bluuebunny/crossref_metadata_2025 huggingface dataset:
White matter microstructure and cognitive functioning across healthy older adults with different APOE alleles
Authors: Lacey Colleen , Gawryluk Jodie
Published: December 2021

Background

APOE alleles play an important neurobiological role in the development of Alzheimer’s Disease (AD), including modifying structure of white matter in the brain and cognitive decline (Gold et al., 2012; Reas et al., 2019). However, certain alleles (i.e., APOE‐e4) have be studied more than others (i.e., APOE‐e2 & e3), and have been primarily studied in individuals already diagnosed with AD, rather than in healthy older adults. While APOE‐e4 is well establish risk factor for AD, APOE‐e2 may play a role in protective mechanisms against AD, and APOE‐e3 may be neutral, yet their underlying neural mechanisms and association with cognitive functioning in the healthy aging brain are equivocal (Suri et al., 2013). Thus, the current study aimed to investigate the influence of different APOE alleles on white matter microstructure and cognition in healthy older adults.

Method

White matter microstructure, memory, and executive functioning (EF) were compared between cognitively normal older adults with either APOE‐e2+ (n= 16, mean age= 76), APOE e3e3 (n= 64, mean age= 74), or APOE‐e4+ (n=35, mean age=73). White matter microstructure was compared using Diffusion Tensor Imaging (DTI) Track‐based spatial statistics (TBSS) methods to derive fractional anisotropy (FA). Whole‐brain mean FA was compared first between e3e3 and e2+ and then between e3e3 and e4+ groups. Memory and executive functioning composite scores were compared, including covariates of age, sex, and education levels, using multivariate analysis of covariance (MANCOVA). All data were retrieved from the Alzheimer’s Disease Neuroimaging Initiative (ADNI).

Result

No significant differences in white matter microstructure (FA; p> 0.05, corrected) were observed. Further, groups were not significantly different in memory, EF, age, sex, or education levels (p=0.59).

Conclusion

These results indicate that white matter microstructure, memory, and EF changes are not evident in the healthy brain as a function of APOE allele presence. DTI may not be sensitive to APOE‐related changes in the healthy brain; nonetheless, future investigations should evaluate whether other structural (e.g., grey matter volume) and functional (e.g., fMRI) differences are evident across different APOE alleles in this population, as well as examine other cognitive domains.
UW Project ECHO‐Dementia: Implementation of a virtual clinic and telementoring program to improve dementia diagnosis and treatment in rural and under‐resourced primary care settings
Authors: Rhoads Kristoffer , Isenberg Nancy , Schrier Allyson
Published: December 2021

Background

Primary care providers are on the front lines of dementia care and frequently the first point of contact for individuals and families concerned about changes in memory and thinking. In addition to the challenges of managing complex medical comorbidities, primary care providers in rural or lower‐resource settings often lack access to specialists, interdisciplinary teams or other programs and services to aid in diagnosis and care of individuals with mild cognitive impairment and dementia. The current project extends an existing technology‐based hub and spoke model virtual clinic, Project ECHO (Extension for Community Healthcare Outcomes, University of New Mexico), to improve diagnosis and care of dementia in primary care.

Method

The current project is an extension of work related to the Washington State Plan for Alzheimer's Disease and Other Dementias with implementation supported by legislative funding. The program includes an interdisciplinary expert panel (“hub”) meeting with participants (“spokes”) including primary and allied health care providers from healthcare systems, group practices, and solo practitioners. The twice‐monthly virtual clinic sessions include a brief didactic followed by case‐based learning in an “all‐teach, all‐learn” format emphasizing expertise and experience of spoke sites as well as the hub. Participants are provided with resources discussed during the clinic session, ongoing opportunities for consultation, and free continuing education credits.

Results

Launching amid the COVID‐19 pandemic, the program has provided over 250 hours of education to more than 50 providers across 20 unique sites. Post session surveys indicate that the program is well‐received with 2 in 3 providers indicating that they will change their practice based on learning. Surveys also demonstrate significant increases in both knowledge and confidence in dementia‐specific diagnosis and care.

Conclusion

The success of the current project demonstrates both the feasibility and benefit of leveraging technology to deliver dementia‐related education to primary care providers in rural and under‐resourced settings. While initially hampered by disruptions in care due to the COVID‐19 pandemic, increased technological proficiency on the provider and systems level has appeared to be a benefit in terms of resources and comfort participating in a virtual education program to scale Dementia Capable Care in Primary Care.
Association of the Mediterranean diet with cognition in a Western population
Authors: Sabeti Neda , O'Leary Fiona , Flood Victoria M , Valenzuela Michael , Radd‐Vagenas Sue , Noble Yian , Rangel Carolina Almendrales , Gracham Ali , Heffernan Megan , Sachdev Perminder S , Brodaty Henry , Lautenschlager Nicola T , Singh Maria A Fiatarone
Published: December 2021

Background

The Mediterranean‐style diet (MD) is promoted as one of the healthiest dietary patterns and has been shown to reduce cognitive decline in some randomised controlled trials (RCTs). This pattern is plant‐based with a focus on vegetables, legumes, fish, and olive oil, with low intake of red meats and foods high in sugar and saturated fats. The Maintain Your Brain (MYB) study is an online multi‐domain RCT targeting modifiable risk factors for dementia, including diet. This study investigated cross‐sectional associations between adherence to a MD pattern and cognition.

Methods

Participants enrolled in MYB were recruited from the Sax Institute’s larger 45 and Up Study, and included those with all baseline MYB assessments (n=6236). Diet was assessed using the validated Mediterranean Diet and Culinary Index tool. This 50‐item tool assesses intake of nine desirable and four undesirable features of the MD diet and allows derivation of the Mediterranean Diet Adherence Screener (MEDAS). Computerised cognitive tests, administered through the MYB digital platform, were used to assess domains of executive function, complex attention, learning and memory and global cognition.

Results

Participants were 46% male, with mean (SD) age 65.0 (5.8) years, BMI 26.6 (4.9) kg/m2 and well educated (46% with tertiary education). Higher MEDAS scores were associated with being female, younger, better educated and having a lower BMI (all p<0.001). Overall participant adherence to a MD pattern was low; MEDAS score 6.1 (2.1)/14. After covariate adjustment and correction for multiple analyses in hierarchical linear regression models, better MEDAS scores were significantly associated with worse (lower) z‐scores for executive function (β ‐0.018, p=0.003). For every 1‐point higher MEDAS score, executive function z‐scores were 0.018 lower. This unexpected negative association was clinically very small. There were no significant associations with other cognitive domains.

Conclusion

Adherence to a MD was sub‐optimal in this well‐educated Australian sample. The one unexpected finding is likely not clinically meaningful given its size. Additionally, as this was a cross‐sectional study, reverse causality cannot be ruled out. Results from the main MYB RCT will provide data on MD acceptance and impact in a Western dietary environment.
Cultural adaptation and validation of the Addenbrooke’s Cognitive Examination III in a Taiwanese population (T‐ACE‐III) presenting to hospital with suspected dementia
Authors: Yu Ruan‐Ching , Mukadam Naaheed , Kapur Narinder , Stott Joshua , Livingston Gill
Published: December 2021

Background

The Addenbrooke’s Cognitive Examination III (ACE‐III) is an effective cognitive test for detecting dementia in many countries and covers a wide range of cognitive domains. However, there has been no study about the usefulness of the ACE‐III in patients with suspected dementia in Taiwan where patients use Traditional Chinese, unlike mainland China. We therefore aimed to culturally adapt and find the sensitivity and specificity of the ACE‐III for investigating people with possible dementia presenting to hospital in Taiwan.

Method

We used the guideline for cross‐cultural adaptation process to culturally adapt the simplified Chinese version (C‐ACE‐III) for Taiwanese populations (T‐ACE‐III). We recruited consenting patients who had presented to clinics with suspected dementia in Northern Taiwan and had been through the diagnostic process. We timed the interviews and conducted receiver operating characteristic (ROC) curve analysis to test the ability of the T‐ACE‐III to differentiate between dementia and non‐dementia using clinical diagnosis as the gold standard. We used linear regression to find significant predictors of ACE‐T score entering age, education, sex, language group, and dementia status as possible predictors.

Result

110 participants were invited, of whom 91 Chinese/ Hokkien‐speaking individuals aged 49 to 93 years consented to take part and ninety completed the test: 24 males and 33 females with dementia and 12 males and 21 females without. It took on average 16.3 and 24.0 minutes to administer in non‐dementia and dementia group, respectively. The T‐ACE‐III demonstrated a sensitivity of 100.0% and a specificity of 78.8%, for distinguishing dementia from non‐dementia with a cut‐off value of 86/87, a sensitivity of 89.5% and a specificity of 100.0%, with a cut‐off value of 73/74. The area under the curve (AUC) = 0.99 in T‐ACE‐III. The diagnosis of dementia, and language used were significant predictors accounting for 68.1% of the variance in T‐ACE‐III scores.

Conclusion

The culturally adapted T‐ACE‐III is a brief, reliable, and acceptable tool for discriminating dementia from non‐dementia cases in a Taiwanese population in a memory clinic setting.
Differential associations of modifiable and non‐modifiable dementia risk factors with memory decline and hippocampal volume loss in Aβ‐ and Aβ+ cognitively normal older adults
Authors: Rosenich Emily , Pase Matthew P , Yassi Nawaf , Fripp Jurgen , Laws Simon M , Fowler Christopher J , Rowe Christopher C , Masters Colin L , Maruff Paul T , Lim Yen Ying , Group AIBL Research
Published: December 2021

Background

The extent to which modifiable and non‐modifiable risk factors contribute to cognitive decline in older people remains unclear. We sought to determine the association of modifiable and non‐modifiable components included in the Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) score with memory decline and brain volume loss in cognitively normal (CN) older adults, taking Aβ status into account.

Method

AIBL study participants (age range: 60‐90) who completed ≥2 neuropsychological assessments and an Aβ PET scan (N=626) were included in this study. We computed the standard CAIDE (age, sex, APOE ε4 status, education, hypertension, body mass index, hypercholesterinemia, physical inactivity), and a modifiable CAIDE (modCAIDE; education, modifiable vascular risk factors) for each participant. Aβ+ was classified using a Centiloid ≥25. Linear mixed models assessed interactions between each CAIDE score on episodic memory (EM) and hippocampal volume (HV) over time in Aβ‐ and Aβ+ CNs. Non‐modifiable variables from the standard CAIDE (age, sex, ε4) were included as separate predictors in all modCAIDE models to assess differential associations.

Result

We observed a significant standard CAIDE x time interaction on EM decline in Aβ+ (β=‐0.08(0.04); p=0.02) and Aβ‐ participants (β=‐4.07(1.13); p<0.001), and a significant standard CAIDE x time interaction on HV loss in Aβ+ participants only (β=‐0.06(0.02); p=0.003). When modifiable and non‐modifiable CAIDE components were considered separately, we observed a significant ε4 x time interaction only for EM decline (β=‐0.32(0.07); p<0.001) and HV loss (β=‐0.13(0.04); p<0.001) in Aβ+ participants, but no significant modCAIDE x time interaction (both p’s>0.29). In Aβ‐ participants, we observed a significant modCAIDE x time interaction on memory decline (β=‐0.04(0.02); p=0.02), but no significant ε4 x time interaction (β=‐0.07(0.04); p=0.11). No significant ε4 x time or modCAIDE x time interactions were observed for HV loss in Aβ‐ participants.

Conclusion

Our results are consistent with previous studies showing that ε4 is associated with an increased rate of EM decline and HV loss in Aβ+ CNs. In Aβ‐ CNs, lower prevalence of modifiable cardiovascular risk factors was associated with better EM performance over time, suggesting interventions to reduce modifiable risk factors could be beneficial in this group.
API generation program: Active immunotherapy CAD106 slows amyloid deposition in cognitively unimpaired APOE4 homozygotes
Authors: Riviere Marie‐Emmanuelle , Turner Raymond Scott , Sui Yihan , Laurent Nathalie , Langbaum Jessica B. , Cazorla Pilar , Ricart Javier , Seneca Nicholas , Caputo Angelika , Reiman Eric M. , Tariot Pierre N. , Graf Ana
Published: December 2021

Background

The Alzheimer’s Prevention Initiative (API) Generation Study 1 (NCT0256551) evaluated CAD106, an active immunotherapy against Aβ, in delaying the clinical onset of Alzheimer’s disease in a cohort of cognitively unimpaired APOE4 homozygotes. Effect of CAD106 on brain amyloid burden after 2 years was measured by amyloid PET. Previous studies in mild AD showed that doses up to 450μg CAD106 induced sustained Aβ‐antibody response with no major safety concerns (Vandenberghe, 2017).

Method

Cognitively unimpaired APOE4 homozygotes age 60‐75 were enrolled using a 5:3 randomization ratio (CAD106 450μg:placebo). Intramuscular injections were administered at 0, 6, 12 weeks and then quarterly with alum as adjuvant. PET scans were conducted at baseline and 2 years mainly with florbetapir. Standard uptake value ratios (SUVRs) were calculated using cortical composite region in reference to cerebellum and converted to centiloids.

Result

Out of 65 randomized participants (42:23 CAD106:placebo) 59 were followed for 18 months or longer. Mean age at baseline was 65 years, 68% were female. Mean baseline RBANS total score was 106. Year 2 PET scans were acquired in 35 CAD106 and 16 placebo participants with centiloid mean baseline of 49.5 (38.7).

CAD106 induced measurable Aβ‐specific IgG titers in all treated participants. Mean (SD) annualized centiloid change from baseline was +8.4 (6.7) on placebo without change with CAD106 ((‐0.9 (5.7), p<0.0001). The effect was more pronounced in amyloid positives: +9.4 (7.7) on placebo and ‐1.8 (6.0) with CAD106, vs in amyloid negatives: +6.7 (4.7) on placebo and +2.2 (2.8) with CAD106. In the CAD106 arm, the effect on PET correlated with antibody titers, especially for amyloid positive subgroup.

Higher incidences for psychiatric (21% vs 13%) and general disorders / injection site (64% vs 22%) adverse events were reported with CAD106 vs placebo. Three cases of ARIA (2 ARIA‐H and 1 ARIA‐E) occurred on CAD106 (none on placebo). Cognition scores remained stable for 18 months in both groups.

Conclusion

CAD106 is the first active immunotherapy shown to slow amyloid deposition in humans. Treatment with CAD106 might have a positive risk/benefit profile for prevention of amyloid deposition in high‐risk populations.
The cerebrospinal fluid interleukin 8 (IL‐8) concentration in Alzheimer’s disease (AD)
Authors: Doroszkiewicz Julia , Kulczynska‐Przybik Agnieszka , Dulewicz Maciej , Borawska Renata , Krawiec Anita , Slowik Agnieszka , Mroczko Barbara
Published: December 2021

Background

Alzheimer disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia. The hallmarks underlying AD pathology are amyloid‐β peptides, phosphorylated tau proteins and neuroinflammation. In vitro studies on cultured human microglia display a significant role of Interleukin 8 in neuroinflammation. Furthermore, CXCR2, IL‐8 receptor, was found in dystrophic neurites which suggests connection to neuroinflammation in AD. Literature data indicates that gene polymorphism in IL‐8 may affect the predisposition of Alzheimer's disease. It has been observed that IL‐8 may increase Tau phosphorylation and subsequent NFTs formation. Thus, the aim of our research was to measure the concentration of IL‐8 in cerebrospinal fluid of AD patients and non‐demented controls. Moreover, we compare them to the concentrations of classical AD biomarkers, such as Aβ‐42, Aβ‐42/Aβ‐40, Tau and pTau181.

Method

The concentrations of IL‐8 and classical AD biomarkers, such as Aβ‐42, Aβ‐42/Aβ‐40, Tau and pTau181 were measured in cerebrospinal fluid (CSF) of 15 AD patients and 16 non‐demented controls using immunoenzyme assays.

Result

IL‐8 concentrations were significantly higher in AD patients in comparison to non‐demented controls. Moreover, increased CSF levels of IL‐8 correlated with Aβ‐42/Aβ‐40 ratio, MMSE, Tau and pTau181 in the whole study group.

Conclusion

Findings of our research suggest a potential role of IL‐8 in pathology of AD. However, follow‐up studies on larger study group are needed. Acknowledgement: The study was conducted with the use of equipment purchased by Medical University of Białystok as part of the RPOWP 2007‐2013 funding, Priority I, Axis 1.1, contract No. UDA‐RPPD.01.01.00‐20‐001/15‐00 dated 26.06.2015.
Diagnosis of Alzheimer's disease before dementia: A study of UK psychiatrists
Authors: Walpert Madeleine , Mitchell Susan , Bamford Claire , Ivenso Chineze , McKirdy Stuart , Pattan Vivek , Rodda Joanne , Sikdar Sudip , Barber Robert
Published: December 2021

Background

Alzheimer’s disease (AD) is increasingly conceptualised as a continuum spanning presymptomatic, symptomatic pre‐dementia and dementia stages. With potential disease modifying treatments emerging, this study explored the views of clinicians working in Old Age Psychiatry in the UK regarding the diagnosis of symptomatic AD before dementia, including the role of biomarkers, and the preparedness of services to deliver future disease modifying treatments.

Method

This study, conducted by the Royal College of Psychiatrists and Alzheimer's Research UK, used a two‐stage quantitative and qualitative approach consisting of an online survey (n=493) followed by focus groups (n=42) of clinicians.

Result

Conceptualising AD as a continuum was considered a helpful framework for thinking about disease pathology, progression and treatment. However, translating this framework into clinical practice generated a number of challenges including uncertainties about diagnostic nomenclature and criteria with at least seven diagnostic terms possible. Overall, terms referencing “mild cognitive impairment” were considered more helpful than those explicitly stating AD. Hesitancy to reference AD at this stage was influenced by concerns about the accuracy of diagnostic criteria, limitations linked to biomarkers and potential negative impacts on individuals, especially in the absence of disease modifying treatments. Access to biomarkers other than CT was sub‐optimal, 96% of responders reported insufficient or no access to CSF and 93% to PET Aβ, limited access negatively impacted on the clinician’s confidence in their utility (P<0.001).

Psychiatrists indicated that it was important their services offer disease modifying treatments if licensed but recognised that services faced significant challenges to be prepared, including capacity, resources and staff expertise.

Conclusion

Diagnosing AD before the onset of dementia is likely to become increasingly relevant if new treatments are licensed, but this study highlights a number of important challenges to achieve this including concerns about the reliability and validity of the diagnostic criteria and access to key biomarkers. There was a clear view that Old Age Psychiatry services should be able to provide any future treatments alongside their usual care but recognition that this would require better access to biomarkers, clearer diagnostic criteria, up‐skilling of staff and changes to training as well as changes to care pathways.
The association between retinal neurodegeneration and plasma neurofilament light chain: A population‐based study
Authors: Garzone Davide , Finger Robert P. , Mauschitz Matthias M. , Santos Marina , Breteler Monique M.B. , Aziz N. Ahmad
Published: December 2021

Background

Both plasma neurofilament light chain (NfL) levels and retinal layer volumes have emerged as biomarkers of central neurodegeneration, the former highlighting neuroaxonal damage, the latter as an extension of the brain susceptible to similar injuries. To date, the extent to which plasma NfL levels and retinal layer volumes could be used as complementary biomarkers of brain health is unknown. Therefore, we assessed their association in the general population

Method

The study is based on the first 5000 participants of the Rhineland Study, a population‐based cohort study in people aged 30 years and above in Bonn (Germany). We included all participants with complete spectral‐domain optic coherence tomography (SD‐OCT) and plasma NfL data (N=4396, after removal of three outliers due to extreme values). We applied multivariable regression analysis to investigate associations between different retinal layer volumes and plasma NfL levels, assessing effect modification by age, sex, hypertension, smoking and presence of neurological diseases (N=95, including stroke, dementia and multiple sclerosis).

Result

NfL levels increased, while ganglion cell layer (GCL) volume decreased exponentially with advancing age. Among the different retinal layers, GCL volume was most closely associated with NfL levels, with a strong age‐dependent association: while no association was evident in young individuals, in older individuals lower GCL volume was related to higher NfL levels (std. beta for the interaction effect of GCL with highest tertile of age = ‐0.032, 95% CI [‐0.06 ‐ ‐0.005],p=0.02). Similarly, smaller GCL volume was associated with higher NfL levels in participants with hypertension (std.beta ‐0.06, 95% CI [‐0.011 ‐ ‐0.02],p=0.003) or a neurological disease (std. beta ‐0.018, 95%CI [‐0.035 ‐ ‐0.001], p=0.037), but not in those without disease.

Conclusion

Our findings indicate that retinal layers volume,in particular GCL, more closely reflect neuroaxonal damage in higher age or in the presence of cardiovascular risk factors and neurological diseases.
Alzheimer’s disease CSF biomarker assays: Impact of methodology changes in clinical practice
Authors: Campbell Michelle R. , Kian Susan Ashrafzadeh , Petersen Ronald C. , Bornhorst Joshua A , Algeciras‐Schimnich Alicia
Published: December 2021

Background

Decreased amyloid β1‐42 (Aβ42) and increased tau (t‐Tau and p‐Tau) concentrations in cerebrospinal fluid (CSF) reflect the pathological changes of Alzheimer’s disease (AD) and aid in the diagnosis of AD dementia. In the United States, the ADmark® assay has been almost exclusively used for the measurement of these biomarkers in clinical practice. Recently, our institution switched from the ADmark® assay to the Roche Elecsys assays. The goal of this study was to determine if differences exist between these methods in classification of patients as having changes indicative of AD pathology.

Method

Patients undergoing ADMark® testing (n= 73) were recruited to participate in this IRB‐approved study. Two simultaneous CSF aliquots were obtained. For ADMark®, 2.0mL were collected into a 5mL polypropylene (PP) tube and shipped frozen to Athena Diagnostics per collection instructions for testing (Innotest® immunoassays for Aβ42, t‐Tau, and p‐Tau). For the Roche Elecsys assays (Aβ42, t‐Tau, and p‐Tau), 2.0mL were collected into a 2.5mL low bind PP tube, frozen, and then tested at Mayo Clinic Laboratories. Comparative analysis was performed between the two testing methodologies and to clinical findings.

Result

Overall concordance between the ADMark® Aβ42/t‐Tau index (ATI) and Roche p‐Tau/Aβ42 was 89% with 8 (11%) discrepant cases. Four cases were classified as normal by the Roche p‐Tau/Aβ42 but borderline (n=3) or abnormal (n=1) by ADMark® ATI. Four cases were classified as abnormal by the Roche p‐Tau/Aβ42 and borderline by ADMark® ATI. In these cases, the normal Roche p‐Tau/Aβ42 result was most consistent with clinical diagnosis. When compared to clinical diagnosis, cases with clinical suspicion of AD dementia were abnormal in 84% and 92% of cases with the ADMark® ATI and the Roche p‐Tau/Aβ42, respectively. In cases without clinical suspicion of AD dementia, results were abnormal in 19% and 21% of cases with the ADMark® ATI and the Roche p‐Tau/Aβ42, respectively. There were 2 cases with clinical suspicion of AD dementia and 5 cases without suspicion of AD dementia that were classified as borderline by ADMark® ATI.

Conclusion

Roche p‐Tau/Aβ42 showed comparable performance to ADMark® ATI when correlating results to clinical diagnosis of AD dementia.
Gender differences in the association between persistent pain and cognitive decline over 14 years among Mexicans aged 50 and older
Authors: Milani Sadaf Arefi , Gutierrez Sirena , Wong Rebeca , Samper‐Ternent Rafael , Downer Brian
Published: December 2021

Background

Pain is associated with cognitive decline, but research has not considered low‐ and middle‐income countries (LMICs) such as Mexico and gender differences. This is an important gap, as individuals living in Mexico have a large burden of chronic pain due to exposure to risk factors over the life course.

Methods

Using data from the Mexican Health and Aging Study (MHAS), a nationally representative study of Mexicans aged 50 and older, we assessed the association of persistent pain with cognition from 2001 to 2015. Persistent pain was defined as moderate or severe pain reported in 2001 and 2003. Non‐persistent pain was defined as pain that was not moderate or severe in 2001 and 2003. Cognition was measured using the MHAS cognitive battery and was standardized for global cognition, memory, and non‐memory domains. We used linear mixed models to evaluate the association between persistent pain and cognition over time, adjusting for demographic, socioeconomic, and health factors. We evaluated heterogeneity by respondent’s gender.

Results

Our sample was 55.8% female with a mean baseline age of 61.8 (n=10,053). About 13% of participants reported persistent pain and 45% reported non‐persistent pain. Persistent pain was associated with a higher rate of decline for global (β: −0.005, 95% CI: ‐0.008, ‐0.002), memory (β: −0.004, 95% CI: ‐0.008, ‐0.001), and non‐memory (β: ‐0.005, 95% CI: ‐0.009, ‐0.002) domains, compared to no pain. Among women, persistent pain was associated lower global (β: ‐0.006, 95% CI: ‐0.010, ‐0.002), memory (β: ‐0.005, 95% CI: ‐0.009, ‐0.0003), and non‐memory (β: ‐0.008, 95%CI: ‐0.012, ‐0.003) scores over time, while among men, persistent pain was only associated with lower memory (β: ‐0.008, 95% CI: ‐.014, ‐0.002) scores over time. Non‐persistent pain was not associated with cognition for women, while for men, it was associated with lower global (β: −0.004, 95% CI: ‐0.006, ‐0.001) and memory (β: −0.004, 95%CI: ‐0.007, ‐0.001) scores over time.

Conclusions

Persistent pain may impact cognitive decline for years and differentially impact individuals by gender. Treatment may result in population‐level benefits in cognition for those living with persistent pain. This is important in LMICs, where most individuals requiring pain relief have their needs unmet.
Tool and chemical probe development for emerging targets in Alzheimer’s disease: The Emory‐Sage‐SGC TREAT‐AD Center
Authors: Mangravite Lara M , Betarbet Ranjita , Carter Gregory W , Frye Stephen V. , Fu Haian , Gileadi Opher , Greenwood Anna K , Leal Karina , Longo Frank M. , Omberg Larsson , Pearce Kenneth H. , Edwards Aled M , Levey Allan I
Published: December 2021

Background

Alzheimer’s disease (AD) is the most common form of dementia, with no effective preventative strategies or treatments. The drug development pipeline in AD has been marked by repeated failures to find an effective treatment. Increasing evidence supports the need for greater pipeline target diversity and new approaches to target the disease. The Emory‐Sage‐SGC TREAT‐AD Center (https://treatad.org) was established to forge a new path forward with the aim of developing drugs for emerging targets in AD beyond the two pathological hallmarks. By casting a wider net, we aim to develop tools and chemical probes that target the multifaceted dysregulation in the brains of AD patients, and expand the portfolio of therapeutic approaches to break the cycle of failure. We believe that this more‐inclusive perspective will enrich the AD field and advance the discovery of potential drug targets for AD.

Method

The Emory‐Sage‐SGC TREAT‐AD Center has selected a diverse set of novel AD targets derived from systems biology studies within the Accelerating Medicines Partnership in AD (AMP‐AD) consortium and further evaluated using data from multiple AD consortia and existing literature. Targets nominated through the AMP‐AD consortium were scored based on unbiased bioinformatic assessments across multiple lines of evidence including genetic, multi‐omic, neuropathological, and literature‐based metrics and were mapped to mechanistic hypotheses residing in distinct biological domains that are altered in AD. Target Enabling Packages, including expression constructs, knockout cell lines, assays, antibodies and crystal structures, are being generated for 20 proteins prioritized using this approach. Hit characterization and chemical probe development has started for targets in which the evidence for AD biology is strong. All data and reagents will be publicly shared through standard repositories and cataloged at the Agora site (https://agora.adknowledgeportal.org).

Result

The Emory‐Sage‐SGC Center goals are: to identify and prioritize novel emerging targets for AD; to generate reagents and tools for emerging targets to encourage the community to expand the pipeline of potential AD therapeutic targets; and to share all data, tools, and reagents openly, rapidly, and without restriction.

Conclusion

All data, protocols, reagent sets, and chemical tools and will be made widely available. For more information see www.treatad.org.
Brain state instability as a biomarker of Alzheimer’s disease progression: A dynamic functional network connectivity study
Authors: Sendi Mohammad S.E. , Zendehrouh Elaheh , Miller Robyn L , Mormino Elizabeth C. , Salat David H , Calhoun Vince D
Published: December 2021

Background

Finding a biomarker predicting the Alzheimer’s disease (AD) progression from a healthy stage to mild cognitive impairment (MCI), mild dementia (MD) and further to AD is an essential step toward early medical intervention. In recent years, dynamic functional network connectivity (dFNC) from resting state‐fMRI, which estimates brain states during the scan, revealed excellent knowledge about AD progression's underlying mechanism. The current study explored whether the AD brain produces similar and stable dFNC states across different scanning sessions and introduced dFNC state (or brain) instability as a potential biomarker of AD progression.

Method

The data from the longitudinal Open Access Series of Imaging Studies (OASIS)‐3 cohort were used in this study. The dataset contains two rs‐fMRI sessions on the same day of 1048 healthy controls or HC (clinical dementia rating sum of boxes or CDR‐SOB=0, age= 70.80± 8.57), 193 MCI (4.5=<CDR‐SOB<=9, age= 71.00±9.48), and 75 MD patients (with clinical dementia rating 4.5=<CDR‐SOB<=9, age=71.90±9.65). We did not observe a significant age and gender difference across groups (ttest p>0.2). We used Group‐independent component analysis to extract independent components of the whole‐brain for each subject. Next, we applied the sliding window with Pearson correlation to estimate dFNC of each individual in each session. Subsequently, k‐means clustering (k=3, L1‐norm as a distance metric, and 1000 iterations) separately was applied to put the dFNCs of each group and session in three distinct states. Pearson correlation between the cluster (state) centroid was used to assess the similarity of state across two sessions.

Result

We found that HC and MCI groups generate similar dFNC states in both sessions in which The correlation between inter‐session “matched” states for HCs and MCIs was more than 0.99 (p<0.0001). But, MD patients did not generate similar brain states across two sessions. This points to a degradation in the stability of functional brain integration among MD patients.

Conclusion

Our findings highlight brain instability as a potential biomarker of Alzheimer’s disease progression. Also, the instability of dFNC observed in mild dementia patients suggests a need for multiple scanning sessions to analyze rs‐fMRI data in this group of patients.
Association between body weight change in late life and risk of dementia: A population‐based cohort study
Authors: Guo Jie , Marseglia Anna , Shang Ying , Dove Abigail , Grande Giulia , Fratiglioni Laura , Xu Weili
Published: December 2021

Background

Adiposity in midlife is a modifiable risk factor for dementia. However, the effect of adiposity in late life on dementia remains unclear. We investigated the association of body mass index (BMI) and weight changes after age 60 with the incidence of dementia.

Method

Within the Swedish National Study on Aging and Care‐Kungsholmen, 1,673 dementia‐free participants with data on BMI/weight both at baseline and the 6‐year follow‐up were followed to detect subsequent incident dementia cases. BMI change was assessed as the percentage of the difference between BMI at baseline and the initial 6‐year follow‐up and categorized into large (>10%) or moderate (5–10%) loss, stable (≤5%), and moderate (5–10%) or large (>10%) gain. Weight change (difference between weight at baseline and the 6‐year follow‐up) was categorized into large (>7.5 kg) or moderate (2.5–7.5 kg) loss, stable (≤2.5 kg), and moderate (2.5–7.5 kg) or large (> 7.5 kg) gain. Dementia was diagnosed following the DSM‐IV criteria. Data were analyzed using Cox regression models.

Result

During the follow‐up (median 5.78 years), 102 incident dementia cases were identified. BMI/weight change showed U‐shaped associations with dementia. Compared with stable BMI, the hazard ratios (95% confidence intervals) of dementia were 2.93 (1.72−4.91) for large BMI loss and 2.61 (1.09−5.54) for large BMI gain. Similar results were observed for a large weight loss (2.92 [1.67−5.07]) or gain (2.95 [1.16−6.53]). BMI and weight loss/gain were dose‐dependently related to dementia risk. These associations became stronger among participants carrying an ApoE ɛ4 allele or with diabetes. No significant associations between moderate BMI and weight loss/gain and dementia were detected.

Conclusion

Both large bodyweight loss and gain are associated with almost 3‐fold higher risk of dementia. ApoE ɛ4 and diabetes appear to play a role in this association.
The cumulative effect of cognitive engagement on cognitive function in middle‐aged adults
Authors: Bransby Lisa , Buckley Rachel F , Yassi Nawaf , Pase Matthew P , Lim Yen Ying
Published: December 2021

Background

Engagement in cognitively stimulating work and activities is proposed to slow cognitive decline and delay dementia. Few studies have considered the cumulative effect of multiple cognitively engaging factors on cognitive function. In middle‐aged adults, this study aimed to determine the individual and combined associations of four cognitive engagement factors (i.e., educational attainment, occupational complexity, social engagement and cognitively stimulating leisure activities) with objectively measured cognitive performance and subjective ratings of cognitive function.

Method

A total of 1864 cognitively normal middle‐aged adults (aged 40‐70) enrolled in the Healthy Brain Project, a study with an online remote assessment platform seeking to understand midlife risk factors for dementia. Cognitive engagement factors were measured by online self‐report questionnaires. The Cogstate Brief Battery was used to measure cognitive domains of attention and memory. Subjective ratings of cognitive function were measured using the Cognitive Function Instrument.

Result

After controlling for age, sex, ethnicity and mood symptomatology, participants with high educational attainment or high occupational complexity performed significantly better on attention and memory tasks and reported less subjective ratings of cognitive concern. Higher participation in cognitively engaging leisure activities was significantly associated with better attention and memory performance, but not with subjective ratings of cognitive function. Social engagement was not associated with any outcome. The magnitude of these effects was small and trivial (Cohen’s d ranging from 0‐0.17). Participants were then classified into five groups based on whether they rated highly in 0‐4 cognitive engagement factors. Compared to participants with no factors, participants scoring highly in 2 or more factors performed significantly better on the memory tasks, with the magnitude of difference moderate (Cohen’s d ranging from 0.30‐0.49).

Conclusion

These results suggest a cumulative relationship between high cognitive engagement across several domains of life and better memory performance in cognitively normal middle‐aged adults.
Apathy in Dementia Methylphenidate Trial 2 (ADMET2): Results of a phase III, placebo‐controlled, double‐blind, 6‐month, multi‐center, randomized clinical trial
Authors: Mintzer Jacobo E. , Scherer Roberta , Drye Lea T. , Lanctôt Krista L. , Rosenberg Paul B. , Herrmann Nathan , Padala Prasad R , Brawman‐Mintzer Olga , Lerner Alan J. , Levey Allan I , Porsteinsson Anton P. , van Dyck Christopher H
Published: December 2021

Background

Apathy is one of the most common and debilitating neuropsychiatric symptoms of Alzheimer’s Disease (AD). Two previous trials that suggested methylphenidate was safe and efficacious involved only 60 participants each, followed for 6 weeks. A larger, longer‐lasting trial was required to confirm those promising findings.

Methods

ADMET 2 was a phase III, placebo‐controlled, 6‐month, multi‐center, randomized (1:1, 20 mg methylphenidate per day or placebo) clinical trial that randomized 200 participants with AD and apathy. Primary outcomes included: (1) the mean difference on the Neuropsychiatric Inventory Apathy (NPI‐A) subscale scores measured as change from baseline to 6 months, and/or (2) the odds of a rating of improvement on the modified AD Cooperative Study Clinical Global Impression of Change (ADCS‐CGIC) at month 6 compared with baseline. Secondary outcomes included change in cognition, safety, and cost‐effectiveness measured monthly for up to 6 months.

Results

200 individuals were randomized (65.8% were males; 34.2% were females; avg age=76 years; 75.3% had some college education or greater; mean Mini‐Mental State Examination score at baseline was 18.9). There was a larger difference in the methylphenidate group compared with the placebo group in NPI‐A score from baseline to 6 months using a mixed model (Mean difference = ‐1.25; 95% CI: ‐2.03, ‐0.47, p = 0.002) with the largest change observed during the first two months. At 6 months, the ADCS‐CGIC showed that 43.8% (39/89) of participants in the methylphenidate group improved compared with 35.2% (32/91) of study participants in the placebo group (odds ratio 1.90 (95% CI: 0.95, 3.84), favoring methylphenidate, but not reaching statistical significance (p = 0.071)). There were no significant differences in other assessments. The safety profile was similar between the two groups.

Conclusion

ADMET 2 showed a small to medium benefit for methylphenidate in the treatment of apathy in AD. The effect was observed at 2 months and was sustained throughout the 6 months of the study. Adverse events were mild. These results support previous observations in smaller studies. Methylphenidate offers a viable treatment for patients suffering from apathy in AD.
The estimation of the global prevalence of dementia from 1990‐2019 and forecasted prevalence through 2050: An analysis for the Global Burden of Disease (GBD) study 2019
Authors: Nichols Emma , Vos Theo
Published: December 2021

Background

Given projected increases in population growth and population aging, the number of people with dementia is expected to increase in the future. Characterizing the distribution and magnitude of the anticipated growth is critical for public health planning and prioritization of resources. This study aimed to improve on prior forecasts of dementia prevalence by producing country‐level estimates and by incorporating information on trends in dementia risk factors.

Method

Dementia prevalence from 1990‐2019 was estimated using meta‐analytic techniques. We then forecasted dementia prevalence attributable to the three risk factors included in the Global Burden of Disease (GBD) study (BMI, fasting plasma glucose, and smoking), using relative risks and forecasted risk factor prevalence to predict future risk‐attributable prevalence. Finally, using linear regression models with other dementia risk factors included as predictors, we forecasted dementia prevalence not attributable to GBD risks. To assess the relative contribution of changes in prevalence, population growth and population aging, we conducted decomposition analysis.

Result

We estimated the number of people with dementia would increase from an estimated 57.4 (50.4 to 65.1) million cases globally in 2019 to an estimated 152.8 (130.8 to 175.6) million cases in 2050. There was geographic heterogeneity in projected increases, with the highest increases observed in eastern sub‐Saharan Africa and North Africa and the Middle East. Despite large increases in the number of projected dementia cases, age‐standardized rates remained largely stable. Decomposition analysis suggested that projected increases in cases could largely be attributed to population growth and aging, although the relative importance of these two factors varied by world region.

Conclusion

The number of individuals with dementia is expected to grow, due largely to population growth and population aging. However, heterogeneity in expected rates of growth was observed across countries, and the country‐level estimates from this study can be used to inform policy decisions around funding for research and public health planning efforts at the national and international levels. Multifaceted approaches, including scaling up interventions to address modifiable risk factors and investing in research on etiologic disease mechanisms, will be critical in addressing expected increases in the number of individuals affected by dementia.
Differential correlation of white matter hyperintensity with Alzheimer’s pathology within A/T groups
Authors: Alban Sierra , Choupan Jeiran , Ringman John M. , Toga Arthur W. , Chui Helena C. , Sepehrband Farshid
Published: December 2021

Background

White Matter Hyperintensities (WMH) of brain MRI have been linked to cerebral amyloid angiopathy, a hallmark of Alzheimer’s Disease (AD). Particular biomarkers, such as Florbetapir and Flotaucipir PET measures of β‐amyloid and neurofibrillary tangles, respectively, have been utilized to quantify AD pathology (A/T). Here we investigated WMH association with AD pathology across A/T groups.

Method

Imaging was gathered from ADNI (N=286, 137 male). Participants were stratified based on A/T. For Aβ classification, amyloid PET SUVR data was analyzed. Flortaucipir SUVR PET in metatemporal regions was used (Jack et al. 2017). The cutoffs used to categorize A+ and T+ were any values above 1.25 and 0.79 respectively. A deep convolutional neural network was used for mapping WMH in MRI (Sepehrband et al., 2020). Regression and Pearson correlation analysis were used to assess the association and correlation between WMH and amyloidosis (controlling for age, sex, education and scanner manufacturer).

Result

WMH volume was positively correlated with amyloidosis (Figure 1A; r=0.28, p=6e‐7). We observed a significant effect of the WMH volume on global amyloid SUVR (F(1, 309) = 7.95, p = 0.008). WMH volume of participants with Amyloid (A+) or Tau (T+) pathology was higher than controls (A‐/T‐) (Figure 1B). WMH volume of AD participants(A+/T+) was significantly higher than controls (A‐/T‐) (p = 0.007, Cohen’s d = 0.4). A+/T‐ participants had higher WMH than control (p = 0.002, Cohen’s d = 0.5).

We observed significant positive correlation between WMH and amyloid in the A+/T‐ group (r=0.36, p=0.0008) (Figure 1C). A marginal positive correlation was observed among A‐/T+ participants (r=0.58, p=0.0498), and a positive non‐significant correlation among the A+/T+ group (r=0.23, p=0.09). We observed neither a correlation nor an association between WMH and Tau uptake (Figure 1D: correlation p=0.25; association p=0.4).

Conclusion

Increased global flortaucipir uptake was associated with an increase in overall WMH volume. The strongest relationship between WMH and amyloid accumulation was when neurodegeneration was not present (A+/T‐). These findings are consistent with autopsy studies showing correlations between cerebral amyloid angiopathy and WMH. The combination of significant WMH and a positive amyloid PET scan raises possibility of underlying amyloid angiopathy.
CSF total tau/α‐synuclein ratio improved the diagnostic performance for Alzheimer’s disease as an indicator of tau phosphorylation
Authors: Kang Min Ju , Shim Kyu Hwan , Suh Jeewon , Pyun Jung Min , Ryoo Nayoung , Park Young Ho , Youn Young Chul , Jang Jae‐Won , Jeong Jee Hyang , Park Kyung Won , Choi Seong Hye , Suk Kyoungho , Lee Ho‐Won , Ko Pan‐Woo , Lee Chan‐Nyoung , Lim Tae Sung , An Seong Soo , Kim Sangyun
Published: December 2021

Background

Recently, several studies suggested potential involvements of α‐synuclein in Alzheimer's disease (AD) pathophysiology. Higher concentrations of α‐synuclein were reported in cerebrospinal fluid (CSF) of AD patients with a positive correlation towards CSF tau, indicating its possible role in AD. We analyzed the CSF biomarkers to verify whether α‐synuclein could be an additional supported biomarker in AD diagnosis.

Method

In this cross‐sectional study, CSF samples of 71 early‐onset AD, 34 late‐onset AD, 11 mild cognitive impairment, 17 subjective cognitive decline, 45 Parkinson’s disease, and 32 healthy control (HC) were collected. CSF amyloid‐β1‐42 (A), total tau (N), and phosphorylated tau181 (T) were measured by commercial ELISA kits, and in‐house ELISA kit was developed to quantify α‐synuclein. The cognitive assessments and amyloid‐PET imaging were also performed.

Result

CSF α‐synuclein manifested a tendency to increase in AD and to decreased in Parkinson’s disease compared to HC. The equilibrium states of total tau and α‐synuclein concentrations were changed significantly in AD, and the ratio of total tau/α‐synuclein (N/αS) was dramatically increased in AD than HC. Remarkably, N/αS revealed a strong positive correlation with tau phosphorylation rate. Also, the combination of N/αS with amyloid‐β1‐42/phosphorylated tau181 had the best diagnosis performance (AUC = 0.956, sensitivity = 96%, specificity = 87%). In concordance analysis, N/αS showed the higher diagnostic agreement with amyloid‐β1‐42 and amyloid‐PET. Analysis of biomarker profiling with N/αS had distinctive characteristics and clustering of each group. Especially, among the group of suspected non‐Alzheimer's disease pathophysiology, all A‐T+N+ patients with N/αS+ were reintegrated into AD.

Conclusion

The high correlation of α‐synuclein with tau and the elevated N/αS in AD supported the involvement of α‐synuclein in AD pathophysiology. Importantly, N/αS improved the diagnostic performance, confirming the needs of incorporating α‐synuclein as a biomarker for neurodegenerative disorders. The incorporation of a biomarker group [N/αS] could contribute to provide better understanding and diagnosis of neurodegenerative disorders.