Ultrastructural characterization of cerebellar diffuse plaques in Alzheimer's disease.

We examined the ultrastructural localization of beta/A4 protein in cerebellar diffuse plaques (DP) in three Alzheimer's disease brains by the indirect immunoperoxidase technique. Intense immunoreaction products were scattered in the DP; they were strongly suggested to be located between small cell processes. Reaction products were dot-like and/or amorphous, and occasionally fibrillar. Adjacent semithin sections of regions immunoreactive for beta/A4 protein revealed only very small amounts of amyloid fibrils between cell processes and/or small numbers of degenerating neurites. The small degenerating neurites which appeared in most DP lacked paired helical filaments (PHF) and neurofilaments (NF). These findings suggest that the majority of the beta/A4-immunoreactive substance in cerebellar DP is non-fibrillar pre-amyloid found between cell processes and barely detectable by routine electron microscopy.     

Blood-brain barrier permeability correlates with medial temporal lobe atrophy but not with amyloid-beta protein transport across the blood-brain barrier in Alzheimer's disease

BACKGROUND/AIMS: Alterations in the blood-brain barrier (BBB) may play an important role in the pathogenesis and treatment of Alzheimer's disease (AD). We investigated BBB disturbance and its influence on the equilibrium of amyloid-beta protein (Abeta) between plasma and cerebrospinal fluid (CSF) in AD patients. METHODS: We analyzed albumin ratio as a marker of the BBB permeability and correlated it with the severity of dementia, brain atrophy on MRI, apolipoprotein E isoform, CSF levels of total tau, CSF and plasma levels of Abeta 1-40 (Abeta40) and 1-42 (Abeta42), and CSF/plasma ratios of Abeta40 and Abeta42 in 42 AD patients. RESULTS: The albumin ratio was positively correlated with the severity of medial temporal lobe atrophy but not with the other parameters including CSF/plasma ratios of Abeta40 or Abeta42. CONCLUSION: Our results suggest that progression of medial temporal lobe atrophy is associated with increased BBB permeability and that the transport of Abeta across the BBB is not influenced by the BBB alteration in AD.     

Grey-matter atrophy in Alzheimer's disease is asymmetric but not lateralized

In Alzheimer's disease (AD), brain atrophy has been proposed to be left lateralized. Here, we reinvestigated the asymmetry and lateralization (i.e., asymmetry directed toward one hemisphere) of grey-matter (GM) distribution in 35 patients with AD, 24 patients with amnestic mild cognitive impairment (aMCI, a state of increased risk for AD), and 30 age-matched healthy controls (HC). We analyzed GM distribution by applying voxel-based morphometry (VBM) including analyses for asymmetry and lateralization. When comparing MCI with AD patients, VBM revealed GM loss in the entorhinal, temporoparietal, dorsofrontal, and occipital cortices as well as in the precuneus; when comparing HCs with MCI patients, we found similar differences, which were less pronounced especially within the temporoparietal cortex and precuneus. Analyses of regional asymmetry and regional lateralization as well as global lateralization did not yield significant results. However, lobar asymmetry of the temporal, parietal, and occipital lobes increased from HC to AD. Moreover, in aMCI and AD patients, performance of language-based neuropsychological tests correlated with lateralization of GM loss to the left hemisphere. We conclude that, in principle, brain atrophy in AD is asymmetric rather than lateralized. At the individual level however, asymmetry contributes to cognitive deficits.     

Brain β-spectrin is a component of senile plaques in Alzheimer's disease

Spectrin is a multifunctional cortical membrane skeleton protein. We report here that the β-subunit of spectrin is an integral component of β-amyloid plaques in Alzheimer's disease (AD). We prepared anti-β-spectrin antibodies by using synthetic peptides corresponding to the N-terminal and C-terminal domains of β-spectrin variants. When tissues from post-mortem AD brains were immunostained with these domain-specific affinity purified β-spectrin antibodies, β-amyloid plaques were specifically stained in the cortical parenchyma in approximately one third of the cases. The staining was unaffected by preadsorption of β-spectrin antibodies with A₄/β_1–40 peptide. The sodium dodecyl sulfate-insoluble amyloids were also stained by the β-spectrin antibodies. The anti-α-spectrin antibody stained neuronal processes, but not amyloid plaques. The presence of β-spectrin in the amyloid plaques in a subset of sporadic AD cases suggests that distinct biochemical pathways are involved in the formation or deposition of β-amyloid plaques, and that an abnormality of β-spectrin structure or function may be involved in the formation or deposition of β-amyloid plaques in this subset of AD cases.     

Alterations in Alzheimer's disease-associated protein in Alzheimer's disease frontal and temporal cortex.

Alzheimer's disease (AD)-associated protein is present in brain and cerebrospinal fluid of patients with AD but not in adult, nondemented, normal controls. This protein may represent an abnormal epitope of the "tau" microtubule-associated protein and has been detected before the appearance of senile plaques and neurofibrillary tangles. The amount of AD-associated protein in the frontal and temporal cortices in 93 cases of neuropathologically confirmed AD was compared with the amount that was present in 20 cases without AD. The amount of AD-associated protein was significantly increased in the cases of AD for both brain regions compared with that in the cases without AD. The presence of high levels of this protein is a useful adjunct, postmortem marker of the presence of AD and may eventually lead to tests that allow early detection of individuals at risk for this disease.     

Prion protein is reduced in aging and in sporadic but not in familial Alzheimer's disease

The cellular form of the prion protein (PrPC) has been shown to inhibit the production of amyloid-β which is critically involved in the pathogenesis of Alzheimer's disease (AD). We examined the expression of PrPC by immunoblot analysis in the hippocampus and temporal cortex in sporadic AD, familial AD, and appropriate age-matched controls, and in an aging series (age 20 to 88 years) of brains. PrPC was reduced by 53% (p=0.032) in the hippocampus in sporadic AD as compared to the age-matched controls. No such reduction in PrPC was seen in familial AD. PrPC was reduced in the hippocampus with aging (rs=0.03). The reduction in PrPC in sporadic but not familial AD suggests that reduced PrPC expression reflects a primary mechanism of disease and is not merely a secondary consequence of other AD-associated changes. The reduction of PrPC in the brain with aging suggests that age-related decreases in PrPC may contribute to the increased incidence of AD in older people.     

BAG1 is a protective factor for sporadic frontotemporal lobar degeneration but not for Alzheimer's disease

BCL2-associated athanogene 1 (BAG1) is an anti-apoptotic factor that interacts with tau and regulates its proteasomal degradation. A significant increase of the BAG-1M isoform was found in Alzheimer's disease (AD) brains, and the protein co-localized with tau and amyloid. We carried out an association study of BAG1 in a population of 291 patients clinically diagnosed with frontotemporal lobar degeneration (FTLD), none of whom was a carrier of mutations in progranulin or microtubule associated protein tau genes and 374 with AD as compared with 314 age- and gender-matched controls. In addition, another candidate named Chromatin-modifying protein 5 (CHMP5) and located in the same linkage disequilibrium block, has been included in this study. The distribution of the two single nucleotide polymorphism (SNPs), rs844239 in CHMP5 and rs706118 in BAG1, covering 100% gene variability, were determined. A statistically significant decreased allelic frequency of the BAG-1 rs706118 SNP was observed in patients with FTLD as compared with controls (16.7 versus 23.9%; p = 0.007, OR: 0.35, CI: 0.25-0.50), whereas allelic frequency of the SNP in patients with AD was similar to controls (24.3%, p > 0.05). Conversely, no significant association was found as regards CHMP5 rs844239. Stratifying according to gender, no differences were observed. BAG-1 rs706118 SNP likely acts as protective factor for sporadic FTLD, but not for AD, suggesting its specific role in a pathogenic event in FTLD. Nevertheless, a replication study would be needed to confirm these preliminary results.     

Calretinin-immunoreactive neurons in the normal human temporal cortex and in Alzheimer's disease

Calretinin-containing neurons (CR) were visualized by immunocytochemistry in the human temporal cortex. The morphology of calretinin-positive neurons ranged from bipolar, bitufted, fusiform to double bouquet cells, whose long axis was parallel to the radial axis of the cortex. Calretinin-immunoreactive cells were more abundant in layers II, III and less frequent in layer VI and white matter. In layer I, large horizontal neurons resembling Cajal-Retzius cells were observed. Layers IV and V contained few labeled cells. The CR-immunoreactive neuropil was abundant, especially in supragranular layers. However, the most prominent feature of the pattern of calretinin staining was the presence of long, vertically oriented bundles of calretinin-immunoreactive processes. These bundles formed a widespread, regular columnar system descending throughout layers II to VI. Despite the virtually identical morphological features of CR-immunoreactive neurons and certain calbindin-immunoreactive neurons, colocalization studies for both antibodies against calretinin and calbindin, revealed little coexistence (in supragranular layers) or none (in infragranular layers). Thus, double bouquet cells could be considered as forming a chemically heterogeneous neuronal population. In addition, four brains from patients with Alzheimer's disease were immunostained for calretinin. No major differences from normal brains were found; the distribution, morphology and the characteristic, vertically oriented bundles resembled those described in normal brains. These data suggest that these calcium-binding protein-containing interneurons are present in normal human brain and that they are resistant to degeneration in Alzheimer's disease.     

Neuropeptidergic systems in plaques of Alzheimer's disease

Polyclonal antibodies directed against substance P, somatostatin, neurotensin, cholecystokinin (CCK), leucine enkephalin, and vasoactive intestinal polypeptide (VIP) were employed to determine the immunoreactivities of neurites of senile plaques (SP) in Alzheimer's disease (AD). All of the antibodies labeled some neurites in some SP. The transmitter specificities of immunoreactive neurites tended to reflect the distribution of transmitter-associated fibers in normal tissue. This investigation also documented the presence of abnormal axons (as distinct from neurites within plaques) in the neuropil in brains of individuals with AD and in some aged controls. These findings suggest that a variety of transmitter systems are involved in the formation of neuropil abnormalities of SP. They also indicate that a greater number of neuronal systems are affected in AD than have been documented by neurochemical studies.     

Variant Alzheimer's disease with spastic paraparesis and cotton wool plaques is caused by PS-1 mutations that lead to exceptionally high amyloid-beta concentrations

We describe 3 new families affected by Alzheimer's disease with spastic paraparesis. In affected individuals, including the earliest known patient with this clinical syndrome, neuropathological examination revealed large "cotton wool" plaques similar to those we have previously described in a Finnish family. In the families in which DNA was available, presenilin-1 mutations were observed. Transfection of cells with these mutant genes caused exceptionally large increases in secreted Abeta42 levels. Furthermore, brain tissue from individuals with this syndrome had very high amyloid-beta concentrations. These findings define the molecular pathogenesis of an important subgroup of Alzheimer's disease and have implications for the pathogenesis of the disease in general.     

Apolipoprotein E phenotype alone does not influence survival in Alzheimer's disease: a population-based longitudinal study

Apolipoprotein E4 (ApoE4) phenotype is a known risk factor for development of Alzheimer's disease (AD). Contradictory results exist concerning the role of ApoE4 in the rate of decline and mortality in AD. Conflicting findings have also been reported about ApoE and gender interactions with respect to survival. We examined the survival of subjects with AD and non-AD controls with respect to ApoE phenotype and gender in a population-based longitudinal study. Cognitive evaluation was performed for a total of 980 subjects (then aged 69-78 years), and 48 cases with AD were identified. ApoE4 phenotype was more frequently present among subjects with AD. In the whole study population, survival was not related to the presence of AD or ApoE4 phenotype. Risk of death was increased for men compared to women, independently of the ApoE4 phenotype (HR 0.5, 95% confidence interval 0.44-0.69). In subjects with AD, the presence of ApoE4 alone did not influence survival. However, in the AD group, ApoE4-negative men had significantly increased risk of mortality compared to the risk in ApoE4-negative women (p < 0.01). We conclude that the presence of ApoE4 phenotype or AD did not influence mortality in the aged population. Once AD had become manifest, ApoE4 alone did not relate to survival. However, in subjects with AD not carrying ApoE4, men had reduced survival compared to women.     

Delusional thoughts and regional frontal/temporal cortex metabolism in Alzheimer's disease

OBJECTIVE: Delusional thoughts are common in patients with Alzheimer's disease and contribute prominently to morbidity. The pathophysiologic underpinnings for delusions in Alzheimer's disease are not well understood. In this study the authors examined the relationship between delusional thoughts and regional cortical metabolism in patients with Alzheimer's disease. METHOD: Twenty-five patients with probable Alzheimer's disease were included. None was taking psychotropic medication. Severity of delusions and other neuropsychiatric symptoms was assessed by using a semistructured interview and the Neurobehavioral Rating Scale just before the imaging procedure. [(18)F]Fluorodeoxyglucose positron emission tomography was used to measure resting cerebral glucose metabolic rates in the cortical lobes and in anatomically defined subregions of the frontal and temporal cortexes. RESULTS: A linear regression model, controlling for the effects of cognitive deficits, revealed a significant relationship between severity of delusional thought and the metabolic rates in three frontal regions: the right superior dorsolateral frontal cortex (Brodmann's area 8), the right inferior frontal pole (Brodmann's area 10), and the right lateral orbitofrontal region (Brodmann's area 47). Bivariate partial correlation analysis indicated that severity of delusions was associated with hypometabolism in additional prefrontal and anterior cingulate regions. Robust relationships with metabolism in regions of the temporal cortex were not apparent. CONCLUSIONS: Dysmetabolism in specific regions of the right prefrontal cortex may be associated with delusional thought in Alzheimer's disease. Delusions appear to reflect the pathophysiologic state of particular cortical regions. Activity across distributed neuronal networks and the specific content of delusional thoughts may modulate these relationships.     

Minicolumn thinning in temporal lobe association cortex but not primary auditory cortex in normal human ageing

The cerebral cortex undergoes changes during normal ageing with increasing effect on cognition. Disruption of minicolumnar organization of neurons is found with increased cognitive impairment in primates. We measured the minicolumn spacing and organization of cells in Heschl’s gyrus (primary auditory cortex, A1), the Planum Temporale (Tpt, BA22), and middle temporal gyrus (MTG, BA21) of 17 normally aged human adults. Age-associated minicolumn thinning was found in temporal lobe association cortex (Tpt and MTG) but not primary auditory cortex (HG). Minicolumn thinning was also associated with greater plaque load, although this effect was present in all areas. The regional variability of age-associated minicolumn thinning reflects the regionally selective progression of tangle pathology in Alzheimer’s Disease (AD). The generalized effect of plaque load persists when controlling for age. Therefore plaque load combines with age to increase minicolumn thinning, which may reflect increasing risk of AD. Since old age is the greatest risk factor for dementia, the transition to dementia may involve an extension of normal ageing processes.     

Selective increase in lipid peroxidation in the inferior temporal cortex in Alzheimer's disease

The concentration of a product of lipid peroxidation (malondialdehyde) was determined in six areas of neocortex of 8 subjects with Alzheimer's disease and 8 control subjects. Malondialdehyde concentration was significantly increased by incubation with iron and ascorbate in all samples. Both basal and iron/ascorbate-stimulated malondialdehyde concentration were higher in the inferior temporal cortex of Alzheimer subjects than corresponding controls; other regions were unaffected. Basal concentrations of malondialdehyde correlated with age in both the inferior parietal lobule and the sensory/motor cortex.     

Differential involvement of the posterior temporal cortex in mentalizing but not perspective taking

Understanding and predicting other people''s mental states and behavior are important prerequisites for social interactions. The capacity to attribute mental states such as desires, thoughts or intentions to oneself or others is referred to as mentalizing. The right posterior temporal cortex at the temporal–parietal junction has been associated with mentalizing but also with taking someone else''s spatial perspective onto the world—possibly an important prerequisite for mentalizing. Here, we directly compared the neural correlates of mentalizing and perspective taking using the same stimulus material. We found significantly increased neural activity in the right posterior segment of the superior temporal sulcus only during mentalizing but not perspective taking. Our data further clarify the role of the posterior temporal cortex in social cognition by showing that it is involved in processing information from socially salient visual cues in situations that require the inference about other people''s mental states.     

Kappa-1 opioid receptors of the temporal cortex are preserved in Alzheimer's disease

Summary The binding of [³H]-U-69593 and [³H]-CI-997 to kappa-1 opioid receptors has been examined in the temporal cortex of postmortem brains from patients with Alzheimer's disease and age-matched controls using quantitative autoradiography. There was no significant difference between Alzheimer and control subjects in the level of [³H]-U-69593 and [³H]-CI-977 binding, but ChAT activity was markedly reduced (by 73% compared to controls). These results are not consistent with a presynaptic localisation of kappa-1 receptors on cholinergic terminals in human temporal cortex.