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Biomedical subjects

R N Kalaria

Publications and source records attributed to R N Kalaria.

At least 37 records · Page 2Linked to original sources
PubMed2000

Hereditary vascular dementia linked to notch 3 mutations. CADASIL in British families.

The most common form of familial vascular dementia is considered to be CADASIL or cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, which is now also increasingly manifest in the United Kingdom. CADASIL has been previously dubbed as a familial form of Binswanger disease. However, unlike in Binswanger disease CADASIL does not involve hypertension or other risk factors associated with cardiovascular disease. CADASIL appears to be essentially a disorder of the arteries that is linked to single missense mutations in the NOTCH 3 gene locus on chromosome 19. The pathogenesis of the disorder or the genetic mechanism leading to brain infarcts and dementia is not known. The elucidation of the microvascular pathology evident in CADASIL may be an interesting way to delineate effects of defective genes on brain cells from systemic vascular influences.

Cardiovascular Diseases↗
PubMed2000

Elevation in late-life depression of intercellular adhesion molecule-1 expression in the dorsolateral prefrontal cortex.

OBJECTIVE: Late-life depression may be associated with vascular disease. The authors investigated this association by determining whether intercellular adhesion molecule-1 (ICAM-1), a marker of ischemia-induced inflammation, is elevated in the dorsolateral prefrontal cortex in depression. METHOD: The authors studied postmortem tissue from 20 depressed subjects and a matched comparison group of 20 nondepressed subjects. They used immunocytochemistry to stain ICAM-1 in blood vessels on sections of the dorsolateral prefrontal cortex and occipital cortex and quantitative true color image analysis to measure the proportion of vessels expressing ICAM-1. RESULTS: ICAM-1 was significantly higher in both the gray and white matter of the depressed subjects' dorsolateral prefrontal cortex than the comparison subjects' dorsolateral prefrontal cortex. The difference between these groups was much smaller in the gray and white matter of the occipital cortex. CONCLUSIONS: These findings support the vascular depression hypothesis, which has important implications for the understanding and management of late-life depression.

Age Factors↗
PubMed2000

Distribution of cranial MRI abnormalities in patients with symptomatic and subclinical CADASIL.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare, inherited cause of early stroke and dementia, with a poor prognosis. This study was performed to clarify lesion appearance and pattern of lesion distribution in CADASIL. 20 members of a single family were tested for the CADASIL gene mutation and studied with cranial MRI. Scans were evaluated for lesion load and pattern of lesion distribution. 19 patients had cranial MRI, of whom 11 had normal MRI scans, were clinically unaffected and tested negative for the CADASIL gene mutation. The remaining eight patients had abnormal cranial MRI scans: seven patients were positive for the CADASIL gene mutation and one (untested) patient was severely clinically affected. Three of the patients who tested positive for the CADASIL gene mutation were clinically unaffected at the time of imaging. All eight patients with abnormal cranial MRI had subcortical white matter abnormalities, mostly in frontal and temporal lobes. Lesions involving the corpus callosum were present on sagittal T2 weighted images in four of five clinically affected and one of three clinically unaffected patients. Lesions involving the deep grey nuclei and the brain stem were common. On T1 weighted images, lesions were either poorly defined (confluent white matter hypointensity) or well defined (cystic infarcts or enlarged perivascular spaces). Atrophy was infrequent. Familiarity with the range of cranial MRI appearances may aid diagnosis of CADASIL. Recognition of cranial imaging features in asymptomatic CADASIL patients could prompt earlier diagnosis.

Adult↗
PubMed1999

A DLST genotype associated with reduced risk for Alzheimer's disease.

Recent studies suggest that variants of the DLST gene alter the risk of AD. DLST encodes the core subunit of the mitochondrial alpha-ketoglutarate dehydrogenase complex, which is deficient in AD. The authors report that in 247 US white subjects, homozygosity for DLST A19,117, T19,183 was associated with a reduced risk of AD (odds ratio [OR] = 0.35, p = 0.018). The reduced risk was marked in subjects who did not carry the apolipoprotein (APOE)-4 allele (OR = 0.16, p = 0.014). Further study of DLST in AD appears warranted.

Acyltransferases↗
PubMed1999

Intravascular infusions of soluble beta-amyloid compromise the blood-brain barrier, activate CNS glial cells and induce peripheral hemorrhage.

Vascular wall levels of soluble beta-amyloid1-40 (Abeta1-40) are elevated in Alzheimer's disease (AD). Moreover, plasma Abeta levels are increased in familial AD, as well as in some cases of sporadic AD. To determine the histopathologic and behavioral consequences of elevated vascular Abeta levels, Abeta1-40 (50 micrograms in distilled water) or vehicle was intravenously infused twice daily into 3-month old male Sprague-Dawley rats for 2 weeks. Intravenous Abeta infusions impaired blood-brain barrier integrity, as indicated by substantial perivascular and parenchyma IgG immunostaining within the brain. Also evident in Abeta-infused animals was an increase in GFAP immunostaining around cerebral blood vessels, and an enhancement of OX-42 microglial immunostaining in brain white matter. Gross pulmonary hemorrhage was noted in most Abeta-infused animals. All the observed changes occurred in the absence of Congo red birefringence. No significant cognitive deficits were present in Abeta-infused animals during water maze acquisition and retention testing, which was conducted during the second week of treatment. These results indicate that circulating Abeta can: (1) induce vessel dysfunction/damage in both the brain and the periphery without complex Abeta fibril formation/deposition, and (2) induce an activation of brain astrocytes and microglia. Taken together, our results suggest that if circulating Abeta is elevated in AD, it is likely to have a pathophysiologic role.

Amyloid beta-Peptides↗
PubMed1999

Microglia and Alzheimer's disease.

Microglia play a major role in the cellular response associated with the pathological lesions of Alzheimer's disease. As brain-resident macrophages, microglia elaborate and operate under several guises that seem reminiscent of circulating and tissue monocytes of the leucocyte repertoire. Although microglia bear the capacity to synthesize amyloid beta, current evidence is most consistent with their phagocytic role. This largely involves the removal of cerebral amyloid and possibly the transformation of amyloid beta into fibrils. The phagocytic functions also encompass the generation of cytokines, reactive oxygen and nitrogen species, and various proteolytic enzymes, events that may exacerbate neuronal damage rather than incite outgrowth or repair mechanisms. Microglia do not appear to function as true antigen-presenting cells. However, there is circumstantial evidence that suggests functional heterogeneity within microglia. Pharmacological agents that suppress microglial activation or reduce microglial-mediated oxidative damage may prove useful strategies to slow the progression of Alzheimer's disease.

Alzheimer Disease↗
PubMed1999

The blood-brain barrier and cerebrovascular pathology in Alzheimer's disease.

The pathology of Alzheimer's disease (AD) is not limited to amyloid plaques and neurofibrillary tangles. Recent evidence suggests that more than 30% of AD cases exhibit cerebrovascular pathology, which involves the cellular elements that represent the blood-brain barrier. Certain vascular lesions such as microvascular degeneration affecting the cerebral endothelium, cerebral amyloid angiopathy and periventricular white matter lesions are evident in virtually all cases of AD. Furthermore, clinical studies have demonstrated blood-brain barrier dysfunction in AD patients who exhibit peripheral vascular abnormalities such as hypertension, cardiovascular disease and diabetes. Whether these vascular lesions along with perivascular denervation are coincidental or causal in the pathogenetic processes of AD remains to be defined. In this chapter, I review biochemical and morphological evidence in context with the variable but distinct cerebrovascular pathology described in AD. I also consider genetic influences such as apolipoprotein E in relation to cerebrovascular lesions that may shed light on the pathophysiology of the cerebral vasculature. The compelling vascular pathology associated with AD suggests that transient and focal breach of the blood-brain barrier occurs in late onset AD and may involve an interaction of several factors, which include perivascular mediators as well as peripheral circulation derived factors that perturb the endothelium. These vascular abnormalities are likely to worsen cognitive disability in AD.

Alzheimer Disease↗
PubMed1999

Modulation by DLST of the genetic risk of Alzheimer's disease in a very elderly population.

The mitochondrial alpha-ketoglutarate dehydrogenase complex (KGDHC) is deficient in Alzheimer's disease (AD). The DLST gene encodes the core, dihydrolipoyl succinyltransferase (DLST) component of KGDHC, and recent reports indicate an association between polymorphisms of DLST and AD in both white and Japanese patients. We therefore examined the relationship between AD and the DLST and apolipoprotein E (APOE) genes in elderly (89 +/- 7 years) AD patients, in whom the epsilon4 allele of APOE (APOE4) is a weak risk factor for AD. Polymorphisms of DLST (A19,117G and T19,183C), shown to be of interest in previous studies, were analyzed by restriction fragment length polymorphism analysis after polymerase chain reaction amplification. In a series of 429 white subjects from two Jewish nursing homes, an association of APOE4 with AD was found only in patients homozygous for the G,C allele of DLST. Similar relationships occurred in the "very elderly" (> or =85 years, n = 302) subgroup of this series, and also in an autopsy series (n = 225) that included white subjects from the Jewish nursing homes as well as other white subjects. These findings suggest a relationship between APOE4 and a DLST locus in the pathogenesis of AD in very elderly subjects.

Acyltransferases↗
PubMed1998

Vascular endothelial growth factor in Alzheimer's disease and experimental cerebral ischemia.

Several growth factors have been implicated in the pathogenesis of Alzheimer's disease (AD). We considered whether the vascular endothelial growth factor (VEGF) is involved in the vascular pathology associated with most cases of AD. We observed enhanced VEGF immunoreactivity in clusters of reactive astrocytes in the neocortex of subjects with AD compared to elderly controls. VEGF reactivity was also noted in walls of many large intraparenchymal vessels and diffuse perivascular deposits. In addition, we established that astrocytic and perivascular VEGF reactivity was enhanced in cerebral cortex of rats subjected to cerebral ischemia and to chronic hypoxia; experimental conditions known to be associated with astrogliosis and angiogenesis. We suggest the increased VEGF reactivity, also observed in infarcted human brain tissue, implicates compensatory mechanisms to counter insufficient vascularity or reduced perfusion (oligemia) apparent in AD.

Adult↗
PubMed1998

Enhanced localization of amyloid beta precursor protein in the rat hippocampus following long-term adrenalectomy.

Using various antibodies to the amyloid ss precursor protein (APP) associated with Alzheimer's disease, we investigated changes in the distribution of APP in the hippocampus and neocortex of adrenalectomized (ADX) rats. In contrast to sham-operated controls, ADX rats euthanised after a survival period of 5 months showed striking APP reactivity in the CA1-CA4 fields and in the surviving cells in the dentate gyrus. Our results suggest the enhanced APP reactivity in hippocampal neurons may pertain to previous observations on the accumulation of APP fragments in the neocortex during ischemic or traumatic injury. Thus, long-term hormone deprivation would be another factor, which may influence the expression of APP in brain.

Adrenalectomy↗
PubMed1998

Identification and expression of the Na+/H+ exchanger in mammalian cerebrovascular and choroidal tissues: characterization by amiloride-sensitive [3H]MIA binding and RT-PCR analysis.

We report the initial characterization of [3H]5-(N-methyl-N-isobutyl)amiloride (MIA) binding to the Na+/H+ exchanger (NHE) and expression of its gene in mammalian cerebrovascular, choroidal and neocortical tissues. [3H]MIA bound reversibly to particulate fractions of rat, pig and human cerebral microvessels, choroid plexus and cerebral cortex. Scatchard analyses revealed binding to a single amiloride-sensitive site with dissociation constants (Kd) ranging from 20 to 90 nM for the various tissue preparations. The maximal binding capacities (Bmax) were between 2 to 17 pmol/mg protein and were several-fold greater in cerebral microvessels compared to the cerebral cortex. Amiloride, MIA, 5-(N, N-hexamethylene)amiloride (HMA), 5-(N, N-dimethyl)amiloride (DMA) and 5-(N-methyl-N-isopropyl)amiloride (IPA) variably displaced [3H]MIA binding to the microvessels in the following rank order: MIA>HMA>/=IPA>DMA>amiloride. Benzamil, a potent ligand of the Na+/Ca+ transporter was the least sensitive. These binding results were most compatible with the existence of the amiloride-sensitive NHE type 1 in the brain vascular and choroidal tissues. To substantiate this, we utilized reverse transcription polymerase chain reaction (RT-PCR) techniques to search for NHE-1 mRNA. Using primers corresponding to conserved sequences of the human growth factor-activatable NHE gene, RT-PCR revealed strong expression of NHE-1 mRNA in cerebral microvessels, choroid plexus, pial vessels and vascular smooth muscle cells relative to neocortical tissues from several species including rat, pig, cow, monkey and human subjects. Further confirmation of NHE-1 isoform mRNA expression in the cerebrovascular tissues was obtained by HpaII restriction digestion analysis and by subcloning and sequencing of the PCR amplified products. Our study suggests that mammalian cerebrovascular and choroidal tissues contain high amounts of the ubiquitous amiloride-sensitive [3H]MIA binding proteins consistent with the expression of NHE type 1 mRNA.

Amiloride↗
PubMed1998

Ascorbate-stimulated lipid peroxidation and non-heme iron concentrations in Alzheimer disease.

Lipid peroxidation has been suggested to be a potential cause of neuronal damage in neurodegenerative diseases. Changes in several parameters of lipid peroxidation, including basal (unstimulated) lipid peroxidation, stimulated lipid peroxidation, tissue iron concentrations, and the concentrations of some oxygen radical scavengers, have been reported in neurodegenerative diseases. However, the in vitro interaction of oxygen radical scavengers and stimulated lipid peroxidation in neurodegenerative disease has been less well-studied. The purpose of the present study was to determine the effects of oxygen radical scavengers on ascorbate-stimulated lipid peroxidation in Alzheimer disease (AD). We have found that some parameters of ascorbate-stimulated lipid peroxidation are altered in AD and that the effects of superoxide dismutase (SOD) on ascorbate-stimulated lipid peroxidation are significantly different in AD as compared to aged.

Aged↗
PubMed1997

Cerebrovascular degeneration is related to amyloid-beta protein deposition in Alzheimer's disease.

Current evidence is not inconsistent with the suggestion that cerebrovascular functions decline during normal aging with pronounced effects in both sporadic and familial Alzheimer's disease (AD). The primary causes of these changes remain unknown. It is possible that amyloid beta (A beta) protein is involved in the degeneration of both the larger penetrating vessels as well as the cerebral capillaries that represent the blood-brain barrier (BBB). A beta-induced endothelial changes could also alter muscular tone, resulting not only in increased expression of vascular amyloid precursor protein (APP) and production of A beta, but also in oxidative injury. We used immunochemical methods to examine the status of the perfusing cerebral vessels and the microvascular endothelium in relation to deposition of A beta in AD and non-AD aging control subjects. Double-immunostaining with antibodies to vascular markers revealed marked loss of smooth muscle in larger vessels and absence or attenuation of the endothelium in capillary profiles that still appeared to retain their basement membranes. These vascular changes were predominantly restricted to neocortical regions abundant in A beta deposits. Quantitative studies showed that the microvascular abnormalities were correlated to A beta deposition rather than neurofibrillary tangles or neuronal numbers. Our studies suggest that A beta, irrespective of its origin within vascular myocytes or brain parenchyma, is responsible not only for cerebral amyloid angiopathy, but also for the degeneration of the cerebral microvasculature, which may profoundly affect brain perfusion and BBB functions.

Alzheimer Disease↗
PubMed1997

Amyloid-beta protein angiopathies masquerading as Alzheimer's disease?

Current evidence from genetic and epidemiological studies supports the view that Alzheimer's disease (AD) is a heterogeneous disorder. While the disease is pathologically defined by the presence of specified lesions in form of amyloid plaques and neurofibrillary tangles within the parenchyma, other features of pathology are often either neglected or considered coincidental. Our studies suggest that cerebrovascular pathology is inherently part of the disorder, which could be an important factor in a cause or effect manner. We have recently identified subjects having died with severe amyloid beta (A beta) protein cerebral amyloid angiopathy (CAA) in the absence of a profound Alzheimer pathology. These subjects, diagnosed with dementia had a late onset disease and were found at autopsy to exhibit severe CAA but paucity of typical AD changes. Immunocytochemical studies showed numerous microvascular abnormalities as well as characteristic degeneration of the vascular smooth muscle in both surface and intracortical vessels. The pathology was also characterized by occasional intracerebral hemorrhages and multiple infarcts. Further assessment of the abnormalities and amyloid infiltrated cerebral vessels with antibodies to the carboxyl terminus of A beta indicated that the longer, more pathogenic form of A beta(1-42) was found to be highly associated with intracerebral hemorrhages. Our observations suggest that these mild AD cases with a predominantly vascular pathology are variants of AD and bear resemblance to the familial Dutch and Flemish versions of cerebral amyloidosis. We propose that AD is a group of diseases with a variable pathology analogous to the prion diseases, in which a vascular variant also exists.

Aged↗