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Circadian disruptions impact nearly all people with Alzheimer's disease (AD), emphasizing both their potential role in pathology and the critical need to investigate the therapeutic potential of circadian-modulating interventions. Here, we show that time-restricted feeding (TRF) without caloric restriction improved key disease components including behavioral timing, disease pathology, hippocampal transcription, and memory in two transgenic (TG) mouse models of AD. We found that TRF had the remarkable capability of simultaneously reducing amyloid deposition, increasing Aβ42 clearance, improving sleep and memory, and normalizing daily transcription patterns of multiple genes, including those associated with AD and neuroinflammation. Thus, our study unveils for the first time the pleiotropic nature of timed feeding on AD, which has far-reaching effects beyond metabolism, ameliorating neurodegeneration and the misalignment of circadian rhythmicity. Since TRF can substantially modify disease trajectory, this intervention has immediate translational potential, addressing the urgent demand for accessible approaches to reduce or halt AD progression.

BACKGROUND: Multiple System Atrophy is a rare neurodegenerative disease with alpha-synuclein aggregation in glial cytoplasmic inclusions and either predominant olivopontocerebellar atrophy or striatonigral degeneration, leading to dysautonomia, parkinsonism, and cerebellar ataxia. One prior genome-wide association study in mainly clinically diagnosed patients with Multiple System Atrophy failed to identify genetic variants predisposing for the disease. OBJECTIVE: Since the clinical diagnosis of Multiple System Atrophy yields a high rate of misdiagnosis when compared to the neuropathological gold standard, we studied only autopsy-confirmed cases. METHODS: We studied common genetic variations in Multiple System Atrophy cases (N = 731) and controls (N = 2898). RESULTS: The most strongly disease-associated markers were rs16859966 on chromosome 3, rs7013955 on chromosome 8, and rs116607983 on chromosome 4 with P-values below 5 × 10-6 , all of which were supported by at least one additional genotyped and several imputed single nucleotide polymorphisms. The genes closest to the chromosome 3 locus are ZIC1 and ZIC4 encoding the zinc finger proteins of cerebellum 1 and 4 (ZIC1 and ZIC4). INTERPRETATION: Since mutations of ZIC1 and ZIC4 and paraneoplastic autoantibodies directed against ZIC4 are associated with severe cerebellar dysfunction, we conducted immunohistochemical analyses in brain tissue of the frontal cortex and the cerebellum from 24 Multiple System Atrophy patients. Strong immunohistochemical expression of ZIC4 was detected in a subset of neurons of the dentate nucleus in all healthy controls and in patients with striatonigral degeneration, whereas ZIC4-immunoreactive neurons were significantly reduced inpatients with olivopontocerebellar atrophy. These findings point to a potential ZIC4-mediated vulnerability of neurons in Multiple System Atrophy. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

La Teoría general de los derechos fundamentales de Gregorio Peces-Barba no tiene mucha resonancia en Francia. Este artículo trata de explicarlo. Una pri­mera razón parece residir en el hecho que su proposición teórica no corresponde ni a las preocupaciones de la dogmática jurídica que centra su trabajo esencial­mente en el estudio técnico del derecho positivo, ni a las preocupaciones de los teóricos o filósofos del derecho franceses que, de todos modos, no son numero­sos. Una segunda razón puede ser que el concepto de “derechos fundamentales” construido y defendido por Peces-Barba es bastante diferente del que finalmente se ha extendido en Francia y que, en cualquier caso, no es objeto de una teoriza­ción significativa, ni de una comprensión unificada.

IntroductionDementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are characterized by cognitive alterations, visual hallucinations, and motor impairment. Diagnosis is based on type and timing of clinical manifestations; however, determination of clinical subtypes is challenging. The utility of blood DNA methylation as a biomarker for Lewy body disorders (LBD) is mostly unexplored.MethodsWe performed a cross-sectional analysis of blood methylation in 42 DLB and 50 PDD cases applying linear models to compare groups and logistic least absolute shrinkage and selection operator regression to explore the discriminant power of methylation signals.ResultsDLB blood shows differential methylation compared to PDD. Some methylation changes associate with core features of LBD. Sets of probes show high predictive value to discriminate between variants.DiscussionOur study is the first to explore LBD blood methylation. Despite overlapping clinical presentation, we detected differential epigenetic signatures that, if confirmed in independent cohorts, could be developed into useful biomarkers.

We review evidence supporting the role of early life programming in the susceptibility for adult neurodegenerative diseases while highlighting questions and proposing avenues for future research to advance our understanding of this fundamental process. The key elements of this phenomenon are chronic stress, neuroinflammation triggering microglial polarization, microglial memory and their connection to neurodegeneration. We review the mediating mechanisms which may function as early biomarkers of increased susceptibility for neurodegeneration. Can we devise novel early life modifying interventions to steer developmental trajectories to their optimum?

Recent discoveries demonstrate a critical role for circadian rhythms and sleep in immune system homeostasis. Both innate and adaptive immune responses - ranging from leukocyte mobilization, trafficking, and chemotaxis to cytokine release and T cell differentiation -are mediated in a time of day-dependent manner. The National Institutes of Health (NIH) recently sponsored an interdisciplinary workshop, "Sleep Insufficiency, Circadian Misalignment, and the Immune Response," to highlight new research linking sleep and circadian biology to immune function and to identify areas of high translational potential. This Review summarizes topics discussed and highlights immediate opportunities for delineating clinically relevant connections among biological rhythms, sleep, and immune regulation.

Abstract Alzheimer’s disease (AD) manifested before age 65 is commonly referred to as early-onset AD (EOAD) (Reitz et al. Neurol Genet. 2020;6:e512). While the majority (> 90%) of EOAD cases are not caused by autosomal-dominant mutations in PSEN1, PSEN2, and APP, they do have a higher heritability (92–100%) than sporadic late-onset AD (LOAD, 70%) (Wingo et al. Arch Neurol. 2012;69:59–64, Fulton-Howard et al. Neurobiol Aging. 2021;99:101.e1–101.e9). Although the endpoint clinicopathological changes, i.e., Aβ plaques, tau tangles, and cognitive decline, are common across EOAD and LOAD, the disease progression is highly heterogeneous (Neff et al. Sci Adv Am Assoc Adv Sci. 2021;7:eabb5398). This heterogeneity, leading to temporally distinct age at onset (AAO) and stages of cognitive decline, may be caused by myriad combinations of distinct disease-associated molecular mechanisms. We and others have used transcriptome profiling in AD patient-derived neuron models of autosomal-dominant EOAD and sporadic LOAD to identify disease endotypes (Caldwell et al. Sci Adv Am Assoc Adv Sci. 2020;6:eaba5933, Mertens et al. Cell Stem Cell. 2021;28:1533–1548.e6, Caldwell et al. Alzheimers Demen. 2022). Further, analyses of large postmortem brain cohorts demonstrate that only one-third of AD patients show hallmark disease endotypes like increased inflammation and decreased synaptic signaling (Neff et al. Sci Adv Am Assoc Adv Sci. 2021;7:eabb5398). Areas of the brain less affected by AD pathology at early disease stages—such as the primary visual cortex—exhibit similar transcriptomic dysregulation as those regions traditionally affected and, therefore, may offer a view into the molecular mechanisms of AD without the associated inflammatory changes and gliosis induced by pathology (Haroutunian et al. Neurobiol Aging. 2009;30:561–73). To this end, we analyzed AD patient samples from the primary visual cortex (19 EOAD, 20 LOAD) using transcriptomic signatures to identify patient clusters and disease endotypes. Interestingly, although the clusters showed distinct combinations and severity of endotypes, each patient cluster contained both EOAD and LOAD cases, suggesting that AAO may not directly correlate with the identity and severity of AD endotypes.

Huntington's disease (HD) is an autosomal-dominant neurodegenerative movement disorder that presents with prominent cognitive and psychiatric dysfunction. Brain-derived neurotrophic factor (BDNF) plays an important role in the pathophysiology of HD, as well as other neurodegenerative and psychiatric disorders, and epigenetic alterations in the complex BDNF promoter have been associated with its deregulation in pathological conditions. BDNF has gained increased attention as a potential biomarker of disease; but currently, the conflicting results from measurements of BDNF in different biofluids difficult the assessment of its utility as a biomarker for HD. Here, we measured BDNF protein levels in plasma (n = 85) and saliva (n = 81) samples from premanifest and manifest HD patients and normal controls using ELISA assays. We further examined DNA methylation levels of BDNF promoter IV using DNA derived from whole blood of HD patients and healthy controls (n = 40) using pyrosequencing. BDNF protein levels were not significantly different in plasma samples across diagnostic groups. Plasma BDNF was significantly correlated with age in control subjects but not in HD patients, nor were significant gender effects observed. Similar to plasma, salivary BDNF was correlated with age only in control subjects, with no gender effects observed. Importantly, we detected significantly lower levels of salivary BDNF in premanifest and manifest HD patients compared to control subjects, with lower BDNF levels being observed in premanifest patients within a predicted 10 years to disease onset. Salivary and plasma BDNF levels were not significantly correlated with one another, suggesting different origins. DNA methylation at four out of the 12 CpG sites studied in promoter IV were significantly altered in HD patients in comparison to controls. Interestingly, methylation at three of these CpG sites was inversely correlated to the Hospital Anxiety and Depression Scale (HADS) scores. BDNF promoter methylation was not correlated with motor or cognitive scores in HD patients, and was not associated with sex or age in neither disease nor control groups. Conclusion: Our studies show that BDNF protein levels are decreased in saliva; and BDNF promoter methylation increased in blood in HD subjects when compared to controls. These findings suggest that salivary BDNF measures may represent an early marker of disease onset and DNA methylation at the BDNF promoter IV, could represent a biomarker of psychiatric symptoms in HD patients.

Neuroinflammation is a common pathological correlate of HIV-associated neurocognitive disorders (HAND) in individuals on antiretroviral therapy (ART). Triggering receptor expressed on myeloid cells 2 (TREM2) regulates neuroinflammation, clears extracellular Amyloid (A)-β, surveys for damaged neurons, and orchestrates microglial differentiation. TREM2 has not been studied in HIV+ brain tissues. In this retrospective study, we investigated TREM2 expression levels and localization to microglia, Aβ protein levels, and tumor necrosis factor (TNF)-α transcript levels in the frontal cortices of 52 HIV+ decedents. All donors had been on ART; 14 were cognitively normal (CN), 17 had an asymptomatic neurocognitive impairment (ANI), and 21 had a minor neurocognitive disorder (MND). Total TREM2 protein levels were increased in the soluble and decreased in the membrane-enriched fractions of MND brain tissues compared to CN; however, brains from MND Hispanics showed the most robust alterations in TREM2 as well as significantly increased TNF-α mRNA and Aβ levels when compared to CN Hispanics. Significant alterations in the expression of total TREM2 protein and transcripts for TNF-α were not observed in non-Hispanics, despite higher levels of Aβ in the non-Hispanic CN group compared to the non-Hispanic MND groups. These findings show that decreased and increased TREM2 in membrane-bound fractions and in soluble-enriched fractions, respectively, is associated with increased Aβ and neuroinflammation in this cohort of HIV+ brains, particularly those identifying as Hispanics. These findings suggest a role for TREM2 in the brain of HIV+ individuals may deserve more investigation as a biomarker for HAND and as a possible therapeutic target. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.

Multiple system atrophy (MSA) is a fatal neurodegenerative disorder characterized by the pathological accumulation of alpha-synuclein (α-syn) in oligodendrocytes. Therapeutic efforts to stop or delay the progression of MSA have yielded suboptimal results in clinical trials, and there are no efficient treatments currently available for MSA patients. We hypothesize that combining therapies targeting different aspects of the disease may lead to better clinical outcomes. To test this hypothesis, we combined the use of a single-chain antibody targeting α-syn modified for improved central nervous system penetration (CD5-D5) with an unconventional anti-inflammatory treatment (lenalidomide) in the myelin basic protein (MBP)-α-syn transgenic mouse model of MSA. While the use of either CD5-D5 or lenalidomide alone had positive effects on neuroinflammation and/or α-syn accumulation in this mouse model of MSA, the combination of both approaches yielded better results than each single treatment. The combined treatment reduced astrogliosis, microgliosis, soluble and aggregated α-syn levels, and partially improved behavioral deficits in MBP-α-syn transgenic mice. These effects were associated with an activation of the Akt signaling pathway, which may mediate cytoprotective effects downstream tumor necrosis factor alpha (TNFα). These results suggest that a strategic combination of treatments may improve the therapeutic outcome in trials for MSA and related neurodegenerative disorders.

Abnormal accumulation and propagation of the neuronal protein α-synuclein has been hypothesized to underlie the pathogenesis of Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. Here we report a de novo-developed compound (NPT100-18A) that reduces α-synuclein toxicity through a novel mechanism that involves displacing α-synuclein from the membrane. This compound interacts with a domain in the C-terminus of α-synuclein. The E83R mutation reduces the compound interaction with the 80-90 amino acid region of α-synuclein and prevents the effects of NPT100-18A. In vitro studies showed that NPT100-18A reduced the formation of wild-type α-synuclein oligomers in membranes, reduced the neuronal accumulation of α-synuclein, and decreased markers of cell toxicity. In vivo studies were conducted in three different α-synuclein transgenic rodent models. Treatment with NPT100-18A ameliorated motor deficits in mThy1 wild-type α-synuclein transgenic mice in a dose-dependent manner at two independent institutions. Neuropathological examination showed that NPT100-18A decreased the accumulation of proteinase K-resistant α-synuclein aggregates in the CNS and was accompanied by the normalization of neuronal and inflammatory markers. These results were confirmed in a mutant line of α-synuclein transgenic mice that is prone to generate oligomers. In vivo imaging studies of α-synuclein-GFP transgenic mice using two-photon microscopy showed that NPT100-18A reduced the cortical synaptic accumulation of α-synuclein within 1 h post-administration. Taken together, these studies support the notion that altering the interaction of α-synuclein with the membrane might be a feasible therapeutic approach for developing new disease-modifying treatments of Parkinson's disease and other synucleinopathies.

BackgroundHIV-associated neurocognitive disorders (HAND) continue to be a common morbidity associated with chronic HIV infection. It has been shown that HIV proteins (e.g., gp120) released from infected microglial/macrophage cells can cause neuronal damage by triggering inflammation and oxidative stress, activating aberrant kinase pathways, and by disrupting mitochondrial function and biogenesis. Previous studies have shown that FK506, an immunophilin ligand that modulates inflammation and mitochondrial function and inhibits calcineurin, is capable of rescuing the neurodegenerative pathology in models of Parkinson's disease, Alzheimer's disease, and Huntington's disease. In this context, the main objective of this study was to evaluate if FK506 could rescue the neuronal degeneration and mitochondrial alterations in a transgenic (tg) animal model of HIV1-gp120 neurotoxicity.MethodsGFAP-gp120 tg mice were treated with FK506 and analyzed for neuropathology, behavior, mitochondrial markers, and calcium flux by two-photon microscopy.ResultsWe found that FK506 reduced the neuronal cell loss and neuro-inflammation in the gp120 tg mice. Moreover, while vehicle-treated gp120 tg mice displayed damaged mitochondria and increased neuro-inflammatory markers, FK506 rescued the morphological mitochondrial alterations and neuro-inflammation while increasing levels of optic atrophy 1 and mitofusin 1. By two-photon microscopy, calcium levels were not affected in the gp120 tg mice and no effects of FK506 were detected. However, at a functional level, FK506 ameliorated the gp120 tg mice hyperactivity in the open field.ConclusionsTogether, these results suggest that FK506 might be potentially neuroprotective in patients with HAND by mitigating inflammation and mitochondrial alterations.

UnlabelledAlzheimer's disease (AD) is characterized by the progressive accumulation of amyloid β (Aβ) and microtubule associate protein tau, leading to the selective degeneration of neurons in the neocortex, limbic system, and nucleus basalis, among others. Recent studies have shown that α-synuclein (α-syn) also accumulates in the brains of patients with AD and interacts with Aβ and tau, forming toxic hetero-oligomers. Although the involvement of α-syn has been investigated extensively in Lewy body disease, less is known about the role of this synaptic protein in AD. Here, we found that reducing endogenous α-syn in an APP transgenic mouse model of AD prevented the degeneration of cholinergic neurons, ameliorated corresponding deficits, and recovered the levels of Rab3a and Rab5 proteins involved in intracellular transport and sorting of nerve growth factor and brain-derived neurotrophic factor. Together, these results suggest that α-syn might participate in mechanisms of vulnerability of selected neuronal populations in AD and that reducing α-syn might be a potential approach to protecting these populations from the toxic effects of Aβ.Significance statementReducing endogenous α-synuclein (α-syn) in an APP transgenic mouse model of Alzheimer's disease (AD) prevented the degeneration of cholinergic neurons, ameliorated corresponding deficits, and recovered the levels of Rab3a and Rab5 proteins involved in intracellular transport and sorting of nerve growth factor and brain-derived neurotrophic factor. These results suggest that α-syn might participate in mechanisms of vulnerability of selected neuronal populations in AD and that reducing α-syn might be a potential approach to protecting these populations from the toxic effects of amyloid β.

BackgroundDeposition of α-synuclein and neuroinflammation are key pathological features of Parkinson's disease (PD). There is no cure for the disease; however, targeting the pathological features might be available to modulate the disease onset and progression. Hypoestoxide (HE) has been demonstrated as a NF-κB modulator, thereby acting as a potential anti-inflammatory and anti-cancer drug.MethodsIn order to assess the effect of HE in a mouse model of PD, mThy1-α-syn transgenic mice received intraperitoneal (IP) injections of either vehicle or HE (5 mg/kg) daily for 4 weeks.ResultsTreatment of HE decreased microgliosis, astrogliosis, and pro-inflammatory cytokine gene expression in α-syn transgenic mice. HE administration also prevented the loss of dopaminergic neurons and ameliorated motor behavioral deficits in the α-syn transgenic mice, and α-synuclein pathology was significantly reduced by treatment of HE. In addition, increased levels of nuclear phosphorylated NF-κB in the frontal cortex of α-syn transgenic mice were significantly reduced by HE administration.ConclusionsThese results support the therapeutic potential of HE for PD and other α-synuclein-related diseases.

BackgroundIn dementia with Lewy bodies (DLB) abnormal interactions between α-synuclein (α-syn) and beta amyloid (Aβ) result in selective degeneration of neurons in the neocortex, limbic system and striatum. However, factors rendering these neurons selectively vulnerable have not been fully investigated. The metabotropic glutamate receptor 5 (mGluR5) has been shown to be up regulated in DLB and might play a role as a mediator of the neurotoxic effects of Aβ and α-syn in vulnerable neuronal populations. In this context, the main objective of the present study was to investigate the role of mGluR5 as a mediator of the neurotoxic effects of α-syn and Aβ in the hippocampus.ResultsWe generated double transgenic mice over-expressing amyloid precursor protein (APP) and α-syn under the mThy1 cassette and investigated the relationship between α-syn cleavage, Aβ, mGluR5 and neurodegeneration in the hippocampus. We found that compared to the single tg mice, the α-syn/APP tg mice displayed greater accumulation of α-syn and mGluR5 in the CA3 region of the hippocampus compared to the CA1 and other regions. This was accompanied by loss of CA3 (but not CA1) neurons in the single and α-syn/APP tg mice and greater loss of MAP 2 and synaptophysin in the CA3 in the α-syn/APP tg. mGluR5 gene transfer using a lentiviral vector into the hippocampus CA1 region resulted in greater α-syn accumulation and neurodegeneration in the single and α-syn/APP tg mice. In contrast, silencing mGluR5 with a lenti-shRNA protected neurons in the CA3 region of tg mice. In vitro, greater toxicity was observed in primary hippocampal neuronal cultures treated with Aβ oligomers and over-expressing α-syn; this effect was attenuated by down-regulating mGluR5 with an shRNA lentiviral vector. In α-syn-expressing neuronal cells lines, Aβ oligomers promoted increased intracellular calcium levels, calpain activation and α-syn cleavage resulting in caspase-3-dependent cell death. Treatment with pharmacological mGluR5 inhibitors such as 2-Methyl-6-(phenylethynyl)pyridine (MPEP) and 3-((2-Methyl-4-thiazolyl)ethynyl)pyridine (MTEP) attenuated the toxic effects of Aβ in α-syn-expressing neuronal cells.ConclusionsTogether, these results support the possibility that vulnerability of hippocampal neurons to α-syn and Aβ might be mediated via mGluR5. Moreover, therapeutical interventions targeting mGluR5 might have a role in DLB.

HIV involvement of the CNS continues to be a significant problem despite successful use of combination antiretroviral therapy (cART). Drugs of abuse can act in concert with HIV proteins to damage glia and neurons, worsening the neurotoxicity caused by HIV alone. Methamphetamine (METH) is a highly addictive psychostimulant drug, abuse of which has reached epidemic proportions and is associated with high-risk sexual behavior, increased HIV transmission, and development of drug resistance. HIV infection and METH dependence can have synergistic pathological effects, with preferential involvement of frontostriatal circuits. At the molecular level, epigenetic alterations have been reported for both HIV-1 infection and drug abuse, but the neuropathological pathways triggered by their combined effects are less known. We investigated epigenetic changes in the brain associated with HIV and METH. We analyzed postmortem frontal cortex tissue from 27 HIV seropositive individuals, 13 of which had a history of METH dependence, in comparison to 14 cases who never used METH. We detected changes in the expression of DNMT1, at mRNA and protein levels, that resulted in the increase of global DNA methylation. Genome-wide profiling of DNA methylation in a subset of cases, showed differential methylation on genes related to neurodegeneration; dopamine metabolism and transport; and oxidative phosphorylation. We provide evidence for the synergy of HIV and METH dependence on the patterns of DNA methylation on the host brain, which results in a distinctive landscape for the comorbid condition. Importantly, we identified new epigenetic targets that might aid in understanding the aggravated neurodegenerative, cognitive, motor and behavioral symptoms observed in persons living with HIV and addictions.

Parkinson’s Disease (PD) is a common neurodegenerative disorder currently diagnosed based on the presentation of characteristic movement symptoms. Unfortunately, patients exhibiting these symptoms have already undergone significant dopaminergic neuronal loss. Earlier diagnosis, aided by molecular biomarkers specific to PD, would improve overall patient care. Epigenetic mechanisms, which are modified by both environment and disease pathophysiology, are emerging as important components of neurodegeneration. Alterations to the PD methylome have been reported in epigenome-wide association studies. However, the extent to which methylation changes correlate with disease progression has not yet been reported; nor the degree to which methylation is affected by PD medication. We performed a longitudinal genome-wide methylation study surveying ~850,000 CpG sites in whole blood from 189 well-characterized PD patients and 191 control individuals obtained at baseline and at a follow-up visit ~2 y later. We identified distinct patterns of methylation in PD cases versus controls. Importantly, we identified genomic sites where methylation changes longitudinally as the disease progresses. Moreover, we identified methylation changes associated with PD pathology through the analysis of PD cases that were not exposed to anti-parkinsonian therapy. In addition, we identified methylation sites modulated by exposure to dopamine replacement drugs. These results indicate that DNA methylation is dynamic in PD and changes over time during disease progression. To the best of our knowledge, this is the first longitudinal epigenome-wide methylation analysis for Parkinson’s disease and reveals changes associated with disease progression and in response to dopaminergic medications in the blood methylome.

Abstract Introduction Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are characterized by cognitive alterations, visual hallucinations, and motor impairment. Diagnosis is based on type and timing of clinical manifestations; however, determination of clinical subtypes is challenging. The utility of blood DNA methylation as a biomarker for Lewy body disorders (LBD) is mostly unexplored. Methods We performed a cross‐sectional analysis of blood methylation in 42 DLB and 50 PDD cases applying linear models to compare groups and logistic least absolute shrinkage and selection operator regression to explore the discriminant power of methylation signals. Results DLB blood shows differential methylation compared to PDD. Some methylation changes associate with core features of LBD. Sets of probes show high predictive value to discriminate between variants. Discussion Our study is the first to explore LBD blood methylation. Despite overlapping clinical presentation, we detected differential epigenetic signatures that, if confirmed in independent cohorts, could be developed into useful biomarkers.

Abstract Background Parkinson's disease (PD) is a multifactorial disease where environmental factors act on genetically predisposed individuals. Although only 5% of PD manifestations are associated with specific mutations, majority of PD cases are of idiopathic origin, where environment plays a prominent role. Concurrent exposure to Paraquat (PQ) and Maneb (MB) in rural workers increases the risk for PD and exposure of adult mice to MB/PQ results in dopamine fiber loss and decreased locomotor activity. While PD is characterized by neuronal loss in the substantia nigra, we previously showed that accumulation of α-synuclein in the limbic system contributes to neurodegeneration by interfering with adult neurogenesis. Results We investigated the effect of pesticides on adult hippocampal neurogenesis in two transgenic models: Line 61, expressing the human wild type SNCA gene and Line LRRK2(G2019S), expressing the human LRRK2 gene with the mutation G2019S. Combined exposure to MB/PQ resulted in significant reduction of neuronal precursors and proliferating cells in non-transgenic animals, and this effect was increased in transgenic mice, in particular for Line 61, suggesting that α-synuclein accumulation and environmental toxins have a synergistic effect. We further investigated the transcription of 84 genes with direct function on neurogenesis. Overexpresion of α-synuclein resulted in the downregulation of 12% of target genes, most of which were functionally related to cell differentiation, while LRRK2 mutation had a minor impact on gene expression. MB/PQ also affected transcription in non-transgenic backgrounds, but when transgenic mice were exposed to the pesticides, profound alterations in gene expression affecting 27% of the studied targets were observed in both transgenic lines. Gene enrichment analysis showed that 1:3 of those genes were under the regulation of FoxF2 and FoxO3A, suggesting a primary role of these proteins in the response to genetic and environmental cues. Conclusions We report that adult neurogenesis is highly susceptible to multiple “risk factors” for PD, including α-synuclein accumulation, LRRK2 G2019 mutation and exposure to environmental toxins. We identified specific groups of genes that are responsive to each stressor, while uncovering a novel function for Fox transcription factors in PD.

Huntington’s disease (HD) is an autosomal-dominant neurodegenerative movement disorder that presents with prominent cognitive and psychiatric dysfunction. Brain-derived neurotrophic factor (BDNF) plays an important role in the pathophysiology of HD, as well as other neurodegenerative and psychiatric disorders, and epigenetic alterations in the complex BDNF promoter have been associated with its deregulation in pathological conditions. BDNF has gained increased attention as a potential biomarker of disease; but currently, the conflicting results from measurements of BDNF in different biofluids difficult the assessment of its utility as a biomarker for HD. Here, we measured BDNF protein levels in plasma (n = 85) and saliva (n = 81) samples from premanifest and manifest HD patients and normal controls using ELISA assays. We further examined DNA methylation levels of BDNF promoter IV using DNA derived from whole blood of HD patients and healthy controls (n = 40) using pyrosequencing. BDNF protein levels were not significantly different in plasma samples across diagnostic groups. Plasma BDNF was significantly correlated with age in control subjects but not in HD patients, nor were significant gender effects observed. Similar to plasma, salivary BDNF was correlated with age only in control subjects, with no gender effects observed. Importantly, we detected significantly lower levels of salivary BDNF in premanifest and manifest HD patients compared to control subjects, with lower BDNF levels being observed in premanifest patients within a predicted 10 years to disease onset. Salivary and plasma BDNF levels were not significantly correlated with one another, suggesting different origins. DNA methylation at four out of the 12 CpG sites studied in promoter IV were significantly altered in HD patients in comparison to controls. Interestingly, methylation at three of these CpG sites was inversely correlated to the Hospital Anxiety and Depression Scale (HADS) scores. BDNF promoter methylation was not correlated with motor or cognitive scores in HD patients, and was not associated with sex or age in neither disease nor control groups. Conclusion: Our studies show that BDNF protein levels are decreased in saliva; and BDNF promoter methylation increased in blood in HD subjects when compared to controls. These findings suggest that salivary BDNF measures may represent an early marker of disease onset and DNA methylation at the BDNF promoter IV, could represent a biomarker of psychiatric symptoms in HD patients.

Asthma: Encouraging doctors to provide written action plans Changes to practice organization and doctors’ perceptions should encourage the provision of written action plans for all asthma patients. International guidelines state that effective long-term treatment of asthma requires educated self-management, regular reviews and provision of a written action plan (WAP). However, many patients have poor asthma control and as few as 30 per cent have a WAP. Fabienne Djandji at the Saint-Justine University Central Hospital in Montreal, Canada, and co-workers conducted a survey of 421 doctors to determine their attitudes and provision of WAPs. Only 5.2 per cent of respondents provided WAPs to patients; those treating children or aiming for long-term asthma control were more likely to do so. The doctors said that incentives to provide WAPs would include requests from patients themselves, being paid to complete WAPs and having extra support from specialists or other health care professionals such as pharmacists.

Neural stem cells (NSCs) have been considered as potential therapy in Alzheimer's disease (AD) but their use is hampered by the poor survival of grafted cells. Supply of neurotrophic factors to the grafted cells has been proposed as a way to augment survival of the stem cells. In this context, we investigated the utility of Cerebrolysin (CBL), a peptidergic mixture with neurotrophic-like properties, as an adjunct to stem cell therapy in an APP transgenic (tg) model of AD. We grafted murine NSCs into the hippocampus of non-tg and APP tg that were treated systemically with CBL and analyzed after 1, 3, 6 and 9 months post grafting. Compared to vehicle-treated non-tg mice, in the vehicle-treated APP tg mice there was considerable reduction in the survival of the grafted NSCs. Whereas, CBL treatment enhanced the survival of NSCs in both non-tg and APP tg with the majority of the surviving NSCs remaining as neuroblasts. The NSCs of the CBL treated mice displayed reduced numbers of caspase-3 and TUNEL positive cells and increased brain derived neurotrophic factor (BDNF) and furin immunoreactivity. These results suggest that CBL might protect grafted NSCs and as such be a potential adjuvant therapy when combined with grafting.

Synucleinopathies, neurodegenerative disorders with alpha-synuclein (α-syn) accumulation, are the second leading cause of neurodegeneration in the elderly, however no effective disease-modifying alternatives exist for these diseases. Multiple system atrophy (MSA) is a fatal synucleinopathy characterized by the accumulation of toxic aggregates of α-syn within oligodendroglial cells, leading to demyelination and neurodegeneration, and the reduction of this accumulation might halt the fast progression of MSA. In this sense, the involvement of microRNAs (miRNAs) in synucleinopathies is yet poorly understood, and the potential of manipulating miRNA levels as a therapeutic tool is underexplored. In this study, we analyzed the levels of miRNAs that regulate the expression of autophagy genes in MSA cases, and investigated the mechanistic correlates of miRNA dysregulation in in vitro models of synucleinopathy. We found that microRNA-101 (miR-101) was significantly increased in the striatum of MSA patients, together with a reduction in the expression of its predicted target gene RAB5A. Overexpression of miR-101 in oligodendroglial cell cultures resulted in a significant increase in α-syn accumulation, along with autophagy deficits. Opposite results were observed upon expression of an antisense construct targeting miR-101. Stereotaxic delivery of a lentiviral construct expressing anti-miR-101 into the striatum of the MBP-α-syn transgenic (tg) mouse model of MSA resulted in reduced oligodendroglial α-syn accumulation and improved autophagy. These results suggest that miRNA dysregulation contributes to MSA pathology, with miR-101 alterations potentially mediating autophagy impairments. Therefore, therapies targeting miR-101 may represent promising approaches for MSA and related neuropathologies with autophagy dysfunction.

Quelle que soit la représentation précise que l’on se fasse du processus concrétisation des droits de l’homme, il est conventionnellement possible de s’accorder sur le fait que ce processus renvoie à la question générale du passage du devoir être à l’être ou, en d’autres termes, de l’énoncé de la norme juridique à sa mise en œuvre dans le monde. D’un point de vue théorique, cette question se heurte à plusieurs difficultés ou écueils, qu'est-ce que traitée dès le début de l’article. D’un point de vue pratique, elle est à l’origine de l’institution de multiples mécanismes qui visent à maximiser les chances de succès du passage problématique entre le devoir être et l’être, problème qu’on examine deuxièmement. Restera ensuite, à la troisième partie de l’article, s‘interroger sur les éventuelles spécificités des difficultés posées par la concrétisation des droits de l’homme par rapport à celle des normes juridiques en général.

Objective. We aimed to identify key enablers of physician prescription of a long-term controller in patients with persistent asthma. Methods. We conducted a mailed survey of randomly selected Quebec physicians. We sent a 102-item questionnaire, seeking reported management regarding one of 4 clinical vignettes of a poorly controlled adult or child and endorsement of enablers to prescribe long-term controllers. Results. With a 56% participation rate, 421 physicians participated. Most (86%) would prescribe a long-term controller (predominantly inhaled corticosteroids, ICS) to the patient in their clinical vignette. Determinants of intention were the recognition of persistent symptoms (OR 2.67), goal of achieving long-term control (OR 5.31), and high comfort level in initiating long-term ICS (OR 2.33). Decision tools, pharmacy reports, reminders, and specific training were strongly endorsed by ≥60% physicians to support optimal management. Physicians strongly endorsed asthma education, lung function testing, specialist opinion, accessible asthma clinic, and paramedical healthcare professionals to guide patients, as enablers to improve patient adherence to and physicians’ comfort with long-term ICS. Interpretation. Tools and training to improve physician knowledge, skills, and perception towards long-term ICS and resources that increase patient adherence and physician comfort to facilitate long-term ICS prescription should be considered as targets for implementation.

Pour livrer une analyse de la jurisprudence du Conseil constitutionnel sur les droits fondamentaux, comme d’ailleurs sur d’autres aspects de sa jurisprudence, il semble opportun de partir d’un rappel simple et pourtant souvent négligé : contrairement à d’autres cours constitutionnelles, le Conseil constitutionnel français n’a pas été créé pour protéger les droits et libertés. Il a avant tout été conçu comme un instrument de rationalisation du parlementarisme destiné à contenir les excès dans lesquels les parlements de la IIIème et de la IVème République ont pu sombrer. C’est ainsi qu’en 1958, les fonctions essentielles du Conseil constitutionnel étaient de s’assurer que le parlement respecte la répartition nouvelle qu’opère la constitution entre le domaine de la loi défini à l’article 34 et le domaine réglementaire, de contrôler la constitutionnalité des règlements intérieurs de chacune des assemblées parlementaires, de veiller à la régularité des opérations électorales nationales (élections présidentielles, législatives, sénatoriales et référendum) et de contrôler certains aspects du statut des parlementaires (compatibilité des fonctions, déchéance…). Sous les Républiques antérieures, ces dernières fonctions ne faisaient l’objet d’aucun contrôle ou étaient assurées par le parlement lui-même…

Il s’agit ici d’analyser le caractère « fondamental » de certains droits et libertés et de découvrir les nuances et enjeux de cette qualification. Pour cela, il a fallu parcourir la doctrine, la jurisprudence et le droit positif français.

Transcriptional dysregulation has emerged as a central pathogenic mechanism in Huntington's disease (HD), which is associated with neuropathological changes predominantly in the striatum. Here we demonstrate that expression of Bcl11b (a.k.a. CTIP2), a transcription factor exhibiting highly-enriched localization in adult striatum, is significantly decreased in HD cells, mouse models and human subjects and that overexpression of Bcl11b attenuates toxic effects of mutant huntingtin in cultured striatal neurons. We show that Bcl11b directly activates the proximal promoter regions of striatal-enriched genes and can increase mRNA levels of striatal-expressing genes. We further demonstrate an interaction between Bcl11b and huntingtin protein in cultured cells and brain homogenates from HD R6/1 and YAC72 transgenic mice. We propose that sequestration and/or decreased expression of Bcl11b in HD is responsible, at least in part, for the dysregulation of striatal gene expression observed in HD and may contribute to the specificity of pathology observed in this disease.

We have explored genome-wide expression of genes related to glycobiology in exon 1 transgenic Huntington's disease (HD) mice using a custom-designed GLYCOv2 chip and Affymetrix microarray analyses. We validated, using quantitative real-time PCR, abnormal expression levels of genes encoding glycosyltransferases in the striatum of R6/1 transgenic mice, as well as in postmortem caudate from human HD subjects. Many of these genes show differential regional expression within the CNS, as indicated by in situ hybridization analysis, suggesting region-specific regulation of this system in the brain. We further show disrupted patterns of glycolipids (acidic and neutral lipids) and/or ganglioside levels in both the forebrain of the R6/1 transgenic mice and caudate samples from human HD subjects. These findings reveal novel disruptions in glycolipid/ganglioside metabolic pathways in the pathology of HD and suggest that the development of new targets to restore glycosphingolipid balance may act to ameliorate some symptoms of HD.

Neuronal stem cell (NSC) grafts have been investigated as a potential neuro-restorative therapy in Parkinson's disease (PD) but their use is compromised by the death of grafted cells. We investigated the use of Cerebrolysin (CBL), a neurotrophic peptide mixture, as an adjunct to NSC therapy in the α-synuclein (α-syn) transgenic (tg) model of PD. In vehicle-treated α-syn tg mice, there was decreased survival of NSCs. In contrast, CBL treatment enhanced the survival of NSCs in α-syn tg groups and ameliorated behavioral deficits. The grafted NSCs showed lower levels of terminal deoxynucleotidyl transferase dUTP nick end labeling positive cells in the CBL-treated mice when compared with vehicle-treated α-syn tg mice. No evidence of tumor growth was detected. Levels of α-syn were similar in the vehicle in CBL-treated tg mice. In conclusion, CBL treatment might be a potential adjuvant for therapeutic NSC grafting in PD.

OBJECTIVE: To assess the efficacy of phenobarbital treatment for epileptic patients in rural Mali. METHODS: Epileptic patients were treated at home with phenobarbital at daily dosages ranging from 50 mg for children to 200 mg for adults and their condition was monitored. Advice was given to patients, their families, and the village authorities in order to achieve compliance. An uninterrupted supply of generic phenobarbital was provided and a rural physician made two follow-up visits to each village to ensure that the drug was taken in the correct doses. The physician gave information to the population, distributed the phenobarbital in sufficient quantities to cover the periods between visits, and monitored the patients' responses to treatment. During the first year the physician visited the patients every two months. The frequency of visits was subsequently reduced to once every four months. FINDINGS: In the six months preceding treatment the average rate of seizures among patients exceeded four per month. After a year of treatment, 80.2% of the patients experienced no seizures for at least five months. A total of 15.7% of patients experienced a reduction in seizures. In many cases no further seizures occurred and there were improvements in physical health, mental health and social status. There were very few side-effects and no cases of poisoning were reported. The cost of treatment per patient per year was US$ 7 for generic phenobarbital and US$ 8.4 for logistics. CONCLUSION: Low doses of phenobarbital were very effective against epilepsy. However, there is an urgent need for programmes involving increased numbers of physicians in rural areas and, at the national level, for the inclusion of epilepsy treatment in the activities of health care facilities. Internationally, an epilepsy control programme providing free treatment should be developed.

HIV involvement of the CNS continues to be a significant problem despite successful use of combination antiretroviral therapy (cART). Drugs of abuse can act in concert with HIV proteins to damage glia and neurons, worsening the neurotoxicity caused by HIV alone. Methamphetamine (METH) is a highly addictive psychostimulant drug, abuse of which has reached epidemic proportions and is associated with high-risk sexual behavior, increased HIV transmission, and development of drug resistance. HIV infection and METH dependence can have synergistic pathological effects, with preferential involvement of frontostriatal circuits. At the molecular level, epigenetic alterations have been reported for both HIV-1 infection and drug abuse, but the neuropathological pathways triggered by their combined effects are less known. We investigated epigenetic changes in the brain associated with HIV and METH. We analyzed postmortem frontal cortex tissue from 27 HIV seropositive individuals, 13 of which had a history of METH dependence, in comparison to 14 cases who never used METH. We detected changes in the expression of DNMT1, at mRNA and protein levels, that resulted in the increase of global DNA methylation. Genome-wide profiling of DNA methylation in a subset of cases, showed differential methylation on genes related to neurodegeneration; dopamine metabolism and transport; and oxidative phosphorylation. We provide evidence for the synergy of HIV and METH dependence on the patterns of DNA methylation on the host brain, which results in a distinctive landscape for the comorbid condition. Importantly, we identified new epigenetic targets that might aid in understanding the aggravated neurodegenerative, cognitive, motor and behavioral symptoms observed in persons living with HIV and addictions.

Alpha-synuclein (α-Syn) accumulation/aggregation and mitochondrial dysfunction play prominent roles in the pathology of Parkinson's disease. We have previously shown that postmortem human dopaminergic neurons from PD brains accumulate high levels of mitochondrial DNA (mtDNA) deletions. We now addressed the question, whether alterations in a component of the mitochondrial import machinery--TOM40--might contribute to the mitochondrial dysfunction and damage in PD. For this purpose, we studied levels of TOM40, mtDNA deletions, oxidative damage, energy production, and complexes of the respiratory chain in brain homogenates as well as in single neurons, using laser-capture-microdissection in transgenic mice overexpressing human wildtype α-Syn. Additionally, we used lentivirus-mediated stereotactic delivery of a component of this import machinery into mouse brain as a novel therapeutic strategy. We report here that TOM40 is significantly reduced in the brain of PD patients and in α-Syn transgenic mice. TOM40 deficits were associated with increased mtDNA deletions and oxidative DNA damage, and with decreased energy production and altered levels of complex I proteins in α-Syn transgenic mice. Lentiviral-mediated overexpression of Tom40 in α-Syn-transgenic mice brains ameliorated energy deficits as well as oxidative burden. Our results suggest that alterations in the mitochondrial protein transport machinery might contribute to mitochondrial impairment in α-Synucleinopathies.

Alors qu’elles restaient relativement stables et balisées jusqu’au début des années 1980, les relations entre l’État français et les manifestations de la liberté religieuse connaît un forme nouvelle de contentieux avec les affaires dites du «voile à l’école» qui surgit à la fin des années 1980. Dans un premier temps, la réponse des autorités publiques a eu tendance à privilégier le pragmatisme à l’égard des usagers du service public, mais la fermeté à l’égard des agents du service public. Dans un second temps, à partir des années 2000, on assiste à une surenchère entre les manifestations radicales d’appartenance religieuse et une volonté politique de rappeler la primauté des principes républicains au nombre desquels figurent le principe de la laïcité. Cette évolution a pour résultat un durcissement des discours législatifs qui, du contrôle de l’expression de l’appartenance religieuse des élèves dans les établissements scolaires, en est récemment venu à un contrôle vestimentaire de toute personne dans l’espace public.

An ever-growing number of doctors are being trained at the Faculties of Medicine of French-speaking Africa and Madagascar, and yet the shortage of general practitioners in rural and periurban areas continues to be a cause for concern, even though there are more unemployed young medical graduates than ever. More than 20 years ago, the non-governmental organization (NGO) Santé Sud developed the concept of community-based general medicine, along with a professional mechanism that enabled more than 200 doctors to set up practice in Mali, Madagascar and Benin. Five external assessments are now available for evaluating the relevance and feasibility of this new form of local healthcare provision and determining under what conditions it might be extended or integrated into existing healthcare systems. The creation of mixed public/private bodies, with funding allocated under the International Health Partnership (IHP+), is put forward as a desirable way of spreading this experience.

The universally conserved J-domain proteins (JDPs) are obligate cochaperone partners of the Hsp70 (DnaK) chaperone. They stimulate Hsp70's ATPase activity, facilitate substrate delivery, and confer specific cellular localization to Hsp70. In this work, we have identified and characterized the first functional JDP protein encoded by a bacteriophage. Specifically, we show that the ORFan gene 057w of the T4-related enterobacteriophage RB43 encodes a bona fide JDP protein, named Rki, which specifically interacts with the Escherichia coli host multifunctional DnaK chaperone. However, in sharp contrast with the three known host JDP cochaperones of DnaK encoded by E. coli, Rki does not act as a generic cochaperone in vivo or in vitro. Expression of Rki alone is highly toxic for wild-type E. coli, but toxicity is abolished in the absence of endogenous DnaK or when the conserved J-domain of Rki is mutated. Further in vivo analyses revealed that Rki is expressed early after infection by RB43 and that deletion of the rki gene significantly impairs RB43 proliferation. Furthermore, we show that mutations in the host dnaK gene efficiently suppress the growth phenotype of the RB43 rki deletion mutant, thus indicating that Rki specifically interferes with DnaK cellular function. Finally, we show that the interaction of Rki with the host DnaK chaperone rapidly results in the stabilization of the heat-shock factor σ(32), which is normally targeted for degradation by DnaK. The mechanism by which the Rki-dependent stabilization of σ(32) facilitates RB43 bacteriophage proliferation is discussed.