bluuebunny/crossref_metadata_2025 huggingface dataset:
PROGRESS TOWARDS AN A‐SYNUCLEIN PET TRACER
Authors: Tempest Paul , Tai Chin‐Yin , Ono Maiko , Skaddan Marc B , Wilcox Kyle C , Reed Aimee , Vaidyanathan Srirajan , Christoffersen Claus T , Kallunki Pekka , Bang‐Andersen Benny , Margolin Richard A , Kao Tzu‐Huei , Higuchi Makoto , Jang Ming‐Kuei
Published: December 2022

Background

The high value for Parkinson’s disease and related disorders of the availability of a potent, selective, brain penetrant α‐synuclein (α‐Syn) PET tracer is widely acknowledged. We aimed to develop such an agent by applying an established radiotracer development strategy that has been successfully used with another misfolded CNS protein target.

Method

We used a proprietary collection of CNS‐focused aggregated protein binding agents that APRINOIA had previously created to map the structure‐activity relationship of its tau PET tracer programs, including [18F]APN‐1607. This tracer has a unique binding site on aggregated tau and has recently been characterized by cryo‐EM.

The collection was first screened for selective binding of α‐Syn aggregates vs. tau aggregates using recombinant fibrils. This was followed by fluorescence‐based binding to DLB and MSA tissues. These assays identified 16 promising compounds for progression into autoradiography and homogenate binding assays.

Result

Tritiation was successful for 13 of the hits. Self‐blocking studies confirmed specific binding in human brain tissue sections and homogenates. A lead compound was selected, and preliminary PK experiments in wild type mice indicated that brain uptake and clearance properties were compatible with a desirable PET tracer profile in a non‐diseased state. Further studies to evaluate the binding properties in the diseased state and optimize the lead are ongoing.

Conclusion

The compound collection and tracer development strategy have led to the development of an advanced lead or potentially a viable α‐synuclein PET tracer.
Medical and Psychiatric Risk Factors for Dementia in Veterans with and without Traumatic Brain Injury (TBI): A Nationwide Cohort Study
Authors: Gardner Raquel C. , Barnes Deborah E , Bahorik Amber L , Li Yixia , Peltz Carrie , Yaffe Kristine
Published: December 2022

Background

Traumatic brain injury (TBI) is an important risk factor for dementia and is especially common among Veterans. It is unknown whether TBI exposure moderates the effect of other common medical/psychiatric comorbidities that are also important risk factors for dementia in Veterans. If treatable or preventable comorbidities are either especially common or risky in TBI‐exposed Veterans, then this may have important public health implications for dementia prevention.

Method

We conducted a retrospective cohort study using the Nationwide Veterans Health Administrative inpatient and outpatient data (2001‐2019). We identified all Veterans age 55 years with prior TBI and without baseline dementia (N = 95,139) and age/sex/race‐matched 1:2 with Veterans without prior TBI or baseline dementia (N = 190,278). We compared prevalence of seven common medical/psychiatric comorbidities (hypertension, coronary artery disease (CAD), diabetes, cerebrovascular disease (CVD), epilepsy, depression, and post‐traumatic stress disorder (PTSD)) and associated risk of incident dementia among Veterans with versus without prior TBI. We tested for interaction of each comorbidity with TBI on risk of dementia. We calculated risk of dementia associated with each comorbidity using multivariable hazard ratios (adjusting for demographics and all other comorbidities) and Fine‐Grey competing risk of death. We estimated population attributable risk (PAR) of dementia due to each comorbidity.

Result

All comorbidities were more prevalent among Veterans with TBI compared to those without TBI: hypertension +12.5%, CAD +13.6%, diabetes +7.9%, CVD +10.8%, epilepsy +5.7%, depression +21.5%, PTSD +14.9%). All comorbidities were associated with elevated risk for dementia among Veterans with and without TBI. However, there was a significant interaction with TBI such that point estimates were slightly lower among Veterans with TBI (adjusted HRs 1.02‐1.31) versus Veterans without TBI (adjusted HRs 1.03‐1.82). However, the overall PARs for dementia were higher in Veterans with versus without TBI for several comorbidities (depression 8.7% vs. 7.4%; hypertension 3.8% vs. 1.6%; CVD 3.7% vs. 2.0%; epilepsy 2.1% vs. 1.1%), due to their higher prevalence in Veterans with TBI.

Conclusion

While treating or preventing medical/psychiatric comorbidities among all Veterans remains a high public health priority, targeting depression, hypertension, CVD, and epilepsy may be especially important for dementia risk reduction among Veterans with prior TBI.
Fluctuations in blood pressure measurement: the impact of time of day and ethnicity‐ A HABS‐HD Study
Authors: Large Stephanie E , Petersen Melissa , Hall James , O'Bryant Sid E. , Johnson Leigh
Published: December 2022

Background

Vascular risks including hypertension are significant factors in the development of Alzheimer’s and related dementias . Multiple blood pressure (BP) measurements are commonly used in clinical and research practice to assess this vascular risk. Anecdotal evidence suggests that the first BP measurement taken is more elevated than the second measurement as a participant may be nervous about the study. This study explores if the first measurement is elevated compared to the second and then explores the differences between morning and afternoon measurements.

Method

Data from 1705 participants (non‐Hispanic Whites and Mexican Americans) was collected from a community‐based epidemiological study of aging. The average age was 66, and the average education was 12 years. Participants are scheduled either for AM or PM visit. BP measurements are taken post the consent and then after the participant interview prior to the start of neuropsychological testing. The systolic (SBP) and diastolic blood pressure (DBP) changes were calculated by subtracting the second measurement from the first. T‐tests were performed comparing AM to PM groups. Chi‐square tests compared ethnicity and cognitive status in the AM and PM groups. One‐way ANOVAs examined group differences (ethnicity and AM/PM draw groups) in BP measurement.

Result

Results showed significant differences in SBP change between the AM (M = ‐0.52, SD = 12.74) and PM (M = ‐4.03, SD = 10.89); t(1666)= 6.07, p < 0.000) draw and DBP change in the AM (M = 0.16, SD = 7.68) and PM (M = ‐2.32, SD = 6.68); t(1670)=7.09, p <0.000). Chi‐square tests demonstrated significant differences between the AM and PM groups in ethnicity X2(1, N= 1705) = 33.27, p = 0.000. There were no significant differences between the AM and PM regarding cognitive status (normal, MCI, dementia). ANOVAs demonstrated significant differences between the groups in SBP change (F[3, 1672] = 12.76, p <0.000) and DBP change (F[3, 1672] = 17.10, p <0.000).

Conclusion

The study results demonstrate that there was a relationship between BP and measurement time, which supports evaluating when BP measurements are taken and how this may affect outcomes. Future studies should examine how the blood pressure measurements relate to current guidelines.
Motivational Interviewing Promotes Self‐Determination of LGBTQ Adults with Dementia and Caregivers in First Intervention Study
Authors: Petros Ryan , Fredriksen‐Goldsen Karen , Teri Linda
Published: December 2022

Background

LGBTQ adults experience higher rates of dementia and rely more heavily on informal social support to meet care needs compared to cisgender, heterosexual peers. As dementia progresses and they enter new systems of care, LGBTQ adults must make important choices not only about health promoting behaviors and care plans generally, but also about identity disclosure, building and maintaining a care team with families of choice, and navigating potential discrimination specific to their identities as sexual and gender minorities. A culturally relevant intervention is urgently needed to protect self‐determination and meet their unique care needs.

Method

Using findings from a longitudinal study of LGBTQ adults, a team of interventionist researchers adapted Reducing Disabilities in Alzheimer’s Disease (RDAD) by integrating culturally relevant modifications and enhanced empowerment strategies through motivational interviewing (MI). The team developed and implemented a training protocol for study interventionists called “coaches,” trialed the intervention with 150 dyads of adults with dementia and care providers in the LGBTQ community, and collected case reports from coaches and qualitative data from trial participants to inform intervention adaptations.

Result

MI added unique theoretical and practical contributions, resulting in a culturally relevant, efficacious intervention (Aging with Pride: IDEA), designed for adults with dementia and care providers in the LGBTQ community and adapted for online delivery during the COVID pandemic. Qualitative data from the trial demonstrates that participants discovered “new possibilities for managing changes” as dementia progressed and finished feeling “empowered rather than stuck.”

Conclusion

MI uniquely supported trial participants’ self‐determination to develop and implement strategies for dementia care and coping. Practice examples are included to illustrate applications of MI and relevant theory to promote self‐determination and implementation of strategies to navigate dementia for LGBTQ adults.
Hemispheric asymmetry and atypical lobar progression of Alzheimer‐type tauopathy
Authors: Tremblay Cécilia , Serrano Geidy E , Intorcia Anthony J , Sue Lucia I , Nelson Courtney M , Walker Jessica , Arce Richard , Fleisher Adam S , Pontecorvo Michael J. , Atri Alireza , Montine Thomas J. , Chen Kewei , Beach Thomas G
Published: December 2022

Background

Neurofibrillary tau pathology spread in Alzheimer’s disease (AD) mostly shows a stereotypical pattern of topographical progression. Atypical patterns have also been described and associated with interhemispheric asymmetry. As histopathological studies that used bilateral sampling are limited, this study aimed to assess interhemispheric tau pathology differences and the presence of topographically atypical cortical spreading patterns.

Method

Immunohistochemical staining for detection of tau pathology was performed in 23 regions of interest of 57 autopsy cases and compared between cortical regions and hemispheres.

Result

Frequent mild (82% of cases) and occasional moderate (32%) interhemispheric density discrepancies were observed while marked discrepancies were uncommon (7%) and restricted to occipital regions. Left and right hemispheric tau pathology dominance was observed with similar frequencies, except in Braak stage VI that favored a left dominance. Interhemispheric Braak stage differences were observed in 16% of cases and was more frequent in advanced (IV‐VI) than early stages (I‐III). One atypical lobar topographical pattern, where occipital tau pathology density exceeded frontal lobe scores, was identified in 4 cases, favoring a left dominant asymmetry.

Conclusion

We speculate that asymmetry and atypical topographical progression patterns may be associated with described atypical AD clinical presentations and progression characteristics, which should be tested by comprehensive clinicopathological correlations.
Reaching the Underserved in Dementia Research: IDEA (Innovations in Empowerment and Action)
Authors: Fredriksen‐Goldsen Karen , Teri Linda , Kim Hyun‐Jun , Jones Brittany R , La Fazia David M. , McKenzie Glenise , Petros Ryan , Brown Char , Emlet Charles A
Published: December 2022

Background

Existing research has documented higher levels of cognitive impairment among marginalized populations, including among LGBT (lesbian, gay, bisexual, and transgender) older adults. Research has also found LGBT older adults living with cognitive impairment experience a unique and challenging context compared to their heterosexual and cisgender peers. However, there remains a paucity of research regarding culturally appropriate dementia interventions and services that are responsive to the needs, risks, and protective factors of such underserved populations.

Method

Aging with Pride: IDEA (Innovations in Dementia Empowerment and Action) is the first federally funded study to test an intervention designed to address the distinct needs of LGBT older adults with cognitive impairment and their caregivers. The study design compares a specialized LGBT enhanced program to a pre‐existing standard dementia program (RDAD), which provided the foundation for the project. This presentation will examine the ways in which the demographic profile and the recruitment and retention findings differ for this population compared to most existing dementia intervention research.

Result

Among the LGBT older adults living with cognitive impairment in this study, 74.8% identified as gay or lesbian and 7% as bisexual; 6.3% as transgender. Among caregivers, this was 69.9%, 15.4%, and 7%, respectively. People of color accounted for 16.8% of care recipients and 23.1% of caregivers. Care recipients were significantly more likely to initiate contact to enlist in the randomized controlled trial (RCT) compared to caregivers. One‐third of care recipients had a non‐partner/spouse caregiver supporting them in this dyadic intervention; 15.4% had a friend in the care partner role. The most common reason for study ineligibility was not having a care partner to participate and about 12% terminated from the program because of difficulty within the care partner/care recipient dyad.

Conclusion

The current study built a strong research‐community partnership necessary for the development and implementation of the intervention. The information gained in this study regarding recruitment, retention, and implementation is valuable for developing interventions that can be tailored to the distinct needs of communities that have traditionally been underserved in dementia research.
Prognostic value of plasma Amyloid‐β 42/40 ratio in early and pre‐clinical AD
Authors: Vogelgsang Jonathan , Klafki Hans , Morgado Barbara , Jahn‐Brodmann Anke , Esselmann Hermann , Bauer Chris , Schuchhardt Johannes , Peters Oliver , Priller Josef , Schneider Anja , Fliessbach Klaus , Jessen Frank , Duzel Emrah , Buerger Katharina , Perneczky Robert , Teipel Stefan , Laske Christoph , Spottke Annika , Heneka Michael T. , Ramirez Alfredo , Wiltfang Jens
Published: December 2022

Background

In 2021 Adacanumab, the first antibody that might potentially treat causal neuropathology associated to Alzheimer’s disease (AD), was approved by the FDA. However, early, most likely pre‐cognitive treatment is required raising a high need for early and low‐invasive diagnostic biomarker. Here, we present plasma Amyoid‐beta (Aβ) measurements in a large longitudinal observational study from the German Center for Neurodegenerative Diseases (DZNE, DZNE‐Longitudinal Cognitive Impairment and Dementia (DELCODE) study).

Method

Plasma Aβ40 and Aβ42 of 1049 baseline samples from the DELCODE cohort were measured in a semi‐automated fashion according to our recently published protocol. Aβ immunoprecipitation and Mesoscale immuno‐measurement were controlled for batch effects. All samples were well balanced and Mesoscale Aβ measurements were performed in two technical replicates on the same assay plate. 41 samples with a coefficient of variation > 10% between the two technical replicates were re‐measured. Corresponding CSF and plasma Aβ measurements were available for 377 samples for further downstream analysis.

Result

Interassay variability from a QC sample using 6 replicates was 8.3%, 8.0%, and 6.9% for Aβ40, Aβ42, and the Aβ42/40 ratio, respectively.

CSF and plasma Aβ42 and Aβ42/40 ratio correlated with r=0.169 (p<0.001) and r=0.466 (p<0.0001), respectively. No correlation was observed for Aβ40. Plasma Aβ42/40 was able to distinguish samples from donors with a CSF Aβ42/40 ratio classified as pathological or normal with an AUC of 0.82. ApoE inclusion increased the AUC for plasma Aβ42/40 to 0.87 with a specificity of 0.73 and a sensitivity of 0.87.

Importantly, plasma Aβ42/40 was not only able to differentiate participants with high vs. low CSF Aβ42/40 in general, but also predicted Aβ status in patients with milder or no cognitive impairments: in controls, the AUC for the plasma Aβ42/40 ratio was 0.78, in SCI 0.76, and in MCI 0.71. There was only one dementia case with a normal CSF Aβ profile, thus no further comparison could be performed for donors in dementia stage.

Conclusion

Plasma Aβ can differentiate CSF pathological vs normal AD patients. Further analysis including follow‐up data to identify the early predictive value of plasma Ab will be performed including neurocognitive measurements to include all plasma Aβ measurements.
Evaluation of a functional assessment tool in patients with mild cognitive impairment or Alzheimer’s disease in Lima, Peru
Authors: Custodio Nilton , Montesinos Rosa , Chambergo‐Michilot Diego , Herrera‐Perez Eder , Caipa Maritza Pintado , Seminario G Wendy , Cuenca José , Mesia Laura , Failoc‐Rojas Virgilio E , Diaz Monica M
Published: December 2022

Background

Functional assessment screening tools are crucial for dementia evaluations. The Alzheimer’s Disease Cooperative Study‐Activities of Daily Living (ADCS‐ADL) scale is a versatile functional assessment screening tool that can be used to monitor functional decline of patients with Alzheimer’s disease (AD). We sought to evaluate the validity and reliability of the ADCS‐ADL scale in Peruvian patients with mild cognitive impairment (MCI) or AD.

Method

This was a cross‐sectional study of older adults from a multidisciplinary neurology institute in Lima, Peru in one of three groups: cognitively healthy controls, MCI or AD. ANOVA or chi‐square tests were used. Psychometric properties evaluated included reliability (intraclass correlation coefficient, ICC; internal consistency, Cronbach’s alpha) and validity (external and convergent).

Result

We included 276 patients in the analysis. Age, sex, educational level, and depressive symptoms did not vary significantly between the groups, but the Mini Mental State Examination and Addenbrooke’s Cognitive Examination scores were significantly different between groups. ICC was 0.996 and Cronbach’s alpha was 0.937 for the ADCS‐ADL. The ADCS‐ADL could not differentiate patients with MCI from cognitively healthy controls, but it accurately differentiated degrees of cognitive impairment within the AD group. The ADCS‐ADL correlated highly with all functional assessment and cognitive screening tools, except for the Alzheimer’s Disease Assessment Scale‐Cognitive subscale.

Conclusion

The ADCS‐ADL scale is reliable in a population of patients with AD in Lima, Peru, and correlated with most functional assessment scales used to evaluate patients with AD.
Distinct Patterns of Brain Atrophy in MCR and amnestic MCI pre‐dementia syndromes
Authors: Nagamalla Vineela M , Verghese Joe , Ayers Emmeline , Barzilai Nir , Beauchet Olivier , Lipton Richard B. , Shimada Hiroyuki , Srikanth Velandai K , Blumen Helena M
Published: December 2022

Background

Both amnestic Mild Cognitive Impairment (aMCI) and the Motoric Cognitive Risk (MCR) syndrome are reliable predictors of Alzheimer’s Disease (AD). There is also some evidence for that MCR is a stronger predictor of vascular dementia (VaD) than AD. The current study directly compared cortical and hippocampal atrophy patterns in MCR and aMCI to inform the development of interventions targeted to these pre‐dementia syndromes. We hypothesized that MCR would be associated with a widespread pattern of cortical atrophy while aMCI would be associated with atrophy restricted to hippocampal and neighboring temporal regions.

Method

Cross‐sectional data from 733 older adults without dementia and functional disabilities from the MCR‐consortium were examined. MCR was operationalized as slow gait and subjective cognitive complaint, using previously established cohort‐specific criteria. aMCI was operationalized as 1.5 standard deviation or more below standardized performance on episodic memory measures. FreeSurfer v6.0 was applied to T‐1 weighted MRIs to examine cortical thickness and hippocampal atrophy patterns in MCR and aMCI relative to those without MCR and aMCI, respectively. Separate general linear models (GLMs) examined the associations between overall and regional cortical thickness, hippocampal volume, and MCR and aMCI. All GLMs were adjusted for age, sex, education, total intracranial volume, white matter lesion burden, and study site.

Result

The mean age of the sample was 74.4 years (45.4% women). The prevalence of MCR and aMCI was 7.6% and 2.6 %, respectively. Both MCR and aMCI was associated with overall cortical atrophy. Yet, while MCR was associated widespread cortical atrophy – that included prefrontal, insular, cingulate, motor, parietal and temporal regions – aMCI was associated with a restricted pattern of atrophy that primarily included temporal and hippocampal regions.

Conclusion

This study revealed distinct patterns of atrophy in older adults with MCR and aMCI pre‐dementia syndromes. A widespread pattern of cortical atrophy – that is more consistent with VaD or mixed dementia than AD – was observed in MCR. A more restricted pattern of atrophy – that is more consistent with AD than VaD or mixed dementia – was observed in aMCI. Thus, the biological underpinnings of MCR and aMCI likely differ, and may require tailored interventions.
An introduction to GENFI and the development of novel behavioural and cognitive measures for genetic FTD
Authors: Rohrer Jonathan D.
Published: December 2022

Background

The Genetic FTD Initiative (GENFI) is the largest familial FTD cohort study worldwide and over its initial ten years has created a network of nearly 30 research centres across Europe and Canada, and a cohort of over 1000 participants.

Method

GENFI was established to develop robust biomarkers that could be used in clinical trials. In terms of clinical and cognitive measures, the study has used a set of novel symptom scales as well as a detailed neuropsychological battery, all harmonized across the network, to identify new rating scales and composite measures.

Result

The study has characterized behavioural and neuropsychological changes across the different genetic forms of FTD, highlighting the earliest prodromal changes that occur in different domains, including emotion recognition, semantic knowledge and executive dysfunction. GENFI data has also been used to validate two core clinical/cognitive scales, highlighting their utility for clinical trials in genetic FTD: the CDR plus NACC FTLD and the FTD Rating Scale (FRS). An extension to the CDR plus NACC FTLD with motor and neuropsychiatric domains highlights the contribution of symptoms outside of classical behavioural and language domains to accurately measuring disease progression. The study has also combined neuropsychological measures to create a cognitive composite measure (GENFI‐Cog), individualized to each genetic group, which greatly reduces sample sizes required for clinical trials.

Conclusion

The GENFI study has developed and validated a number of clinical and cognitive measures that are now being implemented in clinical trials for novel therapeutics in familial FTD. Future studies in GENFI will help to refine these even further.
Magnetic resonance imaging biomarkers in genetic FTD
Authors: Rowe James B
Published: December 2022

Background

MRI provides a suite of tools for safe, non‐invasive, repeatable and scalable assessment of the changes in brain structure and function associated with neurodegenerative disease. MRI has been part of the principal assessment in the international Genetic Frontotemporal Dementia Initiative since 2012 (GENFI). This presentation reviews the goals and achievements of MRI in GENFI, and considers future directions to elucidate disease mechanisms, inform clinical trials design, and provide single subject prognosis.

Method

GENFI established protocols for harmonisation and standardisation of MRI, and coordinated infrastructure for curation and quality control. 3T MRI sequences have been optimised and closely approximated across diverse vendors, for whole‐brain qualification of volume (T1w), diffusion (DWI), perfusion (ASL), macro‐molecular environment (T2) and function (BOLD fMRI), with >2500 assessments from>1000 participants: including symptomatic people with mutations in MAPT, C9orf72 and GRN; pre‐symptomatic mutation‐carriers; and asymptomatic non‐carriers from the same families. There are >20 peer‐reviewed open‐access MRI‐based publications to date.

Results

GENFI MRI revealed a long pre‐symptomatic phase in people with FTD‐associated mutations, with atrophy present and progressive in frontotemporal regions >10 years before estimated onset. For some mutations, differences in mutation carriers (vs non‐carriers) are evident in early adulthood. The pre‐symptomatic structural change is associated with subtle cognitive and behavioural change. It is prognostic and non‐linear, accelerating with aging towards symptom onset. Intriguingly, functional integration is maintained in macro‐scale brain networks of pre‐symptomatic carriers, suggesting a mechanism of functional resilience to progression of underlying neuropathology. The consequences of mutations are not confined to frontotemporal regions: GENFI has highlighted behaviourally‐relevant changes in volume and shape, white‐matter hyperintensity and diffusivity in parietal lobe, basal ganglia, thalamus and cerebellum. The MRI tools can be used to identify stages and subtypes of genetic‐FTD.

Conclusion

Over ten years, GENFI has shown how MRI can be delivered at scale in multi‐centre studies of genetic FTD, revealing the long pre‐symptomatic phase, with gene‐specific mechanisms and consequences. The sensitivity, reliability and progression of gene‐specific changes in diverse MRI modalities are ideal to support clinical trials of novel therapeutic agents.
International collaboration and the FTD Prevention Initiative
Authors: Russell Lucy L
Published: December 2022

Background

The Frontotemporal dementia Prevention Initiative (FPI) is a collaborative group made up of familial FTD (fFTD) research groups across the world. This includes the Genetic FTD Initiative (GENFI) in Europe and Canada, ARTFL‐LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) in the USA, the Multi‐partner consortium to expand dementia research in Latin America (ReDLat), the Dominantly Inherited Non‐Alzheimer’s Dementias (DINAD) in Australia, and The New Zealand Genetic FTD Study (FTDGeNZ). Initial efforts have been focused on individuals from families who are known to carry mutations in the C9orf72, GRN and MAPT genes.

Methods

To advance therapeutic trials for fFTD, data has been shared within the FPI across the different cohort studies to understand the stratification and disease progression of mutation carriers. As well as the development of a large network of ‘trial‐ready’ participants for upcoming trials, with further extension of this network to Asia, the FPI also aims to develop a set of principles for fFTD trials that will guide data and sample sharing.

Results

An initial FPI project has shown the range of ages at symptom onset (AAO), death and duration in fFTD, with relatively poor correlation of individual AAO with both parental and family AAO, particularly in those with C9orf72 and GRN mutations. Further work has shown the ability of blood neurofilament light chain protein levels to predict subsequent disease progression. Lastly, a combination of clinical, cognitive, imaging and fluid biomarker data has allowed the development of disease progression models that will be useful in future clinical trial design.

Conclusions

The FPI is the first initiative to bring together the academic fFTD community to contribute to a global effort to find therapeutics for this devastating disease. Future work aims to extend the network and continue to establish our partnerships with our families, patient advocacy groups, and industry partners.
Consumption of ultra‐processed foods and cognitive decline in the ELSA‐Brasil study: a prospective study
Authors: Gonçalves Natalia G , Ferreira Naomi Vidal , Khandpur Neha , Steele Euridice Martinez , Levy Renata Bertazzi , Lotufo Paulo A , Bensenor Isabela M , Marchioni Dirce Lobo , Suemoto Claudia Kimie
Published: December 2022

Background

Consumption of ultra‐processed foods (UPF) has progressively increased worldwide in the last 30 years. High intake of UPF is associated with cardiovascular disease and cancer and hypothesized to induce systemic inflammation and oxidative stress. Although UPF may also be a risk factor for cognitive decline through these pathways, little is lnown about the effects of UPF on cognition. We aimed to investigate the longitudinal association between UPF consumption and cognitive decline in the ELSA‐Brasil study during 9 years of follow‐up.

Method

Participants were evaluated in three study waves (2008‐10, 2012‐14 and 2017‐19).Data on diet measured by food frequency questionnaire was categorized according to degree of food processing using NOVA. Cognitive performance was evaluated using a standardized battery of tests ‐ the immediate recall, late recall, recognition, semantic and phonemic verbal fluency and the trail‐making tests. A global composite z‐score was derived from these tests. Association of consumption of UPF (% of total daily gram intake) with cognitive performance over time was evaluated using linear mixed effects models, adjusted for sociodemographic, lifestyle, and clinical variables.

Result

In 8,160 participants (mean 50.6±8.7 y, 56% women, and 55% white) during a median follow‐up of 9 years, the mean baseline calorie intake was 2,842±982 kcal, 28% (493g) of which came from UPF (Table 1). During follow‐up time, consumption of UPF in the fourth and fifth versus the first quintile were related to a decline in the executive funtion (β = ‐0.007, 95% CI = ‐0.013; ‐0.002, p = 0.004) and memory performance (β = ‐0.004, 95% CI = ‐0.009; 0.000, p = 0.048), respectively (Table 2). No association of UPF consumption and verbal fluency was observed (Table 2).

Conclusion

During nine years of follow‐up, high consumption of UPF was associated with cognitive decline, particularly in the memory and executive funtion domains.
Chemical ablation of locus coeruleus terminals in mice dysregulates behavioral features reminiscent of prodromal Alzheimer’s disease
Authors: Korukonda Anuradha , Iannitelli Alexa F , Weinshenker David
Published: December 2022

Background

The prodromal stages of Alzheimer’s disease (AD), which precede cognitive impairment by decades, are characterized by neuropsychiatric symptoms such as anxiety, agitation, impulsivity, and sleep disturbances that significantly impair quality of life. The brainstem noradrenergic locus coeruleus (LC) modulates behaviors that are reminiscent of these prodromal symptoms. Furthermore, the loss of norepinephrine (NE) terminals in LC‐projecting regions is a prominent feature of early AD, implicating LC dysfunction as a possible contributor to prodromal symptoms. However, the behavioral and pathological consequences of LC terminal loss have not been fully investigated.

Method

Adult male and female C57BL/6 mice aged 4‐6 months were administered either saline or the LC‐specific neurotoxin, N‐(2‐chloroethyl)‐N‐ethyl‐bromo‐benzylamine (DSP‐4) (50 mg/kg, i.p.) on day 1 and day 7 (12 animals/group). Performance in behavioral tests that assess arousal (sleep latency), locomotor activity (novelty‐induced and circadian), anxiety (novelty‐suppressed feeding), and associative memory (contextual fear conditioning) commenced one week following the last treatment. In addition, brain sections consisting of LC, hippocampus, and cortical areas were immunostained for tyrosine hydroxylase (TH) to evaluate LC integrity, NE transporter (NET) to determine fiber/terminal density to LC‐projecting regions, and glial fibrillary acidic protein (GFAP) to assess astrogliosis. Fluorescence immunoreactivity (IR) was analyzed with ImageJ.

Result

Animals treated with DSP‐4 displayed significantly increased latency to feed in a novel environment compared to saline‐treated animals, with no treatment differences in the home cage, suggesting elevated neophobic behavior. Furthermore, DSP‐4‐treated animals trended towards decreased locomotor activity in the center of the environment over 1 hour and 23 hours, indicating increased thigmotaxis. No behavioral treatment differences were observed for sleep latency and contextual fear conditioning paradigms. Immunofluorescence revealed no treatment differences in TH IR in the LC but reduced NET IR in LC‐projecting regions of DSP‐4‐treated animals, demonstrating preserved LC cell bodies and LC fiber loss. No significant treatment differences were found for GFAP.

Conclusion

These data suggest that chemical ablation of LC terminals with DSP‐4 can contribute to neophobia and anxiogenic responses, implicating LC terminal loss in mediating prodromal symptoms relevant to AD. Further studies are warranted to identify the physiological and molecular mechanisms underlying LC dysfunction for alleviating prodromal AD symptoms.
Depletion of voltage‐gated potassium channel Kv1.1 contributes to behavioral deficits in transgenic mouse model of Alzheimer’s disease
Authors: Addo‐Osafo Kwaku , Choquette Jessica M , Peters Samuel T. , Fomenko Vira , Xu Jordan , Craft Ryan , Gimlin Kayleen , Vossel Keith
Published: December 2022

Background

Patients with Alzheimer's disease (AD) are at risk for seizures and accelerated cognitive decline. Mechanisms of seizures and related synaptic dysfunction in AD are active areas of investigation. Alterations in ion channels have been identified in transgenic mouse models of AD, but levels of voltage‐gated potassium channels (VGKCs) have not been fully explored. In particular, little is known about Kv1.1 channels in AD. Mutations in Kv1.1 or autoantibodies against Kv1.1 cause neuronal overexcitation in several human diseases, including episodic ataxia type 1, epilepsy, myokymia, and limbic encephalitis, indicating that Kv1.1 is critical for regulating neuronal excitability.

Method

To explore VGKCs in AD, we used hAPP‐J20 mice ages 4‐6 months and determined mRNA and protein levels of four highly expressed VGKCs ‐ Kv1.1, Kv1.2, Kv1.4, and Kv4.2 ‐ in dentate gyrus, entorhinal cortex, motor cortex, and somatosensory cortex (SSC).

Result

Using RT‐qPCR, we identified reductions in Kv1.1 mRNA in the SSC of hAPP‐J20 mice. Western blotting revealed reductions in the Kv1.1 channel in the SSC of hAPP‐J20 mice and human parietal cortex in mild and moderate stages of AD. Immunolabeling revealed that the reductions in Kv1.1 channels in the SSC occurred in pyramidal cells and GABAergic interneurons. Kv1.1 levels in the SSC were lower in hAPP‐J20 mice, which overexpress mutant hAPP and have high Aβ(1‐42) levels, than in the wild‐type hAPP line I5, suggesting some dependence on Aβ(1‐42) levels. Levetiracetam treatment (75 mg/kg/day) administered for 28 days did not affect Kv1.1 levels in hAPP‐J20 mice. To assess Kv1.1 depletion in an AD model, we crossed Kv1.1 heterozygous mice (Kv1.1 +/‐) with hAPP‐J9 mice, which have lower expression of mutant hAPP than J20 mice. We performed behavioral tests on mice ages 4‐9 months. While Kv1.1 +/‐ mice and hAPP‐J9 mice had normal survival, the double mutant (Kv1.1 +/‐ hAPP‐J9) mice had premature mortality and impairments in elevated plus maze and light‐dark box tests (n=16‐25 mice/genotype) of anxiety.

Conclusion

These data indicate that elevated Aβ(1‐42) levels may act synergistically with Kv1.1 depletion to exacerbate cognitive deterioration in AD. Ongoing investigation will further characterize the relationships between Kv1.1 loss and AD‐related hyperexcitability.
Physical Activity Relates to Lower Astrocytic Activation and Axonal Breakdown in Clinically Normal Older Adults
Authors: VandeBunte Anna M , Lee Shannon Y. , Paolillo Emily W , Rojas Julio C. , Chan Brandon , Lago Argentina Lario , Kramer Joel H. , Casaletto Kaitlin B
Published: December 2022

Background

Physical activity is associated with >30% reduced risk of dementia. However, the biological mechanisms underlying exercise as a protective factor against cognitive decline remain unclear. Astrocytic activation and axonal breakdown, as measured by plasma glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL), respectively, are pathways disrupted early in cognitive aging and neurodegenerative disease. We aimed to examine whether an objective measure of physical activity (FitbitTM) related to plasma levels of GFAP and NfL in clinically normal older adults.

Method

57 clinically normal older adults completed 30‐day FitbitTM Flex2 monitoring (average daily steps and calories burned estimated) and a blood draw with plasma analyzed via Quanterix SIMOA for GFAP and NfL. A subset (n = 48) completed an amyloid PET scan (18F‐AV45 or 11C‐PIB). Pairwise correlations and linear regression models adjusting for age and cerebral amyloid burden evaluated the associations among Fitbit metrics and plasma markers of interest.

Result

Higher Fitbit calories burned and step count correlated with lower levels of GFAP (r = ‐0.33 to ‐0.54, p<0.01) and NfL (r = ‐0.36 to ‐0.45, p<0.01). After controlling for age, average calories burned remained significantly associated with GFAP (β = ‐0.40, p< 0.01) and NfL (β = ‐0.30, p<0.01), while the associations attenuated between total steps with GFAP (β = ‐0.14, p = 0.31) and NfL (β = ‐0.17, p = 0.18). Effect sizes for all models remained similar further adjusting for amyloid PET centiloid levels (calories burned: GFAP: β = ‐0.44, p< 0.01; NfL: β = ‐0.29, p = 0.06; and total steps: GFAP: β = ‐0.23, p = 0.14; NfL: β = ‐0.26, p = 0.10). Interactions between Fitbit metrics and amyloid PET centiloids were not statistically significant for GFAP or NFL (ps >0.5).

Conclusion

Greater step count and, particularly, calories burned was associated with markers of lower astrocytic inflammation and axonal degeneration in older adults. Our results demonstrate that calories burned may have a more direct (and positive) impact on axonal and astrocytic health in comparison to overall movement. Consequently, these findings suggest higher intensity calorie burning activities may be an important brain health recommendation for older adults. Careful understanding which aspects of physical activity map onto which biological pathways of brain health could inform more precise exercise recommendations and intervention.
Cross‐sectional and longitudinal comparison of 18F‐MK6240 and 18F‐Flortaucipir in populations matched for centiloid, age and MMSE
Authors: Bourgeat Pierrick , Krishnadas Natasha , Dore Vincent , Mulligan Rachel S , Tyrrell Regan , Bozinovski Svetlana , Huang Kun , Lamb Fiona , Fripp Jurgen , Villemagne Victor L , Rowe Christopher
Published: December 2022

Background

Longitudinal tau quantification may provide a useful outcome measure in disease‐specific therapeutic trials. Different tau PET tracers may have different sensitivity to longitudinal changes, but without a head‐to‐head comparison, equating results from different cohorts using different tracers can be biased. In this study, we aim to minimise this bias by matching participants in two cohorts imaged using 18F‐MK6240 and 18F‐Flortaucipir (FTP).

Method

A subset of 93 participants from AIBL and 93 from ADNI, imaged at baseline and 1 year later using 18F‐MK6240 and 18F‐FTP, respectively, were matched based on baseline clinical diagnosis, MMSE, age, and Centiloid value (CL). PET images were analysed with CapAIBL. Amyloid positivity (+/‐) was defined based on a threshold of 25CL. Subjects were grouped as 34 cognitively unimpaired amyloid negative (CU‐) and 24 positive (CU+), 18 mild cognitive impairment positive (MCI+) and 17 Alzheimer’s disease positive (AD+). Tracer retention was measured in the mesial temporal (Me), meta‐temporal (MT), temporoparietal (Te) and rest of the cortex (R). T‐tests were employed to assess group separation at baseline using SUVR and longitudinally using SUVR/Yr.

Result

As per selection criteria, there were no significant differences in age, MMSE or Centiloid between the cohorts using 18F‐MK6240 or 18F‐FTP in each subgroups. Baseline SUVR were significantly different between CU‐/CU+, CU+/MCI+ and CU+/AD+ in all regions for both tracers, except for CU‐/CU+ in R for 18F‐MK6240 (Figure 1). Using 18F‐MK6240, rate of change in CU+ was significantly higher than CU‐ in MT and Te, and both MCI+ and AD+ were higher than CU+ in R (Figure 2.Left). Using 18F‐FTP, rate of change in MCI+ was significantly higher than CU+ in Te, and AD+ higher than CU+ in MT, Te and R (Figure 2.Right).

Conclusion

In our matched cohorts using 18F‐MK6240 or 18F‐FTP, we found that, at baseline, both tracers can detect significant differences between clinical groups. However, 18F‐MK6240 was able to detect higher rates of accumulation at preclinical stages (CU+). These results in well‐matched cohorts indicate that 18F‐MK6240 might be a more sensitive tracer to detect early accumulation. Longitudinal head‐to‐head comparison will be required to confirm these results.
Multi‐tracer comparison in Alzheimer’s disease, Corticobasal Degeneration and Progressive Supranuclear Palsy brains
Authors: Malarte Mona‐Lisa , Kumar Amit , Nordberg Agneta K
Published: December 2022

Background

Recent CryoEM studies in tauopathies clearly bought forward one more time the complexity of these pathologies, and showed that it goes beyond the tau isoforms. Tau PET tracers play an important role in the understanding of this aspect. We have observed in post‐mortem brain tissue from Alzheimer’s disease (AD) patients that the second‐generation of tau PET tracers 3H‐PI2620, 3H‐MK6240, 3H‐RO948, all show similar regional distribution, but also comparable binding affinities to multiple binding sites in AD brain large hemispherical tissue section autoradiography and homogenates. In vitro autoradiography can mirror the in vivo binding pattern of PET tracers and be useful in pre‐clinical validations. The aim of this study was to perform a comparative multi‐tracer study in AD, PSP, CBD and control brains with several second generation tau‐tracers to obtain a deeper insight into tau spatial distribution and discriminative power of tau tracers in degenerative proteinopathies. We also want to study how the binding of the tracers correlate with other pathological hallmarks such as amyloid‐β and reactive astrogliosis.

Methods

we performed radioligand binding assays in brain homogenates, in small tissue sections and large frozen hemispherical brain sections autoradiography using tau PET tracers (3H‐PI2620, 3H‐MK6240, 3H‐RO948, and 3H‐JNJ067) in comparison to reactive astrogliosis PET tracers (3H‐BU99008 and 3H‐Deprenyl) and amyloid tracer (3H‐PIB).

Results

In ongoing studies, 3H‐PI2620, 3H‐MK6240 and 3H‐RO948 clearly followed a two binding sites model in AD brains. 3H‐PI2620 bound to two binding sites in the frontal cortex of both AD and CBD but to one site in PSP brains, but in similar high affinity range in the three pathologies. 3H‐RO948 and 3H‐MK6240 showed low binding in comparison to 3H‐PI2620 in CBD and PSP.

Conclusion

Tau PET tracers showed similar affinities to multiple binding sites and similar regional distribution in AD brains. 3H‐MK6240 and 3H‐RO948 displayed selectivity for AD brains, while 3H‐PI2620 also showed similar binding affinity for CBD and PSP brains. Ongoing studies with several PET tracers targeting different pathological hallmarks will increase possible discriminative properties and provide new knowledge on the spatial distribution of tau and its correlation with other biomarkers in different tauopathies.
Herpes Viruses in the Baltimore Longitudinal Study of Aging:Associations with Brain Volumes, Cognitive Performance and Plasma Biomarkers
Authors: Duggan Michael R , Peng Zhongsheng , An Yang , Kitner‐Triolo Melissa , Shafer Andrea T , Davatzikos Christos , Erus Guray , Karikkineth Ajoy , Lewis Alexandria , Moghekar Abhay , Walker Keenan A
Published: December 2022

Background

Although an infectious etiology of Alzheimer’s Disease (AD) has received renewed attention, the longitudinal effects of symptomatic herpes viruses (sHHV) infection on brain structure and cognition remain poorly understood, as does the effect of sHHV on AD/neurodegeneration biomarkers.

Method

Using data from the Baltimore Longitudinal Study of Aging (BLSA), we characterize the association of sHHV diagnoses – defined using ICD‐9 classification – with longitudinal changes in total and regional brain volumes obtained from 3T magnetic resonance imaging (MRI), and cognitive performance across five cognitive domains. Additionally, we relate sHHV to plasma biomarkers of AD (Ab42/40), astrogliosis (glial fibrillary acidic protein [GFAP]) and neurodegeneration (neurofilament light [NfL]). The study design is illustrated in Figure 1.

Result

A total of 1,009 participants were included in the primary MRI analysis, 98% of whom were cognitively normal at baseline MRI. Having a sHHV diagnosis (N = 119) was associated with longitudinal reductions in white matter volume (annual additional rate of change ‐0.34 cm3; p = 0.035), particularly in the temporal cortex; however, there was no association between sHHV and change in total brain, total gray matter, or AD signature region volume (Table 1; Figure 2). Among the 119 participants with sHHV infection, exposure to antiviral treatment attenuated declines in occipital white matter (annual reduction in rate of change 0.10 cm3; p = 0.036). Although the sHHV group (N = 290) had higher cognitive scores on certain cognitive domains at baseline, sHHV diagnosis was associated with accelerated longitudinal declines in attention (annual additional rate of change ‐0.01 Z‐score; p = 0.008) (Figure 3). In cross‐sectional analyses, sHHV diagnosis (N = 83) was associated with elevated plasma GFAP (Figure 4). However, sHHV was unrelated to plasma Ab42/40 and NfL levels.

Conclusion

These findings suggest an association of sHHV infection with white matter volume loss, attentional decline, and astrogliosis. Although the findings link sHHV to several neurocognitive features, the results do not support an association between sHHV and AD‐specific disease processes.