Ganong's Review of Medical Physiology, 23rd Edition

294
SECTION III
Central & Peripheral Neurophysiology

the environment. In strange surroundings, one is alert and on
guard, whereas in familiar surroundings, vigilance is relaxed.
An inappropriate feeling of familiarity with new events or in
new surroundings is known clinically as the
déjà vu phenom-
enon,
from the French words meaning “already seen.” The
phenomenon occurs from time to time in normal individuals,
but it also may occur as an aura (a sensation immediately pre-
ceding a seizure) in patients with temporal lobe epilepsy.

SUMMARY

In summary, much is still to be learned about the encoding of
explicit memory. However, according to current views, infor-
mation from the senses is temporarily stored in various areas of
the prefrontal cortex as working memory. It is also passed to
the medial temporal lobe, and specifically to the parahippoc-
ampal gyrus. From there, it enters the hippocampus and is pro-
cessed in a way that is not yet fully understood. At this time, the
activity is vulnerable, as described above. Output from the hip-
pocampus leaves via the subiculum and the entorhinal cortex
and somehow binds together and strengthens circuits in many
different neocortical areas, forming over time the stable remote
memories that can now be triggered by many different cues.

ALZHEIMER DISEASE &

SENILE DEMENTIA

Alzheimer disease
is the most common age-related neurode-
generative disorder. Memory decline initially manifests as a
loss of episodic memory, which impedes recollection of recent
events. Loss of short-term memory is followed by general loss
of cognitive and other brain functions, the need for constant
care, and, eventually, death.
It was originally characterized in middle-aged people, and
similar deterioration in elderly individuals is technically
senile
dementia
of the alzheimer type, though it is frequently just
called Alzheimer disease. Most cases are sporadic, but some

are familial. Senile dementia can be caused by vascular disease

and other disorders, but Alzheimer disease is the most com-

mon cause, accounting for 50–60% of the cases. It is present in

about 17% of the population aged 65–69, but its incidence

increases steadily with age, and in those who are 95 and older,

the incidence is 40–50%. Thus, Alzheimer disease plus the

other forms of senile dementia are a major medical problem.

Figure 19–5 summarizes some of the risk factors, patho-

genic processes, and clinical signs linked to cellular abnor-

malities that occur in Alzheimer disease. The cytopathologic

hallmarks of Alzheimer disease are intracellular

neurofibril-

lary tangles,

made up in part of hyperphosphorylated forms

of the tau protein that normally binds to microtubules, and

extracellular

senile plaques,

which have a core of

β

-amyloid

peptides (A

β

)

surrounded by altered nerve fibers and reactive

glial cells. Figure 19–6 compares a normal nerve cell to one

showing abnormalities associated with Alzheimer disease.

The A

β

peptides are products of a normal protein,

amyloid

precursor protein (APP),

a transmembrane protein that

projects into the extracellular fluid (ECF) from all nerve cells.

This protein is hydrolyzed at three different sites by

α

-secre-

tase,

β

-secretase, and

γ

-secretase, respectively. When APP is

hydrolyzed by

α

-secretase, nontoxic peptide products are pro-

duced. However, when it is hydrolyzed by

β

-secretase and

γ

• secretase, polypeptides with 40 to 42 amino acids are produced;
  the actual length varies because of variation in the site at which
  γ
  -secretase cuts the protein chain. These polypeptides are
  toxic, the most toxic being A
  βσ
  1–42
  . The polypeptides form
  extracellular aggregates, which can stick to AMPA receptors
  and Ca
  2+
  ion channels, increasing Ca
  2+
  influx. The polypep-
  tides also initiate an inflammatory response, with production
  of intracellular tangles. The damaged cells eventually die.
  An interesting finding that may well have broad physiologic
  implications is the observation—now confirmed in a rigorous
  prospective study—that frequent effortful mental activities,
  such as doing difficult crossword puzzles and playing board
  games, slow the onset of cognitive dementia due to Alzheimer
  disease and vascular disease. The explanation for this “use it or

FIGURE 19–5
Relationships of risk factors, pathogenic processes, and clinical signs to cellular abnormalities in the brain during
Alzheimer disease.
(From Kandel ER, Schwartz JH, Jessell TM [editors]:
Principles of Neural Science,
4th ed. McGraw-Hill, 2000.)

Risk factors*

• Age


• Presenilin 1 mutations (chromosome 14)


• Presenilin 2 mutations (chromosome 1)


• Amyloid precursor protein gene
  mutations (chromosome 21)


• apoE alleles (chromosome 19)


• Trisomy 21

* Recently a mutation in the α-2 macroglobulin gene

has been implicated in the late-onset disease

Vulnerable neurons

Monoaminergic systems,

basal forebrain cholinergic

system, hippocampus,

entorhinal cortex, and

neocortex

Cytopathology

Neurofibrillary tangles,

neurites, Aβ peptide

deposition, other cellular

abnormalities

End-stage disease

Senile plaques,

death of neurons,

gliosis

Pathogenic mechanisms

Clinical signs

Memory loss,

cognitive deficits