scholarly journals Benfotiamine and Cognitive Decline in Alzheimer’s Disease: Results of a Randomized Placebo-Controlled Phase IIa Clinical Trial

2020 ◽  
Vol 78 (3) ◽  
pp. 989-1010
Author(s):  
Gary E. Gibson ◽  
José A. Luchsinger ◽  
Rosanna Cirio ◽  
Huanlian Chen ◽  
Jessica Franchino-Elder ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Placebo Group ◽  
Cognitive Decline ◽  
Controlled Trial ◽  
Amyloid Β ◽  
Cognitive Outcomes ◽  
Disease Assessment ◽  
Clinical Dementia Rating ◽  
Positron Emission

Background: In preclinical models, benfotiamine efficiently ameliorates the clinical and biological pathologies that define Alzheimer’s disease (AD) including impaired cognition, amyloid-β plaques, neurofibrillary tangles, diminished glucose metabolism, oxidative stress, increased advanced glycation end products (AGE), and inflammation. Objective: To collect preliminary data on feasibility, safety, and efficacy in individuals with amnestic mild cognitive impairment (aMCI) or mild dementia due to AD in a placebo-controlled trial of benfotiamine. Methods: A twelve-month treatment with benfotiamine tested whether clinical decline would be delayed in the benfotiamine group compared to the placebo group. The primary clinical outcome was the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog). Secondary outcomes were the clinical dementia rating (CDR) score and fluorodeoxyglucose (FDG) uptake, measured with brain positron emission tomography (PET). Blood AGE were examined as an exploratory outcome. Results: Participants were treated with benfotiamine (34) or placebo (36). Benfotiamine treatment was safe. The increase in ADAS-Cog was 43% lower in the benfotiamine group than in the placebo group, indicating less cognitive decline, and this effect was nearly statistically significant (p = 0.125). Worsening in CDR was 77% lower (p = 0.034) in the benfotiamine group compared to the placebo group, and this effect was stronger in the APOE ɛ4 non-carriers. Benfotiamine significantly reduced increases in AGE (p = 0.044), and this effect was stronger in the APOE ɛ4 non-carriers. Exploratory analysis derivation of an FDG PET pattern score showed a treatment effect at one year (p = 0.002). Conclusion: Oral benfotiamine is safe and potentially efficacious in improving cognitive outcomes among persons with MCI and mild AD.

scholarly journals Neurophysiological signatures in Alzheimer’s disease are distinctly associated with TAU, amyloid-β accumulation, and cognitive decline

2020 ◽  
Vol 12 (534) ◽  
pp. eaaz4069 ◽  
Author(s):  
Kamalini G. Ranasinghe ◽  
Jungho Cha ◽  
Leonardo Iaccarino ◽  
Leighton B. Hinkley ◽  
Alexander J. Beagle ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Amyloid Β ◽  
Tracer Uptake ◽  
Therapeutic Approaches ◽  
Regional Patterns ◽  
Positron Emission ◽  
Network Synchrony ◽  
Network Disruptions

Neural synchrony is intricately balanced in the normal resting brain but becomes altered in Alzheimer’s disease (AD). To determine the neurophysiological manifestations associated with molecular biomarkers of AD neuropathology, in patients with AD, we used magnetoencephalographic imaging (MEGI) and positron emission tomography with amyloid-beta (Aβ) and TAU tracers. We found that alpha oscillations (8 to 12 Hz) were hyposynchronous in occipital and posterior temporoparietal cortices, whereas delta-theta oscillations (2 to 8 Hz) were hypersynchronous in frontal and anterior temporoparietal cortices, in patients with AD compared to age-matched controls. Regional patterns of alpha hyposynchrony were unique in each neurobehavioral phenotype of AD, whereas the regional patterns of delta-theta hypersynchrony were similar across the phenotypes. Alpha hyposynchrony strongly colocalized with TAU deposition and was modulated by the degree of TAU tracer uptake. In contrast, delta-theta hypersynchrony colocalized with both TAU and Aβ depositions and was modulated by both TAU and Aβ tracer uptake. Furthermore, alpha hyposynchrony but not delta-theta hypersynchrony was correlated with the degree of global cognitive dysfunction in patients with AD. The current study demonstrates frequency-specific neurophysiological signatures of AD pathophysiology and suggests that neurophysiological measures from MEGI are sensitive indices of network disruptions mediated by TAU and Aβ and associated cognitive decline. These findings facilitate the pursuit of novel therapeutic approaches toward normalizing network synchrony in AD.

scholarly journals The Temporal Relationships between White Matter Hyperintensities, Neurodegeneration, Amyloid β, and Cognition

2020 ◽  
Author(s):  
Mahsa Dadar ◽  
Richard Camicioli ◽  
Simon Duchesne ◽  
D. Louis Collins ◽  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
White Matter ◽  
Cognitive Decline ◽  
White Matter Hyperintensities ◽  
Amyloid Β ◽  
Disease Assessment ◽  
White Matter Hyperintensity ◽  
List Type ◽  
Temporal Relationships

ABSTRACTINTRODUCTIONCognitive decline in Alzheimer’s disease is associated with amyloid-β accumulation, neurodegeneration and cerebral small vessel disease, but the temporal relationships between these factors is not well established.METHODSData included white matter hyperintensity (WMH) load, grey matter (GM) atrophy and Alzheimer’s Disease Assessment Scale-Cognitive-Plus (ADAS13) scores for 720 participants and cerebrospinal fluid amyloid (Aβ1-42) for 461 participants from the Alzheimer’s Disease Neuroimaging Initiative. Linear regressions were used to assess the relationships between baseline WMH, GM, and Aβ1-42 to changes in WMH, GM, Aβ1-42, and cognition at one-year follow-up.RESULTSBaseline WMHs and Aβ1-42 predicted WMH increase and GM atrophy. Baseline WMHs, GM, and Aβ1-42 predicted worsening cognition. Only baseline Aβ1-42 predicted change in Aβ1-42.DISCUSSIONBaseline WMHs lead to greater future GM atrophy and cognitive decline, suggesting that WM damage precedes neurodegeneration and cognitive decline. Baseline Aβ1-42 predicted WMH increase, suggesting a potential role of amyloid in WM damage.Research in ContextSystematic Review: Both amyloid β and neurodegeneration are primary pathologies in Alzheimer’s disease. White matter hyperintensities (indicative of presence of cerebrovascular disease) might also be part of the pathological changes in Alzheimer’s. However, the temporal relationship between white matter hyperintensities, amyloid β, neurodegeneration, and cognitive decline is still unclear.Interpretation: Our results establish a potential temporal order between white matter hyperintensities, amyloid β, neurodegeneration, and cognitive decline, showing that white matter hyperintensities precede neurodegeneration and cognitive decline. The results provide some evidence that amyloid β deposition, in turn, precedes accumulation of white matter hyperintensities.Future Directions: The current findings reinforce the need for future longitudinal investigations of the mechanisms through which white matter hyperintensities impact the aging population in general and Alzheimer’s disease patients, in particular.

scholarly journals Characterization of Alzheimer’s tau biomarker discordance using plasma, CSF, and PET

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Yu Guo ◽  
◽  
Yu-Yuan Huang ◽  
Xue-Ning Shen ◽  
Shi-Dong Chen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Amyloid Β ◽  
Regions Of Interest ◽  
Emission Tomography ◽  
Braak Stage ◽  
Positron Emission ◽  
Tau Pet

Abstract Background We aimed to investigate the tau biomarker discrepancies of Alzheimer’s disease (AD) using plasma tau phosphorylated at threonine 181 (p-tau181), cerebrospinal fluid (CSF) p-tau181, and AV1451 positron emission tomography (PET). Methods In the Alzheimer’s Disease Neuroimaging Initiative, 724 non-demented participants were categorized into plasma/CSF and plasma/PET groups. Demographic and clinical variables, amyloid-β (Aβ) burden, flortaucipir-PET binding in Braak regions of interest (ROIs), longitudinal changes in clinical outcomes, and conversion risk were compared. Results Across different tau biomarker groups, the proportion of participants with a discordant profile varied (plasma+/CSF− 15.6%, plasma−/CSF+ 15.3%, plasma+/PET− 22.4%, and plasma−/PET+ 6.1%). Within the plasma/CSF categories, we found an increase from concordant-negative to discordant to concordant-positive in the frequency of Aβ pathology or cognitive impairment, rates of cognitive decline, and risk of cognitive conversion. However, the two discordant categories (plasma+/CSF− and plasma−/CSF+) showed comparable performances, resulting in similarly reduced cognitive capacities. Regarding plasma/PET categories, as expected, PET-positive individuals had increased Aβ burden, elevated flortaucipir retention in Braak ROIs, and accelerated cognitive deterioration than concordant-negative persons. Noteworthy, discordant participants with normal PET exhibited reduced flortaucipir uptake in Braak stage ROIs and slower rates of cognitive decline, relative to those PET-positive. Therefore, individuals with PET abnormality appeared to have advanced tau pathological changes and poorer cognitive function, regardless of the plasma status. Furthermore, these results were found only in individuals with Aβ pathology. Conclusions Our results indicate that plasma and CSF p-tau181 abnormalities associated with amyloidosis occur simultaneously in the progression of AD pathogenesis and related cognitive decline, before tau-PET turns positive.

Insomnia Moderates the Relationship Between Amyloid-β and Cognitive Decline in Late-Life Adults without Dementia

2021 ◽  
pp. 1-10
Author(s):  
Wei Xu ◽  
Chen-Chen Tan ◽  
Juan-Juan Zou ◽  
Xi-Peng Cao ◽  
Lan Tan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Amyloid Β ◽  
Cognitive Disorders ◽  
Linear Mixed Effects ◽  
Positron Emission ◽  
Prodromal Ad ◽  
Neuropsychological Evaluations ◽  
The Relationship

Background: It is suggested that not all individuals with elevated Aβ will develop dementia or cognitive impairment. Environment or lifestyle might modulate the association of amyloid pathology with cognition. Insomnia is a risk factor of cognitive disorders including Alzheimer’s disease. Objective: To investigate if insomnia moderated the relationship between amyloid-β (Aβ) and longitudinal cognitive performance in non-demented elders. Methods: A total of 385 Alzheimer’s Disease Neuroimaging Initiative participants (mean age = 73 years, 48% females) who completed 4 + neuropsychological evaluations and a [18F] florbetapir positron emission tomography scan were followed up to 8 years. Linear mixed-effects regression models were used to examine the interactions effect between insomnia and Aβ on longitudinal cognitive sores, including four domains (memory [MEM], executive function [EF], language [LAN], and visuospatial function [VS]). Results: The Aβ-positive status (A+) but not insomnia independently predicted faster cognitive decline in all domains. Furthermore, the relationship between Aβ and cognitive decline was moderated by insomnia (MEM: χ 2 = 4.05, p = 0.044, EF: χ 2 = 4.38, p = 0.036, LAN: χ 2 = 4.56, p = 0.033, and VS: χ 2 = 4.12, p = 0.042). Individuals with both elevated Aβ and insomnia experienced faster cognitive decline than those with only elevated Aβ or insomnia. Conclusion: These data reinforced the values of insomnia management in preventing dementia, possibly by interacting Aβ metabolism. Future efforts are warranted to determine whether sleep improvement will postpone the onset of dementia, specifically among populations in stages of preclinical or prodromal AD.

Season of Birth and Vulnerability to the Pathology of Alzheimer’s Disease: an in Vivo Positron Emission Tomography Study

2021 ◽  
Author(s):  
Fumihiko Yasuno ◽  
Hiroyuki Minami
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Positron Emission Tomography ◽  
Amyloid Β ◽  
Standardized Uptake Value ◽  
Analysis Of Covariance ◽  
Emission Tomography ◽  
Disease Assessment ◽  
Positron Emission

Abstract This study used positron emission tomography to examine whether the seasonal birth effect as an exogenic indicator of early life environmental factors influenced vulnerability to Alzheimer’s disease (AD) pathology in the elderly. We analyzed datasets from the Alzheimer’s Disease Neuroimaging Initiative, which included the data for 234 cognitively normal individuals and patients with mild cognitive impairment (n = 115) and AD dementia (n = 38). As an index of amyloid β (Aβ)/tau accumulation, the AV-45/AV-1451-standardized uptake value ratios (SUVRs) were compared between groups of spring-to-summer births and fall-to-winter births by analysis of covariance. Seasonal birth difference was a good predictor of AV-1451 SUVR. We found that participants with a fall-to-winter birth showed lower AV-1451 SUVRs than those with a spring-to-summer birth, after accounting for the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS) score and other factors that could possibly affect tau accumulation. Our findings showed a vulnerability to tau pathology in participants with a fall-to-winter birth, which may be caused by perinatal or postnatal brain damage due to the risk factors associated with the cold season.

scholarly journals Orthostatic Blood Pressure Recovery Is Associated With the Rate of Cognitive Decline and Mortality in Clinical Alzheimer’s Disease

2020 ◽  
Vol 75 (11) ◽  
pp. 2169-2176
Author(s):  
Rianne A A de Heus ◽  
Daan L K de Jong ◽  
Anne Rijpma ◽  
Brian A Lawlor ◽  
Marcel G M Olde Rikkert ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Blood Pressure ◽  
Alzheimer's Disease ◽  
Confidence Interval ◽  
Cognitive Decline ◽  
Controlled Trial ◽  
Intervention Group ◽  
Disease Assessment ◽  
Progression Rate ◽  
Initial Drop

Abstract Background Impaired recovery of blood pressure (BP) after standing has been shown to be related to cognitive function and mortality in people without dementia, but its role in people with Alzheimer’s disease (AD) is unknown. The aim of this study was to investigate the association of the orthostatic BP response with cognitive decline and mortality in AD. Methods In this post hoc analysis of a randomized controlled trial (Nilvad), we measured the beat-to-beat response of BP upon active standing in mild-to-moderate AD. This included the initial drop (nadir within 40 seconds) and recovery after 1 minute, both expressed relative to resting values. We examined the relationship between a small or large initial drop (median split) and unimpaired (≥100%) or impaired recovery (<100%) with 1.5-year change in Alzheimer’s Disease Assessment—cognitive subscale (ADAS-cog) scores and all-cause mortality. Results We included 55 participants (age 73.1 ± 6.2 years). Impaired BP recovery was associated with higher increases in ADAS-cog scores (systolic: β [95% confidence interval] = 5.6 [0.4–10.8], p = .035; diastolic: 7.6 [2.3–13.0], p = .006). During a median follow-up time of 49 months, 20 participants died. Impaired BP recovery was associated with increased mortality (systolic: HR [95% confidence interval] = 2.9 [1.1–7.8], p = .039; diastolic: HR [95% confidence interval] = 5.5 [1.9–16.1], p = .002). The initial BP drop was not associated with any outcome. Results were adjusted for age, sex, and intervention group. Conclusions Failure to fully recover BP after 1 minute of standing is associated with cognitive decline and mortality in AD. As such, BP recovery can be regarded as an easily obtained marker of progression rate of AD.

Attenuation in the Progression of Cognitive Deterioration in Alzheimer's Disease With Rivastigmine: A Dose-Dependent Effect

CNS Spectrums ◽  
2000 ◽  
Vol 5 (6) ◽  
pp. 21-22 ◽  
Author(s):  
Martin Farlow ◽  
John Messina ◽  
Ravi Anand ◽  
Richard Hartman ◽  
Jeffrey Veach
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Controlled Trial ◽  
Weighted Least Squares ◽  
Disease Assessment ◽  
Cognitive Deterioration ◽  
Attrition Rates ◽  
Cognitive Subscale ◽  
Rate Of Decline

AbstractObjectives: Possible disease-modifying effects of rivastigmine have been suggested by analyses using a variation of the randomized start design; however, the results were somewhat confounded by differing attrition rates. We report on an alternative method investigating whether increasing doses reduce the rates of cognitive decline in patients who continue treatment.Methods: The effect of dose on the rate of cognitive decline seen on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) was explored for patients in a long-term (130-week) extension of a 26-week placebo-controlled trial using two methods: a weighted leas squares regression analysis using each individual's slope, and a weighted analysis of variance (ANOVA) comparing the slopes of patients categorized by dose (≤6 mg/d or >6 mg/d).Results: The results from 408 patients included in the weighted least squares analysis estimated the rate of decline to attenuate by approximately 1 point/y for every 3 mg/d increase (P<.0001). The average annual rate of decline for patients whose mean dose was >6 mg/d was 4.5 points (95% Cl, 5.1–3.9), while for patients with a mean dose of≥6 mg/d a decline of 8.2 points (95% Cl, 9.1–7.3) was seen.Conclusion: These data further support earlier results suggesting that rivastigmine reduces the rate of progression of cognitive deterioration in Alzheimer's disease.

Pharmacogenetics of Angiotensin-Converting Enzyme Inhibitors in Patients with Alzheimer's Disease Dementia

2018 ◽  
Vol 15 (4) ◽  
pp. 386-398 ◽  
Author(s):  
Fabricio Ferreira de Oliveira ◽  
Elizabeth Suchi Chen ◽  
Marilia Cardoso Smith ◽  
Paulo Henrique Ferreira Bertolucci
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Angiotensin Converting Enzyme ◽  
Cognitive Decline ◽  
Enzyme Inhibitors ◽  
Late Onset ◽  
Amyloid Β ◽  
Converting Enzyme ◽  
Converting Enzyme Inhibitors ◽  
Alzheimer’S Disease Dementia

Background: While the angiotensin-converting enzyme degrades amyloid-β, angiotensinconverting enzyme inhibitors (ACEis) may slow cognitive decline by way of cholinergic effects, by increasing brain substance P and boosting the activity of neprilysin, and by modulating glucose homeostasis and augmenting the secretion of adipokines to enhance insulin sensitivity in patients with Alzheimer’s disease dementia (AD). We aimed to investigate whether ACE gene polymorphisms rs1800764 and rs4291 are associated with cognitive and functional change in patients with AD, while also taking APOE haplotypes and anti-hypertensive treatment with ACEis into account for stratification. Methods: Consecutive late-onset AD patients were screened with cognitive tests, while their caregivers were queried for functional and caregiver burden scores. Prospective pharmacogenetic correlations were estimated for one year, considering APOE and ACE genotypes and haplotypes, and treatment with ACEis. Results: For 193 patients, minor allele frequencies were 0.497 for rs1800764 – C (44.6% heterozygotes) and 0.345 for rs4291 – T (38.9% heterozygotes), both in Hardy-Weinberg equilibrium. Almost 94% of all patients used cholinesterase inhibitors, while 155 (80.3%) had arterial hypertension, and 124 used ACEis. No functional impacts were found regarding any genotypes or pharmacological treatment. Either for carriers of ACE haplotypes that included rs1800764 – T and rs4291 – A, or for APOE4- carriers of rs1800764 – T or rs4291 – T, ACEis slowed cognitive decline independently of blood pressure variations. APOE4+ carriers were not responsive to treatment with ACEis. Conclusion: ACEis may slow cognitive decline for patients with AD, more remarkably for APOE4- carriers of specific ACE genotypes.

scholarly journals 24(S)-Saringosterol Prevents Cognitive Decline in a Mouse Model for Alzheimer’s Disease

Marine Drugs ◽  
2021 ◽  
Vol 19 (4) ◽  
pp. 190
Author(s):  
Nikita Martens ◽  
Melissa Schepers ◽  
Na Zhan ◽  
Frank Leijten ◽  
Gardi Voortman ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Cognitive Decline ◽  
Inflammatory Marker ◽  
Amyloid Β ◽  
Liver Fat ◽  
Gas Chromatography Mass Spectrometry ◽  
Memory Decline ◽  
Plaque Load

We recently found that dietary supplementation with the seaweed Sargassum fusiforme, containing the preferential LXRβ-agonist 24(S)-saringosterol, prevented memory decline and reduced amyloid-β (Aβ) deposition in an Alzheimer’s disease (AD) mouse model without inducing hepatic steatosis. Here, we examined the effects of 24(S)-saringosterol as a food additive on cognition and neuropathology in AD mice. Six-month-old male APPswePS1ΔE9 mice and wildtype C57BL/6J littermates received 24(S)-saringosterol (0.5 mg/25 g body weight/day) (APPswePS1ΔE9 n = 20; C57BL/6J n = 19) or vehicle (APPswePS1ΔE9 n = 17; C57BL/6J n = 19) for 10 weeks. Cognition was assessed using object recognition and object location tasks. Sterols were analyzed by gas chromatography/mass spectrometry, Aβ and inflammatory markers by immunohistochemistry, and gene expression by quantitative real-time PCR. Hepatic lipids were quantified after Oil-Red-O staining. Administration of 24(S)-saringosterol prevented cognitive decline in APPswePS1ΔE9 mice without affecting the Aβ plaque load. Moreover, 24(S)-saringosterol prevented the increase in the inflammatory marker Iba1 in the cortex of APPswePS1ΔE9 mice (p < 0.001). Furthermore, 24(S)-saringosterol did not affect the expression of lipid metabolism-related LXR-response genes in the hippocampus nor the hepatic neutral lipid content. Thus, administration of 24(S)-saringosterol prevented cognitive decline in APPswePS1ΔE9 mice independent of effects on Aβ load and without adverse effects on liver fat content. The anti-inflammatory effects of 24(S)-saringosterol may contribute to the prevention of cognitive decline.

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