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2022 ◽  
Vol 13 ◽  
Author(s):  
Roos J. Jutten ◽  
Dorene M. Rentz ◽  
Jessie F. Fu ◽  
Danielle V. Mayblyum ◽  
Rebecca E. Amariglio ◽  
...  

Introduction: We investigated whether monthly assessments of a computerized cognitive composite (C3) could aid in the detection of differences in practice effects (PE) in clinically unimpaired (CU) older adults, and whether diminished PE were associated with Alzheimer's disease (AD) biomarkers and annual cognitive decline.Materials and Methods:N = 114 CU participants (age 77.6 ± 5.0, 61% female, MMSE 29 ± 1.2) from the Harvard Aging Brain Study completed the self-administered C3 monthly, at-home, on an iPad for one year. At baseline, participants underwent in-clinic Preclinical Alzheimer's Cognitive Composite-5 (PACC5) testing, and a subsample (n = 72, age = 77.8 ± 4.9, 59% female, MMSE 29 ± 1.3) had 1-year follow-up in-clinic PACC5 testing available. Participants had undergone PIB-PET imaging (0.99 ± 1.6 years before at-home baseline) and Flortaucipir PET imaging (n = 105, 0.62 ± 1.1 years before at-home baseline). Linear mixed models were used to investigate change over months on the C3 adjusting for age, sex, and years of education, and to extract individual covariate-adjusted slopes over the first 3 months. We investigated the association of 3-month C3 slopes with global amyloid burden and tau deposition in eight predefined regions of interest, and conducted Receiver Operating Characteristic analyses to examine how accurately 3-month C3 slopes could identify individuals that showed >0.10 SD annual decline on the PACC-5.Results: Overall, individuals improved on all C3 measures over 12 months (β = 0.23, 95% CI [0.21–0.25], p < 0.001), but improvement over the first 3 months was greatest (β = 0.68, 95% CI [0.59–0.77], p < 0.001), suggesting stronger PE over initial repeated exposures. However, lower PE over 3 months were associated with more global amyloid burden (r = −0.20, 95% CI [−0.38 – −0.01], p = 0.049) and tau deposition in the entorhinal cortex (r = −0.38, 95% CI [−0.54 – −0.19], p < 0.001) and inferior-temporal lobe (r = −0.23, 95% CI [−0.41 – −0.02], p = 0.03). 3-month C3 slopes exhibited good discriminative ability to identify PACC-5 decliners (AUC 0.91, 95% CI [0.84–0.98]), which was better than baseline C3 (p < 0.001) and baseline PACC-5 scores (p = 0.02).Conclusion: While PE are commonly observed among CU adults, diminished PE over monthly cognitive testing are associated with greater AD biomarker burden and cognitive decline. Our findings imply that unsupervised computerized testing using monthly retest paradigms can provide rapid detection of diminished PE indicative of future cognitive decline in preclinical AD.


Biomedicines ◽  
2022 ◽  
Vol 10 (1) ◽  
pp. 169
Author(s):  
Jung Eun Park ◽  
Tamil Iniyan Gunasekaran ◽  
Yeong Hee Cho ◽  
Seong-Min Choi ◽  
Min-Kyung Song ◽  
...  

Potential biomarkers for Alzheimer’s disease (AD) include amyloid β1–42 (Aβ1–42), t-Tau, p-Tau181, neurofilament light chain (NFL), and neuroimaging biomarkers. Their combined use is useful for diagnosing and monitoring the progress of AD. Therefore, further development of a combination of these biomarkers is essential. We investigated whether plasma NFL/Aβ1–42 can serve as a plasma-based primary screening biomarker reflecting brain neurodegeneration and amyloid pathology in AD for monitoring disease progression and early diagnosis. We measured the NFL and Aβ1–42 concentrations in the CSF and plasma samples and performed correlation analysis to evaluate the utility of these biomarkers in the early diagnosis and monitoring of AD spectrum disease progression. Pearson’s correlation analysis was used to analyse the associations between the fluid biomarkers and neuroimaging data. The study included 136 participants, classified into five groups: 28 cognitively normal individuals, 23 patients with preclinical AD, 22 amyloid-negative patients with amnestic mild cognitive impairment, 32 patients with prodromal AD, and 31 patients with AD dementia. With disease progression, the NFL concentrations increased and Aβ1–42 concentrations decreased. The plasma and CSF NFL/Aβ1–42 were strongly correlated (r = 0.558). Plasma NFL/Aβ1–42 was strongly correlated with hippocampal volume/intracranial volume (r = 0.409). In early AD, plasma NFL/Aβ1–42 was associated with higher diagnostic accuracy than the individual biomarkers. Moreover, in preclinical AD, plasma NFL/Aβ1–42 changed more rapidly than the CSF t-Tau or p-Tau181 concentrations. Our findings highlight the utility of plasma NFL/Aβ1–42 as a non-invasive plasma-based biomarker for early diagnosis and monitoring of AD spectrum disease progression.


Neurology ◽  
2022 ◽  
pp. 10.1212/WNL.0000000000013299
Author(s):  
Pontus Tideman ◽  
Erik Stomrud ◽  
Antoine Leuzy ◽  
Niklas Mattsson-Carlgren ◽  
Sebastian Palmqvist ◽  
...  

Background and Objectives:The neuropathological changes underlying Alzheimer´s disease (AD) start before overt cognitive symptoms arise, but it is not well-known how they relate to the first subtle cognitive changes. The objective for this study was to examine the independent associations of the AD hallmarks β-amyloid (Aβ), tau, and neurodegeneration with different cognitive domains in cognitively unimpaired (CU) individuals.Methods:In this cross-sectional study, CU participants from the prospective BioFINDER-2 study were included. All had CSF biomarkers (Aβ42 and P-tau181), MRI (cortical thickness of AD-susceptible regions), Aβ-PET (neocortical uptake), tau-PET (entorhinal uptake), and cognitive test data for i) memory, ii) executive function, iii) verbal function, iv), and visuospatial function. Multivariable linear regression models were performed, using either CSF Aβ42, P-tau181 and cortical thickness or Aβ-PET, tau-PET, and cortical thickness, as predictors of cognitive function. The results were validated in an independent cohort (ADNI).Results:316 CU participants were included from the BioFINDER-2 study. Abnormal Aβ-status was independently associated with the executive measure, regardless of modality (CSF Aβ42 β=0.128, p=0.024; Aβ-PET β=0.124, p=0.049), while tau was independently associated with memory (CSF P-tau181 β=0.132, p=0.018; tau-PET β=0.189, p=0.002). Cortical thickness was independently associated with the executive measure and verbal fluency in both models (p=0.005-0.018). To examine the relationships in the earliest stage of preclinical AD, only participants with normal biomarkers of tau and neurodegeneration were included (n=217 CSF-based; n=246 PET-based). Again, Aβ-status was associated with executive function (CSF Aβ42, β=0.189, p=0.005; Aβ-PET, β=0.146, p=0.023), but not with other cognitive domains. The results were overall replicated in the ADNI cohort (n=361).Discussion:These findings suggest that Aβ is independently associated with worse performance on an executive measure but not with memory performance, which instead is associated with tau pathology. This may have implications for early preclinical AD screening and outcome measures in AD trials targeting Aβ pathology.


2022 ◽  
Vol 1 ◽  
pp. 146
Author(s):  
Ioannis TARNANAS ◽  
Panagiotis Vlamos ◽  
Dr Robbert Harms ◽  

Parkinson's disease (PD) is the fastest growing neurodegeneration and has a prediagnostic phase with a lot of challenges to identify clinical and laboratory biomarkers for those in the earliest stages or those 'at risk'. Despite the current research effort, further progress in this field hinges on the more effective application of digital biomarker and artificial intelligence applications at the prediagnostic stages of PD. It is of the highest importance to stratify such prediagnostic subjects that seem to have the most neuroprotective benefit from drugs. However, current initiatives to identify individuals at risk or in the earliest stages that might be candidates for future clinical trials are still challenging due to the limited accuracy and explainability of existing prediagnostic detection and progression prediction solutions. In this brief paper, we report on a novel digital neuro signature (DNS) for prodromal-PD based on selected digital biomarkers previously discovered on preclinical Alzheimer's disease. (AD). Our preliminary results demonstrated a standard DNS signature for both preclinical AD and prodromal PD, containing a ranked selection of features. This novel DNS signature was rapidly repurposed out of 793 digital biomarker features and selected the top 20 digital biomarkers that are predictive and could detect both the biological signature of preclinical AD and the biological mechanism of a-synucleinopathy in prodromal PD. The resulting model can provide physicians with a pool of patients potentially eligible for therapy and comes along with information about the importance of the digital biomarkers that are predictive, based on SHapley Additive exPlanations (SHAP). Similar initiatives could clarify the stage before and around diagnosis, enabling the field to push into unchartered territory at the earliest stages of the disease.


2021 ◽  
Vol 2021 ◽  
pp. 1-30
Author(s):  
Yuri Mizuno ◽  
Nona Abolhassani ◽  
Guianfranco Mazzei ◽  
Kunihiko Sakumi ◽  
Takashi Saito ◽  
...  

Oxidative stress is a major risk factor for Alzheimer’s disease (AD), which is characterized by brain atrophy, amyloid plaques, neurofibrillary tangles, and loss of neurons. 8-Oxoguanine, a major oxidatively generated nucleobase highly accumulated in the AD brain, is known to cause neurodegeneration. In mammalian cells, several enzymes play essential roles in minimizing the 8-oxoguanine accumulation in DNA. MUTYH with adenine DNA glycosylase activity excises adenine inserted opposite 8-oxoguanine in DNA. MUTYH is reported to actively contribute to the neurodegenerative process in Parkinson and Huntington diseases and some mouse models of neurodegenerative diseases by accelerating neuronal dysfunction and microgliosis under oxidative conditions; however, whether or not MUTYH is involved in AD pathogenesis remains unclear. In the present study, we examined the contribution of MUTYH to the AD pathogenesis. Using postmortem human brains, we showed that various types of MUTYH transcripts and proteins are expressed in most hippocampal neurons and glia in both non-AD and AD brains. We further introduced MUTYH deficiency into AppNL-G-F/NL-G-F knock-in AD model mice, which produce humanized toxic amyloid-β without the overexpression of APP protein, and investigated the effects of MUTYH deficiency on the behavior, pathology, gene expression, and neurogenesis. MUTYH deficiency improved memory impairment in AppNL-G-F/NL-G-F mice, accompanied by reduced microgliosis. Gene expression profiling strongly suggested that MUTYH is involved in the microglial response pathways under AD pathology and contributes to the phagocytic activity of disease-associated microglia. We also found that MUTYH deficiency ameliorates impaired neurogenesis in the hippocampus, thus improving memory impairment. In conclusion, we propose that MUTYH, which is expressed in the hippocampus of AD patients as well as non-AD subjects, actively contributes to memory impairment by inducing microgliosis with poor neurogenesis in the preclinical AD phase and that MUTYH is a novel therapeutic target for AD, as its deficiency is highly beneficial for ameliorating AD pathogenesis.


2021 ◽  
pp. 1-12
Author(s):  
Alireza Salami ◽  
Rolf Adolfsson ◽  
Micael Andersson ◽  
Kaj Blennow ◽  
Anders Lundquist ◽  
...  

Background: The Apolipoprotein E (APOE) ɛ4 allele has been linked to increased tau phosphorylation and tangle formation. APOE ɛ4 carriers with elevated tau might be at the higher risk for AD progression. Previous studies showed that tau pathology begins early in areas of the medial temporal lobe. Similarly, APOE ɛ4 carriers showed altered hippocampal functional integrity. However, it remains unknown whether elevated tau accumulation on hippocampal functional changes would be more pronounced for APOE ɛ4 carriers. Objective: We related ɛ4 carriage to levels of plasma phosphorylated tau (p-tau181) up to 15 years prior to AD onset. Furthermore, elevated p-tau181 was explored in relation to longitudinal changes in hippocampal function and connectivity. Methods: Longitudinal population-based study. Plasma p-tau181 was analyzed in 142 clinically defined Alzheimer’s disease (AD) cases and 126 controls. The longitudinal analysis involved 87 non-demented individuals with two waves of plasma samples and three waves of functional magnetic resonance imaging during rest and memory encoding. Results: Increased p-tau181 was observed for both ɛ4 carriers and non-carriers close to AD, but exclusively for ɛ4 carriers in the early preclinical groups (7- and 13-years pre-AD). In ɛ4 carriers, longitudinal p-tau181 increase was paralleled by elevated local hippocampal connectivity at rest and subsequent reduction of hippocampus encoding-related activity. Conclusion: Our findings support an association of APOE ɛ4 and p-tau181 with preclinical AD and hippocampus functioning.


2021 ◽  
pp. 1-20
Author(s):  
Satya V.V.N. Kothapalli ◽  
Tammie L. Benzinger ◽  
Andrew J. Aschenbrenner ◽  
Richard J. Perrin ◽  
Charles F. Hildebolt ◽  
...  

Background: Currently, brain tissue atrophy serves as an in vivo MRI biomarker of neurodegeneration in Alzheimer’s disease (AD). However, postmortem histopathological studies show that neuronal loss in AD exceeds volumetric loss of tissue and that loss of memory in AD begins when neurons and synapses are lost. Therefore, in vivo detection of neuronal loss prior to detectable atrophy in MRI is essential for early AD diagnosis. Objective: To apply a recently developed quantitative Gradient Recalled Echo (qGRE) MRI technique for in vivo evaluation of neuronal loss in human hippocampus. Methods: Seventy participants were recruited from the Knight Alzheimer Disease Research Center, representing three groups: Healthy controls [Clinical Dementia Rating® (CDR®) = 0, amyloid β (Aβ)-negative, n = 34]; Preclinical AD (CDR = 0, Aβ-positive, n = 19); and mild AD (CDR = 0.5 or 1, Aβ-positive, n = 17). Results: In hippocampal tissue, qGRE identified two types of regions: one, practically devoid of neurons, we designate as “Dark Matter”, and the other, with relatively preserved neurons, “Viable Tissue”. Data showed a greater loss of neurons than defined by atrophy in the mild AD group compared with the healthy control group; neuronal loss ranged between 31% and 43%, while volume loss ranged only between 10% and 19%. The concept of Dark Matter was confirmed with histopathological study of one participant who underwent in vivo qGRE 14 months prior to expiration. Conclusion: In vivo qGRE method identifies neuronal loss that is associated with impaired AD-related cognition but is not recognized by MRI measurements of tissue atrophy, therefore providing new biomarkers for early AD detection.


2021 ◽  
Vol 18 ◽  
Author(s):  
Kangzhi Chen ◽  
Yefan Lv ◽  
Xiaoyan Long ◽  
Weiping Liu ◽  
Jinxia Zhou

: The prevalence of sleep disorders and cognitive dysfunction has overwhelmingly increased, with insomnia and Alzheimer’s disease (AD) being the most common form. A multitude of studies have linked the alterations in sleep continuity or sleep architecture with cognitive impairment bilaterally, but the management of disrupted sleep patterns in preclinical AD could be more beneficial since there is no cure for AD. This review mainly focuses on the altered sleep patterns in insomnia, and summarizes potential pathways underlying the relationship between insomnia and cognitive impairment, aiming to establish certain sleep pattern changes as biomarkers for cognitive decline and explore potential therapeutic targets based on evidence from research advances.


2021 ◽  
Vol 1 ◽  
pp. 146
Author(s):  
Ioannis TARNANAS ◽  
Panagiotis Vlamos ◽  

Parkinson's disease (PD) is the fastest growing neurodegeneration and has a prediagnostic phase with a lot of challenges to identify clinical and laboratory biomarkers for those in the earliest stages or those 'at risk'. Despite the current research effort, further progress in this field hinges on the more effective application of digital biomarker and artificial intelligence applications at the prediagnostic stages of PD. It is of the highest importance to stratify such prediagnostic subjects that seem to have the most neuroprotective benefit from drugs. However, current initiatives to identify individuals at risk or in the earliest stages that might be candidates for future clinical trials are still challenging due to the limited accuracy and explainability of existing prediagnostic detection and progression prediction solutions. In this brief paper, we report on a novel digital neuro signature (DNS) for prodromal-PD based on selected digital biomarkers previously discovered on preclinical Alzheimer's disease. (AD). Our preliminary results demonstrated a standard DNS signature for both preclinical AD and prodromal PD, containing a ranked selection of features. This novel DNS signature was rapidly repurposed out of 793 digital biomarker features and selected the top 20 digital biomarkers that are predictive and could detect both the biological signature of preclinical AD and the biological mechanism of a-synucleinopathy in prodromal PD. The resulting model can provide physicians with a pool of patients potentially eligible for therapy and comes along with information about the importance of the digital biomarkers that are predictive, based on SHapley Additive exPlanations (SHAP). Similar initiatives could clarify the stage before and around diagnosis, enabling the field to push into unchartered territory at the earliest stages of the disease.


2021 ◽  
Vol 17 (S6) ◽  
Author(s):  
Jori Tomassen ◽  
Anouk den Braber ◽  
Bart N.M. Van Berckel ◽  
Maqsood Yaqub ◽  
Dorret I Boomsma ◽  
...  

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