225 research outputs found
Cerebral hypoperfusion accelerates cerebral amyloid angiopathy and promotes cortical microinfarcts
Cortical microinfarcts (CMIs) observed in brains of patients with Alzheimerβs disease tend to be located close to vessels afflicted with cerebral amyloid angiopathy (CAA). CMIs in Alzheimerβs disease are preferentially distributed in the arterial borderzone, an area most vulnerable to hypoperfusion. However, the causal association between CAA and CMIs remains to be elucidated. This study consists of two parts: (1) an observational study using postmortem human brains (nΒ =Β 31) to determine the association between CAA and CMIs, and (2) an experimental study to determine whether hypoperfusion worsens CAA and induces CMIs in a CAA mouse model. In postmortem human brains, the density of CMIs was 0.113/cm2 in mild, 0.584/cm2 in moderate, and 4.370/cm2 in severe CAA groups with a positive linear correlation (rΒ =Β 0.6736, pΒ <Β 0.0001). Multivariate analysis revealed that, among seven variables (age, disease, senile plaques, neurofibrillary tangles, CAA, atherosclerosis and white matter damage), only the severity of CAA was a significant multivariate predictor of CMIs (pΒ =Β 0.0022). Consistent with the data from human brains, CAA model mice following chronic cerebral hypoperfusion due to bilateral common carotid artery stenosis induced with 0.18-mm diameter microcoils showed accelerated deposition of leptomeningeal amyloid Ξ² (AΞ²) with a subset of them developing microinfarcts. In contrast, the CAA mice without hypoperfusion exhibited very few leptomeningeal AΞ² depositions and no microinfarcts by 32Β weeks of age. Following 12Β weeks of hypoperfusion, cerebral blood flow decreased by 26% in CAA mice and by 15% in wild-type mice, suggesting impaired microvascular function due to perivascular AΞ² accumulation after hypoperfusion. Our results suggest that cerebral hypoperfusion accelerates CAA, and thus promotes CMIs
Mechanism of nitrogen metabolism-related parameters and enzyme activities in the pathophysiology of autism
<p>Abstract</p> <p>Background</p> <p>There is evidence that impaired metabolism play an important role in the etiology of many neuropsychiatric disorders. Although this has not been investigated to date, several recent studies proposed that nitrogen metabolism-related parameters may have a pathophysiological role in autism.</p> <p>Methods</p> <p>The study enrolled 20 Saudi boys with autism aged 4 to 12 years and 20 healthy controls matched for age and gender. Levels of creatine, urea, ammonia, gamma-aminobutyric acid (GABA), glutamate:glutamine (Glu:Gln) ratio, and enzymatic activities of glutamate dehydrogenase, 5'-nucleotidase, and adenosine deaminase (ADA) were determined in plasma samples from both groups.</p> <p>Results</p> <p>We found a significant elevation of creatine, 5'-nucleotidase, GABA, and glutamic acid and a significant decrease in the enzymatic activity of ADA and glutamine level in patients with autism compared with healthy controls. The most significant variation between the two groups was found in the Glu:Gln ratio.</p> <p>Conclusion</p> <p>A raised Glu:Gln ratio together with positive correlations in creatine, GABA, and 5'-nucleotidase levels could contribute to the pathophysiology of autism, and might be useful diagnostic markers. The mechanism through which these parameters might be related to autism is discussed in detail.</p
Prolonged oral cannabinoid administration prevents neuroinflammation, lowers Ξ²-amyloid levels and improves cognitive performance in Tg APP 2576 mice
Background: Alzheimerβs disease (AD) brain shows an ongoing inflammatory condition and non-steroidal antiinflammatories
diminish the risk of suffering the neurologic disease. Cannabinoids are neuroprotective and antiinflammatory
agents with therapeutic potential.
Methods: We have studied the effects of prolonged oral administration of transgenic amyloid precursor protein
(APP) mice with two pharmacologically different cannabinoids (WIN 55,212-2 and JWH-133, 0.2 mg/kg/day in the
drinking water during 4 months) on inflammatory and cognitive parameters, and on 18F-fluoro-deoxyglucose
(18FDG) uptake by positron emission tomography (PET).
Results: Novel object recognition was significantly reduced in 11 month old Tg APP mice and 4 month
administration of JWH was able to normalize this cognitive deficit, although WIN was ineffective. Wild type mice
cognitive performance was unaltered by cannabinoid administration. Tg APP mice showed decreased 18FDG
uptake in hippocampus and cortical regions, which was counteracted by oral JWH treatment. Hippocampal GFAP
immunoreactivity and cortical protein expression was unaffected by genotype or treatment. In contrast, the density
of Iba1 positive microglia was increased in Tg APP mice, and normalized following JWH chronic treatment. Both
cannabinoids were effective at reducing the enhancement of COX-2 protein levels and TNF-a mRNA expression
found in the AD model. Increased cortical b-amyloid (Ab) levels were significantly reduced in the mouse model by
both cannabinoids. Noteworthy both cannabinoids enhanced Ab transport across choroid plexus cells in vitro.
Conclusions: In summary we have shown that chronically administered cannabinoid showed marked beneficial
effects concomitant with inflammation reduction and increased Ab clearanceThis work was supported by the Spanish Ministry of Science and
Technology (SAF 2005-02845 to M.L.C). A.M.M-M. was recipient a fellowship
from the Ministry of Education and Scienc
Extensive innate immune gene activation accompanies brain aging, increasing vulnerability to cognitive decline and neurodegeneration: a microarray study
BACKGROUND: This study undertakes a systematic and comprehensive analysis of brain gene expression profiles of immune/inflammation-related genes in aging and Alzheimerβs disease (AD). METHODS: In a well-powered microarray study of young (20 to 59βyears), aged (60 to 99βyears), and AD (74 to 95βyears) cases, gene responses were assessed in the hippocampus, entorhinal cortex, superior frontal gyrus, and post-central gyrus. RESULTS: Several novel concepts emerge. First, immune/inflammation-related genes showed major changes in gene expression over the course of cognitively normal aging, with the extent of gene response far greater in aging than in AD. Of the 759 immune-related probesets interrogated on the microarray, approximately 40% were significantly altered in the SFG, PCG and HC with increasing age, with the majority upregulated (64 to 86%). In contrast, far fewer immune/inflammation genes were significantly changed in the transition to AD (approximately 6% of immune-related probesets), with gene responses primarily restricted to the SFG and HC. Second, relatively few significant changes in immune/inflammation genes were detected in the EC either in aging or AD, although many genes in the EC showed similar trends in responses as in the other brain regions. Third, immune/inflammation genes undergo gender-specific patterns of response in aging and AD, with the most pronounced differences emerging in aging. Finally, there was widespread upregulation of genes reflecting activation of microglia and perivascular macrophages in the aging brain, coupled with a downregulation of select factors (TOLLIP, fractalkine) that when present curtail microglial/macrophage activation. Notably, essentially all pathways of the innate immune system were upregulated in aging, including numerous complement components, genes involved in toll-like receptor signaling and inflammasome signaling, as well as genes coding for immunoglobulin (Fc) receptors and human leukocyte antigens I and II. CONCLUSIONS: Unexpectedly, the extent of innate immune gene upregulation in AD was modest relative to the robust response apparent in the aged brain, consistent with the emerging idea of a critical involvement of inflammation in the earliest stages, perhaps even in the preclinical stage, of AD. Ultimately, our data suggest that an important strategy to maintain cognitive health and resilience involves reducing chronic innate immune activation that should be initiated in late midlife
Microglia, Amyloid, and Glucose Metabolism in Parkinson's Disease with and without Dementia
[(11)C](R)PK11195-PET measures upregulation of translocator protein, which is associated with microglial activation, [(11)C]PIB-PET is a marker of amyloid, while [(18)F]FDG-PET measures cerebral glucose metabolism (rCMRGlc). We hypothesize that microglial activation is an early event in the Parkinson's disease (PD) spectrum and is independent of the amyloid pathology. The aim of this study is to evaluate in vivo the relationship between microglial activation, amyloid deposition, and glucose metabolism in Parkinson's disease dementia (PDD) and PD subjects without dementia. Here, we evaluated 11 PDD subjects, 8 PD subjects without dementia, and 24 control subjects. Subjects underwent T1 and T2 MRI, [(11)C](R)PK11195, [(18)F]FDG, and [(11)C]PIB PET scans. Parametric maps of [(11)C](R)PK11195 binding potential, rCMRGlc, and [(11)C]PIB uptake were interrogated using region of interest and SPM (statistical parametric mapping) analysis. The PDD patients showed a significant increase of microglial activation in anterior and posterior cingulate, striatum, frontal, temporal, parietal, and occipital cortical regions compared with the controls. The PD subjects also showed a statistically significant increase in microglial activation in temporal, parietal, and occipital regions. [(11)C]PIB uptake was marginally increased in PDD and PD. There was a significant reduction in glucose metabolism in PDD and PD. We have also demonstrated pixel-by-pixel correlation between mini-mental state examination (MMSE) score and microglial activation, and MMSE score and rCMRGlc. In conclusion, we have demonstrated that cortical microglial activation and reduced glucose metabolism can be detected early on in this disease spectrum. Significant microglial activation may be a factor in driving the disease process in PDD. Given this, agents that affect microglial activation could have an influence on disease progression
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