The major cortical degenerative disease is________
What is the principal clinical
manifestation of alzeimer's disease?
dementia, that is, progressive loss of cognitive function independent of the state of attention.
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.
- 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).
Regardless of etiology, dementia is
not part of normal aging and always represents a pathologic process.
____________) is the most common cause of dementia in the elderly.
Alzheimer disease (AD)
When does AD becomes clinically apparent?
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, indicating severe cortical dysfunction.
Eventually, in 5 to 10 years, the
affected individual becomes profoundly disabled, mute, and immobile.
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_____________
1% for the 60- to 64-year-old
and reaching 40% or more for the 85- to 89-year-old cohort.
increase in the incidence of the AD with age has given rise to major medical, social, and
economic problems in 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.
What is the definitive diagnosis of AD?
examination of brain tissue remains necessary 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.
What is the gross appearance of AD?
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 parenchyma and reduced brain volume.
Structures of the medial temporal lobe, including hippocampus, entorhinal cortex and
amygdala, are involved early in the course and are usually severely atrophied in the later
What is the major microscopic abnormalitiy in AD which also forms the basic histologic diagnosis?
neuritic (senile) plaques 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.
What are neuritic plaques in AD?
Neuritic plaques are focal, spherical collections of dilated, tortuous, neuritic processes
(dystrophic neurites) often around a central amyloid core, which may 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.
In AD where can you find the Plaques ?
- and neocortex,
- although there is usually relative sparing of primary motor and sensory cortices (this also applies to neurofibrillary tangles).
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 ).
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.
Aβ40 and Aβ42
What are diffuse plaques in AD?
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.
What appears to represent an early stage of plaque dev in AD?
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.
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 ________
What are Neurofibrillary tangles?
These are bundles of filaments in the cytoplasm of the neurons that
displace or encircle the nucleus.
How are AD neurofibillary tangles in pyramidal neurons?
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.
Where can you commonly find neurofibrillary tangles?
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.
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.
“ghost” or “tombstone”
Ultrastructurally, neurofibrillary tangles are composed predominantly of ____________
paired helical filaments along with some straight filaments that appear to have a comparable composition.
What is the major component of paired helical filaments?
A major component of paired helical filaments is abnormally hyperphosphorylated forms of the protein tau,
What is a protein tau?
an axonal microtubule-associated protein that enhances microtubule assembly (Fig. 28-37E )
The other components of neurofibrillary tangles are:
Other components include MAP2 (another microtubule-associated protein) and
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
Tangles are not specific to AD, being found in other diseases as well.
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 )
Cerebral amyloid angiopathy (CAA).
What is Granulovacuolar degeneration?
It is the formation of small (∼5
μm in diameter), clear intraneuronal cytoplasmic vacuoles, each of which contains an
While it occurs with normal aging, it is most commonly found in great
abundance in hippocampus and olfactory bulb in AD.
What are Hirano bodies?
- 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.
Since both plaques and tangles may be present in low abundance in nondemented
individuals, the diagnosis of Alzheimer disease is based on a ______________
combination of clinical and
Note: The progression of changes is fairly constant.
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.
(specifically plaques, tangles, and the associated neuronal loss and glial reaction)
How are plaques are assessed?
- semiquantitatively (absent, sparse, moderate, abundant) in each cortical area
While tangles are assessed based on?
on how widespread they are in the brain. [38,] 
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
The fundamental abnormality in AD is the deposition of_______________ ( Fig. 28-38 ).
A β peptides, which are derived through
processing of APP
What is an APP ?
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
There are two potential pathways, determined by the type of initial proteolytic event.
- nonamyloidogenic pathway
- amyloidogenic pathway
What is the nonamyloidogenic pathway?
If the first cut occurs at the α-secretase site within the Aβ sequence, then Aβ
is not generated (the nonamyloidogenic pathway).
Where is the nonamyloidogenic commonly occurs?
This mostly occurs at the cell surface, since
the various enzymes with α-secretase activity are involved in the shedding of surface proteins.
What is the amyloidogenic pathway?
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).
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____________
The variation in peptide length (Aβ40 vs Aβ42)
arises from alterations in the exact location of the γ-secretase cleavage.
complex—containing presenilin, nicastrin, pen-2, and aph-1—is also responsible for processing
of Notch, a cell fate-determining molecule, as well as many other membrane proteins. 
generated, Aβ is highly prone to aggregation—first into small oligomers (which may be the toxic
form responsible for neuronal dysfunction), and eventually into large aggregates and fibrils.,
Familial forms of AD have provided support for the central role of _________ as a critical
step for at least initiation of AD pathogenesis
. 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.
Note: A similar gene dosage effect is produced by localized
chromosome 21 duplications that span the APP locus in some patients with familial AD. 
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.
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.
two presenilins (PS1 on chromosome 14 and PS2 on chromosome 1).
What aret the consequences of the Aβ peptides readily aggregate, and can be directly neurotoxic?
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.  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. 
- Additional consequences of the activation of these inflammatory cascades may include alterations in tau phophosrylation, along with oxidative injury to the neurons
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
apolipoprotein E (ApoE)
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.
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.  The newly evolving approach of
genome-wide association screening may help locate these loci with weaker effects
Because neurofibrillary tangles contain the ________, there has been much interest in the role
of this protein in AD.
What is a Tau protein?
Tau is a microtubule-associated protein 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
. It is, however, thought that the primary abnormality in AD is in Aβ and not in tau,
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
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.
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.
What is the clinical feature of AD?
The progression of AD is slow but relentless, with a symptomatic course often running more
than 10 years
What is the initial symptom of AD?
. Initial symptoms are:
- forgetfulness and
- other memory disturbances;
In the progression of AD, what are the other symptoms that emerge?
- including language deficits,
- loss of mathematical skills,
- and loss of learned motor skills
In the late stage of AD, what are the clinical manifestations?
. In the final stages of AD, affected individuals may become :
- and unable to walk.
What is the intercurrent disease in the terminal event of AD?