Search PubMed⌕ Search

Biomedical subjects

R N Kalaria

Publications and source records attributed to R N Kalaria.

At least 55 records · Page 3Linked to original sources
PubMed1997

Evaluation of risk factors for Alzheimer's disease in elderly east Africans.

A number of biological risk factors have been implicated for Alzheimer's disease (AD). The investigation of prevalence rates of AD in crosscultural populations has much potential in validating these factors. We previously assessed brain amyloid beta (A beta) protein deposition and other lesions associated with AD as possible markers for preclinical AD in elderly nondemented East Africans. In further analysis, we demonstrate that 17-19% of elderly East African subjects without clinical neurological disease exhibited neocortical A beta deposits and minimal neurofibrillary changes at necropsy that was qualitatively and quantitatively similar to that in an age-matched elderly control sample from Cleveland, OH. A beta deposits varied from numerous diffuse to highly localized neuritic plaques and were predominantly reactive for the longer A beta 42 species. In parallel studies, we evaluated another recently implicated factor in AD, the apolipoprotein E genotype. We found relatively high frequencies of the apolipoprotein E-epsilon 4 allele in elderly nondemented East Africans. The frequencies were comparable to those in other African populations but higher than in subjects from developed countries. Our limited study suggests that elderly East Africans acquire cerebral lesions found in AD subjects but the apolipoprotein E-epsilon 4 allele may not be a highly specific factor for the disease among East Africans.

Africa, Eastern↗
PubMed1997

Apolipoprotein E polymorphism in elderly east Africans.

Current advances have shown the apolipoprotein E (APOE)-epsilon 4 allele to be highly associated with late-onset familial and sporadic Alzheimer's disease (AD) in Western populations. The association of APOE allele frequencies and dementia remain unknown in populations from developing countries. We recently initiated a project to examine APOE frequencies in non-demented and demented elderly East Africans. Blood DNA collected from two hospital-based populations showed that the APOE allele frequencies in a group of non-demented 67 Tanzanians over the age of 65 years were found to be 14% for epsilon 2, 61% for epsilon 3 and 25% for epsilon 4. By comparison, the frequency of APOE-epsilon 4 in an age-matched demented group was also 25%. Assessment of APOE genotypes in the group of elderly Kenyan subjects from Nairobi also revealed high frequencies of the epsilon 4 allele with no clear difference in frequency between demented and non-demented subjects. Our preliminary observations suggest that elderly East Africans with no apparent clinical AD possess relatively high APOE-epsilon 4 allele frequencies compared to normal ageing subjects from Western countries including African-Americans. These results appear similar to those reported in a recent study in Nigerian Africans where a lack of correlation between APOE-epsilon 4 allele frequency and Alzheimer type of dementia was noted, and imply that APOE-epsilon 4 allele may not necessarily be a risk factor in some populations of Africa.

Aged↗
PubMed1996

Activation of nitric oxide synthase gene expression by hypoxia in central and peripheral neurons.

In the present study we examined the effects of hypobaric hypoxia on neuronal (n) and endothelial (e) nitric oxide synthase (NOS) gene expression in the central and peripheral nervous system. Adult rats were exposed either to normoxia (room air) on to hypobaric hypoxia (0.4 atm) for 4, 12 or 24 h and cerebellum and nodose ganglion representing the central and peripheral neurons, respectively, were removed. Messenger RNAs encoding n- and eNOS as well as beta-actin were analyzed by reverse transcriptase polymerase chain reaction (RT-PCR) technique. Hypoxia increased nNOS mRNA expression with maximal changes occurring after 12 h wherein mRNA levels were increased by 10.4 +/- 1.3 and 2 +/- 0.4 fold in nodose ganglion and cerebellum, respectively. Hypoxia, on the other hand, had no significant effect on eNOS and beta-actin mRNA levels. Analysis of nNOS protein and enzyme activity showed near doubling of these variables in both tissues after 24 h of hypoxia, indicating that nNOS protein levels are increased and that the protein is functionally active. These observations demonstrate that 12-24 h of hypobaric hypoxia selectively activates nNOS gene expression, which is reflected in an increase in nNOS protein in central and peripheral neurons. It is suggested that up-regulation of nNOS leads to increased generation of nitric oxide, which in turn may contribute to the readjustments of cardio-respiratory systems during the early stages of chronic hypoxia.

Animals↗
PubMed1996

The amiloride-sensitive Na+/H+ exchange antiporter and control of intracellular pH in hippocampal brain slices.

The intracellular pH, 7.54 +/- 0.03 (mean +/- S.D., n = 15), determined with the Neutral red method, of the hippocampal brain slice preparation under baseline incubation conditions is considerably more alkaline than the bath buffer pH. Neutralization by amiloride suggests that the alkalinity was due to Na+/H+ exchange antiporter activation. To characterize the brain Na+/H+ exchange antiporter we compared the inhibitory effects of MIA, amiloride and other 5-N substituted analogues on proton extrusion after acid loading by transient exposure to ammonium chloride in the isolated hippocampal brain slice preparation. The potencies of amiloride compounds on the initial recovery rate of intracellular pH after acid-loading were DMA > MIA > HMA = MHA > or = IPA-HCI > IPA > MNPA = Amil > Benzamil. The greater potency of the 5-N substituted analogs of amiloride over amiloride and benzamil strongly suggest that Na+/H+ exchange antiporter is the mechanism responsible for alkalinization in the isolated hippocampal brain slice in vitro.

Acids↗
PubMed1996

Abundance of the longer A beta 42 in neocortical and cerebrovascular amyloid beta deposits in Swedish familial Alzheimer's disease and Down's syndrome.

Recent studies have demonstrated the deposition of amyloid beta (A beta) protein with carboxyl- and aminoterminal heterogeneity in cortical and cerebrovascular deposits of Alzheimer's disease (AD). Using carboxyl end-terminal specific antibodies to A beta peptides, we examined the immunocytochemical distribution of A beta 40 and A beta 42 species in brain tissue from a Swedish subject with familial AD (FAD) bearing the double mutation at codons 670/671 in the amyloid beta precursor protein (A beta PP), and from subjects with Down's syndrome and sporadic AD. In the Swedish subject, we found profound parenchymal A beta deposits and cerebral amyloid angiopathy in all four cortical lobes and cerebellum. A beta 42 was evident in almost all parenchymal deposits as well as many vascular deposits. Although A beta 40 was present in meningeal and intraparenchymal vessels, deposits containing this shorter peptide reactivity were sparse. Surprisingly, our observations in Swedish FAD showing a remarkable abundance of A beta 42 in both parenchymal and vascular deposits were qualitatively similar to the Down's syndrome and most sporadic AD cases, and to previously published A beta PP717 FAD. While previous transfection studies in different cell cultures indicate substantially increased soluble A beta production and A beta 40 species to be predominant, it would appear that the double A beta PP mutations in Swedish FAD largely result in the deposition of the longer A beta 42 in vivo.

Adult↗
PubMed1996

Apolipoprotein E alleles and brain vascular pathology in Alzheimer's disease.

The presence of apolipoprotein E (ApoE)-E4 allele has been implicated as a risk factor for Alzheimer's disease (AD). We examined the occurrence of ApoE 4 alleles in AD associated with cerebral amyloid angiopathy and other vascular lesions. We found significantly high frequency of the ApoE 4 allele in AD with moderate to severe CAA. The frequency of the allele was also high in AD cases with other vascular lesions such as multiple infarcts and lacunes. As previously reported, we confirm a greater frequency of the ApoE 4 allele in the diffuse Lewy body variant of AD. Our results suggest ApoE 4 allele to be a significant factor in the development of CAA in AD. While this may be related to increased brain amyloid load as a consequence of ApoE genotype, the possibility exists that ApoE may be a specific factor in vascular abnormalities associated with AD.

Aged↗
PubMed1996

Altered expression of amyloid beta precursor mRNAs in cerebral vessels, meninges, and choroid plexus in Alzheimer's disease.

Altered tissue-specific processing or production of the amyloid precursor protein (APP) is thought to be central to amyloid deposition in cerebrovascular and the neocortical tissues in Alzheimer's disease (AD). We demonstrate that A beta peptide(s) is readily detectable and increased in cerebral vessels, meninges and choroid plexus obtained at autopsy from AD subjects compared to age-matched controls. Using the reverse transcription (RT)-polymerase chain reaction (PCR), we further found that A beta transcripts encoding the A beta sequence in all forms of APP containing exons 16 and 17 (of APP770) were significantly increased in vessel samples in AD subjects. This was also evident in the neocortical samples and not related to pre-mortem factors or postmortem interval. It is possible that the increased A beta mRNAs reflect enhanced expression of the L-APP isoform (APP770 without exon 15) expressed in leukocytes and glia alike. We also found evidence for changed proportions of APP 770, 756 and 695 mRNAs in cerebral vessel samples from AD subjects compared to controls. Whereas APP770 and APP751, the predominant forms, were significantly decreased, APP695 transcript was increased in vessel samples from AD subjects. Such changes were not evident in neocortical samples from the same subjects. These observations suggest tissue-specific changes in expression of APP isoforms implicating one of the mechanisms for increased accumulation of A beta in cerebrovascular tissues in AD.

Aged↗
PubMed1996

Cellular aspects of the inflammatory response in Alzheimer's disease.

Cerebral amyloid beta protein deposition in Alzheimer's disease is associated with a predominantly local acute phase response that kindles release of various inflammatory and immune system mediators. The molecular events are accompanied by a profound cellular response which is largely orchestrated by microglia. Current evidence suggests microglia are primarily involved in phagocytic activity and may be responsible for inducing further neuronal damage by generating reactive oxygen species and proteolytic enzymes. Antiinflammatory measures that target complement activation as well as microglial-mediated oxidative damage would provide rational therapeutic strategies.

Alzheimer Disease↗
PubMed1996

Production and increased detection of amyloid beta protein and amyloidogenic fragments in brain microvessels, meningeal vessels and choroid plexus in Alzheimer's disease.

Recent advances indicate soluble amyloid beta (A beta) protein is produced constitutively during normal metabolism of the amyloid precursor protein (APP). This has not been directly examined in human brain vascular tissues. Using a panel of well-characterized antibodies, here we show that increased amounts of soluble A beta were found in isolated vascular tissues from AD subjects compared to age-matched controls without significant Alzheimer pathology. Immunocytochemical analyses of isolated vessel preparations showed characteristic transverse patterns of A beta deposits in large vessels with smooth muscle, however, fine A beta deposits were apparent even in capillaries. A proportion of such A beta protein and potentially amyloidogenic carboxyl terminal fragments were released by solubilization and disruption of the vascular basement membrane by collagenase treatments. We further demonstrated by in vitro metabolic labelling that soluble A beta or an A beta-like peptide is associated and produced by cerebral microvessels, meningeal vessels and the choroid plexus isolated postmortem from human as well as rat brain. Compared to those from young rats, cerebral microvessels from aging rats showed increased release of carboxyl terminal fragments of APP and A beta-like peptide. Our observations provide the first direct demonstration that human vascular tissues produce soluble A beta, a product of the secretory pathway in APP processing. Our findings also suggest that aging associated alterations in the basement membranes are a factor in A beta accumulation that results in vascular amyloid deposition, the principal feature of cerebral amyloid angiopathy.

Aged↗
PubMed1996

Cerebral vessels in ageing and Alzheimer's disease.

The integrity of the cerebral vasculature is crucial to the maintenance of cognitive functions during ageing. Prevailing evidence suggests that cerebrovascular functions decline during normal ageing, with pronounced effects in Alzheimer's disease (AD). The causes of these changes largely remain unknown. While previous studies recorded ageing-related impairments, such as atherosclerosis and loss of innervation in basal surface arteries of the brain, it only recently has been realized that a number of subtle alterations in both the intracranial resistance vessels and the smaller capillaries is apparent in both ageing animals and humans. The dominant changes include alterations in composition of connective tissues and smooth muscle of large vessel walls, thickening of the vascular basement membrane, thinning of the endothelium in some species, loss of endothelial mitochondria and increased pericytes. Some of these attributes appear more affected in AD. Other abnormalities entail profound irregularities in the course of microvessels, unexplained inclusions in the basement membrane and changes in unique proteins and membrane lipids associated with the blood-brain barrier. Brain imaging and permeability studies show no clear functional evidence to support the structural and biochemical anomalies, but it is plausible that focal and transient breach of the blood-brain barrier in ageing, and more notably in AD, occurs. Thus, circumscribed neuronal populations in certain brain regions could become vulnerable. Furthermore, the characteristic deposition of amyloid in vessels in AD may exacerbate the decline in vascular function and promote chronic hypoperfusion. Although not explicit from current studies, it is likely that the brain vasculature is continually modified by growth and repair mechanisms in attempts to maintain perfusion during ageing and disease.

Aging↗
PubMed1996

Cerebral amyloid beta protein deposits and other Alzheimer lesions in non-demented elderly east Africans.

There is little knowledge of the existence of Alzheimer disease (AD) or Alzheimer type of dementia in indigenous populations of developing countries. In an effort to evaluate this, we assessed the deposition of amyloid beta (A beta) protein and other lesions associated with AD in brains of elderly East Africans. Brain tissues were examined from 32 subjects, aged 45 to 83 years with no apparent neurological disease, who came to autopsy at two medical Institutions in Nairobi and Dar es Salaam. An age-matched sample from subjects who had died from similar causes in Cleveland was assessed in parallel. Of the 20 samples from Nairobi, 3 (15%) brains exhibited neocortical A beta deposits that varied from numerous diffuse to highly localized compact or neuritic plaques, many of which were also thioflavin S positive. Two of the cases had profound A beta deposition in the prefrontal and temporal cortices and one of these also exhibited moderate to severe cerebral amyloid angiopathy. Similarly, 2 of the 12 samples from Dar es Salaam exhibited diffuse and compact A beta deposits that were also predominantly reactive for the longer A beta 42 species compared to A beta 40. We also noted that A beta plaques were variably immunoreactive for amyloid associated proteins, apolipoprotein E, serum amyloid P and complement C3. Tau protein reactive neurofibrillary tangles (NFT) were also evident in the hippocampus of 4 subjects. By comparison, 4 (20%) of the 20 samples from randomly selected autopsies performed in Cleveland showed A beta deposits within diffuse and compact parenchymal plaques and the vasculature. These observations suggest A beta deposition and some NFT in brains of non-demented East Africans are qualitatively and quantitatively similar to that in age-matched elderly controls from Cleveland. While our small scale study does not document similar prevalence rates of preclinical AD, it suggests that elderly East Africans are unlikely to escape AD as it is known in developed countries.

Aged↗
PubMed1996

Investigations on the point mutations at nt 5460 of the mtDNA in different neurodegenerative and neuromuscular diseases.

Point mutations of the mitochondrial genome are often considered to be the cause of certain neurodegenerative disorders and mitochondrial myopathies. Recently, there has been a report on Alzheimer's disease (AD) point mutations at position 5460 of the mitochondrial genome located within the ND2 gene. Using allele-specific PCR with a sensitivity of detection of less than 1% mutated mtDNA, we investigated postmortem brain samples from 48 patients with AD and blood samples of 15 patients with clinically diagnosed AD. In addition, we investigated tissue samples of patients with different neuromuscular disorders and patients with Downs syndrome. Independent of the tissue analysed very few of all the tested samples of patients showed a point mutation at nt 5460 with a base substitution from G to A. Two out of 19 brain and 48 blood samples from controls carried this mutation. The G to T transversion was not found in any of the so far tested samples. Our results do not support the previously reported significant high frequency of these mutations in AD.A polymorphism seems more likely.

Alleles↗
PubMed1996

Apolipoprotein E-epsilon4 alleles in cerebral amyloid angiopathy and cerebrovascular pathology associated with Alzheimer's disease.

The presence of apolipoprotein E-epsilon4 (APOE-epsilon4) allele has been implicated as a risk factor for Alzheimer's disease (AD). We examined the frequencies of APOE-epsilon4 alleles in age-matched controls and subgroups of 190 AD subjects exhibited cerebral amyloid angiopathy (CAA) and other frequently associated lesions. CAA was evident in 96% of the AD subjects, which were divided into two groups, one bearing mild or no apparent CAA and the other with moderate to severe CAA. APOE-epsilon4 allele frequency (48%) in the latter advanced CAA group was six times higher than in those who exhibited mild CAA. In the advanced CAA subjects, the occurrence of an epsilon4 allele was increased by a factor of 17 (95% confidence interval, 7.56 to 38.9). This was despite the fact that neocortical amyloid-beta plaque densities in the two groups were similar and that all of the AD subjects had met the accepted neuropathological criteria. We also observed that the degree of CAA severity was greatest in the group of subjects with the epsilon4/epsilon4 genotype. The association between CAA and APOE-epsilon4 was further implicated in two non-AD subjects among neurological controls with severe CAA. These two subjects, both homozygous for the APOE-epsilon4 allele, were primarily diagnosed as having Creutzfeldt-Jakob disease and Pick's disease in the absence of significant neocortical amyloid deposition. Allele frequency comparisons between neurological control subjects with CAA and those without likewise accorded a strong relationship between the APOE-epsilon4 allele and the presence of CAA. More remarkably, the epsilon4 allele frequency was highly associated with AD subjects exhibiting lobar or intracerebral hemorrhage, all of whom had advanced CAA. We observed that 36% of the AD subjects had concomitant cerebrovascular pathology resulting from single infarcts, multiple microinfarcts, ischemic white matter lesions, or petechial hemorrhages. Although the difference in APOE genotype distribution between subjects with and without cerebrovascular lesions did not reach statistical significance, we did note that the frequency of the epsilon4 allele was significantly higher in subjects with such pathology as compared with those without. However, we found no evidence to suggest that the acquisition of an APOE-epsilon4 allele or one of the alleles, epsilon2 or epsilon3, was a factor in the occurrence of atherosclerosis localized in the basal surface arteries. Analyses of our sample also confirm that there was a lower frequency of the APOE-epsilon2 allele in AD subjects and that the frequency of the epsilon4 allele in AD subjects with concomitant diffuse Lewy body disease was intermediate between controls and AD subjects. Our results suggest that the APOE-epsilon4 allele is a significant factor in the development of CAA in AD and reveal the possibility that APOE is an independent factor in CAA and other vascular abnormalities associated with AD.

Aged↗
PubMed1995

Increased collagen content of cerebral microvessels in Alzheimer's disease.

Based on previous evidence suggesting abnormalities in the brain microvasculature, we examined basement membrane collagen in isolated cerebral microvessels (CMV) from subjects with Alzheimer's disease (AD) and age-matched controls. Concentrations of hydroxyproline, the principal constituent of collagen IV, were significantly increased by 55% in CMV from AD subjects compared to controls. This result was corroborated by the finding of 60% increased total collagen content in CMV as evident by the selective binding of Sirius red dye. Hydroxyproline and collagen concentrations in samples of cerebral cortex assayed in parallel were 6-20 times smaller than in CMV and were not changed between controls and AD subjects. To further differentiate AD and control samples, fractions of CMV were solubilized and the pepsin digested collagen proteins resolved by SDS-PAGE. Upon immunoblotting, AD samples with increased collagen revealed proportionally greater specific immunoreactivities detected by antibodies to collagen IV. Our observations suggest altered collagen IV content of cerebral vessels in subjects with AD that may affect brain microvascular functions.

Aged↗
PubMed1995

Differential degeneration of the cerebral microvasculature in Alzheimer's disease.

We used immunocytochemical methods to define abnormalities in the cerebral endothelium and the vascular basement membrane in patients with Alzheimer's disease (AD) and in aging control subjects. Double immunostaining with antibodies to the endothelial cell markers CD34 and CD31 revealed an absence of endothelial staining in many capillary profiles that still appeared to retain their basement membranes stained by antibodies to collagen IV. Such differential labeling, clearly suggesting capillaries with collapsed or degenerated endothelium, was frequently (> 90% of cases) evident in AD but relatively lacking in brain regions or other diseases and controls (< 30%) free of amyloid beta (A beta) deposits. We suggest that this profound vascular phenomenon is concomitant with A beta deposition and implies abnormalities in the integrity of brain microvasculature related to neuronal degeneration in AD.

Adult↗