Christopher P. Chen

Hydrogen Sulfide Is a Mediator of Cerebral Ischemic Damage

Background and Purpose— We observed recently that elevated plasma cysteine levels are associated with poor clinical outcome in acute stroke patients. In a rat stroke model, cysteine administration increased the infarct volume apparently via its conversion to hydrogen sulfide (H2S). We therefore investigated the effects of H2S and the inhibition of its formation on stroke. Methods— Cerebral ischemia was studied in a rat stroke model created by permanent occlusion of the middle cerebral artery (MCAO). The resultant infarct volume was measured 24 hours after occlusion. Results— Administration of sodium hydrosulfide (NaHS, an H2S donor) significantly increased the infarct volume after MCAO. The NaHS-induced increase in infarct volume was abolished by the administration of dizolcilpine maleate (an N-methyl-d-aspartate receptor channel blocker). MCAO caused an increase in H2S level in the lesioned cortex as well as an increase in the H2S synthesizing activity. Administration of 4 different inhibitors of H2S synthesis reduced MCAO-induced infarct volume dose dependently. The potency of these inhibitors in effecting neuroprotection in vivo appeared to parallel their potency as inhibitors of H2S synthesis in vitro. It also appeared that most of the H2S synthesizing activity in the cortex results from the action of cystathionine β-synthase. Conclusions— The present results strongly suggest that H2S plays a part in cerebral ischemic damage after stroke. Inhibition of H2S synthesis should be investigated for its potential as a novel neuroprotective stroke therapy.

Cholinergic-serotonergic imbalance contributes to cognitive and behavioral symptoms in Alzheimer's disease

Neuropsychiatric symptoms seen in Alzheimers disease (AD) are not simply a consequence of neurodegeneration, but probably result from differential neurotransmitter alterations, which some patients are more at risk of than others. Therefore, the hypothesis of this study is that an imbalance between the cholinergic and serotonergic systems is related to cognitive symptoms and psychological syndromes of dementia (BPSD) in patients with AD. Cholinergic and serotonergic functions were assessed in post-mortem frontal and temporal cortex from 22 AD patients who had been prospectively assessed with the Mini-Mental State examination (MMSE) for cognitive impairment and with the Present Behavioral Examination (PBE) for BPSD including aggressive behavior, overactivity, depression and psychosis. Not only cholinergic deficits, but also the cholinacetyltransferase/serotonin ratio significantly correlated with final MMSE score both in frontal and temporal cortex. In addition, decreases in cholinergic function correlated with the aggressive behavior factor, supporting a dual role for the cholinergic system in cognitive and non-cognitive disturbances associated to AD. The serotonergic system showed a significant correlation with overactivity and psychosis. The ratio of serotonin to acetylcholinesterase levels was also correlated with the psychotic factor at least in women. It is concluded that an imbalance between cholinergic-serotonergic systems may be responsible for the cognitive impairment associated to AD. Moreover, the major findings of this study are the relationships between neurochemical markers of both cholinergic and serotonergic systems and non-cognitive behavioral disturbances in patients with dementia.

Noradrenergic changes, aggressive behavior, and cognition in patients with dementia

BACKGROUND We wished to examine the integrity of the noradrenergic system in patients with Alzheimers disease, mixed/other dementias and controls, and possible relationships between changes in the noradrenergic system and the presence of behavioral and psychiatric signs and symptoms in dementia. METHODS Alpha(2) adrenoceptor sites were measured by radioligand binding in three cortical regions of 46 individuals with dementia and 33 elderly normal controls together with cortical noradrenaline concentration and locus coeruleus cell and neurofibrillary tangle counts. RESULTS The alpha(2) adrenergic receptor density was unaltered in patients with Alzheimers disease, mixed/other dementias compared with controls; however, there was a loss of locus coeruleus cells in subjects with dementia, reaching 50% within the rostral nucleus. In addition, a significant reduction was seen in the midtemporal cortical noradrenaline concentration (31% decrease) in patients with Alzheimers disease. In subjects with dementia, there was a positive correlation between aggressive behavior and magnitude of rostral locus coeruleus cell loss, while the reduction in noradrenaline concentration correlated with cognitive impairment. CONCLUSIONS Subgroups of patients with Alzheimers disease may have different neurochemical changes from patients lacking these changes. Therefore, this study may have implications for the treatment of behavioral and psychiatric signs and symptoms in dementia, particularly aggressive behavior in patients with dementia.

Reduced serotonin 5-HT1A receptor binding in the temporal cortex correlates with aggressive behavior in Alzheimer disease

Previous studies have implicated brain serotonin 5-HT(1A) receptors in several CNS functions, including cognition, mood and emotional states. In Alzheimer disease (AD), cognitive impairment and behavioral symptoms are the main clinical features. However, the biochemical basis of such changes is poorly understood. Results from recent in vivo studies suggest that 5-HT(1A) receptors may be related to aggressive traits in healthy subjects. The present study investigated the state of 5-HT(1A) receptors in the postmortem neocortex of 33 AD patients prospectively assessed for cognition and behavioral symptoms, together with 20 matched controls, by saturation [(3)H]8-OH-DPAT binding assays. 5-HT(1A) receptor binding affinity (K(D)) and density (B(max)) were unchanged in the overall AD group compared with controls. Within the AD group, 5-HT(1A) receptor B(max) in the temporal cortex inversely correlated with aggression and dementia severity. However, multiple regression analyses showed that 5-HT(1A) receptor B(max) remained the best predictor for aggression, while temporal cortical neurofibrillary tangle grading was the best predictor for dementia severity. This suggests that 5-HT(1A) receptor alteration is directly related to aggression in AD, while dementia severity is more strongly related to the neurodegenerative process. Our data indicate further study of 5-HT(1A) receptors as a pharmacological target for the treatment of behavioral symptoms in AD.

Low-molecular-weight heparin compared with aspirin for the treatment of acute ischaemic stroke in Asian patients with large artery occlusive disease: a randomised study

Summary Background Acute stroke patients with large artery occlusive disease (LAOD) have a distinct pathophysiology and may respond differently to anticoagulation treatments. We compared the efficacy of a low-molecular-weight heparin (LMWH), nadroparin calcium, with aspirin in Asian acute stroke patients with LAOD. Methods Acute ischaemic stroke patients with onset of symptoms less than 48 h and LAOD (diagnosed by transcranial doppler imaging, carotid duplex scan, or magnetic resonance angiography) were recruited. Patients were randomly assigned to receive either subcutaneous nadroparin calcium 3800 anti-factor Xa IU/0·4 mL twice daily or oral aspirin 160 mg daily for 10 days, and then all received aspirin 80–300 mg once daily for 6 months. This study is registered at www.strokecenter.org/trials (number 493). Findings Among 603 patients recruited, 353 (180 LMWH, 173 aspirin) had LAOD (300 had intracranial LAOD only, 42 had both intracranial and extracranial disease, and 11 had extracranial disease only). The proportion of patients with good outcomes at 6 months (Barthel index ≥85) was 73% in the LMWH group and 69% in the aspirin group (absolute risk reduction 4%; 95% CI −5 to 13). Analysis of prespecified secondary outcome measures showed a benefit in outcome for LMWH versus aspirin on the modified Rankin scale dichotomised at 0–1 (odds ratio 1·55, 95% CI 1·02–2·35). Haemorrhagic transformation of infarct and severe adverse events were similar in both groups. Post-hoc analyses of patients without LAOD, and all treated patients, showed similar proportions with a good outcome in aspirin and LMWH groups (78% vs 79% and 73% vs 75%, respectively). Interpretation Overall, the results do not support a significant benefit of LMWH over aspirin in patients with LAOD. The benefits indicated in most outcome measures warrant further investigation into the use of anticoagulation for acute stroke in patients with large artery atherosclerosis, particularly in intracranial atherosclerosis.

South Asian Patients With Ischemic Stroke Intracranial Large Arteries Are the Predominant Site of Disease

Background and Purpose— South Asians are the most prevalent ethnic group in the world. Intracranial disease is the most common vascular lesion worldwide. Methods— We prospectively studied 200 consecutive ethnic South Asian patients with acute ischemic stroke in Singapore. Results— Intracranial large-artery disease was prevalent among 54% of all stroke subtypes and was independently associated with hypertension and higher serum erythrocyte sedimentation rate. Conclusions— Among ethnic South Asian patients with ischemic stroke, intracranial large arteries are the predominant site of disease.

Immunocytochemical study of the dorsal and median raphe nuclei in patients with Alzheimer’s disease prospectively assessed for behavioural changes

The dorsal and median raphe nuclei were examined with immunocytochemistry to display the 5‐HT neurones in 16 cases of post‐mortem‐proven Alzheimer’s disease (AD) and 12 age and sex‐matched controls. The AD cases had been prospectively assessed during life for expression of behavioural changes as well as for cognitive decline. A significant (P < 0.001) 41% reduction in density of dorsal raphe neurones was found along with a significant (P < 0.02) 29% reduction in density of median raphe neurones in AD. There were significantly more neurofibrillary tangles in both dorsal and median raphe nuclei in AD than in controls (P < 0.001). There was no correlation between reduction in neurone density in these nuclei and behavioural change, cognitive decline, neurofibrillary tangle counts in these nuclei or plaque and tangle pathology in frontal and temporal cortex. It was concluded from these findings that the raphe nuclei are significantly affected by the pathology of AD and that plasticity in the 5‐HT system is the probable reason for the lack of correlation of reduced 5‐HT neurone density and clinical disease parameters.

Loss of serotonin 5-HT2A receptors in the postmortem temporal cortex correlates with rate of cognitive decline in Alzheimer's disease.

RationalePrevious studies have demonstrated reductions of serotonin 5-HT2A receptors in the neocortex of Alzheimer’s disease (AD) patients. However, it is unclear whether such losses play a role in the cognitive decline of AD.ObjectivesTo correlate neocortical 5-HT2A receptor alterations with cognitive decline in AD.MethodsPostmortem frontal and temporal cortical 5-HT2A receptors were measured by [3H]ketanserin binding in aged controls as well as in a cohort of AD patients who had been longitudinally assessed for cognitive decline and behavioral symptoms.Results5-HT2A receptor densities in both regions were reduced in severely demented AD patients compared to age-matched controls. In the temporal cortex, this reduction also correlated with the rate of decline of Mini-Mental State Examination (MMSE) scores. The association between 5-HT2A receptor loss and cognitive decline was independent of the effects of choline acetyltransferase (ChAT) activity and presence of behavioral symptoms.ConclusionsOur data suggest that loss of neocortical 5-HT2A receptors may predict for faster cognitive decline in AD, and point to serotomimetics as potentially useful adjuvants to cholinergic replacement therapies.

Postmortem serotoninergic correlates of cognitive decline in Alzheimer's disease

Serotonin1A receptor density and serotonin concentration were measured in the postmortem neocortex of 17 AD patients who had been prospectively assessed every four months with the Mini-Mental State Examination (MMSE) for a mean of 2.6 years till death. In the frontal cortex, serotonin levels correlated negatively with the annual rate of MMSE decline, while serotonin1A receptor density was positively correlated with the rate of MMSE decline. Our study suggests that reduced serotonin levels and increased serotonin1A receptor density are markers for accelerated cognitive decline in AD, and provides support for the use of serotonin1A antagonists in the treatment of AD.

Visual impairment, age-related eye diseases, and cognitive function: the Singapore Malay Eye study.

OBJECTIVE To describe the associations of visual impairment and major age-related eye diseases with cognitive function in an older Asian population. METHODS A population-based, cross-sectional study of 1179 participants aged 60 to 80 years from the Singapore Malay Eye study was conducted. Visual acuity was measured using the logMAR vision chart. Cataract and age-related macular degeneration were graded using the Wisconsin Cataract Grading System and the Wisconsin Age-Related Maculopathy Grading System, respectively. Glaucoma was diagnosed using the International Society Geographical and Epidemiological Ophthalmology criteria. Diabetic retinopathy was graded using the modified Airlie House classification system. Cognitive dysfunction was defined as a locally validated Abbreviated Mental Test using education-based cutoff scores. RESULTS After adjusting for age, sex, education level, income, and type of housing, persons with visual impairment before refractive correction (odds ratio [OR]=2.59; 95% CI, 1.89-3.56) or after refractive correction (OR=1.96; 95% CI, 1.27-3.02) and those with visual impairment due to cataract (OR=2.75; 95% CI, 1.35-5.63) were more likely to have cognitive dysfunction. Only moderate to severe diabetic retinopathy was independently associated with cognitive dysfunction (OR=5.57; 95% CI, 1.56-19.91) after controlling for concurrent age-related eye diseases. No significant independent associations were observed between cataract, age-related macular degeneration, or glaucoma and cognitive dysfunction. CONCLUSIONS Older persons with visual impairment, particularly those with visual impairment due to cataract, were more likely to have cognitive dysfunction. Furthermore, among the major age-related eye diseases, only diabetic retinopathy was associated with cognitive dysfunction.