bluuebunny/crossref_metadata_2025 huggingface dataset:
Diabetes, cognitive decline and mild cognitive impairment among diverse Hispanics/Latinos: Hispanic Community Health Study/Study of Latinos (HCHS‐SOL) investigation of cognitive aging results
Authors: Gonzalez Hector M. , Tarraf Wassim , Gonzalez Kevin A , Fornage Myriam , Zeng Donglin , Gallo Linda , Talavera Gregory A , Daviglus Martha , Lipton Richard B. , Kaplan Robert , Ramos Alberto R , Lamar Melissa , Cai Jianwen , DeCarli Charles , Schneiderman Neil
Published: December 2020

Background

Hispanics/Latinos are the largest ethnic/racial group in the US, have the highest prevalence of diabetes and are at increased risk for neurodegenerative disorders. Additionally, Latinos have the highest prevalence of undiagnosed and untreated diabetes in the United States. Currently, little is known about the relationship between diabetes, cognitive decline and disorders among diverse Hispanics/Latinos. The purpose of this study is to clarify these relationships in diverse middle‐aged and older Hispanics/Latinos.

Method

The Study of Latinos‐Investigation of Neurocognitive Aging (SOL‐INCA) is an ancillary study of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). HCHS/SOL is a multisite (Bronx, NY, Chicago, IL, Miami, FL, San Diego, CA), probability sampled (i.e., representative of targeted populations), and prospective cohort study. Visit 1 baseline enrollment occurred between 2008‐2011. At HCHS/SOL Visit 2 (2016‐2018), SOL‐INCA enrolled diverse Hispanics/Latinos ages 50‐years and older (n=6,377). Global cognitive decline and Mild Cognitive Impairment (MCI) were the primary outcomes. Diabetes status (prevalent, Visit 1 to Visit 2 incident, and no diabetes) was the primary exposure. Associations between the cognitive outcomes and the exposure were examined using survey generalized linear models adjusting for pertinent covariates and confounders.

Result

Prevalent diabetes at Visit 1, but not new incident cases of diabetes at Visit 2, was associated with significantly steeper 7‐year global cognitive decline (βGC= ‐0.16; CI= [‐0.25;‐0.07]; p<0.001), domain specific cognitive decline, and higher odds of MCI (OR=1.74; CI=[1.34; 2.26]; p<0.001) compared to persons without diabetes, in age‐ and sex‐adjusted models.

Conclusion

Diabetes was associated with significant 7‐year cognitive decline and increased MCI prevalence among diverse middle‐aged and older Hispanics/Latinos, but primarily among those with prevalent diabetes at Visit 1. Our findings suggest that significant cognitive decline and MCI may be considered additional disease complications of diabetes among diverse middle‐aged and older Hispanics/Latinos.
Examining the preliminary effect of a randomized control trial of Tele‐Savvy, an online psychoeducation program, on insomnia and sleep quality
Authors: Brewster Glenna S , Higgins Melinda , Yeager Kate , Bliwise Donald , Hepburn Kenneth
Published: December 2020

Background

Sleep disturbance is prevalent among caregivers of persons living with dementia. Tele‐Savvy is an online psychoeducation program that seeks to improve caregivers’ knowledge and skill about their role, and reduce their distress. Caregivers (N=220) were recruited into an NIA‐sponsored trial and randomly assigned to immediate participation in Tele‐Savvy, an attention control condition (Healthy Living), or usual care. This study aims to examine the preliminary impact of Tele‐Savvy on sleep quality (Pittsburgh Sleep Quality Index) and insomnia (Insomnia Severity Index) in the first 20 cohorts of caregivers using data gathered at baseline, 3 and 6 months. Improving sleep quality was not an expected outcome of the study, but we sought to examine whether an active mastery‐focused intervention or an attention condition focused on healthy living might affect this important domain.

Methods

Multilevel mixed models were used to test for group, time, and group‐by‐time effects for sleep quality and insomnia.

Results

On average, caregivers were 64 years old; 72% were White and 23% were African American. At baseline, 50% of the caregivers had poor sleep quality (PSQI > 5). In addition, African Americans had significantly worse insomnia (p=.012; African Americans: Mean (M)‐10.5, standard deviation (SD)‐7.8; Whites: M‐6.2, SD‐5.8;) and sleep quality (p=.006; African Americans: M‐8.0, SD‐4.0; Whites: M‐5.4, SD‐4.1) scores. We found no significant group‐by‐time effect on insomnia (p=.22) or sleep quality (p=.20). For sleep quality, the Tele‐Savvy group reported small decreases over time with the mean remaining above the clinical cut‐off of 5 (7.2 at baseline, 6.6 at 6 months). In contrast, the attention control and waitlist control groups experienced worsening of sleep quality (attention control: 5.9 at baseline to 6.5 at 6 months; waitlist control: 5.6 at baseline to 6.5 at 6 months).

Conclusion

At this intermediate point of analysis, that neither the Tele‐Savvy intervention nor the control condition focused on health and well‐being (but not on sleep), were effective at improving caregivers’ sleep quality. It is necessary to develop interventions specific to sleep disturbance or to integrate behavioral or psychoeducational components that target the sleep disturbance into psychoeducational interventions.
Cognitive impairment and risk factors of LATE in the oldest old: The 90+ Study
Authors: Sajjadi S. Ahmad , Phelan Michael , Yan Rui , Scambray Kiana Alexis , Ho Chu‐Ching , Woodworth Davis C. , Corrada Maria M.M. , Kawas Claudia H.
Published: December 2020

Background

Limbic predominant age related TDP‐43 encephalopathy (LATE) is a newly proposed term to denote the contribution of TDP‐43 pathology to dementia at older age. The aim of this work was to study the role of LATE in cognitive impairment and its risk factors in the oldest old.

Method

240 participants of The 90+ Study with comprehensive clinical, neuropsychology, and neuropathology data were included. Dementia status, clinical syndrome, and impaired cognitive domains were determined at multi‐disciplinary post‐mortem case conferences blind to autopsy data. Alzheimer’s disease neuropathology (ADNP) was defined as CERAD neuritic plaque score≥2 and Braak neurofibrillary tangle stage≥5. We defined LATE as those with at least amygdala and hippocampal TDP‐43 pathology (stage>2). We explored the association of LATE and ADNP with cognition measures as outcome by logistic regression analyses adjusting for age, sex, and education. We separately explored the association between medical histories (as potential risk factors) and LATE and ADNP as outcomes adjusting for the above covariates.

Result

52% of the participants (N=125) died with dementia and of those, 33% were LATE positive (Table 1). There was no association between LATE and sex, age at death, or education. Compared with ADNP, LATE was as important a predictor of dementia and clinical diagnosis of Alzheimer’s at death (Table 2). Both pathologies were associated with impaired memory, language, visuospatial ability, and orientation. Only ADNP, but not TDP‐43, was associated with impaired executive function. Lower likelihood of LATE was associated with histories of hypertension (but not hypertension medications), cataract, alcohol use (median 1 drink/day), and macular degeneration (trended toward significant association). History of COPD was significantly associated and history of autoimmune conditions (thyroid or rheumatological diseases) trended towards an association with a higher likelihood of LATE (Figure). None of the above relationships were seen for ADNP.

Conclusion

LATE is an important degenerative pathology in the oldest old comparable to ADNP in its relation to dementia and clinical diagnosis of Alzheimer’s. The intriguing associations of LATE with other health conditions warrant further investigation of the potential effect of autoimmunity, reduced brain perfusion, and chronic hypoxia in its development.
The in silico search for endogenous anti‐Alzheimer's compounds
Authors: Weaver Donald F , Barden Christopher , Gupta Mayuri , Meek Autumn , Reed Mark , Wang Yanfei , Wu Fan
Published: December 2020

Background

Since many peptide and proteins are susceptible to oligomerization analogous to Aβ and tau, there is evolutionary pressure to inhibit deleterious protein misfolding; likewise, the immunoinflammatory cascade triggered by such misfolding is also subject to homeostatic regulation. Accordingly, it is reasonable to postulate the existence of endogenous molecules within the human brain that could modulate or even interrupt the neurotoxic cascade of AD by blocking both the proteopathy and immunopathy of Alzheimer's disease (AD). Such compounds would constitute platforms for future drug development.

Method

We sought to identify a single anti‐proteopathic and anti‐immunopathic agent endogenous to the human central nervous system; to find this compound, we created a comprehensive library of 1,376 molecules (molecular weight < 600 Da) naturally occurring within the human brain and employed an in silico screening assay. Using computer‐aided screening with a molecular mechanics force field, we docked these endogenous molecules against computer models of in Aβ(HHQK16LVFF), tau(KKAK144), IL‐1R1(HKEK80), IL‐1β(KLRK76), C1qA(KKGH225), IFN‐gamma(KKKR112) and RANTES(RKNR70). Additional molecular dynamics simulations were done to refine the docking. Finally, multiple in vitro assays were done, verifying that the in silico hits had correctly predicted the ability to block oligomerization and to bind to multiple immunopeptides.

Result

Several zwitterionic and aromatic‐anionic compounds capable of binding to these multiple amyloid, tau and immunoprotein targets were identified. Strong in silico hits included 2‐aminoethanesulfonic acid, L‐phosphoserine, 5‐hydroxytryptamine and 3‐hydroxyanthranilic acid. These predictions were verified using in vitro assays, including the kinetic Thioflavin T [ThT] aggregation assay.

Conclusion

Searching for an “endogenous anti‐AD compound” represents an unexplored concept. Our in silico and in vitro studies suggest that compounds endogenous to the human brain can inhibit pathological both the proteopathic and immunopathic pathogeneses of AD. The value of a novel in silico screening assay to identify such endogenous agent capable of "one‐drug‐multiple‐targets" has also been demonstrated.
Effect of antihypertensive treatment Lisinopril on central arterial stiffness and cognitive functions in Dahl‐S rat model of vascular dementia
Authors: Fedorova Olga V. , Fenner Rachel C. , Grigorova Yulia N. , McDevitt Ross , Juhasz Ondrej , Ajamu Samuel , Wei Wen , Zernetkina Valentina I. , Petrashevskaya Natalia , Long Jeffrey M. , Rapp Peter R. , Lakatta Edward G.
Published: December 2020

Background

Dahl salt‐sensitive rats (DSS) represent a model of vascular dementia, because they demonstrate an age‐associated increase in blood pressure (BP) and central arterial stiffness (CAS) accompanied by cognitive decline independent of a high salt intake. We hypothesized that treatment with an anti‐hypertensive drug ACE inhibitor Lisinopril will lower CAS and improve cognitive function in the adult hypertensive DSS.

Method

Male DSS were kept on a normal salt diet for 12 months. Six‐month old rats received vehicle (control; DSS‐C; n = 20) or Lisinopril (15 mg/kg/day; DSS‐LIS; n = 20) for 6‐mo. Systolic BP (SBP), pulse wave velocity (PWV), a marker of CAS (by Doppler echocardiography), open field test (OFT) to assess anxiety‐like behavior and locomotion, and cued reaction time task (CRTT) to assess executive functioning were performed at BL (before treatment), after 3 and 6‐mo of treatment. Morris Water maze (MWM) test was performed to assess hippocampal spatial memory. Aortae were stained for elastin and collagen (immunohistochemistry). Statistical analysis: 2‐way ANOVA repeated measures and t‐test; data presented as mean ± SEM.

Result

All non‐treated DSS were hypertensive. DSS‐LIS have lower SBP vs. BL and vs. age‐matched DSS‐C. PWV was lower in 12‐mo DSS‐LIS vs. BL and vs. age‐matched DSS‐C (Table). In MWM, DSS‐LIS had a higher path efficiency and traveled shorter distance to find the invisible platform vs. DSS‐C. In CRTT, DSS‐LIS had less premature responses than DSS‐C 3‐mo post treatment (Table). There was no change in total distance and distance traveled in the center in OFT at all time points in DSS‐LIS vs. DSS‐C (Table). 12‐mo old DSS‐LIS had lower heart and aortic weight, less aortic medial wall collagen and greater elastin/collagen ratio vs. DSS‐C (Table).

Conclusion

Chronic treatment with Lisinopril effectively lowered SBP, CAS and reduced aortic collagen in aged hypertensive DSS rats. Lisinopril resulted in improved hippocampal spatial memory and reduced impulsive behavior demonstrating a beneficial cognitive effect in the DSS model of vascular dementia. Further studies will need to elucidate the effect of Lisinopril on cerebral blood vessels and whether ACE inhibitor has a direct effect of the brain in addition to its effect on CAS. Supported by the Intramural Research Program of the NIA/NIH.
Fenchol ameliorates Alzheimer’s disease like phenotypes by modulating microbiome/proteolysis/senescence axis
Authors: Razazan Atefeh , Karunakar Prashantha , Mishra Sidharth P. , Sharma Shailesh , Yadav Hariom
Published: December 2020

Background

Alzheimer’s disease (AD) is progressive debilitating public health problem, with no successful preventive and therapeutic strategy. Emerging evidence indicate that the gut microbiome and its metabolites like short chain fatty acids (SCFAs; such as acetate, propionate, butyrate) contribute in AD pathology. SCFAs function as gut microbiome sensors on distinct cell types including neurons through activating G‐couple protein receptors like free fatty acid receptor 2/3 (FFAR2/3). Therefore, targeting this signaling can be a novel strategy to ameliorate AD pathology.

Method

Upon screening of >144,000 natural compounds library with human FFAR2 docking patterns, and selected 14 compounds were further studied for FFAR2 signaling agonism by measuring phosph‐ERK1/2, cAMP and calcium levels in SK‐N‐SH cells that express FFAR2. In addition, selected compound (Fenchol) investigated for its beneficial effects on life‐span, Aβ accumulation, neurodegeneration and cognitive functions in Caenorhabditis (C.) elegans and cells.

Result

We demonstrated that FFAR2 expressed in neuronal cells, and its inhibition aggravates Aβ‐induced neuronal cell death. We screened >144,000 natural compound library with human FFAR2 docking patterns, and selected 14 compounds, based on higher binding energy. Further, among them, Fenchol shows highest FFAR2 signaling activation in terms of phospho‐ERK1/2, inhibition in cAMP and increase in intracellular calcium in SK‐N‐SH cells. Interestingly, Fenchol enhanced longevity in wild‐type (N2), and human Aβ42 over‐expressing CL2600 Caenorhabditis (C.) elegans strains. Fenchol also reduced Aβ aggregates, neurodegeneration induced paralysis and cognitive memory (by chemotaxis assay) in C. elegans. In addition, Fenchol induced reduction in Aβ aggregates are linked with significantly increased proteolysis and reduced senescence (β‐galactosidase staining) in C. elegans and neuronal cells.

Conclusion

Overall, results demonstrate that Fenchol (a microbiome sensor through FFAR2 agonist) ameliorates Aβ aggregation in neuronal cells through activation of proteolysis and reduces senescence which ultimately can ameliorate AD pathology.
Genetically predicted telomere length and Alzheimer’s disease endophenotypes: A Mendelian randomization study
Authors: Vilor‐Tejedor Natalia , Rodríguez‐Fernández Blanca , Milà‐Alomà Marta , Arenaza‐Urquijo Eider M , Suárez‐Calvet Marc , Sanchez‐Benavides Gonzalo , Grau‐Rivera Oriol , Minguillón Carolina , Fauria Karine , Zetterberg Henrik , Blennow Kaj , Kollmorgen Gwendlyn , Eichenlaub Udo , Gispert Juan Domingo , DeVivo Immaculata , Sala‐Vila Aleix , Molinuevo Jose Luis , Crous‐Bou Marta ,   ALFA Study
Published: December 2020

Background

Telomere length (TL) is a putative biomarker of biological aging and aging‐related outcomes. Observational studies are limited to conclude whether TL is causally associated with AD or a marker of an underlying pathological process. Mendelian randomization (MR) was developed for assessing causality using genetic variants in epidemiological research. Our main objective was to test the potential causal role of TL in cognitive performance, brain vulnerability and AD core biomarkers through an MR analysis.

Methods

Our analysis was conducted in the context of the ALFA (ALzheimer and FAmilies) study. We created episodic memory, executive function and global cognitive composites. We calculated an AD signature as a composite measure reflecting cortical thickness of specific AD vulnerable regions. We measured cerebrospinal fluid (CSF) levels of amyloid‐β(Aβ)42, Aβ40, p‐tau, t‐tau and neurofilament light (NfL) using NeuroToolKit and Elecsys® immunoassays (Roche Diagnostics). Genome‐wide genotyping was performed. MR analyses using 3 Single Nucleotide Polymorphisms (SNPs) (rs2736100, rs9420907, rs755017) associated with TL identified in Genome‐wide Association studies (GWAS) were used as instrumental variables to determine the predicted effect of TL on AD endophenotypes: cognitive performance, AD signature, and AD biomarkers. Causal effects of TL were estimated using the inverse‐variance weighted method. Stratified analyses by APOE‐ɛ4 status were conducted.

Results

MR analysis revealed a significant association between SNPs predicting shorter TL and increased levels of NfL, supporting a potential causal role of TL on biomarkers of neuronal injury (Table 1; Figure 1). Additionally, we observed suggestive evidence of causality between shorter TL and worse episodic memory, and reduced cortical thickness in the AD signature (Table 1). Effect modification by APOE‐ɛ4 genotype was also suggested: associations between SNPs predicting short TL and worse cognitive performance, reduced thickness in the AD signature, and increased levels of NfL were only observed among APOE‐ɛ4 non‐carriers (Table 2).

Conclusions

Preliminary results of our MR analysis showed an association between SNPs predicting shorter TL and AD endophenotypes, suggesting a potential causal role of telomeres in AD vulnerability, specifically in individuals not at increased genetic risk of AD. Further observational and genetic analyses in larger datasets are warranted to better understand these associations.
The effect of physical activity on CSF biomarkers of Alzheimer’s disease differs between men and women
Authors: Milà‐Alomà Marta , Salvadó Gemma , Gispert Juan Domingo , Vilor‐Tejedor Natalia , Grau‐Rivera Oriol , Sala‐Vila Aleix , Sanchez‐Benavides Gonzalo , Arenaza‐Urquijo Eider M , Crous‐Bou Marta , González‐de‐Echávarri José Maria , Minguillón Carolina , Fauria Karine , Simon Maryline , Kollmorgen Gwendlyn , Rodríguez‐Lantero Juan , Ashton Nicholas J , Zetterberg Henrik , Blennow Kaj , Molinuevo Jose Luis , Suárez‐Calvet Marc ,   ALFA study
Published: December 2020

Background

Increasing evidence suggests that sex influences several aspects of Alzheimer’s disease (AD). Cardiovascular risk factors are associated with AD, and men and women differ in the prevalence of these risk factors. We aimed at determining whether (1) sex and cardiovascular risk factors have an effect on CSF biomarkers; (2) sex modifies the association between cardiovascular risk factors and CSF biomarkers in middle aged cognitively unimpaired individuals of the ALFA+ study.

Method

We measured CSF Ab42, Ab40, p‐tau, t‐tau, neurofilament light (NfL), neurogranin, sTREM2, YKL40, GFAP, S100, IL6, sVCAM1, sICAM1, MCP1 and α‐synuclein in 381 participants of the ALFA+ study (34.4% Ab‐positive, 65.6% Ab‐negative; Ab42/40 cutoff = 0.071). Biomarker measurements were performed using MSD, Roche NeuroToolKit and Elecsys® immunoassays. The following cardiovascular risk variables were studied: hypertension, smoking, dyslipidaemia, physical activity, LDL and HDL cholesterol, glucose, Hb1Ac, triglycerides, BMI and systolic and diastolic blood pressure. ANCOVA was performed to test the effect of sex on each biomarker and potential interaction effects between sex and cardiovascular variables.

Result

We found that CSF NfL, GFAP, IL6, sVCAM1 and MCP1 were higher in men, while CSF neurogranin and YKL40 were higher in women. These differences were still significant after adjusting for Ab pathology. Regarding cardiovascular variables, men had higher diastolic blood pressure, glucose and triglycerides, while women had higher total, LDL and HDL cholesterol. After adjusting for these cardiovascular variables, sex differences in CSF NfL were still significant, suggesting that they were not confounded by cardiovascular factors (Table 1). In the whole cohort, we observed that sex modifies the association with physical activity levels and CSF NfL (interaction ‘sex x physical activity’: p=0.019). After stratifying by Ab status, we observed that higher physical activity was associated with lower CSF NfL only in Ab positive men (Figure 1).

Conclusion

Sex affects CSF biomarkers and modifies their association with cardiovascular risk factors. Specifically, physical activity is associated with lower NfL in middle aged men in the preclinical stage of the Alzheimer’s continuum, but not in women. Our results suggest that the impact of cardiovascular risk factors on neurodegeneration differs between men and women.
Multimodal imaging markers of tau, neuroinflammation and atrophy to predict clinical progression in progressive supranuclear palsy
Authors: Malpetti Maura , Passamonti Luca , Jones P Simon , Rittman Timothy , Fryer Tim D , Hong Young T , Street Duncan , Rodríguez Patricia Vázquez , Bevan‐Jones W Richard , Aigbirhio Franklin I , O'Brien John T , Rowe James B
Published: December 2020

Background

Progressive Supranuclear Palsy (PSP) is associated with tau pathology and neurodegeneration, particularly in basal ganglia, diencephalon, and brainstem. Recently, neuroinflammation has been recognized as another key aspect in the pathophysiology of PSP. Understanding whether these three pathological features predict the clinical progression is crucial to develop new prognostic measures. Here, we studied how baseline assessments of in vivo tau pathology (measured by [18F]AV‐1451 PET), neuroinflammation ([11C]PK11195 PET), and atrophy (structural MRI) predicted longitudinal clinical changes in n=17 patients with PSP‐Richardson’s syndrome.

Method

All patients underwent a baseline multi‐modal assessment with [18F]AV‐1451 PET, [11C]PK11195 PET, and structural MRI. They were clinically assessed up to 4 years, with the PSP rating scale. Regional PET binding potentials and grey‐matter volumes across all brain regions were summarised by method‐specific Principal Component Analyses (PCAs). A linear mixed model was applied to the longitudinal PSP rating scale scores to estimate the rate of annual decline in each participant. We regressed the individuals’ estimated rate of clinical progression on neuroimaging components, to identify the prognostic value of PET and MRI markers in different clusters of regions, with age and time between scan and the first clinical assessment as covariates.

Result

PCAs identified four components for each ligand, reflecting the relative expression of tau pathology or neuroinflammation in distinct groups of brain regions, and seven components of grey‐matter volumes. Patients showed an average increase of 6.15 points (p<0.0001) per year on the PSP rating scale. PCA‐derived components reflecting tau burden (r=0.639, p=0.010) and neuroinflammation (r=0.596, p=0.019) in PSP‐related subcortical areas were linked to the annual rate of change of disease severity. These pathology markers components were associated with atrophy of the same regions (tau: r=‐0.626, p=0.007; neuroinflammation: r=‐0.584, p=0.014) but atrophy did not correlate with clinical progression (r=‐0.474, p=0.074).

Conclusion

In vivo PET markers of both tau pathology and neuroinflammation in subcortical regions predicted clinical progression in PSP patients. Our results encourage the application of [18F]AV‐1451 and [11C]PK11195 PET in PSP as stratification measures that inform prognosis, to develop new targeting disease‐modifying therapies and empower clinical trials.
Multiple biological pathways associate with cerebral amyloid load in the early Alzheimer's continuum
Authors: Salvadó Gemma , Molinuevo Jose Luis , Milà‐Alomà Marta , Falcon Carles , Operto Greg , Cacciaglia Raffaele , Arenaza‐Urquijo Eider M , Vilor‐Tejedor Natalia , Shekari Mahnaz , Minguillón Carolina , Fauria Karine , Battle Mark R , Buckley Chris J , Farrar Gill , Simon Maryline , Kollmorgen Gwendlyn , Blennow Kaj , Zetterberg Henrik , Suárez‐Calvet Marc , Gispert Juan Domingo
Published: December 2020

Background

The pathophysiological events associated with the earliest cerebral amyloid deposition are not fully understood. Here, we describe, in cognitively unimpaired individuals, the association between amyloid load and cerebrospinal fluid (CSF) biomarkers of the pathogenic events described in Alzheimer’s disease (AD): core AD biomarkers (Aβ42/40 and pTau), synaptic dysfunction (neurogranin), neurodegeneration (neurofilament light [NfL]), microglial and astroglial‐related response (sTREM2, YKL‐40, GFAP, S100b), neuroinflammation (IL‐6) and α‐synuclein.

Method

The first consecutive 293 participants of the ALFA+ study with both valid CSF biomarker determination and [18F]flutemetamol amyloid PET scans acquired within one year time were included. We measured the CSF biomarkers using the Roche NeuroToolkit robust prototype assays and the commercially available Elecsys® Phospho‐Tau CSF assay. Centiloid (CL) values and SUVr images were derived from [18F]flutemetamol scans using the whole cerebellum as reference region. We sought for correlations between CSF biomarkers and cerebral amyloid deposition both globally, using the Centiloids as outcome variable, and regionally, using a voxel‐wise approach. The final model used for both analyses included: main effects of all CSF biomarkers and also interaction effects between CSF biomarkers with age, sex and APOE‐ε4 status. Interactions were only included if they showed a trend effect (p<0.10) in the global analysis. Neurogranin and pTau were included in the model as a unique vector due to their high collinearity (r>0.9).

Result

In the global analysis, pTau‐neurogranin, NfL, GFAP and YKL‐40 showed a positive correlation with global amyloid burden (Table 1). Significant interaction effects were found between: age*pTau‐neurogranin (older participants show higher amyloid deposition with higher pTau‐neurogranin); sex*sTREM2 (women with higher sTREM2 had higher amyloid deposition); APOE‐ε4*NfL (carriers with higher NfL had higher amyloid deposition) and APOE‐ε4*α‐synuclein (carriers with higher α‐synuclein had lower amyloid deposition), which are shown in Table 1 and Figure 1. Regional main effects are shown in Figure 2 while interactions are shown in Figure 3.

Conclusion

Neurodegeneration and inflammation pathways are associated to early amyloid deposition. The fact that biomarkers of these pathways show interactive effects with the main AD risk factors (age, sex and APOE‐ε4) also suggests that they play different roles in the early stage of the Alzheimer’s continuum.
Do call it screening: How the conceptualisation of dementia screening is intertwined with its practice
Authors: Kapeller Alexandra , Zeiler Kristin , Gunnarson Martin
Published: December 2020

Background

While the value of early detection of dementia is largely agreed upon, the value of population‐based screening as a means to early detection is controversial. Due to this controversial status, population‐based screening is not recommended in the majority of national dementia plans. Some current practices, though, resemble screening but are called 'active case‐finding' or 'opportunistic screening'. Labelled them as such could help to avoid the ethical scrutiny of screening criteria.

Method

Two practices, the Annual Wellness Visit in the USA and the UK hospital 'case‐finding' scheme, are analysed with different conceptualisations of screening and case‐finding from the literature.

Result

Based on this literature, both practices could be called 'opportunistic screening', which, so we argue, should fulfill the same criteria as population‐based screening. Factors distinguishing the practices are the application of clinical judgement, the way the practice is offered, and whether it targets a predefined population.

Conclusion

No matter how a practice is conceptualised, conforming to the ethical standards should always be ensured. We propose a distinction between population‐based screening, opportunistic screening, and case‐finding. A distinction between active and passive case‐finding is deemed unhelpful.
Dementia knowledge among older Chinese adults: A cross‐national comparison between Melbourne and Beijing
Authors: Zhao Mei , Lv Xiaozhen , Lin Xiaoping , You Emily , Zhang Haifeng , Ellis Kathryn A , Yu Xin , Wang Huali , Lautenschlager Nicola T
Published: December 2020

Background

Improving dementia knowledge among older populations has the potential to reduce risk factors or enable early diagnosis and timely treatment. This study compared dementia knowledge between older Chinese adults in Melbourne, Australia, and Beijing, China, and explored similarities and differences in relation to dementia knowledge between these two groups. Ultimately, this study aims to inform the development of tailored dementia education programs for older Chinese adults.

Method

A cross‐sectional design was employed in this study. In total, 379 participants (153 from Melbourne, and 226 from Beijing) completed the questionnaire. Dementia knowledge was assessed with the Alzheimer's Disease Knowledge Scale (ADKS). Demographic characteristics, dementia‐related experience, and mental health status of study participants were also collected.

Result

In general, older Chinese adults in Melbourne and Beijing present a fair level of dementia knowledge (Mean±SD: 17.2±2.9 versus 17.5±2.9, P=0.179) and patterns of scores of dementia knowledge sub‐domains with highest scores in life impact and lowest scores in caregiving. In these seven domains, the correct response rates of life impact were 77% in Melbourne versus 78% in Beijing (P=0.812), treatment and management were 70% versus 72% (P=0.497), course were 66% versus 70% (P=0.096), assessment and diagnosis were 61% versus 62% (P=0.517), symptoms were 60% versus 59% (P=0.744), risk factors were 47% versus 48% (P=0.604), caregiving were both 36% (P=0.647). Multiple linear regression analysis found that younger age (B=‐0.059, P=0.025) and positive self‐report dementia impact (B=2.955, P=0.042) were significantly associated with a higher level of dementia knowledge in Melbourne, whereas the positive family history of dementia (B=1.415, P=0.040) was significantly associated with a higher level of dementia knowledge in Beijing.

Conclusion

Older Chinese adults living in Melbourne and Beijing only had a fair knowledge about dementia, especially about the sub‐domains of risk factors and caregiving information. Different factors associated with dementia knowledge in these two groups. These findings suggest that dementia education programs for older Chinese adults need to focus on risk factors and caregiving.
Amyloid β redirects norepinephrine signaling to activate the pathogenic GSK3β/tau cascade
Authors: Wang Qin
Published: December 2020

Background

Strong genetic and experimental evidence indicates toxic amyloid β (Aβ) peptides as a key driving factor of Alzheimer’s disease (AD) pathogenesis. The microtubule‐associated protein tau is an essential mediator of Aβ toxicity. Yet, the molecular pathway from Ab to tau pathology remains elusive, presenting a major gap in in‐depth understanding of the pathological cascade of AD. The brain noradrenergic system is highly vulnerable in AD; despite of being a sensitive target of Aβ and tau toxicity, whether it is directly involved in AD pathogenesis is unknown.

Method

We examined the activity of α2A adrenergic receptor (α2AAR) in AD animal models and human postmortem brains using pharmacological methods, performed bioinformatic analysis of cases from the National Alzheimer’s Coordinating Center, characterized Aβ binding of α2AAR using biochemical, cell biological and pharmacological methods, and performed pathological and behavioral studies with AD animal models.

Result

In AD human brains and animal models, α2AAR activity is elevated as compared with non‐AD controls. Activation of this receptor is associated with worsened cognitive function in patients with cognitive deficits. Aβ oligomers bind to an allosteric site on α2AAR with nanomolar affinity. Aβ oligomer binding redirect norepinephrine‐elicited signaling through this receptor to glycogen synthase kinase 3β (GSK3β) activation and tau hyperphosphorylation. This norepinephrine‐dependent mechanism sensitizes pathological GSK3β/tau activation in response to nanomolar accumulations of extracellular Aβ, which is 50‐100 fold lower than the amount required to activate GSK3β by Aβ alone. In vivo treatment with an α2AAR blocker reduces Aβ‐induced GSK3β activation and tau hyperphosphorylation. Moreover, this treatment ameliorates AD‐related pathological changes and improves cognitive function in the two independent AD mouse models.

Conclusion

We reveal a previously unappreicated direct role of norepinephrine signaling in connecting Aβ and tau, two key pathological components of AD pathogenesis. The significance of our findings is supported by in vivo evidence in two mouse models, human tissue sample analysis and longitudinal clinical data. Our study provides translational insights into mechanisms underlying Aβ proteotoxicity, which might have strong implications for the interpretation of Aβ clearance trial results and future drug design, and for understanding the selective vulnerability of noradrenergic neurons in AD.
Longitudinal plasma levels of neurofilament light in Down syndrome: A multicenter study
Authors: Alcolea Daniel , Carmona‐Iragui Maria , Barroeta Isabel , Videla Laura , Muñoz Laia , Van Pelt Kathryn L , Schmitt Frederick A , Lightner Donita , Koehl Lisa , Sacco Silvia , Mircher Clotilde , Pape Sarah , Nübling Georg , Levin Johannes , Zaman Shahid , Strydom Andre , Rebillat Anne‐Sophie , Head Elizabeth , Blesa Rafael , Lleó Alberto , Fortea Juan
Published: December 2020

Background

Plasma Neurofilament light (NfL) has been proposed as a useful biomarker to detect Alzheimer’s disease dementia in Down syndrome. To validate its clinical utility and implement it in clinical trials, it is essential to understand the longitudinal changes of this biomarker, and the association of these changes to clinical progression.

Method

We included participants with Down syndrome evaluated in six different centers. All participants provided at least two plasma samples and were clinically classified as asymptomatic (aDS), prodromal Alzheimer’s disease (pDS) or Alzheimer’s disease dementia (dDS). The aDS and pDS participants were subsequently classified as “Progressors” when their diagnosis changed to pDS or dDS, respectively, at any time throughout follow up visits. Plasma NfL levels were measured using commercially available kits for the Simoa SR‐XTM (Quanterix). We performed ANCOVA and Cox regression to evaluate group differences in baseline NfL levels and their association with prognosis. We used linear mixed models to estimate longitudinal trajectories of plasma NfL in all groups.

Result

We analyzed 575 samples from 226 participants classified as aDS (n=165), pDS (n=32) or dDS (n=29). Participants in the pDS and dDS groups were older than aDS (50.6 and 53.3 vs. 38.9, respectively; p<0.001). After adjusting for age, sex and intellectual disability, levels of NfL were 79.9% higher (p<0.001) in dDS and 40.5% higher (p<0.001) in pDS compared to aDS (Figure 1). The highest tertile of baseline plasma NfL was associated to a 5.9 fold risk of clinical progression (p<0.001; Figure 2). Longitudinally, aDS non‐progressors showed an annual increase of 2.7% (0.2%‐5.3%, p=0.036) in NfL levels, significantly different from 12.2% (5.1%‐19.9%, p=0.014) in aDS progressors, 16.1% (8.7%‐24%, p=0.001) in pDS progressors and 21.7% (13.2%‐30.9%, p<0.001) in dDS (Figure 3).

Conclusion

This study confirms the clinical utility of plasma NfL to diagnose symptomatic Alzheimer in Down syndrome, but also shows that the annual increase in NfL levels do not plateau in dementia stages. These longitudinal trajectories enable its use as a theragnostic marker in clinical trials.
Dominantly inherited Alzheimer disease: Frequency, genetic heterogeneity, and clinical phenotype in Latin America
Authors: Guerra Jorge J Llibre , Mendez Patricio Alexis Chrem , Allegri Ricardo F. , Surace Ezequiel , Llibre‐Rodriguez Juan , Ibarrola Mariana Longoria , Cornejo‐Olivas Mari , Sosa‐Ortíz Ana Luisa , Takada Leonel Tadao , Lopera Francisco , Sanchez Victor , Jiménez‐Velazquez Ivonne Z. , Acosta Daisy , Behrens María Isabel , Doering Michelle , Li Yan , Morris John C. , McDade Eric , Bateman Randall J.
Published: December 2020

Background

More than 300 pathogenic variants in APP, PSEN1 and PSEN2 genes have been reported causing Dominant Inhered Alzheimer Disease (DIAD); most of these reports come from Northern hemisphere countries. In recent years, a growing number of familial AD cases have become known in Central and South American countries; however, little is known about epidemiology and clinical‐genetic profile of DIAD in Latin American (LatAm) countries. We aimed to systematically review and describe DIAD cases reported in LatAm populations.

Method

A systematic review for all DIAD cases reported in LatAm was completed between September 2019 to December 2019. The search strategy included the following major databases: MedLine, SciELO, Cochrane, and LILACS. More than 927 records were screened and 106 peer‐reviewed publications on DIAD families from LATAM were included in the final analysis. We extracted individual‐level data on the age at onset(AAO), disease course, and the presence/absence of neurological findings. Findings extracted from literature were updated by local researchers . The combined dataset included 843 family members, of whom 237 were affected by DIAD. Analyses were done using descriptive statistics, comparisons of means and frequencies.

Result

24 DIAD pathogenic variants have been reported in LatAm countries, including 21 PSEN1, two PSEN2 and one APP variant. Countries with higher DIAD frequency were Colombia, Puerto Rico, Mexico, and Cuba, usually related to founders' effects on these regions. AAO differed by causing gene, with a younger age at onset for individuals harboring PSEN1 variants, followed by APP and PSEN2 carriers (43.8 ± 8.9 years vs 48.6 ± 1.6 years vs 52.2 ± 2.1 years respectively, p < 0.0001). The most common clinical presentation was amnestic. Atypical features were described with M146V‐PSEN1(Argentina) and A431E‐PSEN1 (Mexico) presenting with FTD‐like syndrome and spastic paraparesis respectively. We found that affected individuals carrying PSEN1 mutations also experience myoclonus, pyramidal, and cerebellar signs (p < 0.001, p = 0.002, and p = 0.003, respectively).

Conclusion

This work describes an initial overview of DIAD in LatAm. The discovery and clinical characterization of DIAD families from Lain America will inform the development of the DIAN‐observational study in the region and will create a cohort ready population for clinical the upcoming trials.
Evaluation of the efficacy and safety of orally administered BI425809 during a 12‐week treatment period compared with placebo in patients with cognitive impairment due to Alzheimer’s disease
Authors: Wunderlich Glen , Blahova Zuzana , Garcia Miguel , Huang Songqiao , Pollentier Stephane , Jessen Frank
Published: December 2020

Background

Although currently approved therapies for Alzheimer’s dementia (AD) are used to treat impairments in memory and function, there is an unmet need for additional symptomatic therapies in mild‐to‐moderate AD. As N‐methyl‐D‐aspartate (NMDA) receptor hypofunction has been hypothesised to be associated with cognitive impairment in AD, improving post‐synaptic NMDA receptor signalling through glycine transporter 1 (GlyT1) inhibition may improve cognitive function. This proof of clinical concept study investigated the efficacy and safety of the investigational drug BI 425809, a GlyT1 inhibitor, in mild‐to‐moderate AD and evaluated dose‐ranging data to define a suitable dose of BI 425809 in this population.

Method

A Phase II, multicentre, double‐blind, parallel‐group study including patients aged ≥55 years with mild‐to‐moderate AD (according to the recommendations from the National Institute on Aging‐Alzheimer’s Association workgroups on diagnostic guidelines for AD), a mini‐mental state exam score of 15–26 at screening, and a reliable study partner who was in close contact with the patient and could contribute to the neuropsychological rating scales. Concomitant acetylcholinesterase inhibitor use was permitted but not required. Eligible patients were randomised (1:1:1:1:1) to receive BI 425809 2, 5, 10, 25 mg, or placebo once daily for 12 weeks. The primary endpoint was change from baseline in Alzheimer’s Disease Assessment Scale‐cognitive subscale (ADAS‐Cog11) total score at Week 12. Secondary endpoints included change from baseline in the Alzheimer’s Disease Cooperative Study/Activities of Daily Living score and Clinician's Interview‐Based Impression of Change at Week 12. The pre‐specified primary analyses for proof of concept and dose finding was the multiple comparison procedure with modelling for mixed model repeated measures. Adverse events were evaluated throughout the study.

Result

A total of 610 patients were randomised. No significant non‐flat dose‐response relationship was detected for the primary endpoint. Secondary endpoints similarly did not detect any significant benefit for BI 425809 treatment groups compared with placebo. BI 425809 was generally well tolerated with no new safety issues identified.

Conclusion

No clinically meaningful changes from baseline were observed across a range of BI 425809 doses administered to patients with mild‐to‐moderate AD. Funding: Boehringer Ingelheim: Study 1346‐0023 (NCT02788513).
Sex difference in white matter degeneration in MCI adults: Multi‐modal MRI analysis
Authors: Kim Jeongchul
Published: December 2020

Background

Although the development and progression of Alzheimer's disease (AD) are characterized by significant sex differences, the factors underlying sex differences in AD are not well understood. This study explored sex differences in white matter (WM) degeneration patterns among mild cognitive impairment (MCI) adults in an exercise intervention study.

Method

Longitudinal MR images for 32 adults with MCI were acquired as part of a randomized controlled trial investigating an exercise intervention (n=15 aerobic exercise, n=17 stretching control). Brain MRI was acquired at baseline and 6 months later after the exercise intervention on a 3T scanner using a 32‐channel head/neck coil. High‐resolution structural anatomic T1‐weighted and diffusion tensor images of each subject were collected, from which the longitudinal changes of diffusion metrics (FA, MD and Fiber Volume Fraction [FV]) and volume changes (Jacobian Determinant, JD) rate were estimated for 48 WM regions of interest (ROIs) defined by the JHU‐WM Atlas. The total WM degeneration for each individual was defined by counting the number of ROIs demonstrating > 5% changes in diffusion metrics or JD compared to the baseline considering fiber crossing environments (Figs. 1 and 2).

Result

No statistically significant change was observed in FA, MD, FV, JD and WM degeneration for both groups during the 6‐month period. But, increase in FA was observed in Right Posterior Corona Radiata for the whole study population (p=0.0087). A wide distribution of WM degeneration was observed over the different brain regions with a higher probability of WM degeneration in Left Posterior Limb of Internal Capsule (59%), Right Retrolenticular Part of Internal Capsule (56%) and Left Anterior Corona Radiata (56%). Higher WM degeneration was observed in women compared to men (p=0.029) after adjustment for age, exercise intervention and APOE4 status.

Conclusion

Group‐level changes or differences were not observed for most longitudinal MRI measures due to the heterogeneity of WM degeneration in MCI adults. However, a multi‐modal MRI approach integrating morphometric information with diffusion properties could elucidate the sex differences in WM degeneration among MCI adults.
Impact of vascular factors and tau deposition on functional brain network connectivity in participants of the Framingham Heart Study
Authors: Rahimpour Yashar , Himali Jayandra J , Beiser Alexa S , Habes Mohamad , O’Donnell Adrienne , Johnson Keith A , Killiany Ronald J , Seshadri Sudha
Published: December 2020

Background

The goal of this study was to determine whether vascular factors, expressed as the Framingham Stroke Risk Profile (FSRP), and/or tau deposition impact functional brain connectivity within and between functional brain networks i.e. default mode, frontoparietal, dorsal attention, and ventral attention networks. Regional blood flow measured by fMRI has been used to infer functional brain connectivity. Regions with synchronized blood flow are thought to be functionally connected while areas that have desynchronized blood flow are thought to be less functionally connected. Factors such as age have been linked to a reduction in functional connectivity.

Method

224 participants (mean age 54±8, 56% men) from the third generation of the Framingham Heart Study were imaged at Boston University from September 2015 to August 2018. Each participant had a high resolution MPRAGE T1 and a seven‐minute resting state fMRI scan. The T1 scans were processed using Freesurfer v6.0 and the resting state fMRI scans with FSL. Functional networks were constructed using the Yeo 7 network atlas (Yeo, 2011). Correlations within and between the functional brain networks were generated and z corrected. The relationship between FSRP, regional amyloid using the Pittsburgh B ligand, tau deposition using Flortaucipir, and functional connectivity were assessed using linear regression models adjusted for age, sex and interval between FSRP (or amyloid and tau) measurements and fMRI.

Result

Vascular risk factors and tau deposition had opposite impacts on functional connectivity. Increases in the FSRP were linked to increased functional connectivity between the default mode and visual networks, as well as the frontoparietal. Conversely, tau deposition in the inferior temporal, precuneus, and entorhinal cortices was linked to a reduction in functional connectivity within the frontoparietal network, between the default mode and somatomotor, and dorsal attention and somatomotor networks.

Conclusion

Vascular risk factors appear to relate to an enhancement of functional connectivity while regional tau deposition appears to have an adverse impact on both within and between network connectivity. It is plausible that these changes in functional connectivity represent a compensatory response in the brain to alterations in vascular function and the presence of neuropathology in order to maintain cognitive abilities.