Second edition

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Figure 8.1 Note the relative sparing of the pre- and postcentral
gyri compared with the rest of the cortex in this case of
Alzheimer’s disease. (Reproduced from Rees et al. 1996.)
Figure 8.2 This T1-weighted magnetic resonance imaging scan
demonstrates the cortical atrophy and ventricular dilation found
in advanced Alzheimer’s disease. Note in particular that the
hippocampus, indicated by the arrows, has shrunk down to a thin
remnant. (Reproduced from Gillespie and Jackson 2000.)
and an increased level of tau protein (Andreasen et al. 2001;
Galasko et al. 1998; Hampel et al. 2004), and a recent
autopsy study demonstrated a good correlation between
CSF levels of tau protein and the burden of neurofibrillary
tangles (Buerger et al. 2006).
Although single photon emission computed tomography
(SPECT) scanning may show areas of decreased activity
in association with neocortical areas, this technique is
probably not appropriate for routine clinical work as in an
autopsy control study (McNeill et al. 2007) it added little to
diagnostic accuracy over and above a good history and
examination.
Course
8.1 Alzheimer’s disease 337
Although a small minority of patients may experience temporary
plateaus, Alzheimer’s disease, for the most part, is
relentlessly and steadily progressive, death occurring for
most within 5–15 years. At the end, patients are vegetative,
bedfast, and incontinent. Although it is generally held that
cases with an early onset, before the age of 65 years, tend to
run a more rapid course (Koss et al. 1996), not all studies
agree on this (Bracco et al. 1994).
Etiology
Macroscopically, as illustrated in Figure 8.1, there is widespread
cortical atrophy affecting primarily the temporal,
parietal, and frontal lobes, with prominent sparing of the
pre- and post-central gyri; relative to the other lobes the
occipital lobe is less affected. Within the temporal lobe,
the hippocampus (as illustrated in Figure 8.2) and amygdala
are also very prominently involved. Subcortical and
brainstem nuclei, including the nucleus basalis of Meynert
(especially its cholinergic neurons) (Whitehouse et al.
1981), the locus ceruleus (Mann et al. 1984), and the dorsal
raphe nucleus (Yamamoto and Hirano 1985), also
undergo significant damage.
Microscopically (Kidd 1964) there are widespread neurofibrillary
tangles and neuritic plaques (also known as
senile plaques) accompanied by neuronal loss (Terry et al.
1981). Neurofibrillary tangles are fibrillar structures found
in the neuronal cytoplasm that, by electron microscopy,
are seen to be composed of paired helical filaments. These
paired helical filaments are composed of hyperphosphorylated
tau proteins, which are one of the microtubule-associated
proteins (MAP) that ensure the integrity and
stability of the cellular microtubules. Neuritic plaques are
spherical extracellular structures composed of an amyloid
core surrounded by ‘neurites’, or swollen axonal fragments.
The amyloid core of the neuritic plaque is composed
primarily of beta-amyloid.
Interestingly, although the clinical severity of Alzheimer’s
disease correlates with the number of neurofibrillary
tangles, there is little correlation with the number of neuritic
plaques (Arriagada et al. 1992; Bierer et al. 1995).
Furthermore, it appears that, in general, there is an
orderly appearance of neurofibrillary tangles during the
course of the disease, beginning first in the transentorhinal
cortex and then progressing sequentially to the entorhinal
cortex, hippocampus, temporal cortex, parietal and prefrontal
cortex, and finally all neocortical areas (Braak
and Braak 1991; Delacourte et al. 1999). This progression
appears to supply a pathologic underpinning to the
evolution of clinical features noted above, in that damage
to medial temporal structures would be expected to
cause an amnesia, whereas later damage to cortical areas
would account for the appearance of further cognitive
deficits.