Adrelated Synaptic Alterations In Neocortex

Early theories concerning structural mechanisms responsible for AD dementia considered synaptic changes as an important component38'39. This was based in part on prior Golgi studies reporting changes in dendritic arborization and dendritic spines, suggestive of AD-related synaptic pathology40. Two very early studies utilized conventional transmission EM to examine the frontal and temporal cortex in subjects with AD. In the earliest study41, biopsy tissue was obtained from three patients who presented with signs of AD. These subjects were later confirmed to have a substantial amount of AD pathology. Numerous electron-dense dendritic spines were observed in close approximation to normal appearing presynaptic boutons. The second EM study by Gibson in 198324 reported no loss of synaptic numbers in the cortex in three AD subjects. Only one AD subject was included in the temporal lobe analysis and although the synaptic values were very low compared to almost all of the other individuals examined, two of the other 15 subjects were lower. A paper by Paula-Barbosa and colleagues appeared in 1986 and was the first study designed specifically to test for AD-related changes in neocortical synaptic numbers. Biopsy tissue from the superior frontal cortex (Brodmann areas 9 and 10) of severely demented subjects with AD was compared to "control" subjects undergoing biopsy during routine perfusion ventriculographies. The ultrastructural assessment showed no significant differences in the volume density of synapses between the two groups. The authors concluded that the cognitive changes in the AD subjects were probably not related to synaptic loss. It was speculated, that even though there was considerable neuronal loss in AD cortex42-45, AD-related synaptic plasticity may maintain normal synaptic numbers46.

Despite these negative findings, Davies and co-workers47 used EM in an attempt to estimate whether the number of cortical synapses was altered in AD. Biopsy tissue from the middle temporal lobe (Brodmann area 21) was obtained from 12 early-stage AD subjects. The authors reported a significant loss (25-36%) of synaptic volume densities in laminae III and V. Why did this group find a loss of synapses and previous studies did not? A couple of variables may have been important. First, the cortical region analyzed was different. Brodmann area 9 was used in prior studies and area 21 for this analysis. As part of a side investigation, this group does report on 4 AD and 3 control cases with biopsy material for the superior frontal cortex. This limited analysis also found a 27% loss of synapses in AD but only for lamina V. Second, the study of Davies and co-workers only had three control subjects. Third, it is unclear whether or not the control cases in any of these studies were from cognitively normal individuals, and one might add that cognitively normal individuals would probably not be undergoing a brain biopsy. This study is significant in that it is the first quantitative study to report AD-related synapse loss in the cortex. Although all the AD cases were histologically confirmed, no attempt was made to correlate synaptic numbers with the accumulation of senile plaques or NFT.

In the early 1980s immunohistochemistry was beginning to become in vogue within the neuroscience communities and antibodies were developed against synaptic proteins. One of the earliest was the synapse-associated phosphoprotein synapsin I48, which was used in a radioimmunoassay (RIA) to study possible AD-related changes49. Although five different brain regions, including the cingulate gyrus, were studied in autopsy material, only the hippocampus showed a significant change. Synaptophysin, a molecular marker for a presynaptic vesicle membrane protein50, was also developed and gaining considerable popularity. In a seminal paper, Masliah and colleagues exploited the immunohistochemical technique by demonstrating significant declines in reactivity in the parietal, temporal, and frontal cortex of AD subjects51. Densitometric analysis of stained tissue demonstrated a 50% decrease in synaptophysin staining throughout these three cortical regions. The major advantage to this technique, compared to the labor-intensive EM, was the ease of staining and quantification, thus providing a very rapid evaluation of a large number of tissue samples. Subsequent studies demonstrated that this synaptic marker was stable at long PMIs25. One of the drawbacks is that alterations in staining might cause disease-related loss of antigenicity rather than an AD-related loss in the density of synapses. Currently, the synaptophysin antibody is the most commonly used marker to identify synaptic connectivity. It has been used for immunohistochemistry, immunoblotting, and ELISA quantification of synaptic numbers.

4.1. Frontal Cortex (Brodmann Areas 9, 10, 46)

Numerous different regions of the neocortex have been assessed for possible changes in synaptic numbers. Because of its association with executive functions known to be altered in AD, the frontal cortex has been the subject of several investigations. Every study designed specifically to assess synaptic numbers in the frontal cortex (Brodmann areas 9, 10, 46) has reported a disease-related decline. The percentage decline varies widely (11-48%) regardless of whether ultrastructural assessment17,47,52,53 or immunohistochemical methods16,20,26,51,54-59 were employed. The average observed AD-related decline in synaptic numbers within the frontal cortex is 36%. Reasons for the observed disparity between studies could relate to the subject's stage in the disease progression (early versus "end-stage") or to the limited region of analysis (entire cortical depth versus specific cortical lamina). Exactly what tissue is used as appropriate control and whether or not the groups are age and post mortem matched could also be important factors (Figure 29.2).

4.2. Temporal Cortex (Brodmann Areas 20, 21, 22)

The temporal lobe, consisting of the superior (area 22), middle (area 21), and inferior (area 20) regions, is well known for the accumulation of SP and NFT hallmarks of AD60. Several studies have evaluated possible synaptic change in these temporal lobe subregions. Markers for the synaptic protein synaptophysin decline approximately 50% in the superior temporal cortex16'20'29'51 while ultrastructural studies report a 31% decline in AD61. Two different EM studies report a 32-36% loss of synapses in the middle temporal gyrus47,61, while the inferior portion of the temporal lobe demonstrates a 31-49% AD-related decline26,62. These secondary and tertiary association regions of the cortex have reciprocal connections with numerous other cortical regions that are directly linked with limbic structures. The temporal lobe plays an important role in both language and visual-spatial relationships, behaviors that are known to decline in AD.

Figure 29.2. Lateral and Medial View of the Human Neocortex, Cerebellum, and Brainstem. Labels indicate regions of the brain that have been investigated for possible AD-related changes in synaptic numbers. The numbers indicate the percentage synaptic decline observed in the AD subjects compared to control subjects. For some regions there is a range depending upon which study reports the loss. For some regions there was no significant change in synaptic numbers.

Figure 29.2. Lateral and Medial View of the Human Neocortex, Cerebellum, and Brainstem. Labels indicate regions of the brain that have been investigated for possible AD-related changes in synaptic numbers. The numbers indicate the percentage synaptic decline observed in the AD subjects compared to control subjects. For some regions there is a range depending upon which study reports the loss. For some regions there was no significant change in synaptic numbers.

4.3. Inferior Parietal Cortex (Brodmann Areas 39, 40)

Brodmann areas 39/40 (inferior parietal) are also heavily invested with AD pathology63. This cortical region is important in language and synaptic alterations could account for language dysfunction associated with AD64. Immunohistochemical studies using synaptophysin have reported 50% reductions in synaptic numbers in the inferior parietal cortex16'26'51'54'56 with a single ultrastructural report of 31% in end-stage AD subjects62. A single synaptophysin study reported a 32% decline in synaptophysin in the superior parietal cortex (Brodmann area 7), a primary sensory association area. It is interesting that no studies have assessed possible synaptic changes in either primary motor or primary sensory areas, probably because these regions contain little if any SP and NFT65.

4.4. Other Cortical and Subcortical Areas

Several studies have assessed the occipital region of the neocortex and while reporting loss of synaptophysin staining as much as 25%56,59, some of the findings are not significantly different from age-matched controls23,29. Other regions of the neocortex that have synaptic loss appear to be areas known to be involved early in the disease process3,7,66. The cingulate gyrus has been identified as one of these cortical regions that may play an important role early in the progression of the disease. Two studies report a significant loss of synapses in the cingulate gyrus26,67. One study reported synaptic loss in both anterior and posterior cingulate regions with the caveat that lamina 3 of the anterior cingulate declines in synaptic numbers while lamina V does not67. The entorhinal cortex (Brodmann area 28) that is known for its early AD pathology has also been investigated by several groups for possible changes in synaptic numbers. Surprisingly, only two groups have reported significant declines in a synaptic markers68,69 while the others have failed to detect any significant changes in this important limbic structures23,56,70,71. It is interesting that one study found no change in synaptophysin staining in the entorhinal cortex but did observe a decline in the synaptic protein SP669.

Several noncortical structures have been assessed, including the cerebellum, caudate, putamen, substantia nigra, pontine nuclei/mesencephalon, and oculomotor nucleus, all of which show no significant change23,49,56,72,73. The only subcortical structure that did show a noticeable decrease was the nucleus basalis but it is unclear if the loss is significant since it was not quantified56.

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