Objective: Most pathologic studies indicate that significant vascular changes are found in the majority of elderly persons, either alone or in association with neurodegenerative processes such as Alzheimer disease (AD) or dementia with Lewy bodies (DLB). Cumulative burden of cerebrovascular lesions can explain cognitive decline described as vascular cognitive impairment, but because there is a lack of consensus in the best way to quantify vascular pathology, the relationship between cognitive decline and cerebrovascular disease remains uncertain. We developed a rating scheme for cerebrovascular lesions using postmortem brains from patients with dementia from 2 European tertiary care memory clinics. Methods:A total of 135 brains with a neuropathologic diagnosis of vascular dementia (VaD) (n ϭ 26), AD ϩ VaD (n ϭ 39), DLB ϩ VaD (n ϭ 21), AD ϩ DLB ϩ VaD (n ϭ 9), AD (n ϭ 19), and DLB (n ϭ 21) were investigated in this study. Cerebrovascular lesions were rated on large sections from the hippocampus, the temporal lobe, the frontal lobe, and basal ganglia. Results:In patients with dementia, vessel wall modifications such as arteriolosclerosis or amyloid angiopathy are the most common and presumably the earliest changes. Modifications in perivascular spaces and myelin loss are the next most common. Lacunar or regional infarcts may occur as a consequence of an independent process or in the final phase of small vessel diseases. Conclusion:A staging system based on this conceptual model of cerebrovascular pathology could enable the neuropathologic quantification of the cerebrovascular burden in dementia. Further studies are needed to determine whether this system can be used in large-scale studies to understand clinical-cerebrovascular pathologic correlations. Neurology Vascular cognitive impairment (VCI) is regarded as the second most common cause of cognitive disorder after Alzheimer disease (AD).1 VCI is a frequent consequence of various cerebrovascular lesions (CVL) resulting from disrupted circulation or perfusion in different brain regions. Imaging and postmortem studies have shown that CVL may also be found in cognitively normal elderly subjects 2-4 and in more than 50% of cases with neurodegenerative disorders such as AD or dementia with Lewy bodies (DLB). 5Despite considerable efforts, to date there are no consensual neuropathologic criteria for vascular (VaD) and mixed dementia. The postmortem diagnosis of VCI mostly relies on the identification of significant CVL 6 in the absence of other changes that may explain the cognitive decline.7 For mixed cases, neuropathologists are compelled to identify a threshold above which CVL would be considered as significant from a strictly subjective point of view. Such quantification could only be obtained from sampled brain areas since an extensive microscopic examination of the whole brain is impractical. Attempts have been made to identify From the Institute for Ageing and Health

BackgroundThe accumulation of beta amyloid (Aβ) peptides, a hallmark of Alzheimer’s disease (AD) is related to mechanisms leading to neurodegeneration. Among its pleiotropic cellular effects, Aβ accumulation has been associated with a deregulation of sphingolipid metabolism. Sphingosine 1-phosphate (S1P) derived from sphingosine is emerging as a critical lipid mediator regulating various biological activities including cell proliferation, survival, migration, inflammation, or angiogenesis. S1P tissue level is low and kept under control through equilibrium between its synthesis mostly governed by sphingosine kinase-1 (SphK1) and its degradation by sphingosine 1-phosphate lyase (SPL). We have previously reported that Aβ peptides were able to decrease the activity of SphK1 in cell culture models, an effect that could be blocked by the prosurvival IGF-1/IGF-1R signaling.ResultsHerein, we report for the first time the expression of both SphK1 and SPL by immunohistochemistry in frontal and entorhinal cortices from 56 human AD brains. Immunohistochemical analysis revealed a decreased expression of SphK1 and an increased expression of SPL both correlated to amyloid deposits in the entorhinal cortex. Otherwise, analysis of brain tissue extracts showed a decrease of SphK1 expression in AD brains whereas SPL expression was increased. The content of IGF-1R, an activator of SphK1, was found decreased in AD brains as well as S1P1, the major receptor for S1P.ConclusionsCollectively, these results highlight the importance of S1P in AD suggesting the existence of a global deregulation of S1P signaling in this disease from its synthesis by SphK1 and degradation by SPL to its signaling by the S1P1 receptor.

Potentially fatal adverse events occurring during antiretroviral treatment may be avoided by close monitoring of clinical signs and blood lactate levels. If other studies confirm that the cumulative long-term toxicity of antiretroviral drugs results from mitochondrial dysfunction, the incidence of hyperlactataemia and its clinical consequences may become more important.