Pathogenesis Of Dementia Research Articles

Blocking Site-Specific Cleavage of Human Tau Delays Progression of Disease-Related Phenotypes in Genetically Matched Tau-Transgenic Mice Modeling Frontotemporal Dementia.

Studies have recently demonstrated that a caspase-2-mediated cleavage of human tau (htau) at asparate-314 (D314) is responsible for cognitive deficits and neurodegeneration in mice modeling frontotemporal dementia (FTD). However, these animal studies may be confounded by flaws in their model systems, such as endogenous functional gene disruption and inequivalent transgene expression. To avoid these weaknesses, we examined the pathogenic role of this site-specific htau cleavage in FTD using genetically matched htau targeted-insertion mouse lines: rT2 and rT3. Both male and female mice were included in this study. rT2 mice contain a single copy of the FTD-linked htau proline-to-leucine mutation at amino acid 301 (htau P301L), inserted into a neutral site to avoid dysregulation of host gene expression. The similarly constructed rT3 mice harbor an additional D314-to-glutamate (D314E) mutation that blocks htau cleavage. We demonstrate that htau transgene expression occurs primarily in the forebrain at similar levels in rT2 and rT3 mice. Importantly, expression of the cleavage-resistant D314E mutant delays transgene-induced tau accumulation in the postsynaptic density, brain atrophy, hippocampal neurodegeneration, and spatial memory impairment, without altering age-related progression of pathologic tau conformation and phosphorylation. Our comprehensive investigation of age-dependent disease phenotypes associated with the htau P301L variant in precisely engineered FTD-modeling mice unveils a transiently protective effect of blocking htau cleavage at D314. Findings of this study advance our understanding of the contribution of this tau cleavage to the pathogenesis of FTD, and aid the development of effective dementia-targeting therapies.SIGNIFICANCE STATEMENT A site-specific and caspase-2-mediated cleavage of human tau plays a pathologic role in dementia. In this study, we investigate the contribution of this cleavage to the pathogenesis of frontotemporal dementia (FTD) using two genetically matched, tau-transgene targeted-insertion mouse lines that differ only by a cleavage-resistant mutation. The use of these mice avoids confounding effects associated with the random integration of tau transgenes to the mouse genome and allows us to comprehensively evaluate the impact of the tau cleavage on FTD phenotypes. Our data reveal that blocking this tau cleavage delays memory impairment and neurodegeneration of FTD-modeling mice. These findings improve our understanding of the pathogenic mechanisms underlying FTD and will facilitate the development of effective therapeutics.

Beneficial effects of AT1 antagonists treatment, losartan, on cardiovascular and cognitive function on aged male Dahl salt sensitive rats

Introduction and objectiveCardiovascular diseases and hypertension are the major contributors to the pathogenesis of vascular dementia. The Dahl salt‐sensitive (DSS) rat model is characterized by age‐associated cardiovascular remodeling and the development of central arterial stiffness (CAS) in the presence of renin‐angiotensin system disbalance, accompanied by cognitive decline. We hypothesized, that the anti‐hypertensive treatment, antagonist for angiotensin II receptors losartan (LOS), via reducing CAS, will improve cardiovascular parameters and cognitive function in aged DSS male rats.MethodsMale DSS rats (n=30) were kept on a normal salt diet (0.5% NaCl) for the duration of the study. At 6 months of age, rats were given either LOS in drinking water (30mg/kg/day, n=14) or control treatment (n=16) for 6 months. Measurements, including systolic and diastolic BP (SBP, DBP) and pulse wave velocity (PWV), a measure of CAS (by echocardiology), were taken after 6 months of LOS treatment. Rats were tested in an operant chambers (OCh) attention challenge to assess attention and impulsivity; elevated plus maze (EPM) was performed to estimate anxiety‐like behavior. Statistical analyses were performed using 1‐way ANOVA, t‐test and Pearson correlation. Data are presented as mean ± SEM.Resultsfollowing 6 months of treatment, at 12‐mo of age, LOS treated rats had lower BP and PWV vs. control (Table 1). Performance on the OCh indicated that LOS rats had more correct responses vs. control rats (Fig. 1). The LOS group exhibited lower anxiety levels, because they spent less time on the closed shoulder in EPM (Table 1) and demonstrate 1.5‐fold increase of time in the open shoulder (p < 0.01). PWV and SBP was negatively correlated with time on open shoulder, total distance traveled and total correct answers at 12‐mo of age (Fig.2).ConclusionAged male DSS rats show beneficial effects of LOS on cardiovascular and cognitive function. The CAS and BP improvement by LOS was associated with improved attention and lower anxiety levels. The mechanistic basis of LOS effects on cognition via cerebrovascular and brain changes will be further investigated.

The Role of High-Density Lipoprotein in Lowering Risk of Dementia in the Elderly: A Review.

Dementia is one of the major causes of disability and hospitalization in the elderly. As far as non-invasive markers of dementia are concerned, we only have age and Apolipoprotein-E (Apo-E) gene, which can be considered as clinically relevant. Modifiable risk factors have been found to be the cause in one-third of the patients who develop dementia. The compatible data supporting the same, in particular for dyslipidemia, is limited, which in turn makes it difficult to devise prevention and interventional methods for both dementia and mild cognitive impairment. Hence, the objective of the review is to summarize the findings on the relation established between the high-density lipoprotein type C( HDL-C) levels and lower the chance of dementia in the elderly, and the possible role of HDL-C as a potential predictive biomarker for cases of dementia in elderly people.Dyslipidemia, a known risk factor for the occurrence of cardiovascular diseases, seems to be linked to Alzheimer’s disease. Elevated levels of serum cholesterol in mid-adult life increases the risk of dementia in older age. But elevated high-density lipoprotein (HDL) level and its principal apolipoprotein A-I (ApoA-I ) equates with a low risk of dementia in the elderly populationHDL cholesterol has been found to promote endothelial nitric oxide synthase activity which in turn reduces the neural and vascular inflammation and suppresses vascular adhesion thereby exhibiting its vasoprotective function. It has been believed that all these factors have a role to play in the pathogenesis of dementia.The relation between the higher levels of HDL cholesterol or its key protein component ApoA-I and the lower dementia prevalence in the elderly had been documented in numerous observational studies. Some studies have reported conflicting results. Yet, observational studies measuring the baseline HDL level in middle age found a significant association between HDL level and dementia risk in the elderly, whereas those studies measuring HDL cholesterol level only in old age found no association. Likewise, a significant association between HDL cholesterol and dementia risk has been reported with studies that carry through to 10 years or longer. However, the studies with follow-up of fewer than 10 years had failed to document any such association between HDL cholesterol and dementia. HDL assays may also be used as a predictive biomarker for dementia patients to target the interventions. Although statins do not target HDL directly but can be an area of interest for dementia.

Alterations of Striatal Subregions in a Prion Protein Gene V180I Mutation Carrier Presented as Frontotemporal Dementia With Parkinsonism.

ObjectiveTo explore the roles of striatal subdivisions in the pathogenesis of frontotemporal dementia with parkinsonism (FTDP) in a patient resulting from prion protein gene (PRNP) mutation.MethodsThis patient received clinical interviews and underwent neuropsychological assessments, genetic testing, [18F]-fluorodeoxyglucose positron emission tomography ([18F]-FDG PET)/MRI, and [18F]-dihydrotetrabenazine positron emission tomography ([18F]-DTBZ PET)/CT. Region-of-interest analysis was conducted concerning metabolism, and dopamine transport function between this patient and 12 controls, focusing on the striatum subregions according to the Oxford-GSK-Imanova Striatal Connectivity Atlas.ResultsA 64-year-old man initially presented with symptoms of motor dysfunction and subsequently behavioral and personality changes. FTDP was initially suspected. Sequence analysis disclosed a valine to isoleucine at codon 180 in PRNP. Compared to controls, this patient had a severe reduction (> 2SD) of standard uptake value ratio (SUVR) in the limbic and executive subregions but relative retention of metabolism in rostral motor and caudal motor subregions using [18F]-FDG PET/MRI, and the SUVR decreased significantly across the striatal in [18F]-DTBZ PET/CT, especially in the rostral motor and caudal motor subregions.ConclusionThe alteration of frontal striatal loops may be involved in cognitive impairment in FTDP, and the development of parkinsonism in FTDP may be primarily due to the involvement of the presynaptic nigrostriatal loops in PRNP V180I mutation.

ApoE Cascade Hypothesis in the pathogenesis of Alzheimer's disease and related dementias.

The ε4 allele of the apolipoprotein E gene (APOE4) is a strong genetic risk factor for Alzheimer's disease (AD) and several other neurodegenerative conditions, including Lewy body dementia (LBD). The three APOE alleles encode protein isoforms that differ from one another only at amino acid positions 112 and 158: apoE2 (C112, C158), apoE3 (C112, R158), and apoE4 (R112, R158). Despite progress, it remains unclear how these small amino acid differences in apoE sequence among the three isoforms lead to profound effects on aging and disease-related pathways. Here, we propose a novel "ApoE Cascade Hypothesis" in AD and age-related cognitive decline, which states that the biochemical and biophysical properties of apoE impact a cascade of events at the cellular and systems levels, ultimately impacting aging-related pathogenic conditions including AD. As such, apoE-targeted therapeutic interventions are predicted to be more effective by addressing the biochemical phase of the cascade.

Structures of the Wild-Type and S59L Mutant CHCHD10 Proteins Important in Amyotrophic Lateral Sclerosis–Frontotemporal Dementia

The S59L genetic mutation of the mitochondrial coiled-coil-helix-coiled-coil-helix domain-containing protein 10 (CHCHD10) is involved in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The wild-type and mutant forms of this protein contain intrinsically disordered regions, and their structural characterization has been facing challenges. Here, for the first time in the literature, we present the structural ensemble properties of the wild-type and S59L mutant form of CHCHD10 in an aqueous solution environment at the atomic level with dynamics. Even though available experiments suggested that the S59L mutation may not change the structure of the CHCHD10 protein, our structural analysis clearly shows that the structure of this protein is significantly affected by the S59L mutation. We present here the secondary structure components with their abundances per residue, the tertiary structure properties, the free energy surfaces based on the radius of gyration and end-to-end distance values, the Ramachandran plots, the quantity of intramolecular hydrogen bonds, and the principal component analysis results. These results may be crucial in designing more efficient treatment for ALS and FTD diseases.

Expanding the TDP-43 Proteinopathy Pathway From Neurons to Muscle: Physiological and Pathophysiological Functions.

TAR DNA-binding protein 43, mostly referred to as TDP-43 (encoded by the TARDBP gene) is strongly linked to the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). From the identification of TDP-43 positive aggregates in the brains and spinal cords of ALS/FTD patients, to a genetic link between TARBDP mutations and the development of TDP-43 pathology in ALS, there is strong evidence indicating that TDP-43 plays a pivotal role in the process of neuronal degeneration. What this role is, however, remains to be determined with evidence ranging from gain of toxic properties through the formation of cytotoxic aggregates, to an inability to perform its normal functions due to nuclear depletion. To add to an already complex subject, recent studies highlight a role for TDP-43 in muscle physiology and disease. We here review the biophysical, biochemical, cellular and tissue-specific properties of TDP-43 in the context of neurodegeneration and have a look at the nascent stream of evidence that positions TDP-43 in a myogenic context. By integrating the neurogenic and myogenic pathological roles of TDP-43 we provide a more comprehensive and encompassing view of the role and mechanisms associated with TDP-43 across the various cell types of the motor system, all the way from brain to limbs.

Chronic Renin-Angiotensin System Activation Induced Neuroinflammation: Common Mechanisms Underlying Hypertension and Dementia?

Hypertension is a major risk factor for the pathogenesis of vascular dementia and Alzheimer's disease. Chronic activation of the renin-angiotensin system (RAS) contributes substantially to neuroinflammation. We propose that neuroinflammation arising from chronic RAS activation can initiate and potentiate the onset of hypertension and related dementia. Neuroinflammation induced by chronic activation of the RAS plays a key role in the pathogenesis of dementia. Increased levels of pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and transforming growth factor (TGF)-β have been reported in brain tissue of vascular dementia patients and animal models of vascular dementia induced by either angiotensin II infusion or transverse aortic coarctation. It is proposed that neuronal cell death and synaptic dysfunction induced by neuroinflammation lead to cognitive impairment in dementia. The neuroprotective RAS pathway, regulated by angiotensin-converting enzyme 2 (ACE2) which converts angiotensin II into angiotensin-(1-7), can attenuate hypertension and dementia. Furthermore, the use of anti-hypertensive medications in preventing dementia or cognitive decline in hypertensive patients and animal models of dementia have mostly been beneficial. Current evidence suggests a strong link between RAS induced neuroinflammation and the onset of hypertension and dementia, which warrants further investigation. Strategies to counteract an overactive RAS and enhance the neuroprotective arm of the RAS may help prevent or improve cognitive impairment associated with hypertension.

Therapeutic drug targeting in Alzheimer's disease

Alzheimer's disease is the most common form of dementia. It affects 47 million people worldwide and is estimated to rise to 131 million by 2050. This debilitating disease is not fully understood and currently has no cure or prevention. New research suggests that, across populations, age-specific dementia prevalence and incidence are declining, leading to a new focus on lifestyle and environmental factors that can potentially influence the pathogenesis of dementia. This project seeks to investigate medications that could reduce dementia risk with the potential for drug repurposing in collaboration with Cambridge Public Health.

Professor Jun Li Treating Vascular Dementia from Mutual Conclusion of Phlegm and Blood Stasis

Professor Jun Li believes that the main etiology and pathogenesis of vascular dementia is the combination of phlegm and blood stasis. The symptoms include feeling faint and declined senses in organs of the head, caused by mystery reason. To cure phlegm and blood stasis simultaneously, the therapy promotes the notion of “resolving phlegm and stimulating the circulation of blood, liberate brain orifices,” and treatments with the addition and removal of “Naotaitong Decoction,” which has an amazing clinical curative effect. This paper examines Professor Jun Li’s theoretical foundations and ideas from the syndrome differentiation and treatment of phlegm and blood stasis, systematically examines the curative effect and mechanism of Naotaitong Decoction in the treatment of vascular dementia, and examines the prescription and medication of typical cases for readers, in the hopes of providing guidance to clinical diagnosis and treatment of this disease.

Cerebral venous congestion exacerbates cerebral microhemorrhages in mice.

Cerebral microhemorrhages (CMHs; microbleeds), which are small focal intracerebral hemorrhages, importantly contribute to the pathogenesis of cognitive decline and dementia in older adults. Although recently it has been increasingly recognized that the venous side of the cerebral circulation likely plays a fundamental role in the pathogenesis of a wide spectrum of cerebrovascular and brain disorders, its role in the pathogenesis of CMHs has never been studied. The present study was designed to experimentally test the hypothesis that venous congestion can exacerbate the genesis of CMHs. Increased cerebral venous pressure was induced by internal and external jugular vein ligation (JVL) in C57BL/6 mice in which systemic hypertension was induced by treatment with angiotensin II plus L-NAME. Histological analysis (diaminobenzidine staining) showed that mice with JVL developed multiple CMHs. CMHs in mice with JVL were often localized adjacent to veins and venules and their morphology was consistent with venous origin of the bleeds. In brains of mice with JVL, a higher total count of CMHs was observed compared to control mice. CMHs were distributed widely in the brain of mice with JVL, including the cortical gray matter, brain stem, the basal ganglia, subcortical white matter, cerebellum, and the hippocampi. In mice with JVL, there were more CMHs predominantly in cerebral cortex, brain stem, and cerebellum than in control mice. CMH burden, defined as total CMH volume, also significantly increased in mice with JVL. Thus, cerebral venous congestion can exacerbate CMHs. These observations have relevance to the pathogenesis of cognitive impairment associated with right heart failure as well as elevated cerebral venous pressure due to jugular venous reflux in older adults.

Crosstalk of copper and zinc in the pathogenesis of vascular dementia.

Copper and zinc are essential for normal brain functions. Both are localized in presynaptic vesicles and are secreted into synaptic clefts during neuronal excitation. Despite their significance, excesses of copper and zinc are neurotoxic. In particular, excess zinc after transient global ischemia plays a central role in the ischemia-induced neurodegeneration and pathogenesis of vascular type senile dementia. We previously found that sub-lethal concentrations of copper remarkably exacerbated zinc-induced neurotoxicity, and we investigated the molecular pathways of copper-enhanced zinc-induced neurotoxicity. The endoplasmic reticulum stress pathway, the stress-activated protein kinases/c-‍Jun amino-terminal kinases pathway, and mitochondrial energy production failure were revealed to be involved in the neurodegenerative processes. Regarding the upstream factors of these pathways, we focused on copper-derived reactive oxygen species and the disruption of calcium homeostasis. Because excess copper and zinc may be present in the synaptic clefts during ischemia, it is possible that secreted copper and copper-induced reactive oxygen species may enhance zinc neurotoxicity and eventually contribute to the pathogenesis of vascular type senile dementia.

Comparison of Cognitive Performance and Cardiac Function Between Three Different Rat Models of Vascular Dementia

PurposeEstablishing an ideal animal model is essential for studying the pathogenesis, prevention and treatment of vascular dementia (VD). The present study was designed to compare the differences of behavior, cerebral blood flow (CBF), cardiac output and the levels of myocardial enzyme of three different VD rat models.MethodsThe rats were randomly divided into sham-operated group (SHAM), permanent bilateral common carotid artery occlusion group (BCCAO), BCCAO combined with sodium nitroprusside (2.0mg·kg−1) group (BCCAO+2.0SNP) and BCCAO combined with sodium nitroprusside (2.5mg·kg−1) group (BCCAO+2.5SNP). After operation, Morris water maze test, echocardiographic evaluation and the measurement of CBF were performed, then the levels of myocardial enzymes in serum were assessed during euthanasia.ResultsCompared with SHAM rats, the three VD model rats showed different degrees of cognitive impairment, lower cardiac output and CBF, and BCCAO rats showed higher levels of myocardial enzymes. Compared with BCCAO rats, the spatial learning ability of BCCAO+2.0SNP rats and BCCAO+2.5SNP rats was more severely impaired, while the levels of myocardial enzymes of BCCAO+2.0SNP rats were lower. Compared with BCCAO+2.0SNP rats, BCCAO+2.5SNP rats showed no significant difference in cognitive function and cardiac function.ConclusionOur present study demonstrated that all of the three different VD rat models exhibited cognitive and cardiac function impairment. The BCCAO+2.0SNP model and BCCAO+2.5SNP model damaged the spatial learning ability more seriously. The BCCAO+2.5SNP model caused more comprehensive cognitive impairment. In addition, the BCCAO+2.0SNP model and BCCAO+2.5SNP model might cause more serious damage to cardiac function.

Vascular pathology and pathogenesis of cognitive impairment and dementia in older adults.

It is well recognized that brains of older people often harbor cerebrovascular disease pathology including vessel disease and vascular-related tissue injuries and that this is associated with vascular cognitive impairment and contributes to dementia. Here we review vascular pathologies, cognitive impairment, and dementia. We highlight the importance of mixed co-morbid AD/non-AD neurodegenerative and vascular pathology that has been collected in multiple clinical pathologic studies, especially in community-based studies. We also provide an update of vascular pathologies from the Rush Memory and Aging Project and Religious Orders Study cohorts with special emphasis on the differences across age in persons with and without dementia. Finally, we discuss neuropathological perspectives on the interpretation of clinical-pathological studies and emerging data in community-based studies.

An Exploratory Study On Critical Analysis and Understanding of Medhya Rasayana (intelligence enhancer) in Dementia

Dementia is a chronic disorder characterized by a progressive irreversible cognitive deficit. The signs and symptoms along with the pathogenesis of dementia involving neurodegeneration can be understood in terms of dhi dhriti smriti and nasha. The objective of the present study is to critically analyze the role and importance of Medhya Rasayana in the management of dementia. Medha is the retainment of memory for a longer duration. To retain the memory prakrutaavastha of dhi dhriti and smriti are essential factors. Cognitive deficits like memory disorders are more prevalent among the older age group. Impairment of memory is dhi dhriti smriti and nasha which occurs due to vitiation of rajo and tama doshas. Prajnaaparadha is the main causative factor for the vitiation of manasika doshas. So to enhance sattva quality there is a need for Medhya Rasayana. Medhya Rasayana drugs work on the hypothalamus-adrenal axis HPA axis and normalize the secretion of neurotransmitters such as dopamine serotonin and acetylcholine thus improving the mental function.nbsp

Association of Serum Levels of Cystatin C and Cognition in a Cohort of Egyptian Elderly Patients with Chronic Kidney Disease.

Chronic kidney disease (CKD) and dementia are common morbidities of elders. Serum cystatin C has been suggested to be an ideal marker for kidney function. The current study aimed to detect the serum levels of cystatin C in CKD patients and to correlate these levels to cognitive performance. The study involved 90 subjects aged 65 years and more, divided into two groups: Group 1: 60 patients with CKD, and Group 2: 30 control participants. Exclusion criteria included cardiac failure, hepatic failure, thyroid diseases, dialysis for more than one month, polycystic kidney disease, organ transplantation, and immunosuppressive therapy within the past six months. All participants had routine laboratory workup, serum cystatin C using enzyme-linked immunosorbent assay kits, and cognitive assessment using mini-mental state examination (MMSE). Serum cystatin level was significantly high in CKD patients while MMSE scores were significantly lower in CKD patients. A high significant negative correlation was found between serum cystatin C levels and both degree of cognitive impairment and glomerular filtration rate (GFR). Also, a significant positive correlation was found between the degree of cognitive impairment and GFR levels. Serum cystatin levels are significantly associated with cognitive impairment in CKD patients, and this correlation becomes more evident with the worsening of CKD stages. That may help in better understanding of the pathogenesis of dementia in CKD patients with the emergence of therapeutic options depending on these data.

Demonstration Of Age-Related Increase In Blood-Brain Barrier Permeability By Longitudinal Intravital Microscopy

Age-related blood-brain barrier disruption and cerebromicrovascular rarefaction contribute importantly to the pathogenesis of both vascular cognitive impairment and dementia (VCID) and Alzheimer's disease (AD). Recent advances in geroscience research enable development of novel interventions to reverse age-related alterations of the cerebral microcirculation for prevention of VCID and AD. To facilitate this research there is an urgent need for sensitive and easy-to-adapt imaging methods, which enable longitudinal assessment of changes in BBB permeability and brain capillarization in aged mice, that could be used in vivo to evaluate treatment efficiency. To enable longitudinal assessment of changes in BBB permeability in aged mice equipped with a chronic cranial window, we adapted and optimized two different intravital two-photon imaging approaches. By assessing relative fluorescence changes over the baseline within a volume of brain tissue, after qualitative image subtraction of the brain microvasculature, we confirmed that in 24 month old C57BL/6J mice cumulative permeability of the microvessels to fluorescent tracers of different molecular weights (0.3 kDa to 40 kDa) is significantly increased as compared to that of 5 month old mice. Real-time recording of vessel cross-sections showed that apparent solute permeability of single microvessels is significantly increased in aged mice vs. young mice. Cortical capillary density, assessed both by intravital two-photon microscopy and optical coherence tomography (OCT) was also decreased in aged mice vs. young mice. The presented methods have been optimized for longitudinal (over the period of 36 weeks) in vivo assessment of cerebromicrovascular health in preclinical geroscience research.

Oligomer-Targeting Prevention of Neurodegenerative Dementia by Intranasal Rifampicin and Resveratrol Combination - A Preclinical Study in Model Mice.

Amyloidogenic protein oligomers are thought to play an important role in the pathogenesis of neurodegenerative dementia, including Alzheimer’s disease, frontotemporal dementia, and dementia with Lewy bodies. Previously we demonstrated that oral or intranasal rifampicin improved the cognition of APP-, tau-, and α-synuclein-transgenic mice by reducing the amount of Aβ, tau, and α-synuclein oligomers in the brain. In the present study, to explore more effective and safer medications for dementia, we tested the drug combination of rifampicin and resveratrol, which is a multifunctional natural polyphenol with the potential to antagonize the adverse effects of rifampicin. The mixture was intranasally administered to APP-, tau-, and α-synuclein-transgenic mice, and their memory and oligomer-related pathologies were evaluated. Compared with rifampicin and resveratrol alone, the combinatorial medicine significantly improved mouse cognition, reduced amyloid oligomer accumulation, and recovered synaptophysin levels in the hippocampus. The plasma levels of liver enzymes, which reflect hepatic injury and normally increase by rifampicin treatment, remained normal by the combination treatment. Notably, resveratrol alone and the combinatorial medicine, but not rifampicin alone, enhanced the levels of brain-derived neurotrophic factor (BDNF) and its precursor, pro-BDNF, in the hippocampus. Furthermore, the combination showed a synergistic effect in ameliorating mouse cognition. These results show the advantages of this combinatorial medicine with regards to safety and effectiveness over single-drug rifampicin. Our findings may provide a feasible means for the prevention of neurodegenerative dementia that targets toxic oligomers.

How much sleep is enough to avoid dementia or mild cognitive impairment? A systematic review and meta‐analysis of longitudinal studies

AbstractBackgroundDementia remains a global burden in aged populations and its contributing factors are still poorly known. While the lack of sleep has been proposed as a risk factor for dementia, evidence has emerged that excessive sleep might also be associated with increased risk for dementia. The present systematic review and meta‐analysis then aims to quantitatively clarify the correlation between dementia and sleep duration using a novel approach.MethodLiterature databases including PubMed and Embase were searched for studies reporting statistics on the proportion of participants with dementia or mild cognitive impairment (MCI) as well as the corresponding sleep duration. Unlike existing methods that measure odds ratios and relative ratios of developing dementia, the data were used to form a beta distribution that shows the likelihood of developing dementia / MCI given the sleep duration.ResultThe search identified a total of 6,522 articles, of these 10 studies involving 31510 participants in 7 countries were eligible for inclusion. The follow‐up time of these studies varied between 1 to 14 years. The relationship between dementia / MCI was U‐shaped. The distribution was asymmetrical with the implication that excessive sleep was associated with higher risk of dementia / MCI, compared with lack of sleep. In addition, higher risk of dementia rather than MCI was associated with sleep duration below 5 hours or above 9 hours.ConclusionThe asymmetry of the distribution suggests the difference in the pathogenesis of dementia between the lack of sleep and excessive sleep. Coupled with existing findings that excessive sleep does not lead to the deposition of β‐amyloid, it is suggested that excessive sleep directly damages synapses in the absence of β‐amyloid accumulation. While there is still no plausible physiologic explanation for how excessive sleep and dementia is mediated, some have argued that excessive sleep could elevate the level of proinflammatory cytokine that has been suggested to reduce synapses.

Circulating cystatin‐C is associated with dementia in a racial and ethnically diverse cohort: An interaction decomposition analysis

AbstractBackgroundCystatin‐C has an important role in the pathogenesis of dementia, as evidenced by expression in the brain and co‐localization with beta‐amyloid deposits. Circulating Cystatin‐C may be directly implicated in neurodegeneration, or the result of a compensatory mechanism of neuroprotection. Our study aims to understand the relationship between circulating Cystatin‐C and dementia, and to test the interaction between Cystatin‐C and race/ethnicity.MethodsWe performed a cross‐sectional analysis of serum Cystatin‐C levels with dementia and cognitive impairment non‐dementia (CIND) in two waves (2006 and 2008) of the Health and Retirement Study (n=9,984). We used Poisson regression with robust variance to estimate the interactive effect of race/ethnicity and Cystatin‐C >75th on dementia. We calculated three measures of interaction in the additive scale: the excess risk due to interaction (RERI), the attributable proportion, and the synergy index (SI). We decomposed the interaction to calculate the percentage of the excess risk attributable to the effects of race/ethnicity and Cystatin‐C alone.ResultsAfrican Americans and Hispanics had higher levels of Cystatin‐C at every decade of life except for the 80s with respect to Whites (see Figure 1). The prevalence ratio for dementia among African Americans with levels of Cystatin‐C >75th was 7.33 (95%CI: 5.43, 9.89) times of White Americans with Cystatin‐C <75th. A RERI of 1.89 (95%CI: ‐0.17, 3.95) indicates more than an additive interaction; and attributable proportion of 0.26 (95%CI: 0.02, 0.50) suggests than roughly a quarter of the excess risk was due to the interaction of both race and Cystatin‐C; and a synergy index of 1.43 (95%CI: 0.97, 2.10) provided evidence of synergism between the two exposures. We found 26% (95%CI: 2%, 50%) of the excess risk among the doubly exposed group (i.e., African Americans with levels of Cystatin‐C >75th) was attributable to the interaction between Cystatin‐C and race. Similar patterns were observed for Hispanics in relation to Whites.ConclusionElevated levels of circulating Cystatin‐C are implicated in impaired cognition, and the association between Cystatin‐C and cognition varies dramatically by race/ethnicity.