region; **AD pathology** is an eventual **feature of the cognitive impairment of these individuals**. Histologic findings appear in the second and third decades followed by neurologic decline about 20 years later.

Answer 43

21 Note: A **similar gene** dosage effect is produced by **localized chromosome 21**duplications tha**t span the APP locus** in some patients with familial AD. [44] **Point mutations in APP** are another cause of familial AD. Some mutations lie near the β- secretase and γ-secretase cleavage sites, and others sit in the Aβ sequence and increase its propensity to aggregate.

Question 44

The two loci identified as causes of the **majority of early-onset familial AD encode the\_\_\_\_\_\_\_\_\_\_ ** These mutations lead to a **gain of function**, such that the **γ-secretase complex generates increased amounts of Aβ,**particularly**Aβ42.** Thus, the genetic evidence strongly supports the notion that the **underlying pathogenetic event in AD is the accumulation of Aβ.**

Answer 44

** two presenilins** (PS1 on chromosome 14 and PS2 on chromosome 1).

Question 45

What aret the consequences of the Aβ peptides readily aggregate, and can be directly neurotoxic?

Answer 45

There are various lines of evidence indicating that the small aggregates of Aβ can result in : * synaptic dysfunction, such as **blocking of long-term potentiation and changes in other membrane properties. [4]** While aggregates are difficult to degrade, monomeric Aβ can be degraded by a variety of proteases. * Both **small aggregates **and larger deposits elicit an **inflammatory response from microglia and astrocytes. **This response probably assists in the clearance of the aggregated peptide, but may also stimulate the secretion of mediators that cause damage. [43] * Additional consequences of the activation of these inflammatory cascades may include **alterations in tau phophosrylation, along with oxidative injury to the neurons**

Question 46

The genetic locus on chromosome 19 that encodes **\_\_\_\_\_\_\_\_\_\_\_\_** has a strong influence on the **risk of developing AD**. Three alleles exist **(ε2, ε3, and ε4)** based on two amino acid polymorphisms.

Answer 46

**apolipoprotein E (ApoE**)

Question 47

The dosage of the\_\_\_\_\_\_\_\_\_\_\_ **increases the risk of AD** and **lowers the age of onset of the disease,**such that individuals with thise are over-represented in populations of patients with AD.

Answer 47

ε4 allele Note: This ApoE isoform promotes Aβ generation and deposition, although the mechanisms have not been established. Overall, this locus has been estimated to convey about a quarter of the risk for development of sporadic AD. It is likely that other risk factor alleles will have much smaller population effects. [45] The newly evolving approach of genome-wide association screening may help locate these loci with weaker effects

Question 48

Because neurofibrillary tangles contain the **\_\_\_\_\_\_\_\_**, there has been much interest in the role of this protein in AD.

Answer 48

**tau protein**

Question 49

What is a Tau protein?

Answer 49

Tau is a **microtubule-associated protei**n **present in axons** in association with the **microtubular network**. With the development of tangles in AD, it shifts to a **somaticdendritic distribution,**becomes**hyperphosphorylated,**and**loses the ability to bind to microtubules** . It is, however, thought that the **primary abnormality in AD i**s in **Aβ and not in ta**u, because **mutations affecting Aβ lead to the formation of tangles and AD** but mutations in the gene encoding tau, **MAPT, cause one of the frontotemporal demential** (see below) but neither **Aβ** **deposition nor AD**. The mechanism of tangle injury to neurons remains poorly understood

Question 50

While there remains disagreement regarding the best correlate of dementia in individuals with AD, it is **clear that the presence of a large burden** of ________ and _____ is highly associated with severe cognitive dysfunction.

Answer 50

plaques and tangles Note: The number of neurofibrillary tangles 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 loss of choline acetyltransferase, synaptophysin immunoreactivity, and amyloid burden.

Question 51

What is the clinical feature of AD?

Answer 51

The progression of AD is slow but relentless, with a **symptomatic course o**ften running more **than 10 years**

Question 52

What is the initial symptom of AD?

Answer 52

. Initial symptoms are: * forgetfulness and * other memory disturbances;

Question 53

In the progression of AD, what are the other symptoms that emerge?

Answer 53

* including language deficits, * loss of mathematical skills, * and loss of learned motor skills

Question 54

In the late stage of AD, what are the clinical manifestations?

Answer 54

. In the final stages of AD, affected individuals may become : * incontinent, * mute, * and unable to walk.

Question 55

What is the intercurrent disease in the terminal event of AD?

Answer 55

pneumonia