Page 852 - Robbins Basic Pathology by Vinay Kumar, Abul K. Abbas, Jon C. Aster

838 C H A P T E R 22 Central Nervous System
level of phosphorylation causes tau to redistribute from
axons into dendrites and cell bodies, where it aggregates into
tangles, which also contribute to neuronal dysfunction and
cell death.
MORPHOLOGY
Macroscopic examination of the brain shows a variable
degree of cortical atrophy, resulting in a widening of the
cerebral sulci that is most pronounced in the frontal, tempo-
ral, and parietal lobes. With significant atrophy, there is com-
pensatory ventricular enlargement (hydrocephalus ex vacuo).
At the microscopic level, AD is diagnosed by the presence
of plaques (an extracellular lesion); and neurofibrillary
tangles (an intracellular lesion) (Fig. 22–25). Because these
may also be present to a lesser extent in the brains of elderly
nondemented persons, the current criteria for a diagnosis of
AD are based on a combination of clinical and pathologic
features. There is a fairly constant progressive involvement
of different parts of the brain: pathologic changes (specifically whereas when the disease begins in the temporal lobe,
plaques, tangles, and the associated neuronal loss and glial
reaction) are evident first in the entorhinal cortex, then in the These symptoms precede memory disturbances, which can
hippocampal formation and isocortex, and finally in the neo-
cortex. Silver staining or immunohistochemistry methods are
extremely helpful in assessing the true lesional burden.
Neuritic plaques are focal, spherical collections of
dilated, tortuous, silver-staining neuritic processes (dystro-
phic neurites), often around a central amyloid core (Fig.
22–25, A). 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
hippocampus and amygdala as well as in the neocortex,
although there usually is relative sparing of primary motor
and sensory cortices until late in the disease course. The
amyloid core contains Aβ (Fig. 22–25, B). Aβ deposits also
can be found that lack the surrounding neuritic reaction,
termed diffuse plaques; these typically are found in the
superficial cerebral cortex, the basal ganglia, and the cerebel-
lar cortex and may represent an early stage of plaque
development.
Neurofibrillary tangles are bundles of paired helical
filaments visible as basophilic fibrillary structures in the
ABC
Figure 22–25 Alzheimer disease. A, Plaques (arrow) contain a central core of amyloid and a surrounding region of dystrophic neurites (Bielschowsky
stain). B, Immunohistochemical stain for Aβ. Peptide is present in the core of the plaques as well as in the surrounding region. C, Neurons containing
tangles stained with an antibody specific for tau.
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 entorhinal cortex, 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 abnormally hyperphosphorylated
tau (Fig. 22–25, C ). Tangles are not specific to AD, being
found in other degenerative diseases as well.
Frontotemporal Lobar Degeneration
Another major category of disease that results in dementia
is called frontotemporal lobar degeneration (FTLD). These dis-
orders share clinical features (progressive deterioration of
language and changes in personality) stemming from the
degeneration and atrophy of temporal and frontal lobes;
the clinical syndromes commonly are referred to as fronto-
temporal dementias. When the frontal lobe bears the greatest
burden of disease, behavioral changes often dominate,
language problems often are the presenting complaint.
assist in their separation from AD on clinical grounds.
On gross inspection, there is atrophy of the brain that
predominantly affects the frontal and temporal lobes. Dif-
ferent subgroups are characterized by neuronal inclusions
involving the affected regions. In some cases the defining
inclusions contain tau (FTLD-tau), but the configuration of
the tau inclusions differs from the tau-containing tangles
of AD. FTLD-tau sometimes is caused by mutations in the
gene encoding tau. One well-recognized subtype of FTLD-
tau is Pick disease, which is associated with smooth, round
inclusions known as Pick bodies. The other major form of
FTLD is characterized by aggregates containing the DNA/
RNA-binding protein TDP-43 (FTLD-TDP43). This form of
FTLD is associated with predominantly frontal lobe cogni-
tive impairment. It is sometimes caused by mutations in
the gene encoding TDP-43, which is also mutated in a
subset of cases of amyotrophic lateral sclerosis (described
later).