Cerebrovascular lesions and neurofibrillary pathology – Co-incidence or interaction?

Abstracts / Journal of the Neurological Sciences 283 (2009) 240–320

SAH is managed with CCBs to prevent vasospasm and improve clinical outcomes. Nimodipine represents the CCB more investigated in this indication. Former studies did not demonstrate a clear advantage of nicardipine versus nimodipine in SAH. A more recent approach using implants of nicardipine prolonged-release showed a decreased incidence of vasospasm, delayed ischemic deficits and improved clinical outcome after severe SAH. Increasing evidence suggests some benefit of CCBs, particularly nimodipine, in vascular or mixed degenerative and vascular dementia. In this setting, nicardipine has been investigated in more than 6000 patients, with an improvement of cognitive deterioration in more than 60% of patients treated. The pronounced anti-hypertensive activity of nicardipine compared to nimodipine, its safety and effectiveness in cognitive domain, suggest reconsidering this drug in the treatment of cognitive impairment of vascular origin as well as for reducing the risk of recurrent stroke in patients at high risk of it. doi:10.1016/j.jns.2009.02.025

A holistic approach of mild cognitive impairment L. Spiru Day Center of Memory Impairment, Geriatric Geronto-Psychiatry Department/ Elias University Emergency Hospital, Bucharest, Romania Background: The Romanian DESCRIPA Project, developed under EADC auspices and having the European Commission's support in the Framework Program No 5, aims to elaborate a diagnosis guide for Mild Cognitive Impairment. This prospective study includes 700 patients from European Union and 60 patients from Romania. Objectives: The main goals were to develop clinical criteria for pre-dementia conditions, to asses the prevalence of risk factors and co-morbidity in MCI patients, and to validate in Romania the international pattern of risk factors distribution using internationally recognized diagnosis criteria and follow-up methods. Methods: On the 60 Romanian patients, aged 55 or more, demographic data collection, as well as psychometric tests, risk factors and co-morbidity evaluation was performed at baseline in the Elias University Hospital in Bucharest. Results: The first year follow-up revealed that 23.3% of MCI patients developed Alzheimer's Dementia (1.67% in the second year). One death (1.67%) was recorded in the two year follow-up, caused by cardiac arrest. A percent of 23.3% of the patients were lost due to social reasons. Conclusions: Hypertension, angina pectoris and dyslipidemia are prevalent co-morbidities in MCI patients, followed by diabetes type II, osteoporosis senile, transient ischemic attack, hypothyroidism and carotid artery stenosis. There is a sex-dependent co-morbidity distribution: except transient ischemic attack, at baseline any co-morbidity is prevailing in women. The efficacy of the applied personalized treatment algorithms is also depending on sex: remarkable decrease of hypertension, dyslipidemia, angina pectoris, transient ischemic attack and diabetes type II in women, and an increase of osteoporosis and hypothyroidism. Poor or no significant men's responsiveness and even an increase of hypertension and transient ischemic attack need further clarifying studies. Depression remains a challenge for MCI and Alzheimer's disease treatment and care. Hypertension and dyslipidemia seem to be main risk factors for AD development in MCI patients. doi:10.1016/j.jns.2009.02.026

Simvastatin protects neurons from cytotoxicity by up-regulating Bcl-2 mRNA and protein in vivo and in vitro L.N. Johnson-Anunaa, G.P. Eckertb, U. Igbavboaa, W.E. Mullerb, W.G. Wooda a Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA b Department of Pharmacology, ZAFES Biocenter Niederursel, University of Frankfurt, Frankfurt, Germany The cholesterol lowering drugs, statins, are neuroprotective. Bcl-2 protein is neuroprotective. Mechanistically connecting these two seemingly independent molecules is our recent discovery that simvastatin stimulated murine neuronal Bcl2 gene expression and protein levels in vivo and in vitro. Simvastatin pretreatment resulted in a significant reduction in cytotoxicity (caspase-3 activation, LDH release) following a challenge with amyloid beta-protein compared with unchallenged neurons. G3139, an antisense oligonucleotide directed against Bcl-

245

2, abolished the protective effects of simvastatin and eliminated simvastatininduced upregulation of Bcl-2 protein. Effects of simvastatin on Bcl-2 stimulation occurred not only in mice but were replicated in another species, guinea pigs. We demonstrated upregulation of Bcl-2 in cerebral cortex of drug treated guinea pigs and dissociated brain cells from simvastatin treated guinea pigs were protected from neurotoxicity induced by sodium nitroprusside ex vivo. Simvastatin induced neuroprotection was reduced by inactivation of the Bcl-2 protein, similar to effects observed when Bcl-2 protein levels were reduced by G3139. Effects of simvastatin on Bcl-2 stimulation were independent of inhibition of HMG-CoA reductase and data indicated the potential role of endothelin-1 on statin-induced stimulation of Bcl-2. Here we provide novel evidence showing that simvastatin can stimulate expression of Bcl-2 both in vivo and in vitro. These innovative findings provide one of the potential mechanisms for the purported neuroprotective actions of statins. Discovering how statins are stimulating anti-apoptotic genes will offer new insight into the potential use of other cholesterol lowering and lipid related drugs which might have neuroprotective efficacy in specific neurodegenerative diseases and conditions outside of brain in which programmed cell death has been implicated. Supported in part by NIH grants AG-18357 and AG-23524. doi:10.1016/j.jns.2009.02.027

Epidemiology of cholesterol and lipids: Risk and protective factors for AD and VaD M. Kivipelto Aging Research Center, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden Background: There is evidence for a significant AD-VaD overlapping in terms of risk factors and pathology. Objective: This is a brief review of current epidemiological evidence and new findings from the Finnish population based CAIDE study linking cholesterol and dietary fat intake to dementia. Results: Hypercholesterolemia is a known risk factor for atherosclerosis and coronary artery disease, both of which have been associated with VaD and AD. The apolipoprotein E (ApoE) 4 allele, the most important genetic risk factor for AD, is associated with elevated serum cholesterol. Some epidemiological studies have reported an association between high serum cholesterol levels and subsequent dementia. In the CAIDE study, with a mean follow-up time of 21 years, high cholesterol levels (6.5 mmol/l) at midlife more than doubled the risk of late-life AD. However, results of studies with shorter follow-up have been inconsistent. This may be explained by the fact that cholesterol levels often fall several years before the manifestation of dementia. Furthermore, the CAIDE study indicated that high saturated fat intake at midlife may increase the risk whereas moderate intake of unsaturated fats may decrease the risk of late-life dementia, especially among the ApoE4 carriers. Three clinical studies have reported significantly reduced rates (up to 70%) of dementia and AD in subjects that had used statins. However, more recent prospective observational studies and two randomized trials with short followup times (HPS and PROSPER) found no significant effect of statin treatment on cognitive functions. A pilot study in AD reported that atorvastatin may have beneficial effects especially among mild AD patients with elevated cholesterol at baseline. Larger trials with statins in AD are ongoing. Conclusions: There is increasing evidence to support that high serum cholesterol levels and high intake of saturated fats at midlife are associated with an increased risk of dementia. Reducing or postponing the onset of dementia may be possible by influencing the lipid serum profile. A more detailed characterization of the mechanisms behind the association of cholesterol (in both serum and brain) with dementia would allow a better translation of research findings into clinical practice. doi:10.1016/j.jns.2009.02.028

Cerebrovascular lesions and neurofibrillary pathology – Co-incidence or interaction? P.G. Ince Academic Unit of Pathology, University of Sheffield, Sheffield, UK

246

Abstracts / Journal of the Neurological Sciences 283 (2009) 240–320

The link between the components of Alzheimer-type pathology (ATP; cerebral amyloidosis and tauopathy), and between ATP and cerebrovascular disease, remain fundamental enigmas in the pathogenesis of dementia in later life. The strongest evidence of their interdependency comes from data suggesting that major risk factors for Alzheimer's disease (AD) are shared with degenerative vascular disease. Confirmation of a pathogenetic role for vascular risk factors in AD is not achievable from the study of human tissue for a number of reasons: firstly, population-based neuropathology studies show that up to 80% of dementia cases have mixed pathology. Direct experimental evidence is therefore needed to show that the effects of vascular risk factors are mediated through neurodegeneration rather than co-morbid vascular changes. Secondly, data from cohort studies suggest that the relationship between ATP and vascular pathology is additive or synergistic rather than the result of a pathogenetic cascade but such cross-sectional data do not directly address the issue of causation. Thirdly, considerable heterogeneity in the expression of both amyloid pathology and tauopathy is observed across the population, undermining rigid hierarchic schemes of disease progression. Finally, recognition that neuropathologic lesions are markers of variable interindividual expression of complex disease processes, rather than absolute indicators of disease severity, suggests that interpretation of data from human tissue should be cautious. Successful resolution in this complex field requires both experimental work in animal models, allied to corroborative data from autopsy brain tissue, and the findings from an increasing range of in vivo functional and metabolic imaging modalities.

While there is evidence that preclinical neuroprotection can be realized in various in vitro and in vivo experimental designs modeling neurodegenerative disorders using neurotoxic and genetic induced degeneration the translation into clinical practice hampers. The reasons are manifold. For example all in vitro and in vivo models are too specific and the substances used to demonstrate neuroprotection/neurorestauration often are too selective. As the human neurodegenerative disorders are multifactorial, multigenetic meeting multiple neurotransmitter systems substances fulfilling the criteria to be clinically neuroprotective/neurorestaurative have to pharmacologically influence multiple transmitter systems and they have to act synergistically on multiple genetic and molecular mechanisms. The most interesting substance in this regard is rasagiline, a MAO-Binhibitor with multiple-action on aminergic and glutamatergic systems and with high efficacy on neurotrophic and antiapoptotic mechanisms. The ADAGIO-study will be a “proof of principle” for the translation of preclinical into clinical neuroprotection/neurorestauration. doi:10.1016/j.jns.2009.02.031

Cerebrovascular gene regulation in brain diseases L. Edvinsson Department of Internal Medicine, University Hospital, Lund, Sweden

doi:10.1016/j.jns.2009.02.029

Is 27-hydroxycholesterol the missing link between hypercholesterolemia and Alzheimer's disease? I. Bjorkhem Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska University Hospital, Huddinge, Karolinska Institutet, Stockholm, Sweden Hypercholesterolemia is a risk factor for Alzheimer's disease (AD) in spite of the fact that little if any cholesterol is able to pass the blood brain barrier. The possibility has been discussed that there may be effects of cholesterol on microcirculation that could be of importance. Alternatively a circulatory metabolite of cholesterol may pass the blood-brain barrier and affect neurodegeneration. Side-chain oxidized oxysterols are known to pass biomembranes at rates about 3 orders of magnitude faster than cholesterol. We have recently shown both in a human subject and in experimental animals that one such oxysterol, 27-hydroxycholesterol (27OHC), is fluxing from the circulation into the brain. Based on measurements of the concentration difference between an artery and the internal jugular vein we demonstrated a significant net uptake of 27OHC by the human brain of about 5 mg/24 h. The major part of this oxysterol is metabolized into a steroid acid and a minor part is eliminated as unmetabolized oxysterol through cerebrospinal fluid. In accordance with the contention that most of the 27OHC in cerebrospinal fluid originates from circulation, there is a close correlation between levels in cerebrospinal fluid and plasma. Under in vitro conditions, 27OHC is an efficient regulator of cholesterol synthesis. In addition we recently showed that low levels of this oxysterol affects the balance between the – and -secretase activities in cultured neuronal cells in an unfavorable direction. Levels of 27OHC are well correlated to the levels of cholesterol in the circulation. Hypercholesterolemia is thus associated with increased levels of 27OHC in the circulation, likely to increase the flux across the blood-brain barrier. We discuss the possibility that 27OHC is a link between hypercholesterolemia and AD. doi:10.1016/j.jns.2009.02.030

Preclinical versus clinical neuroprotection P.F. Riederer Department of Neurochemistry, Clinic and Policlinic of Psychiatry and Psychotherapy, Wuerzburg, Germany

Stroke is a leading cause of morbidity worldwide; it is caused by the disruption of the blood flow to the brain with rapid onset of neurological symptoms. The brain is especially susceptible to changes in blood flow due to a high metabolic rate. We hypothesize that the cerebral artery smooth muscle cells have a key role in the subsequent ischemic damage. Therefore, we have studied the gene expression in cerebral arteries following experimental SAH using microarray technology with Affymetrix RAE203 A and B chips that contain the sequence corresponding to over 35,000 genes. The major gene groups found regulate inflammatory, extra cellular matrix regulating and apoptosis, as well as genes regulating metabolism. The genes were quantified with real-time PCR. The genes showing highest expression were il6, cxcl2, MMP9 MMP13, iNOS, vitronectin, Scya4 and Gucy1a3. In addition, several receptors previously reported as important after a stroke were also regulated: ETA, ETB, 5-HT2A, 5 HT1B, 5 HT1D, AT1 and AT2. Immunohistochemistry verified that the changes seen in gene regulation were translated into protein and here we showed a significant upregulation of ETB, 5HT1B and 5HT1D. In addition, we performed a microarray investigation in human MCA following a thromboembolic stroke. Here we investigated the gene expression in the MCA leading to the ischemic region and found 82 genes significantly up and 17 down regulated in a significant manner. Among the genes found significantly regulated were genes involved in cellular signaling, intra and extra cellular matrix remodeling. Real time PCR confirmed the expression changes. The real time PCR investigation showed significant upregulation of ETA, ETB and 5-HT1B receptor genes. Immunohistochemistry using specific antibodies showed that there was a significant increase in the amount of protein present for ETA, ETB, 5HT1B and AT1 receptors located on the smooth muscle cells. doi:10.1016/j.jns.2009.02.032

Mitochondrial ATP-sensitive potassium-channel: A novel target of neuroprotection in cerebral hypoperfusion F. Baria, E. Farkasb Department of Physiology, Faculty of Medicine, University of Szeged, Szeged, Hungary b Department of Anatomy, Faculty of Medicine, University of Szeged, Szeged, Hungary

a

Chronic cerebral hypoperfusion, a mild ischemic condition is associated with advancing age and severity of dementia; however, no undisputed therapy has been established to alleviate related neurological symptoms. Considerable interest has recently been generated from studies, in which the activation of mitochondrial (mito)KATP channels has been shown to protect against hypoxic/ischemic stress in the brain. Diazoxide has been identified as