bluuebunny/crossref_metadata_2025 huggingface dataset:
CAN‐THUMBS UP: Recruitment in the Virtual Era
Authors: Nygaard Haakon B. , Slack Penelope , Feldman Howard H. , Chertkow Howard , Belleville Sylvie , Montero‐Odasso Manuel , Anderson Nicole D. , Bennett Daniel , Borrie Michael , Chan Senny , Jarrett Pamela , Lee Ashley , Lupo Jody‐Lynn , Matthews Genevieve , McGibbon Chris A , Revta Carolyn , Robillard Julie M. , Shadyab Alexandre , Shajan Sheetal
Published: December 2023

Background

The Brain Health Support Program (BHSP) of the CAN‐Thumbs Up Study is an online, interactive educational intervention designed to increase dementia literacy, self‐efficacy and address modifiable lifestyle risk factors. Recruiting for a virtual study presented both opportunities and challenges. This included the need to attract participants through means beyond referrals from medical clinics, as well as opportunities to reach geographically diverse Canadian population less feasible with in‐person evaluations.

Methods

A comprehensive recruitment strategy for a virtual environment was implemented. A central website provided any interested candidate with study information, and a link to register and provide basic demographic information via a secure form. Potential participants were directed to the website via traditional recruitment through CCNA specialty clinics or existing cohorts, through geotargeting mailing to specific target populations throughout Canada, social medial advertising, partner organizations, and a coordinated National press release.

Results

The study had an 8‐month open recruitment window. During this time 964 participants agreed to be contacted through our online portal. Of these, 18‐81 were consented to enroll in the study per month. A total of 7,569 geotargeted postcards were sent, with 153 individuals agreeing to be contacted for the study (2%). Social media advertising generated 974 clicks, with 6.8% subsequently agreeing to be contacted for more information. The majority of participants enrolled in the study came from existing clinical cohorts, CCNA clinical sites, and partner organizations. The recruitment cohort was from a diverse geographical location, 45% urban, 35% suburban, and 20% rural. Overall, the target cohort of 350 subjects was successfully enrolled by the end of the recruitment period.

Conclusion

Recruitment for the BHSP intervention demonstrates the value of relatively underutilized clinical trials recruitment strategies, such as geotargeted mailing, and social media advertising. We also show the value of a centralized web site for initial screening of interested participants. While traditional recruitment methods still directed the majority of participants to the recruitment website, geotargeted mailing, social advertising, partner organizations, and earned media can all be scaled up, and will likely play a major role in future recruitments efforts in the broader CAN‐Thumbs Up Study.
Olfaction and cognitive performance in early‐stage Parkinson’s disease
Authors: Serrano‐Rubio Luis Humberto , Young Vanessa M. , Velarde Angel G. , Gaona Carlos A. , Ramirez‐Castaneda Juan , Horn Sarah , Coss Pablo , Vaou Okeanis E. , Saklad Amy R. , Shipp Eric L. , Seshadri Sudha , Gonzalez David A. , Gonzales Mitzi M.
Published: December 2023

Background

Parkinson’s disease (PD) is a neurodegenerative disorder affecting 1% of the global population. While the core clinical symptoms of PD are bradykinesia, rigidity, and tremor, it is also often accompanied by non‐motor symptoms that reduce quality of life and increase health care costs. Of the non‐motor symptoms in PD, hyposmia is one of the most prevalent and often precedes clinical diagnosis by several years. In addition, hyposmia has been associated with accelerated disease progression. As individuals with PD are at elevated risk for dementia, the goal of this pilot study was to objectively evaluate the association between smell sensitivity and cognition in early‐stage PD.

Method

Participants with a clinical diagnosis of PD completed cognitive assessments of verbal and visual learning and memory, processing speed, attention, and executive function. Smell sensitivity was assessed using the University of Pennsylvania Smell Identification Test (UPSIT). Associations between cognitive performance and smell sensitivity were evaluated using partial correlations adjusting for age and education.

Result

Nineteen participants (mean age 69.4+7.9, 25% female) with early‐stage Parkinson’s disease (Hoehn and Yahr stage 1‐2) and free of dementia completed the UPSIT and cognitive assessments (see table 1 for sample characteristics). The average UPSIT score was 5.84+2.12 points and ranged from 2 to 10. Diminished olfactory sensitivity, assessed by the total correct score on the UPSIT, was associated with poorer visual learning (Brief Visual Memory Test Revised (BVMT‐R) immediate recall: r = 0.564, p = 0.18, Figure 1) and memory (BVMT‐R delayed recall: r = 0.610, p = 0.009, Figure 2).

Conclusion

In the early‐stages of PD, diminished smell sensitivity was associated with poorer visual learning and memory, domains preferentially affected by the disease. The findings suggest that olfactory dysfunction may be a biomarker of cognitive decline. Larger, longitudinal studies will be important for evaluating the utility of olfactory function as a predictor of dementia risk in PD.
Class 1 HDACs Modulate Synapse‐Related Genes in Mouse Models of Aging and Alzheimer’s Disease
Authors: McClarty Bryan , Rodriguez Guadalupe , Dong Hongxin
Published: December 2023

Background

Studies have demonstrated that epigenetics plays an important role in both aging and Alzheimer’s disease (AD) pathogenesis, however, whether epigenetic dysregulation during aging can initiate AD development and/or exacerbate AD progression remains unclear. Given aging is the major risk factor of AD, it is critical to determine the epigenetic alterations occurring during aging and how these changes influence AD pathogenesis.

Methods

In this study, 3, 12, and 18‐month‐old APP/PS1 mice and WT littermates were used for a series of behavioral tests to evaluate and compare different memory domains, including recognition, short‐term working, and long‐term spatial reference memory in aging and AD progression. After behavioral testing, the hippocampus and prefrontal cortex (PFC) were collected for biochemical assessment to determine the dynamic changes of class 1 HDACs globally and at gene promoters that are associated with synaptic structure and function, namely Nr2a, GluR1 Glur2, and Psd95. Additionally, synaptic gene expression and H3K9ac levels at the gene promoters were evaluated during aging and AD progression.

Results

Our results showed that recognition and short‐term working memory declined in WT mice only at 18 months of age, but significantly declined in the three memory domains of APP/PS1 mice at both 12 and 18 months of age. Moreover, 18 months of age APP/PS1 mice showed exacerbated recognition and spatial working memory deficits. We also found HDACs modulate the synaptic‐related genes in a genotype and regional manner. More specifically, HDAC 2 modulated synaptic gene expression through dysregulations of H3K9ac levels at the gene promoters in the hippocampus during aging and AD progression. While HDAC 3 modulated synaptic gene expression through dysregulations of H3K9ac levels at gene promoters in the prefrontal cortex during AD progression. The dynamic changes of HDACs and H3K9ac levels during aging and AD progression are associated with specific declines in memory.

Conclusion

Our findings suggest a potential differential HDAC modulation of synaptic gene expression in aging and AD progression, which impacts the decline of different memory domains. Future work will confirm our findings and will begin using genetic manipulation approaches to dissect individual class 1 HDAC contributions to aging and/or AD progression in the hippocampus and PFC.
Effectiveness of the Interdisciplinary Home‐bAsed Reablement Program (I‐HARP) on improving functional independence of people living with dementia and process outcomes
Authors: Jeon Yun‐Hee , Simpson Judy , Norman Richard , Fethney Judith , Krein Luisa , Shim Mirim , Low Lee‐Fay , Woods Bob , Mowszowski Loren , Hilmer Sarah , Clemson Lindy , Naismith Sharon L , Brodaty Henry , Naganathan Vasi , Amberber Amanda Miller , Gitlin Laura N. , Szanton Sarah L
Published: December 2023

Background

This project evaluated a model of care integrating evidence‐based dementia rehabilitation strategies into a time‐limited, home‐based, interdisciplinary rehabilitation package: Interdisciplinary Home‐bAsed Reablement Program (I‐HARP). The aims were: to determine I‐HARP effectiveness on functional independence, mobility, quality of life and depression among people with dementia, their home environmental safety, carer burden and quality of life, and I‐HARP cost‐effectiveness; and to evaluate processes, outcomes and influencing factors of the I‐HARP implementation.

Method

The project was mixed‐methods action research combining a multi‐centre pragmatic RCT and realist evaluation. I‐HARP was a 4‐month model of care for community‐dwelling people with mild‐moderate dementia and family carers, incorporated into community aged care services and hospital‐based geriatric services in Sydney, Australia (2018‐22) and compared with usual care. Outcome assessments were conducted at baseline, 4‐ and 12‐month. Semi‐structured interviews with participants and focus groups with I‐HARP interventionists and participating site managers occurred post intervention. (ACTRN12618000600246)

Result

Of 130 dyads of clients and their carers recruited, 116 dyads (58 per group) completed the trial (89% retention). The I‐HARP group had somewhat better mean results for most outcome measures than usual care at both 4 and 12 months, but the only statistically significant difference was a reduction in home environment hazards at 4 months. Post‐hoc sub‐group analysis of 66 clients with mild‐dementia found significantly better functional independence in the intervention group: 11.2 on Disability Assessment for Dementia (95% CI: 3.4,19.1; p = .005; ES 0.69) at 4 months and 13.7 (95% CI: 3.7,23.7; p = .007; ES 0.69) at 12 months. Preliminary results of economic evaluation pointed to potential benefits of I‐HARP over usual care. Interviews and focus group findings highlighted system and research design barriers (e.g., workforce, hospital system, communication, blinding and recruitment) and program facilitators (focus on enablement, interdisciplinary and teamwork).

Conclusion

The I‐HARP model enhanced functional independence of participants with mild‐dementia but not in those with moderate‐dementia, so did not result in better outcomes in the group overall. A different type of rehabilitation model or strategies may be required as dementia becomes more severe. Key facilitators and barriers to I‐HARP implementation provide further insights to developing dementia rehabilitation model of care.
Maintain Your Brain: outcomes of an online program to prevent cognitive decline with aging.
Authors: Brodaty Henry , Valenzuela Michael , Singh Maria A. Fiatarone , Sachdev Perminder S. , McNeil John , Lautenschlager Nicola T , Maeder Anthony , Jorm Louisa , Millard Michael , Heffernan Megan , Anstey Kaarin J. , Ginige Jeewani Anupama , Chau Tiffany , Jose Juan Carlo San , Welberry Heidi , Briggs Nancy , Popovic Gordana
Published: December 2023

Background

Efforts to prevent cognitive decline with aging have had mixed results with successful interventions delivered in person. While online approaches are more scalable and feasible to deliver at a population level, no multimodal online intervention has yet been demonstrated efficacy. We aimed to reduce cognitive decline with ageing using an online package of interventions delivered intensively for 12 months followed by monthly boosters for 24 months.

Method

Invitations were sent to people aged 55‐77 years from the 45 and Up study, a population‐based cohort study of one in ten people aged 45 years and older in New South Wales, Australia (n = 267,000). Participants were required to be eligible for at least two of four modules addressing physical inactivity and associated health risks (Physical Activity), adherence to a Mediterranean‐type diet and health risks associated with poor nutrition (Nutrition), cognitive activity (Brain Training) and mental well‐being (Peace of Mind). Participants received modules based on their risks, with 1:1 randomized allocation to active personalised coaching modules (intervention) or static information‐based modules (control). The primary outcome was change in an online combined multi‐domain cognitive score measured using COGSTATE and Cambridge Brain Sciences tests. Secondary outcomes included specific cognitive domain and ANU‐ADRI risk scores.

Result

Of 96,418 invitations issued, 14,064 (14%) consented, 11,026 (11%) were eligible and 6,104 (6%) completed all baseline assessments. Over three years, using intention to treat analysis, the intervention group improved significantly more in the global composite cognition (p<0.001). Significant benefits were also found in complex attention, executive function and learning and memory (all p<0.001), as well as on a validated dementia risk instrument (p = 0.007). Results were similar when adjusted for baseline age, gender, dementia risk and number of modules eligible and when analysis was based on those completing follow‐up.

Conclusion

An online platform tailored to individuals’ risk factor profiles over three years significantly delayed cognitive decline in older adults. This platform is scalable; if delivered at a population level with may help reduce the prevalence of dementia globally.
Associations of anemia and cardiovascular disease with longitudinal changes in brain MRI markers and cognitive decline in older adults: A cohort study
Authors: Imahori Yume , Li Yuanjing , Laukka Erika J , Kalpouzos Gregoria , Vetrano Davide Liborio , Qiu Chengxuan
Published: December 2023

Background

Anemia and cardiovascular disease (CVD) are two prevalent chronic conditions causing cerebral hypoxia in older adults. Although anemia and CVD often coexist in older people and potentially share underlying mechanisms, the independent effects of these two diseases with cognitive decline are largely unknown. The objective of this cohort study is to investigate the independent associations of anemia and CVD with cognitive decline in older adults, and further explore their associations with changes in MRI markers of brain aging using longitudinal MRI data.

Method

This cohort study used data from 2244 dementia‐ and stroke‐free participants in the population‐based Swedish National study on Aging and Care in Kungsholmen (age ≥60 years, female 62%). Participants were regularly followed from 2001‐2004 (baseline) through 2013‐2016. Anemia (WHO criteria) and CVD were determined at baseline. Cognitive function was assessed using a neuropsychological test battery across 12 years. A subset of participants (N = 503) underwent brain MRI examinations at baseline, and 327undertook follow‐up MRI scans after 3 and/or 6 years. Brain volumetric measures and markers of cerebral small vessel disease (cSVD) were assessed following standard methods. The associations of anemia or/and CVD with cognitive decline and changes in brain volume and cSVD markers were investigated using linear mixed‐effects models, while controlling for age, sex, lifestyle, vascular risk factors, chronic kidney disease, cancer, serum c‐reactive protein, and APOE genotype.

Result

Of the 2244 participants, 5% had only anemia and 17% had only CVD. Both anemia and CVD were independently associated with a steeper decline in global cognitive composite score (anemia ‐0.01/year; 95%CI ‐0.03 to ‐0.00, CVD ‐0.02/year; 95%CI ‐0.03 to ‐0.02). Anemia was associated with faster decline in category fluency and perceptual speed, while CVD was significantly associated with an accelerated decline in all examined cognitive domains. Both anemia and CVD at baseline were associated with a steeper decline in total brain tissue volume, while CVD was additionally associated with steeper decline in volumes of hippocampus (P<0.05). Neither was significantly associated with changes in cSVD markers (i.e., white‐matter hyperintensities, lacunes).

Conclusion

Both anemia and CVD are risk factors for accelerated cognitive decline and brain atrophy in older adults.
Design of ADEPT‐2, a phase 3, parallel group study to evaluate KarXT [xanomeline‐trospium] as a treatment for psychosis associated with Alzheimer’s disease
Authors: Kang Minsu , Watson Carolyn , Cummings Jeffrey L. , Grossberg George T , Marcus Ronald , Yeung Paul
Published: December 2023

Background

Psychosis represents a major unmet medical need in patients with Alzheimer’s disease (AD) dementia. With no approved medications for AD dementia psychosis (ADP), current treatment relies on off‐label uses of antipsychotics with limited efficacy and significant safety concerns. Xanomeline is an M1/M4 preferring muscarinic receptor agonist that has previously been shown to have antipsychotic effects in subjects with AD (Bodick et al., 1997). While xanomeline had promising efficacy for potentially treating psychosis in AD, cholinergic adverse events limited further clinical development of xanomeline. KarXT is an investigational treatment that combines xanomeline with trospium, an FDA‐approved non‐specific muscarinic receptor antagonist. Unlike xanomeline, trospium does not measurably cross the blood‐brain barrier, providing a mechanism to mitigate peripheral cholinergic effects of xanomeline while maintaining its muscarinic receptor agonist activities in the brain.

Methods

ADEPT‐2 trial is a phase 3, randomized, double‐blind, placebo‐controlled, parallel group study to evaluate the safety and efficacy of KarXT for the treatment of ADP. Subjects aged 55‐90 years with moderate to severe psychosis associated with mild to severe AD dementia will be enrolled into the study. Eligible subjects will be randomized to receive either KarXT or placebo in a double‐blinded manner for 14 weeks and subjects who complete the study will be eligible to participate in a one‐year, open‐label safety extension study.

Results

The primary efficacy endpoint of the study is change from Randomization to End of Treatment in the Neuropsychiatric Inventory‐Clinical (NPI‐C): Hallucinations and Delusions (H+D) score and the key secondary efficacy endpoint is change from Randomization to End of Treatment in the Cohen‐Mansfield Agitation Inventory (CMAI). The safety endpoints include the evaluation of safety and tolerability of KarXT compared with placebo in subjects with ADP. The study is planned to start in 2023 and will enroll approximately 360 subjects with psychosis associated with AD dementia.

Conclusion

ADEPT‐2 is designed to assess the safety and efficacy of KarXT for the treatment of psychosis in patients with AD dementia. If ADEPT‐2 is successful, KarXT has the potential to be the first in a new class of pharmacologic treatment for AD psychosis based on muscarinic receptor agonism.
5‐LOX: blood based biomarker for Alzheimer’s disease (AD) and effect of peptide inhibitor on neurotoxicity developed in AD.
Authors: Yadav Yudhishthir , Nayal Abhilasha , Ashar Suhail , Dey Aparajit Ballav , Dey Sharmistha
Published: December 2023

Background

The inflammatory process plays a key role in neurodegenerative disorder. Pro‐inflammatory molecule, 5‐Lipooxygenase (5‐LOX), protein is involved in pathologic phenotype of AD. It includes Aβ amyloid deposition and tau hyper phosphorylation both but the detail mechanism is still illusive. This study determined the level of 5‐LOX in serum of Alzheimer’s disease (AD) patient, Mild cognitive impairment (MCI), normal elderly and rescue effect by YWCS, a peptide inhibitor of 5‐LOX on neurotoxicity by Aβ amyloid (Aβ25‐35) in neuroblastoma cells SH‐SY5Y.

Method

The level of serum 5‐LOX was estimated by surface plasmon resonance and presence of 5‐LOX in serum was confirmed by western blot. The peptide inhibitor YWCS was synthesized by solid‐phase peptide synthesis (SPPS) using F‐moc and Wang resin chemistry, and the purity of the peptide was verified by analytical RP‐HPLC. The neuroprotective effect of 5‐LOX peptide inhibitor YWCS in Aβ25‐35 induced neurotoxicity was analyzed by MTT assay and western blotting.

Result

The level of serum 5‐LOX was estimated by surface plasmon resonance and presence of 5‐LOX in serum was confirmed by western blot. The peptide inhibitor YWCS was synthesized by solid‐phase peptide synthesis (SPPS) using F‐moc and Wang resin chemistry, and the purity of the peptide was verified by analytical RP‐HPLC. The neuroprotective effect of 5‐LOX peptide inhibitor YWCS in Aβ25‐35 induced neurotoxicity was analyzed by MTT assay and western blotting.

Conclusion

The differential expression of serum 5‐LOX among the study groups suggests, it can be one of potential serum protein marker and therapeutic regimen for AD and MCI. Peptide YWCS, can serve as new platform as 5‐LOX inhibitor which can prevent neurotoxicity developed in AD.
Association of Objective Sleep Duration with Cognition and Brain Aging Biomarkers in Older Adults
Authors: Tang Shi , Liu Rui , Song Lin , Ren Juan , Zhao Mingqing , Wang Yongxiang , Dong Yi , Liu Cuicui , Hou Tingting , Cong Lin , Du Yifeng , Qiu Chengxuan
Published: December 2023

Background

The neuropathological mechanisms linking sleep duration with mild cognitive impairment (MCI) are poorly understood.

Method

This population‐based study included 2032 dementia‐free participants (age ≥60 years; 55.1% women) derived from the baseline survey of the Multimodal Interventions to Delay Dementia and Disability in Rural China; of these, data were available from 841 participants for Alzheimer’s plasma biomarkers (e.g., amyloid‐β [Aβ], total tau, and neurofilament light chain [NfL] protein), 1044 for serum microvascular biomarkers (e.g., soluble adhesion molecules), and 834 for brain MRI biomarkers (e.g., total brain tissue, whiter matter, grey matter, hippocampus, lacunes, enlarged perivascular spaces [EPVS], and white matter hyperintensity [WMH]). We assessed sleep duration using the electrocardiogram‐based cardiopulmonary coupling analysis, global and domain‐specific cognitive function using a neuropsychological test battery, and MCI following the Petersen’s criteria. Data were analyzed with multivariable logistic and general linear models.

Result

In the total sample (n = 2032), 510 participants were diagnosed with MCI, including 438 with amnestic MCI and 72 with non‐amnestic MCI. Objectively‐measured long sleep duration (>8 vs. 6‐8 hours) was significantly associated with an increased likelihood of MCI and lower scores in global cognition, verbal fluency, attention, and executive function (P<.05). In the subsamples, long sleep duration was associated with higher plasma concentrations of Aβ40, total tau, and NfL, a lower Aβ42/Aβ40 ratio, and smaller volumes of total brain tissue, grey matter, and hippocampus (P<.05). There were no significant associations of sleep duration with serum soluble adhesion molecules concentrations, white matter volumes, WMH volumes, global EPVS, and lacunes (P >.05).

Conclusion

Alzheimer’s and neurodegenerative pathologies represent common pathways linking long sleep duration with poor cognition in older adults.
Association of liver dysfunction with incident dementia, cognition, and brain structure
Authors: Gao Pei‐Yang , Ou Ya‐Nan , Wang Hui‐Fu , Ma Ya‐Hui , Wang Zhi‐Bo , Tan Lan , Yu Jin‐Tai
Published: December 2023

Background

An association between liver dysfunction and cognitive impairment has been previously identified; however, further clarification is required due to the lack of comprehensive evidence. This study aimed to investigate the association between liver dysfunction and the risk of different types of incident dementia, cognitive function, and brain structural abnormalities.

Method

A total of 431,754 UK Biobank participants without dementia at baseline were included between 2006 and 2010. The longitudinal associations between liver dysfunction and incident dementia were assessed using the Cox proportional hazards model, and the relationship between cognitive performance and brain structure was investigated using a linger regression model.

Result

After 9.04 (Standard Deviation 2.61) years of follow‐up, 5,627 participants were diagnosed with all‐cause dementia, including 2,438 Alzheimer’s disease and 1,312 vascular dementia cases. We found that decreased alanine transaminase (Hazard Ratio 0.992, 95% Confidential Interval 0.989‐0.995, P<0.001) and increased aspartate aminotransferase (HR 1.006, 95% CI 1.002‐1.011, P = 0.002), increased aspartate aminotransferase to alanine transaminase ratio (HR 1.593, 95% CI 1.471‐1.724, P<0.001), increased direct bilirubin (HR 1.052, 95% CI 1.005‐1.101, P = 0.028), increased gamma‐glutamyl transpeptidase (HR 1.002, 95% CI 1.001‐1.006, P<0.001), alcoholic liver disease (HR 2.870, 95% CI 1.863‐4.420, P<0.001), fibrosis and cirrhosis of liver (HR 2.284, 95% CI 1.454‐3.588, P<0.001), and other liver disease (HR 1.433, 95% CI 1.040‐1.973, P = 0.028) were significantly associated with all‐cause dementia risk. Similar outcomes were obtained for Alzheimer’s disease and vascular dementia. Additionally, liver dysfunction was associated with poor cognition in four different cognitive tests and altered cortical and subcortical brain regions.

Conclusion

Our findings provide amplified evidence to suggest that liver dysfunction is associated with the risk of different types of incident dementia, and a close relationship has been identified between poor cognitive performance and altered brain structure.
Diagnostic performance and clinical applicability of plasma pTau181 to predict dementia risk in a large real‐world cohort of a memory clinic
Authors: Cano Amanda , Puerta Raquel , Núñez‐Llaves Raúl , de Rojas Itziar , García‐González Pablo , Olivé Clàudia , Montrreal Laura , Orellana Adelina , Rosende‐Roca Maitee , onio Ester , Pytel Vanesa Verónica , Alegret Montserrat , Valero Sergi , Tárraga Lluís , Marquié Marta , Boada Mercè , Ruiz Agustin
Published: December 2023

Background

The Alzheimer Association has recently remarked the diagnostic and prognostic revolution that plasma biomarkers will mean for AD diagnosis, and highlighting the need of further research to translate them as a realistic option in the clinical practice. However, many studies to date have assessed them in research cohorts. Here we evaluated the diagnostic performance and clinical applicability of plasma pTau181 as a predictive marker of dementia risk in a real‐world memory clinic cohort.

Method

The ACE cohort encompass 1649 patients with subjective cognitive decline (SCD), mild cognitive impairment (MCI), AD dementia and other dementias, with a complete battery of neurological tests, biochemistry data, and paired CSF and plasma samples of the Ace Alzheimer Center Barcelona memory clinic. CSF AB42, AB40, pTau181 and tTau, and plasma pTau181 were measured using the Lumipulse G1200 automatic platform (Fujirebio Inc.). Complete cohort were divided in the Testing cohort (n = 1000) and Validation cohort (n = 649).

Result

Plasma pTau181 significantly correlated (P<0.0001) with CSF pTau181 in MCI, AD dementia and other dementias, but not in SCD. Sex appeared not significant in plasma pTau181 levels, whereas age significantly influenced in the biomarker’s performance. ROC curve of A+T+ patients vs rest showed an AUC = 0.8250 and P<0.0001. Specifically for MCI patients, ROC curve of MCI A+T+ vs MCI A‐T‐ showed and AUC = 0.8874 and P<0.0001. A cut off value of 1.300 pg/ml of plasma pTau181 exhibited a 93.6% sensibility, 72.4% specificity, 77.8% precision and only 8.3% of false negatives in MCI patients. Hazard ratio of survival of conversion analysis showed that MCI patients above this cut off value exhibited a 4.570 higher risk to convert to dementia than MCI under the cut off value. Validation cohort confirmed these findings.

Conclusion

Plasma pTau181 could be useful as a pre‐screening biomarker of MCI patients with high risk to progress to dementia. However, positive patients will also require a CSF/PET confirmatory test. Plasma pTau181 by itself does not present a suitable performance in SCD patients. Another biomarker or a combination of biomarkers would be needed to this population. Further studies are need to obtain more clinical data and improve the biomarker performance to finally substitute CSF/PET biomarkers.
The neural nitric oxide synthase is associated with cognitive decline and Alzheimer’s disease pathology
Authors: Justo Alberto Fernando Oliveira , Toscano Eliana Cristina de Brito , Leite Renata Elaine Paraizo , Paes Vitor Ribeiro , Grinberg Lea T. , Pasquallucci Carlos Augusto , Jacob‐Filho Wilson , Suemoto Claudia Kimie
Published: December 2023

Background

Although Alzheimer’s disease (AD) etiology is partially explained by the deposition of aggregated forms of β‐amyloid proteins and neurofibrillary tangles in the brain, the process that triggers the deposition of these proteins is still unknown. The neural (nNOS), endothelial (eNOS), and inducible nitric oxide synthases (iNOS) may play an important role in AD pathophysiology according to previous studies in animals. However, studies on humans are scarce. Therefore, we aimed to quantify the expression of NOS enzymes in the hippocampus of individuals with AD compared to individuals without the disease and investigate the association of NOS expression with cognition and AD‐related pathology.

Method

We evaluated the nNOS, eNOS, and iNOS expressions using immunohistochemistry in the cornu ammonis (CA) and the dentate gyrus (DG) from hippocampi from subjects with pure AD and sex‐matched controls. Cognitive abilities were evaluated using the Clinical Dementia Rating (CDR) and AD pathology using Braak staging for neurofibrillary tangles and the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) for neuritic plaque. We used linear regression to examine the association of NOS with cognition and AD pathology.

Results

Sociodemographic and clinical variables were similar between the control and AD groups (Table 1). In individuals with AD, nNOS was overexpressed in the CA (β = 23.62, IC95% = 5.13;42.10, p = 0.01) and DG (β = 16.76, IC95% = 0.35;3.18, p = 0.01), while eNOS and iNOS were increased only in the CA (β = 0.93, IC95% = 0.02;1.84, p = 0.04; β = 0.19, IC95% = 0.09;0.90, p = 0.01, respectively) (Figure 1). Larger nNOS levels in the CA and DG were associated with worse cognitive abilities, higher Braak and CERAD scores (Table 2).

Conclusion

The nNOS, eNOS, and iNOS were increased in the hippocampi of subjects with AD. However, only nNOS overexpression was associated with cognitive impairment and AD‐related pathology.
Computerized serious game‐based cognitive training combined with tDCS for apathy treatment in Mild Neurocognitive Disorders
Authors: Daumas Lyne , Ettore Eric , Zory Raphael , Sacco Guillaume , Giordana Bruno , Guyomar Florent , Ferrandez Marion , Robert Philippe , Manera Valeria
Published: December 2023

Background

Apathy is a clinical syndrome, associated with numerous adverse outcomes, which is pervasive in neurocognitive disorders. Neural bases of apathy rest on dysfunctions of brain structures involved in initiation, execution and control of goal directed behavior, and notably implicate dysfunction of cognitive functions which are required to generate plan of actions. Cognitive training has shown efficacious effects in mild cognitive disorders, and non‐invasive brain stimulation seems to be a promising intervention for cognition and neuropsychiatric symptoms, as suggested by the benefit effects found on depression. The aim of this study is to assess the effectiveness of repeated sessions of computerized serious game‐based cognitive training combined with transcranial direct current stimulation (tDCS) on apathy among older adults with neurocognitive disorders.

Method

The study is an ongoing double‐blind randomized controlled trial. Patients are randomized into a 4‐week intervention of computerized “MeMo” serious game‐based cognitive training combined with either sham or active tDCS. The 4‐week intervention comprise 3 sessions per week, with 20 minutes of cognitive training plus simultaneously sham or active tDCS targeting the left dorsolateral prefrontal cortex with a 2mA of current intensity. The main outcome was the apathy, assessed using the Apathy Diagnostic Criteria, the Apathy Inventory and the self‐reported Apathy Motivation Index questionnaire. Secondary outcomes are cognitive performances, fatigue and daily motor activity.

Result

Preliminary results of the ongoing study will be presented during the AAIC.

Conclusion

These results will provide new evidence about the interest to use combined cognitive training and tDCS as neurorehabilitation intervention, for cognition and apathy treatment in mild neurocognitive disorders.
The utility of the digital clock drawing test as an accurate early screening tool for those with preclinical Alzheimer’s disease
Authors: Ding Huitong , Sunderaraman Preeti , Devine Sherral A. , Karjadi Cody , Ang Ting Fang Alvin , Au Rhoda
Published: December 2023

Background

With new drug treatments emerging, the need for early Alzheimer’s disease (AD) detection methods that can be done in a primary care setting has become urgent. Significant advances have been made in validating blood‐based AD biomarkers, but the absence of a validated, non‐invasive clinical indicator remains a barrier for determining those who might be optimal candidates for treatment. The digital clock drawing test (dCDT) has been previously shown to be related to AD PET biomarkers. However, it is unknown whether and the extent to which dCDT would predict AD as compared to blood‐based AD biomarkers. The current study used an interpretable machine learning approach to determine whether the dCDT, independently and in combination with blood‐based AD biomarkers (e.g., amyloid‐β 42 (Aβ42); total tau (T‐tau)), was predictive of incident AD.

Method

This study included participants from the Framingham Heart Study Generation 2 cohort (Gen 2; n = 527) who had dCDT measures, plasma Aβ42, and T‐tau. The fast interpretable greedy‐tree sums method was used to identify clinical decision rules for AD prediction. Synthetic minority oversampling technique was employed to handle the class imbalance. The predictive ability of plasma Aβ42, T‐tau and dCDT measures was evaluated by both area under the curve (AUC) and standardized partial AUC. The permutation feature importance method was used to show the importance of each measure.

Result

Interpretable clinical decision rules were generated as multivariate biomarker signatures for AD prediction (Figure 1). The dCDT (AUC 0.859) was better at incident AD prediction than AD blood‐based biomarkers (AUC 0.839). The combination of dCDT, Aβ42, and T‐tau best predicted incident AD (AUC 0.884) (Figure 2). The combination of dCDT and blood‐based biomarkers also has higher partial AUC than individual ones (Table 1). The total score and information processing scores were the most important contributing dCDT measures.

Conclusion

These results highlight the efficiency of detecting early AD through the integration of digital measures as a clinical indicator combined with AD specific biomarkers. The interpretable decision rules have the potential to provide automated results that can be used in practical clinical settings, although external validation is warranted.
Potential cognitive enhancers: Discovery and development of multi‐targeting aminoalkyl chalcones
Authors: Singh Manjinder , Sharma Pratibha , Singh Varinder , Singh Thakur Gurjeet
Published: December 2023

Background

Inhibition of acetylcholinesterase (AChE) enzyme is considered as the most promising approach to improve the cognitive deficit complex disorders such as Alzheimer’s disease, dementia etc. The AChE also promote the aggregation of amyloid‐β complexes, mitochondrial dysfunction, a buildup of oxidative stress and neuronal cell death. Consequently, the development of compounds having polyfunctional potential could manage the complex neurodegenerative disorders like Alzheimer’s disease.

Method

The chalcone analogues were developed using bioisosteric replacement and SBDD strategies having improved therapeutic potential. The kinetics and interaction pattern with target protein of designed analogues were further evaluated using in silico methods. The leading compounds were synthesized and evaluated against AChE, AGEs formation with additional radical scavenging potential.

Result

The docking results revealed that synthesized chalcones properly fit into the active gorge of the target enzyme and displayed crucial interactions with the peripheral and catalytic sites of and having drug like properties. The in vitro assays of designed compounds against different targets showed IC50 values in nano to micro molar range.

Conclusion

The dynamic simulations of the designed compounds will be carried out to evaluate the stability of the target‐ligand complex. Thus, the designed chalcones could be taken further to improve cognition deficit mainly in Alzheimer’s disease.
Influence of demographic and clinical characteristics on circulating GFAP levels in Mexican American and non‐Hispanic white older adults
Authors: Gonzales Mitzi M. , Vela Gabriel A. , Philip Vinu , Trevino Hector , LaRoche Ashley , Wang Chen‐Pin , Parent Danielle , Kautz Tiffany F , Satizabal Claudia L. , Tanner Jeremy A. , O'Bryant Sid E. , Maestre Gladys E. , Tracy Russell P. , Seshadri Sudha
Published: December 2023

Background

Circulating levels of glial fibrillary acidic protein (GFAP), an intermediate filament protein of the astrocytic cytoskeleton and putative marker of reactive astrocytosis, increase with cerebral amyloid beta burden and associate with risk of incident all‐cause and Alzheimer’s disease (AD) dementia. However, further validation in diverse cohorts and evaluation of potential health disparities are necessary for broader generalization. The goal of the present study was to examine the associations between demographics, cardiovascular risk factors, and APOE ε4 status with serum GFAP levels among Mexican American and non‐Hispanic white older adults across the continuum from cognitively unimpaired to AD dementia.

Method

Participants included 1,156 Mexican American and 587 non‐Hispanic white adults, aged 55 years and older, who completed a blood draw, clinical and cognitive evaluations, and dementia consensus reviews as part of the Texas Alzheimer’s Research and Care Consortium. Serum levels of GFAP were assayed using a Simoa HD‐1 Analyzer (Quanterix). Associations between demographic and clinical characteristics with serum GFAP levels were evaluated using linear regression. The diagnostic accuracy of serum GFAP was further examined using area under the receiver operating characteristic curves (AUROC) in univariate and adjusted models and optimal cut‐points were derived using the maximum Kolmogorov‐Smirnov metric. All models were also stratified by ethnicity and disease stage.

Result

In the whole sample (Table 1), older age (b = 0.588, p<0.001), APOE ε4 status (b = 0.219, p<0.001), and the presence of cognitive impairment (b = 0.226, p<0.001) positively associated with serum GFAP. In contrast, higher body mass index (b = ‐0.243, p<0.001), diabetes (b = ‐0.110, p<0.001), and tobacco use (b = ‐0.066, p<0.001) were inversely associated with serum GFAP. AUROC values were generally comparable across ethnicities and model fit improved with inclusion of additional covariates (Table 2). However, optimal serum GFAP cut‐off values were consistently lower in Mexican Americans relative to non‐Hispanic whites (Table 3).

Conclusion

The study results highlight the importance of understanding the role of broader demographic and clinical factors on circulating GFAP levels within diverse cohorts in order to enhance precision across clinical, research, and community settings.
Associations among depressive symptoms, hippocampal volume and cognition in community‐dwelling older Latinos
Authors: Giudicessi Averi , Gatchel Jennifer , Vila‐Castelar Clara , Ramirez‐Gomez Liliana A. , Aduen Paula , Noriega Daisy , Félix Nikole A Bonillas , Kaplan Elizabeth , Martinez Jairo E. , Fabrega Sofia , Castillo Crystal , Badillo‐Cabrera Alex L , Garza‐Naveda Ana Paola , Garcia Kelly A. Lopez , Properzi Michael J , Kirn Dylan , Amariglio Rebecca E. , Rentz Dorene M. , Johnson Keith A. , Sperling Reisa A. , Quiroz Yakeel T.
Published: December 2023

Background

Latinos are the fastest growing subpopulation of older adults in the U.S. and have a higher risk for dementia than non‐Latino Whites. Depressive symptoms are prevalent among US Latinos. However, these symptoms often go undiagnosed and are undertreated. Depressive symptoms may be early manifestations of Alzheimer’s Disease (AD) before the onset of mild cognitive impairment and dementia. It’s unclear whether depressive symptoms in the presence of incipient neurodegeneration are associated with cognitive function in older Latino adults. Here, we examined the associations among depressive symptoms, cognition and hippocampal volume in older Latinos.

Method

A total of 65 Spanish‐speaking Latinos enrolled in the Boston Latino Aging Study (BLAST) and the Harvard Aging Brain Study (HABS) were included. Depressive symptoms were assessed with the 30‐item‐Geriatric Depression Scale (GDS) and cognition with the Preclinical Alzheimer’s Cognitive Composite (PACC5), which includes the Mini‐Mental State Examination (MMSE), Digit Symbol Coding, Free and Cued Selective Reminding Test, Category Fluency (animals) and Logical Memory Delayed Recall (NEUROPSI Stories for BLAST participants). A subset of 34 participants also underwent a structural brain MRI on a 3T scanner. Spearman correlations were used to determine cross‐sectional associations among depressive symptoms, hippocampal volume, and cognition. Models were adjusted for age and education.

Results

Participants had a mean age of 66 +/‐ 7.2 years, a mean education of 12.9 +/‐ 5.1 years, and 74% were female. They had a mean MMSE score of 26.7 +/‐ 2.8, a mean GDS score of 6.1 +/‐ 5.5 and a mean adjusted hippocampal volume of 7836.5 +/ = 630.9 mm3. Correlation analyses revealed that higher depressive symptoms were associated with lower years of education (r = ‐0.39, p<0.001), worse performance on cognitive measures (r = ‐0.33, p = 0.009) and smaller hippocampal volume (r = ‐0.61, p = <0.001).

Conclusions

Preliminary results of this ongoing biomarker study suggest that depressive symptoms in older Latinos are associated with markers of neurodegeneration (i.e., hippocampal volume) and worse cognition. Future work will focus on investigating predictors of long‐term emotional and cognitive functioning in Spanish‐speaking, older Latino populations.
Retinal imaging biomarkers of Alzheimer’s disease: clinical evidence and perspectives
Authors: van Wijngaarden Peter
Published: December 2023

A growing body of research is devoted to retinal imaging biomarkers of Alzheimer’s disease (AD). Imaging methods such as optical coherence tomography (OCT) provide qualitative and quantitative measures of retinal and optic nerve neurodegeneration, whereas OCT‐angiography yields depth‐resolved maps of the retinal microvasculature in exquisite detail. Similarly, conventional and widefield retinal photography enable measurements of the retinal vascular geometry. Other emerging technologies, including hyperspectral imaging, retinal curcumin‐fluorescence imaging and fluorescence lifetime imaging ophthalmoscopy, provide insights into retinal changes at the molecular level, such as the accumulation of amyloid beta.

Navigating the evidence in this field is challenging. Of the many studies that have examined associations between retinal imaging findings and AD, most have been based on clinical case ascertainment in the absence of biomarker findings. In this presentation, we will provide an accessible overview of this rapidly evolving field, with an emphasis on studies of retinal imaging biomarkers of the disease that align with the NIA‐AA Research Framework. Underpinning this are the findings of a systematic review and meta‐analysis that we have recently conducted (in press). Drawing on the anatomical and pathological insights provided by fellow speakers in the symposium, we highlight opportunities for further clinicopathological correlation of key imaging biomarkers. Finally, as a prelude to the last talk in the symposium, we highlight gaps in the existing clinical literature and point to efforts to harmonise study methods to generate the evidence needed for adoption of retinal imaging biomarkers of AD in practice.
Analogues Rescues Tau Pathologies and Memory Deficits Inhibiting GSK‐3 Signaling using Scaffold morphing and in silico approaches
Authors: Singh Manjinder , Goyal Shuchi , Thirumal Divya , Sharma Pratibha , Kaur Maninder , Singh Varinder , Singh Thakur Gurjeet
Published: December 2023

Background

Alzheimer’s disease (AD is caused by plaque agglomeration and entanglement in several areas of the neural cells, which leads to apoptosis. The main etiology of AD is senile dementia, which is linked to amyloid‐beta (Aβ) deregulation and tau perivascular pathogeny. Hyperphosphorylated tau has propensity for microtubules, which elevates the instability and tau‐protein congregates, leading to accumulation of neurofibrillary tangles (NFTs). Tau hyperphosphorylation is susceptible to GSK‐3 and is an emerging hypothesis for AD. As a result, attempts are made to conduct investigations and further advancements on new analogues capable of inhibiting the GSK‐3 protein, which are currently in the clinical trials.

Method

In this analysis, we have evaluated certain GSK‐3 inhibitor variants utilizing scaffolding and framework devise technique with pharmacological characteristics, accompanied by computational screenings (pharmacokinetics and docking).

Result

The structure‐based designed analogues interacted effectively with the active amino acids of GSK‐3β target protein. The in silico pharmacokinetic studies revealed their drug‐like properties.

Conclusion

The analogues with best interactions and binding scores will be considered in the future to completely demonstrate their potential relevance as viable GSK ‐ 3 inhibitors.