Association of Higher Cortical #Amyloid Burden With #Loneliness in Cognitively Normal Older Adults
https://lnkd.in/evsmSHU
Conclusions and Relevance We report a novel association of loneliness with cortical amyloid burden in cognitively normal older adults, suggesting that loneliness is a neuropsychiatric symptom relevant to preclinical AD. This work will inform new research into the neural underpinnings and disease mechanisms involved in loneliness and may enhance early detection and intervention research in AD.
https://lnkd.in/evsmSHU
Conclusions and Relevance We report a novel association of loneliness with cortical amyloid burden in cognitively normal older adults, suggesting that loneliness is a neuropsychiatric symptom relevant to preclinical AD. This work will inform new research into the neural underpinnings and disease mechanisms involved in loneliness and may enhance early detection and intervention research in AD.
Jamanetwork
Higher Cortical Amyloid Burden and Loneliness in Older Adults
This cross-sectional study examines the association between higher cortical amyloid burden and loneliness in cognitively normal older adults.
Aβ #Amyloid Pathology Affects the #Hearts of Patients With Alzheimer’s Disease: Mind the Heart
http://content.onlinejacc.org/article.aspx?articleID=2588661
Here, the authors provide the first report of the presence of compromised myocardial function and intramyocardial deposits of Aβ in AD patients. The findings depict a novel biological framework in which AD may be viewed either as a systemic disease or as a metastatic disorder leading to heart, and possibly multiorgan failure. AD and HF are both debilitating and life-threatening conditions, affecting enormous patient populations. Our findings underline a previously dismissed problem of a magnitude that will require new diagnostic approaches and treatments for brain and heart disease, and their combination.
http://content.onlinejacc.org/article.aspx?articleID=2588661
Here, the authors provide the first report of the presence of compromised myocardial function and intramyocardial deposits of Aβ in AD patients. The findings depict a novel biological framework in which AD may be viewed either as a systemic disease or as a metastatic disorder leading to heart, and possibly multiorgan failure. AD and HF are both debilitating and life-threatening conditions, affecting enormous patient populations. Our findings underline a previously dismissed problem of a magnitude that will require new diagnostic approaches and treatments for brain and heart disease, and their combination.
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Prevalence and Outcomes of #Amyloid Positivity Among Persons Without #Dementia in a Longitudinal, Population-Based Setting
https://jamanetwork.com/journals/jamaneurology/article-abstract/2679318?redirect=true
The incident aMCI risk increased more than 2-fold in participants without cognitive impairment who were amyloid positive vs those who were amyloid negative (hazard ratio HR, 2.26; 95% CI, 1.52 to 3.35; P < .001). The risk of AD dementia was 1.86 (95% CI, 0.89 to 3.88; P = .10) for amyloid-positive participants with MCI vs amyloid-negative participants with MCI, 1.63 (95% CI, 0.78 to 3.41; P = .20) for participants with aMCI who were amyloid positive vs amyloid negative, and 2.56 (95% CI, 1.35 to 4.88; P = .004) for amyloid-positive participants who were either without cognitive impairment or had aMCI vs those who were amyloid negative. Global cognitive and memory domain z scores declined significantly in amyloid-positive individuals during follow-up. The mean (SD) follow-up time from baseline was 3.7 (1.9) years to incident aMCI and 3.8 (2.0) years to incident AD dementia.
Conclusions and Relevance Population-based prevalence of amyloid-positive status and progression rates of amyloid positivity provide valid information for designing AD prevention trials and assessing the public health outcomes of AD prevention and interventions.
Prevalence and Outcomes of #Amyloid Positivity Among Persons Without #Dementia in a Longitudinal, Population-Based Setting
https://jamanetwork.com/journals/jamaneurology/article-abstract/2679318?redirect=true
The incident aMCI risk increased more than 2-fold in participants without cognitive impairment who were amyloid positive vs those who were amyloid negative (hazard ratio HR, 2.26; 95% CI, 1.52 to 3.35; P < .001). The risk of AD dementia was 1.86 (95% CI, 0.89 to 3.88; P = .10) for amyloid-positive participants with MCI vs amyloid-negative participants with MCI, 1.63 (95% CI, 0.78 to 3.41; P = .20) for participants with aMCI who were amyloid positive vs amyloid negative, and 2.56 (95% CI, 1.35 to 4.88; P = .004) for amyloid-positive participants who were either without cognitive impairment or had aMCI vs those who were amyloid negative. Global cognitive and memory domain z scores declined significantly in amyloid-positive individuals during follow-up. The mean (SD) follow-up time from baseline was 3.7 (1.9) years to incident aMCI and 3.8 (2.0) years to incident AD dementia.
Conclusions and Relevance Population-based prevalence of amyloid-positive status and progression rates of amyloid positivity provide valid information for designing AD prevention trials and assessing the public health outcomes of AD prevention and interventions.
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#Amyloid-β (1-40) and Mortality in Patients With Non–ST-Segment Elevation Acute #Coronary Syndrome: A Cohort Study
http://annals.org/aim/article-abstract/2681795/amyloid-1-40-mortality-patients-non-st-segment-elevation-acute
Amyloid-β (1-40) was associated with mortality after multivariate adjustment for age, sex, diabetes mellitus, high-sensitivity cardiac troponin T and C-reactive protein, revascularization, and ACS type (Heidelberg cohort hazard ratio HR for 80th vs. 20th percentiles, 1.66 95% CI, 1.06 to 2.61; P = 0.026; APACE cohort HR, 1.50 CI, 1.15 to 1.96; P = 0.003). It was also associated with mortality after adjustment for the GRACE score (Heidelberg cohort HR for 80th vs. 20th percentiles, 1.11 CI, 1.04 to 1.18; P = 0.001; APACE cohort HR, 1.39 CI, 1.02 to 1.88; P = 0.036). Amyloid-β (1-40) correctly reclassified risk for death over the GRACE score (net reclassification index, 33.4% and 47.1% for the Heidelberg and APACE cohorts, respectively) (P < 0.05)
Circulating Aβ40 is a predictor of mortality and improves risk stratification of patients with NSTE-ACS over the GRACE score recommended by clinical guidelines. The clinical application of Aβ40 as a novel biomarker in NSTE-ACS should be further explored and validated
#Amyloid-β (1-40) and Mortality in Patients With Non–ST-Segment Elevation Acute #Coronary Syndrome: A Cohort Study
http://annals.org/aim/article-abstract/2681795/amyloid-1-40-mortality-patients-non-st-segment-elevation-acute
Amyloid-β (1-40) was associated with mortality after multivariate adjustment for age, sex, diabetes mellitus, high-sensitivity cardiac troponin T and C-reactive protein, revascularization, and ACS type (Heidelberg cohort hazard ratio HR for 80th vs. 20th percentiles, 1.66 95% CI, 1.06 to 2.61; P = 0.026; APACE cohort HR, 1.50 CI, 1.15 to 1.96; P = 0.003). It was also associated with mortality after adjustment for the GRACE score (Heidelberg cohort HR for 80th vs. 20th percentiles, 1.11 CI, 1.04 to 1.18; P = 0.001; APACE cohort HR, 1.39 CI, 1.02 to 1.88; P = 0.036). Amyloid-β (1-40) correctly reclassified risk for death over the GRACE score (net reclassification index, 33.4% and 47.1% for the Heidelberg and APACE cohorts, respectively) (P < 0.05)
Circulating Aβ40 is a predictor of mortality and improves risk stratification of patients with NSTE-ACS over the GRACE score recommended by clinical guidelines. The clinical application of Aβ40 as a novel biomarker in NSTE-ACS should be further explored and validated
Small molecule inhibits α- #synuclein aggregation, disrupts #amyloid fibrils, and prevents degeneration of dopaminergic neurons
http://www.pnas.org/content/early/2018/09/18/1804198115
Here, we exploited a high-throughput screening methodology to identify a small molecule (SynuClean-D) able to inhibit α-synuclein aggregation. SynuClean-D significantly reduces the in vitro aggregation of wild-type α-synuclein and the familiar A30P and H50Q variants in a substoichiometric molar ratio.
This compound prevents fibril propagation in protein-misfolding cyclic amplification assays and decreases the number of α-synuclein inclusions in human neuroglioma cells. Computational analysis suggests that SynuClean-D can bind to cavities in mature α-synuclein fibrils and, indeed, it displays a strong fibril disaggregation activity.
The treatment with SynuClean-D of two PD Caenorhabditis elegans models, expressing α-synuclein either in muscle or in dopaminergic neurons, significantly reduces the toxicity exerted by α-synuclein. SynuClean-D–treated worms show decreased α-synuclein aggregation in muscle and a concomitant motility recovery.
More importantly, this compound is able to rescue dopaminergic neurons from α-synuclein–induced degeneration. Overall, SynuClean-D appears to be a promising molecule for therapeutic intervention in Parkinson’s disease.
http://www.pnas.org/content/early/2018/09/18/1804198115
Here, we exploited a high-throughput screening methodology to identify a small molecule (SynuClean-D) able to inhibit α-synuclein aggregation. SynuClean-D significantly reduces the in vitro aggregation of wild-type α-synuclein and the familiar A30P and H50Q variants in a substoichiometric molar ratio.
This compound prevents fibril propagation in protein-misfolding cyclic amplification assays and decreases the number of α-synuclein inclusions in human neuroglioma cells. Computational analysis suggests that SynuClean-D can bind to cavities in mature α-synuclein fibrils and, indeed, it displays a strong fibril disaggregation activity.
The treatment with SynuClean-D of two PD Caenorhabditis elegans models, expressing α-synuclein either in muscle or in dopaminergic neurons, significantly reduces the toxicity exerted by α-synuclein. SynuClean-D–treated worms show decreased α-synuclein aggregation in muscle and a concomitant motility recovery.
More importantly, this compound is able to rescue dopaminergic neurons from α-synuclein–induced degeneration. Overall, SynuClean-D appears to be a promising molecule for therapeutic intervention in Parkinson’s disease.
PNAS
Small molecule inhibits α-synuclein aggregation, disrupts amyloid fibrils, and prevents degeneration of dopaminergic neurons
Parkinson’s disease is characterized by the accumulation of amyloid deposits in dopaminergic neurons, mainly composed of the protein α-synuclein. The disordered nature of α-synuclein and its complex aggregation reaction complicate the identification of molecules…
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Mediterranean #diet adherence and rate of cerebral Aβ- #amyloid accumulation: Data from the Australian Imaging, Biomarkers and Lifestyle Study of Ageing
https://www.nature.com/articles/s41398-018-0293-5
The relationship between MeDi adherence, MeDi components, and change in cerebral Aβ load (baseline to 36 months) was evaluated using Generalised Linear Modelling, accounting for age, gender, education, Apolipoprotein E ε4 allele status, body mass index and total energy intake. Higher MeDi score was associated with less Aβ accumulation in our cohort (β = −0.01 ± 0.004, p = 0.0070). Of the individual MeDi score components, a high intake of fruit was associated with less accumulation of Aβ (β = −0.04 ± 0.01, p = 0.00036).
Our results suggest MeDi adherence is associated with reduced cerebral AD pathology accumulation over time. When our results are considered collectively with previous data linking the MeDi to slower cognitive decline, it is apparent that MeDi adherence warrants further investigation in the quest to delay AD onset.
Mediterranean #diet adherence and rate of cerebral Aβ- #amyloid accumulation: Data from the Australian Imaging, Biomarkers and Lifestyle Study of Ageing
https://www.nature.com/articles/s41398-018-0293-5
The relationship between MeDi adherence, MeDi components, and change in cerebral Aβ load (baseline to 36 months) was evaluated using Generalised Linear Modelling, accounting for age, gender, education, Apolipoprotein E ε4 allele status, body mass index and total energy intake. Higher MeDi score was associated with less Aβ accumulation in our cohort (β = −0.01 ± 0.004, p = 0.0070). Of the individual MeDi score components, a high intake of fruit was associated with less accumulation of Aβ (β = −0.04 ± 0.01, p = 0.00036).
Our results suggest MeDi adherence is associated with reduced cerebral AD pathology accumulation over time. When our results are considered collectively with previous data linking the MeDi to slower cognitive decline, it is apparent that MeDi adherence warrants further investigation in the quest to delay AD onset.
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Microglia and #amyloid precursor protein coordinate control of transient #candida cerebritis with memory deficits
https://www.nature.com/articles/s41467-018-07991-4#ref-CR4
Bloodborne infections with Candida albicans are an increasingly recognized complication of modern medicine. Here, we present a mouse model of low-grade candidemia to determine the effect of disseminated infection on cerebral function and relevant immune determinants.
We show that intravenous injection of 25,000 C. albicans cells causes a highly localized cerebritis marked by the accumulation of activated microglial and astroglial cells around yeast aggregates, forming fungal-induced glial granulomas. Amyloid precursor protein accumulates within the periphery of these granulomas, while cleaved amyloid beta (Aβ) peptides accumulate around the yeast cells..
Mice infected with C. albicans display mild memory impairment that resolves with fungal clearance. Our results warrant additional studies to understand the effect of chronic cerebritis on cognitive and immune function
Microglia and #amyloid precursor protein coordinate control of transient #candida cerebritis with memory deficits
https://www.nature.com/articles/s41467-018-07991-4#ref-CR4
Bloodborne infections with Candida albicans are an increasingly recognized complication of modern medicine. Here, we present a mouse model of low-grade candidemia to determine the effect of disseminated infection on cerebral function and relevant immune determinants.
We show that intravenous injection of 25,000 C. albicans cells causes a highly localized cerebritis marked by the accumulation of activated microglial and astroglial cells around yeast aggregates, forming fungal-induced glial granulomas. Amyloid precursor protein accumulates within the periphery of these granulomas, while cleaved amyloid beta (Aβ) peptides accumulate around the yeast cells..
Mice infected with C. albicans display mild memory impairment that resolves with fungal clearance. Our results warrant additional studies to understand the effect of chronic cerebritis on cognitive and immune function
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Association of #Amyloid Positron Emission Tomography With Subsequent Change in Clinical Management Among Medicare Beneficiaries With Mild Cognitive Impairment or Dementia
https://jamanetwork.com/journals/jama/article-abstract/2729371
Amyloid #PET results were positive in 3817 patients with MCI (55.3%) and 3154 patients with dementia (70.1%). The composite end point changed in 4159 of 6905 patients with MCI (60.2% 95% CI, 59.1%-61.4%) and 2859 of 4504 patients with dementia (63.5% 95% CI, 62.1%-64.9%), significantly exceeding the 30% threshold in each group (P < .001, 1-sided). The etiologic diagnosis changed from Alzheimer disease to non–Alzheimer disease in 2860 of 11 409 patients (25.1% 95% CI, 24.3%-25.9%) and from non–Alzheimer disease to Alzheimer disease in 1201 of 11 409 (10.5% 95% CI, 10.0%-11.1%).
Conclusions and Relevance Among Medicare beneficiaries with MCI or dementia of uncertain etiology evaluated by dementia specialists, the use of amyloid PET was associated with changes in clinical management within 90 days. Further research is needed to determine whether amyloid PET is associated with improved clinical outcomes
Association of #Amyloid Positron Emission Tomography With Subsequent Change in Clinical Management Among Medicare Beneficiaries With Mild Cognitive Impairment or Dementia
https://jamanetwork.com/journals/jama/article-abstract/2729371
Amyloid #PET results were positive in 3817 patients with MCI (55.3%) and 3154 patients with dementia (70.1%). The composite end point changed in 4159 of 6905 patients with MCI (60.2% 95% CI, 59.1%-61.4%) and 2859 of 4504 patients with dementia (63.5% 95% CI, 62.1%-64.9%), significantly exceeding the 30% threshold in each group (P < .001, 1-sided). The etiologic diagnosis changed from Alzheimer disease to non–Alzheimer disease in 2860 of 11 409 patients (25.1% 95% CI, 24.3%-25.9%) and from non–Alzheimer disease to Alzheimer disease in 1201 of 11 409 (10.5% 95% CI, 10.0%-11.1%).
Conclusions and Relevance Among Medicare beneficiaries with MCI or dementia of uncertain etiology evaluated by dementia specialists, the use of amyloid PET was associated with changes in clinical management within 90 days. Further research is needed to determine whether amyloid PET is associated with improved clinical outcomes
NP03, a Microdose #Lithium Formulation, Blunts Early #Amyloid Post-Plaque Neuropathology in McGill-R-Thy1-APP Alzheimer-Like Transgenic Rats
Epidemiological, preclinical, and clinical studies have suggested a role for microdose lithium in reducing Alzheimer’s disease (AD) risk by modulating key mechanisms associated with AD pathology. The novel microdose lithium formulation, NP03, has disease-modifying effects in the McGill-R-Thy1-APP transgenic rat model of AD-like amyloidosis at pre-plaque stages, before frank amyloid-β (Aβ) plaque deposition, during which Aβ is primarily intraneuronal..
During the early Aβ post-plaque stage, we find that NP03 rescues functional deficits in object recognition, reduces loss of cholinergic boutons in the hippocampus, reduces levels of soluble and insoluble cortical Aβ42 and reduces hippocampal Aβ plaque number. In addition, NP03 reduces markers of neuroinflammation and cellular oxidative stress. Together these results indicate that microdose lithium NP03 is effective at later stages of amyloid pathology, after appearance of Aβ plaques.
https://bit.ly/38D9icR
Epidemiological, preclinical, and clinical studies have suggested a role for microdose lithium in reducing Alzheimer’s disease (AD) risk by modulating key mechanisms associated with AD pathology. The novel microdose lithium formulation, NP03, has disease-modifying effects in the McGill-R-Thy1-APP transgenic rat model of AD-like amyloidosis at pre-plaque stages, before frank amyloid-β (Aβ) plaque deposition, during which Aβ is primarily intraneuronal..
During the early Aβ post-plaque stage, we find that NP03 rescues functional deficits in object recognition, reduces loss of cholinergic boutons in the hippocampus, reduces levels of soluble and insoluble cortical Aβ42 and reduces hippocampal Aβ plaque number. In addition, NP03 reduces markers of neuroinflammation and cellular oxidative stress. Together these results indicate that microdose lithium NP03 is effective at later stages of amyloid pathology, after appearance of Aβ plaques.
https://bit.ly/38D9icR
Iospress
NP03, a Microdose Lithium Formulation, Blunts Early Amyloid Post-Plaque Neuropathology in McGill-R-Thy1-APP Alzheimer-Like Transgenic…
Epidemiological, preclinical, and clinical studies have suggested a role for microdose lithium in reducing Alzheimer’s disease (AD) risk by modulating key mechanisms associated with AD pathology. The novel microdose lithium formulation, NP03, has dis
Repetitive negative #thinking is associated with #amyloid, tau, and cognitive decline
https://2medical.news/2020/06/16/repetitive-negative-thinking-is-associated-with-amyloid-tau-and-cognitive-decline/
The Cognitive Debt hypothesis proposes that repetitive negative thinking (RNT), a modifiable process common to many psychological risk factors for Alzheimer’s disease (AD) may itself increase risk. We sought to empirically examine relationships between RNT and markers of AD, compared with anxiety and depression symptoms. ..RNT was associated with decline in global cognition (P = .02); immediate (P = .03) and delayed memory (P = …
https://2medical.news/2020/06/16/repetitive-negative-thinking-is-associated-with-amyloid-tau-and-cognitive-decline/
The Cognitive Debt hypothesis proposes that repetitive negative thinking (RNT), a modifiable process common to many psychological risk factors for Alzheimer’s disease (AD) may itself increase risk. We sought to empirically examine relationships between RNT and markers of AD, compared with anxiety and depression symptoms. ..RNT was associated with decline in global cognition (P = .02); immediate (P = .03) and delayed memory (P = …
#Sleep Disturbance Forecasts β- #Amyloid Accumulation across Subsequent Years
https://2medical.news/2020/09/07/sleep-disturbance-forecasts-%CE%B2-amyloid-accumulation-across-subsequent-years/
Experimental sleep-wake disruption in rodents and humans causally modulates β-amyloid (Aβ) dynamics (e.g., [1, 2, 3]). This leads to the hypothesis that, beyond cross-sectional associations, impaired sleep structure and physiology could represent prospective biomarkers of the speed with which Aβ accumulates over time. Here, we test the hypothesis that initial baseline measures of non-rapid eye movement (NREM) sleep slow-wave activity (SWA) and sleep quality (efficiency) …
https://2medical.news/2020/09/07/sleep-disturbance-forecasts-%CE%B2-amyloid-accumulation-across-subsequent-years/
Experimental sleep-wake disruption in rodents and humans causally modulates β-amyloid (Aβ) dynamics (e.g., [1, 2, 3]). This leads to the hypothesis that, beyond cross-sectional associations, impaired sleep structure and physiology could represent prospective biomarkers of the speed with which Aβ accumulates over time. Here, we test the hypothesis that initial baseline measures of non-rapid eye movement (NREM) sleep slow-wave activity (SWA) and sleep quality (efficiency) …
An Immunomodulatory Therapeutic #Vaccine Targeting Oligomeric #Amyloid-β
https://2medical.news/2020/11/06/an-immunomodulatory-therapeutic-vaccine-targeting-oligomeric-amyloid-%CE%B2/
Background:Aging is considered the most important risk factor for Alzheimer’s disease (AD). Recent research supports the theory that immunotherapy targeting the “oligomeric” forms of amyloid-β (Aβ) may halt the progression of AD. However, previous clinical trial of the vaccine against Aβ, called AN1792, was suspended due to cases of meningoencephalitis in patients. Objective:To develop a peptide sensitized dendritic cells (DCs) vaccine that would target oligomer …
https://2medical.news/2020/11/06/an-immunomodulatory-therapeutic-vaccine-targeting-oligomeric-amyloid-%CE%B2/
Background:Aging is considered the most important risk factor for Alzheimer’s disease (AD). Recent research supports the theory that immunotherapy targeting the “oligomeric” forms of amyloid-β (Aβ) may halt the progression of AD. However, previous clinical trial of the vaccine against Aβ, called AN1792, was suspended due to cases of meningoencephalitis in patients. Objective:To develop a peptide sensitized dendritic cells (DCs) vaccine that would target oligomer …
Synthesis of human #amyloid restricted to #liver results in an #Alzheimer disease–like neurodegenerative phenotype
https://2medical.news/2021/09/30/synthesis-of-human-amyloid-restricted-to-liver-results-in-an-alzheimer-disease-like-neurodegenerative-phenotype/
https://2medical.news/2021/09/30/synthesis-of-human-amyloid-restricted-to-liver-results-in-an-alzheimer-disease-like-neurodegenerative-phenotype/
2Medical.News
Synthesis of human #amyloid restricted to #liver results in an #Alzheimer disease–like neurodegenerative phenotype
Several lines of study suggest that peripheral metabolism of amyloid beta (Aß) is associated with risk for Alzheimer disease (AD). In blood, greater than 90% of Aß is complexed as an apolipoprotein…
Irisin reduces #amyloid-β by inducing the release of neprilysin from #astrocytes following downregulation of ERK-STAT3 signaling
https://2medical.news/2023/09/12/irisin-reduces-amyloid-%CE%B2-by-inducing-the-release-of-neprilysin-from-astrocytes-following-downregulation-of-erk-stat3-signaling/
https://2medical.news/2023/09/12/irisin-reduces-amyloid-%CE%B2-by-inducing-the-release-of-neprilysin-from-astrocytes-following-downregulation-of-erk-stat3-signaling/
2Medical.News
Irisin reduces #amyloid-β by inducing the release of neprilysin from #astrocytes following downregulation of ERK-STAT3 signaling
A pathological hallmark of Alzheimer’s disease (AD) is the deposition of amyloid-β (Aβ) protein in the brain. Physical exercise has been shown to reduce Aβ burden in various AD mouse models, but th…
Scanning #ultrasound-mediated memory and functional improvements do not require #amyloid-β reduction
https://2medical.news/2024/04/06/scanning-ultrasound-mediated-memory-and-functional-improvements-do-not-require-amyloid-%CE%B2-reduction/
https://2medical.news/2024/04/06/scanning-ultrasound-mediated-memory-and-functional-improvements-do-not-require-amyloid-%CE%B2-reduction/
2Medical.News
Scanning #ultrasound-mediated memory and functional improvements do not require #amyloid-β reduction
A prevalent view in treating age-dependent disorders including Alzheimer’s disease (AD) is that the underlying amyloid plaque pathology must be targeted for cognitive improvements. In contrast, we …