scholarly journals Leveraging large multi-center cohorts of Alzheimer Disease endophenotypes to understand the role of Klotho heterozygosity on disease risk

2021 ◽  
Author(s):  
Muhammad Ali ◽  
Yun Ju Sung ◽  
Fengxian Wang ◽  
Maria V. Fernandez ◽  
John C. Morris ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Drug Targets ◽  
Disease Risk ◽  
Transmembrane Protein ◽  
Neuroprotective Effect ◽  
Tau Pathology ◽  
Gene Encoding ◽  
Cognitively Normal ◽  
Positron Emission ◽  
Brain Resilience

Two genetic variants (rs9536314 and rs9527025) in the Klotho gene, encoding a transmembrane protein, implicated on longevity and associated with brain resilience during normal aging, were recently shown to be associated with Alzheimer disease (AD) risk in cognitively healthy individuals that are APOE4 carriers. Specifically, the individuals heterozygous for this variant (KL-SVHET+), showed lower risk of developing AD. Furthermore, a neuroprotective effect of KL-VSHET+ has been suggested against amyloid burden for cognitively normal individuals. However, inconsistent associations and a smaller sample size of existing studies pose significant hurdles in drawing definitive conclusions. Here, we have performed a well-powered association analysis between KL-VSHET+ and five different AD endophenotypes; brain amyloidosis measured by positron emission tomography (PET) scans (n = 5,541) or cerebrospinal fluid Aβ levels (CSF; n = 5,093), as well as biomarkers associated with tau pathology: the CSF Tau (n = 5,127), phosphorylated Tau (pTau; n = 4,778) and inflammation: CSF soluble triggering receptor expressed on myeloid cells 2 (sTREM2; n = 2,123) levels. Our results found nominally significant associations of KL-VSHET+ status with biomarkers for brain amyloidosis (e.g. CSF Aβ positivity; odds ratio [OR] = 0.67 [95% CI, 0.55-0.78], β = 0.72, P = 0.007) and tau pathology (e.g. biomarker negative for CSF Tau; OR = 0.39 [95% CI, 0.19-0.77], β = -0.94, P = 0.007, and pTau; OR = 0.50 [95% CI, 0.27-0.96], β = -0.68, P = 0.04) in elderly (60-80 years old) individuals that are cognitively normal and APOE4 carriers. Our work supports previous findings and suggests that the KL-VSHET+ on a APOE4 genotype background may exert a protective effect by modulating the Aβ, Tau, and pTau burden and resulting cognitive decline in older controls susceptible to AD. The biological mechanism underlying APOE4 and KL-VSHET+ interaction and the neuroprotective effect of KL-related pathways against amyloid accumulation may warrant future investigation as a target for preclinical pharmacological studies to explore novel AD drug targets.

scholarly journals Medial Temporal Tau Pathology Is Associated With Verbal Memory

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 767-767
Author(s):  
Murat Bilgel ◽  
Jacob Ziontz ◽  
Andrea Shafer ◽  
Luigi Ferrucci ◽  
Dean Wong ◽  
...  
Keyword(s):  
Entorhinal Cortex ◽  
Verbal Memory ◽  
Memory Performance ◽  
Cognitive Status ◽  
Therapeutic Interventions ◽  
Tau Pathology ◽  
Cognitively Normal ◽  
Positron Emission ◽  
Normal Individuals ◽  
Baltimore Longitudinal Study

Abstract Medial temporal tau pathology is frequently observed in individuals over 70 regardless of cognitive status. To understand the link between tau and cognitive performance, we evaluated tau pathology using 18F-flortaucipir positron emission tomography among 95 cognitively normal participants from the Baltimore Longitudinal Study of Aging. We examined tau levels in early Braak regions (entorhinal cortex and hippocampus) in relation to verbal episodic memory performance concurrent with and prior to the tau scan using linear mixed effects models adjusted for age, sex, amyloid status, and time from PET scan. Higher hippocampal tau burden had a trend-level association with lower concurrent memory performance (p=0.05). Greater tau pathology in the hippocampus and entorhinal cortex was associated with steeper decline in memory performance prior to tau scan (p=0.013 and 0.026, respectively). These findings suggest that therapeutic interventions targeting tau pathology may need to be administered early among cognitively normal individuals to prevent memory decline.

scholarly journals Neuropsychiatric symptoms predict hypometabolism in preclinical Alzheimer disease

Neurology ◽  
2017 ◽  
Vol 88 (19) ◽  
pp. 1814-1821 ◽  
Author(s):  
Kok Pin Ng ◽  
Tharick A. Pascoal ◽  
Sulantha Mathotaarachchi ◽  
Chang-Oh Chung ◽  
Andréa L. Benedet ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Neuropsychiatric Symptoms ◽  
Posterior Cingulate Cortex ◽  
Metabolic Dysfunction ◽  
Tau Pathology ◽  
Sleep Behavior ◽  
Cognitively Normal ◽  
Preclinical Ad ◽  
Normal Individuals ◽  
Metabolic Dysfunctions

Objective:To identify regional brain metabolic dysfunctions associated with neuropsychiatric symptoms (NPS) in preclinical Alzheimer disease (AD).Methods:We stratified 115 cognitively normal individuals into preclinical AD (both amyloid and tau pathologies present), asymptomatic at risk for AD (either amyloid or tau pathology present), or healthy controls (no amyloid or tau pathology present) using [18F]florbetapir PET and CSF phosphorylated tau biomarkers. Regression and voxel-based regression models evaluated the relationships between baseline NPS measured by the Neuropsychiatric Inventory (NPI) and baseline and 2-year change in metabolism measured by [18F]fluorodeoxyglucose (FDG) PET.Results:Individuals with preclinical AD with higher NPI scores had higher [18F]FDG uptake in the posterior cingulate cortex (PCC), ventromedial prefrontal cortex, and right anterior insula at baseline. High NPI scores predicted subsequent hypometabolism in the PCC over 2 years only in individuals with preclinical AD. Sleep/nighttime behavior disorders and irritability and lability were the components of the NPI that drove this metabolic dysfunction.Conclusions:The magnitude of NPS in preclinical cases, driven by sleep behavior and irritability domains, is linked to transitory metabolic dysfunctions within limbic networks vulnerable to the AD process and predicts subsequent PCC hypometabolism. These findings support an emerging conceptual framework in which NPS constitute an early clinical manifestation of AD pathophysiology.

scholarly journals Diuretics: A possible keystone in upholding cognitive health

2018 ◽  
Vol 8 (1) ◽  
pp. 33-40 ◽  
Author(s):  
Tyler DeLoach ◽  
Jennifer Beall
Keyword(s):  
Alzheimer Disease ◽  
Risk Reduction ◽  
Disease Risk ◽  
Neuroprotective Effect ◽  
Memory Loss ◽  
Antihypertensive Agents ◽  
Hazard Ratio ◽  
Inverse Association ◽  
Drug Classes ◽  
Incident Rate

Abstract Introduction: Dementia encompasses diseases of progressive memory loss and neurological alterations, including Alzheimer disease. Hypertension is one risk factor proposed for development of Alzheimer disease. The objective is to evaluate the current literature for use of diuretics in the prevention of dementia. Methods: Literature was not considered if published before January 1, 2000, or after May 31, 2015. PubMed was used to locate sources. Four search terms were used to find data: Alzheimer disease, antihypertensive agents, diuretics, and dementia. Results: Four studies of efficacy of diuretic usage in the prevention against dementia met criteria. Potassium-sparing diuretics displayed risk reduction of Alzheimer disease and maintenance of cognitive function. Risk reduction was demonstrated when used alone (adjusted hazard ratio [aHR] 0.09, 95% confidence interval [CI] 0.01-0.41) as compared to use of other antihypertensives without potassium-sparing diuretics (aHR 0.76, 95% CI 0.49-1.15). Other antihypertensive drug classes did show some benefit, however. Diuretic and angiotensin receptor blocker users had a lower Alzheimer disease risk versus those with no antihypertensive use (hazard ratio 0.40, 95% CI 0.26-0.61) and (hazard ratio 0.37, 95% CI 0.19-0.72), respectively. Additionally, thiazide diuretics were also shown to reduce Alzheimer risk. Thiazide and potassium-sparing combination significantly reduced risk versus non-antihypertensive users (aHR 0.63, 95% CI 0.42-0.94). Discussion: Available research demonstrates an inverse association between diuretic use and the incident rate of dementia. Specifically, this has been found with thiazide and potassium-sparing diuretics when used alone or in combination. This review suggests that patients receiving diuretics for hypertension may receive an added neuroprotective effect.

Understanding Schizophrenia: Genetic Causes and Treatment

2019 ◽  
Vol 1 (1) ◽  
pp. 6-12
Author(s):  
Fatima Javeria ◽  
Shazma Altaf ◽  
Alishah Zair ◽  
Rana Khalid Iqbal
Keyword(s):  
Copy Number ◽  
Drug Targets ◽  
Disease Risk ◽  
Mental Disease ◽  
Copy Number Variants ◽  
Aminobutyric Acid ◽  
Epigenetic Mechanisms ◽  
Gamma Aminobutyric Acid ◽  
Wide Range ◽  
Severe Mental Disease

Schizophrenia is a severe mental disease. The word schizophrenia literally means split mind. There are three major categories of symptoms which include positive, negative and cognitive symptoms. The disease is characterized by symptoms of hallucination, delusions, disorganized thinking and speech. Schizophrenia is related to many other mental and psychological problems like suicide, depression, hallucinations. Including these, it is also a problem for the patient’s family and the caregiver. There is no clear reason for the disease, but with the advances in molecular genetics; certain epigenetic mechanisms are involved in the pathophysiology of the disease. Epigenetic mechanisms that are mainly involved are the DNA methylation, copy number variants. With the advent of GWAS, a wide range of SNPs is found linked with the etiology of schizophrenia. These SNPs serve as ‘hubs’; because these all are integrating with each other in causing of schizophrenia risk. Until recently, there is no treatment available to cure the disease; but anti-psychotics can reduce the disease risk by minimizing its symptoms. Dopamine, serotonin, gamma-aminobutyric acid, are the neurotransmitters which serve as drug targets in the treatment of schizophrenia. Due to the involvement of genetic and epigenetic mechanisms, drugs available are already targeting certain genes involved in the etiology of the disease.

scholarly journals Cerebrospinal Fluid Hypocretin and Nightmares in Dementia Syndromes

2021 ◽  
pp. 19-25
Author(s):  
Lynn Marie Trotti ◽  
Donald L. Bliwise ◽  
Glenda L. Keating ◽  
David B. Rye ◽  
William T. Hu
Keyword(s):  
Cerebrospinal Fluid ◽  
Alzheimer Disease ◽  
Cholinesterase Inhibitor ◽  
Dementia With Lewy Bodies ◽  
Lewy Bodies ◽  
Cognitively Normal ◽  
Dementia Patients ◽  
Sleep Questionnaires ◽  
Sleep Alterations ◽  
Normal Controls

Background/Aims: Hypocretin promotes wakefulness and modulates REM sleep. Alterations in the hypocretin system are increasingly implicated in dementia. We evaluated relationships among hypocretin, dementia biomarkers, and sleep symptoms in elderly participants, most of whom had dementia. Methods: One-hundred twenty-six adults (mean age 66.2 ± 8.4 years) were recruited from the Emory Cognitive Clinic. Diagnoses were Alzheimer disease (AD; n = 60), frontotemporal dementia (FTD; n = 21), and dementia with Lewy bodies (DLB; n = 20). We also included cognitively normal controls (n = 25). Participants and/or caregivers completed sleep questionnaires and lumbar puncture was performed for cerebrospinal fluid (CSF) assessments. Results: Except for sleepiness (worst in DLB) and nocturia (worse in DLB and FTD) sleep symptoms did not differ by diagnosis. CSF hypocretin concentrations were available for 87 participants and normal in 70, intermediate in 16, and low in 1. Hypocretin levels did not differ by diagnosis. Hypocretin levels correlated with CSF total τ levels only in men (r = 0.34; p = 0.02). Lower hypocretin levels were related to frequency of nightmares (203.9 ± 29.8 pg/mL in those with frequent nightmares vs. 240.4 ± 46.1 pg/mL in those without; p = 0.05) and vivid dreams (209.1 ± 28.3 vs. 239.5 ± 47.8 pg/mL; p = 0.014). Cholinesterase inhibitor use was not associated with nightmares or vivid dreaming. Conclusion: Hypocretin levels did not distinguish between dementia syndromes. Disturbing dreams in dementia patients may be related to lower hypocretin concentrations in CSF.

scholarly journals Long-Term Caloric Restriction Attenuates β-Amyloid Neuropathology and Is Accompanied by Autophagy in APPswe/PS1delta9 Mice

Nutrients ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 985
Author(s):  
Luisa Müller ◽  
Nicole Power Guerra ◽  
Jan Stenzel ◽  
Claire Rühlmann ◽  
Tobias Lindner ◽  
...  
Keyword(s):  
Caloric Restriction ◽  
Neuroprotective Effect ◽  
Resonance Spectroscopy ◽  
Neuroprotective Effects ◽  
Beneficial Effects ◽  
Positron Emission ◽  
Pet Ct ◽  
Amyloid Aβ ◽  
Β Amyloid

Caloric restriction (CR) slows the aging process, extends lifespan, and exerts neuroprotective effects. It is widely accepted that CR attenuates β-amyloid (Aβ) neuropathology in models of Alzheimer’s disease (AD) by so-far unknown mechanisms. One promising process induced by CR is autophagy, which is known to degrade aggregated proteins such as amyloids. In addition, autophagy positively regulates glucose uptake and may improve cerebral hypometabolism—a hallmark of AD—and, consequently, neural activity. To evaluate this hypothesis, APPswe/PS1delta9 (tg) mice and their littermates (wild-type, wt) underwent CR for either 16 or 68 weeks. Whereas short-term CR for 16 weeks revealed no noteworthy changes of AD phenotype in tg mice, long-term CR for 68 weeks showed beneficial effects. Thus, cerebral glucose metabolism and neuronal integrity were markedly increased upon 68 weeks CR in tg mice, indicated by an elevated hippocampal fluorodeoxyglucose [18F] ([18F]FDG) uptake and increased N-acetylaspartate-to-creatine ratio using positron emission tomography/computer tomography (PET/CT) imaging and magnet resonance spectroscopy (MRS). Improved neuronal activity and integrity resulted in a better cognitive performance within the Morris Water Maze. Moreover, CR for 68 weeks caused a significant increase of LC3BII and p62 protein expression, showing enhanced autophagy. Additionally, a significant decrease of Aβ plaques in tg mice in the hippocampus was observed, accompanied by reduced microgliosis as indicated by significantly decreased numbers of iba1-positive cells. In summary, long-term CR revealed an overall neuroprotective effect in tg mice. Further, this study shows, for the first time, that CR-induced autophagy in tg mice accompanies the observed attenuation of Aβ pathology.

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