bluuebunny/crossref_metadata_2025 huggingface dataset:
Plasma GFAP:NfL discriminates FTLD‐tau from FTLD‐TDP
Authors: Cousins Katheryn A Q , Shaw Leslie M. , Chen‐Plotkin Alice , Lee Eddie B , Trojanowski John Q , Van Deerlin Vivianna M , McMillan Corey T , Grossman Murray , Irwin David J.
Published: December 2022

Background

Biomarkers are lacking that can discriminate frontotemporal lobar degeneration (FTLD) with tau (FTLD‐tau) from TDP‐43 (FTLD‐TDP). In FTLD patients with autopsy‐ or mutation‐confirmed pathology, we tested the glial fibrillary acidic protein (GFAP) to neurofilament light chain (NfL) ratio (GFAP/NfL) in plasma. We validated application of GFAP/NfL ratio in an independent sample of frontotemporal dementia (FTD).

Methods

Training sample was composed of 105 FTLD‐TDP and 44 FTLD‐tau participants, with pathology confirmed by either autopsy or pathogenic mutations (MAPT, C9orf72, GRN, TARDBP). Average accumulations of postmortem tau, TDP‐43, and amyloid across neocortical, limbic and brainstem regions were scored on a 0‐3 scale. Regression tested differences in analytes (log transformed) across FTLD‐tau and FTLD‐TDP, covarying for age, interval to death, and sex. Regression tested association of analytes (log transformed) with postmortem tau and TDP‐43 accumulation, covarying for postmortem amyloid‐β and plasma‐to‐death interval. Receiver operating characteristic (ROC) analyses and area under the curve (AUC) analyses were performed in patients with negligible secondary pathology. We defined an optimal cut‐point to discriminate FTLD‐tau from FTLD‐TDP using plasma GFAP/NfL. We tested the defined cut‐point in an independent validation sample of FTD patients with a clinical diagnosis of progressive supranuclear palsy (PSP) with likely tau (FTD‐tau; n=33) or diagnosis of amytrophic lateral sclerosis (ALS) with likely TDP‐43 (FTD‐TDP; n=35).

Results

Plasma GFAP was lower in FTLD‐TDP than FTLD‐tau (β=‐0.24, p=0.021) with small effect size (partial η2=0.082). Plasma NfL was higher in FTLD‐TDP than FTLD‐tau (β=0.57, p=1.0e‐05) with medium effect size (partial η2=0.24). GFAP/NfL was significantly lower in FTLD‐TDP than FTLD‐tau (β=‐0.82, SE=0.13, p=2.2e‐09) with large effect size (partial η2=0.39). Higher plasma GFAP was associated with higher postmortem tau accumulation (β=0.15, p=0.032). Higher levels of plasma NfL were associated with increased TDP‐43 burden (β=0.2, p=0.024). ROC revealed excellent discrimination by plasma GFAP/NfL in the autopsy/test sample (AUC=0.89). In the validation sample, plasma GFAP/NfL had good overall discrimination accuracy (AUC=0.85); there was 0.79 sensitivity and 0.77 specificity when applying the training‐derived GFAP/NfL threshold.

Conclusion

Plasma GFAP and NfL relate to pathological accumulation of tau and TDP‐43, respectively. The plasma ratio of GFAP/NfL is a promising candidate to discriminate FTLD‐tau from FTLD‐TDP.
Spiral Tracing in Alzheimer’s Disease: Less Precise but not Slower
Authors: Koppelmans Vincent , Silvester Benjamin , Ruitenberg Marit F. L. , Van der Geest Jos N. , Duff Kevin M.
Published: December 2022

Background

In the search for novel Alzheimer’s disease (AD) biomarkers, motor functional outcome measures are potential candidates, as motor impairments can precede cognitive dysfunction. Whereas most motor behavioral research in Mild Cognitive Impairment (MCI) and AD has focused on gait function, fine motor skill is affected as well. Here, we use a digitized version of the Archimedes spiral test to assess a variety of speed and accuracy metrics of fine motor function in MCI and AD compared to cognitively normal (CN) individuals.

Method

46 CN, 23 MCI, and 17 AD participants traced an Archimedes spiral 3 times using a digital pen tablet. Spiral outcome measures included: path length, movement time, tracing speed (average and variance), radial distance (i.e., total deviation from the spiral template; average and variance), number of template crossings, and return movements.

Result

Linear regression analysis adjusted for age and sex showed that those with AD had significantly larger radial distance than CN (p = .0056, eta^2 = .096). No other significant group differences were observed (all p>0.14, all eta^2<.028).

Conclusion

Results indicate that individuals with AD are less precise when tracing an Archimedes spiral, despite adequate movement speed and steadiness. These results support a wider examination of fine motor dysfunction in AD as an inexpensive and easily collectable biomarker in AD.
A Machine Learning‐Based Approach for Classification of Alzheimer’s Disease and its Risk Prediction
Authors: Kasani Payam Hosseinzadeh , Kim Jung‐Kyeom , Kassani Peyman Hosseinzadeh , Kim Yeshin , Kim Jeong‐Ah , Park Chihyun , Yun Cheol‐Heui , Choi Seong Hye , Lee Sang‐Ah , Lee Seo‐Young , Jang Jae‐Won
Published: December 2022

Background

Dementia, a clinical syndrome with progressive neurodegenerative disease, is one of the inevitable aging consequences. Alzheimer’s disease (AD) is the most common cause of dementia. Accurate detection and classification of Alzheimer’s disease alongside its conversion from Mild Cognitive Impairment (MCI) to AD at an early stage is of significant clinical importance. However, a reliable diagnosis with a multi‐label classification approach remains a challenging task. This study aimed to measure the effectiveness of machine learning algorithm integrated with feature importance techniques to constitutes a multi‐label classification of AD prediction for clinical practice.

Method

The machine learning algorithms are validated using a nationwide cohort dataset, the Korean Brain Aging Study for the early diagnosis and prediction of AD (KBASE) to identify the most important risk factors, where a database is classified into three classes namely, normal cognition (NC, n = 91), mild cognitive impairment (MCI, n = 61), and Alzheimer’s disease (AD, n = 49). Applying eight state‐of‐the‐art supervised machine learning algorithms namely Support Vector Machine, Naive Bayes, XGBoost, Decision Tree, Logistic Regression, Random Forest, Bagging, and AdaBoost. A stratified 10‐fold cross‐validation was used for every train/test split and several performance measures, including accuracy, precision, recall and f1‐score were used to compare the classifier performances.

Result

Based on the performance evaluation, the XGBoost classifier significantly outperformed all other models and achieved 82.55% accuracy followed by the Bagging classifier (81%). According to the XGBoost model, calculating risk factors to predict performance, the Consortium to Establish a Registry for AD (CERAD) subsets is among the highest ranked feature. It was intriguing that the parameters including job, job levels and retirement achieved a minimal, if any, impact in the final performance.

Conclusion

Collectively, the XGBoost as a Gradient Boosted Tree model can be considered as the best‐supervised machine learning algorithm for multi‐class AD classification. The model also provides a visualization of the contribution of the risk factors. The data mining approach integrated with machine learning models could achieve favorable outcomes in the accurate risk prediction and classification of AD that can be applied to the clinical setting as an assisting diagnostic tool.
Lowering Synaptogyrin‐3 Expression Rescues Tau‐Induced Memory Deficits and Synaptic Loss in the Presence of Microglial Activation
Authors: Largo‐Barrientos Pablo , De Strooper Bart , Spires‐Jones Tara L , de Wit Joris , Uytterhoeven Valerie , Verstreken Patrik
Published: December 2022

Background

Tau is implicated in multiple neurodegenerative disorders, including Alzheimer’s disease. Synaptic loss and neuroinflammation are characteristic feautures of tauopathies, but it is unclear if these pathological events are causally linked and whether they are relevant for cognitive decline. Mutations and/or hyperphosphorylation of Tau leads its accumulation at synapses, where Tau binds to synaptic vesicle‐associated protein Synaptogyrin‐3 resulting in clustering of vesicles and impaired synaptic function. Given that Synaptogyrin‐3 is uniquely present at pre‐synaptic terminals, this allows us to decipher the contribution of pre‐synaptic Tau to overall Tau‐induced pathology.

Method

We generated a synaptogyrin‐3 knockout mouse line using CRISPR‐Cas9 technology. Synaptogyrin‐3−/− and +/− mice are viable and fertile and do not show overt phenotypes. We bred synaptogyrin‐3+/− mice with human Tau P301S‐expressing mice (PS19 line) and aged the offspring. We used several techniques, including electrophysiology, behavioral tests, immunohistochemistry and electron microscopy, to determine the effects of lowering Synaptogyrin‐3 expression in a tauopathy mouse model.

Result

We found that heterozygous knockout of Synaptogyrin‐3 in Tau P301S mice was sufficient to rescue synaptic plasticity and working memory defects. Moreover, lowering Synaptogyrin‐3 expression prevented synaptic degeneration and loss of synaptic markers in Tau P301S mice. Interestingly, proliferation and activation of astrocytes and microglia are observed in Tau P301S; synaptogyrin‐3+/− mice to the same extent as in their Tau P301S littermates.

Conclusion

Our results indicate that Tau induces synaptic loss and neuroinflammation independently, and that neuroinflammation is not sufficient to cause synaptic loss. In addition, pre‐synaptic defects caused by Tau are enough to drive defects in working memory.
Alzheimer disease clinical trials in low and middle income countries: A call for globalization of clinical trials
Authors: Llibre‐Guerra Jorge J , Rodriguez‐Salgado Ana M , Hardi Angela , Heavener Anika , Behrens María Isabel , Brucki Sonia Maria Dozzi , Babulal Ganesh M , Nitrini Ricardo
Published: December 2022

Background

In the absence of clinically meaningful disease‐modifying treatments, the number of adults with dementia worldwide is projected to more than triple. Much of this increase will occur in low and middle‐income countries (LMICs); by 2050, 68% of adults living with dementia will be in LMICs. However, there is a gross under‐representation of LMICs in historical and contemporary AD clinical trial platforms.

Methods

We aimed to determine the global distribution of dementia clinical trials and identify existing barriers for conducting AD clinical trials in LMICs. Our primary data sources to identify trial distribution in LMICs included ClinicalTrials.gov and World Health Organization International Clinical Trials Registry Platform. Data analysis included number of clinical trials per country, regional distribution, funding source, study phase (1, 1/2, 2, 2/3, or 3), and annual growth rate by region relative to population density. An additional systematic review search and expert consensus was conducted to identify barriers for conducting clinical trials in LMICs.

Result

Among 1737 dementia interventional trials, only 17.2% have been or are conducted in LMIC (figure 1). LMICs trial sites participated/conducted 23.6% and 10.9% of phase 3 and phase 1 trials, respectively. We identified several limitations for trial implementation including lack of financial resources, low industry presence, regulatory obstacles and operational barriers, especially related to resources in neuroimaging. Two successful international trials platforms (Dominantly Inherited Alzheimer Network‐Trials Unit [DIAN‐TU] and Worldwide FINGERS) have been able to expand into Latin American countries creating a regional network for trial implementation.

Conclusion

Although LMICs bear the greatest burden of AD in the world, substantial development of clinical trial platforms to address this inequity is lacking. Ongoing LMICs regional trial platforms (e.g., DIAN‐TU and LatAm‐FINGERS) may shed light on alternative strategies to overcome existing barriers and highlight the need for a more thoughtful approach to increase diverse representation in AD clinical trials and expand access to LMIC.
Cognitive assessment in diverse populations: implications for Alzheimer’s disease clinical trials
Authors: Tsoy Elena , VandeVrede Lawren , Rojas Julio C. , Possin Kate L
Published: December 2022

Background

By 2060, racially/ethnically diverse individuals will constitute almost half of all older adults in the US and experience largest increases in dementia burden. Appropriate representation of diverse participants in clinical trials is critical to ensure generalizability of outcomes. Screening/inclusion criteria for trials often involve a brief cognitive assessment to indicate overall disease severity. We examined the Mini‐Mental State Examination (MMSE), the most widely used assessment, as a recruitment tool in diverse older adults.

Method

Data from 10,377 older adults (8,585 controls, 1,752 MCI; 232 Asian, 1,641 Black, 623 Hispanic, 7,841 White) were drawn from the National Alzheimer’s Coordinating Center (NACC) uniform data set. Only MCI participants for whom AD was presumed to be the primary etiology per NACC protocol were included. We performed logistic regressions to examine the likelihood of performing at/above a conventional MMSE cutoff of 24 in MCI participants. Multivariable regressions were performed to examine associations between 1) demographic variables and MMSE performance in controls, and 2) MMSE and CDR Sum of Boxes (CDR‐SB) in all participants.

Result

Compared to White participants, Asian (OR = 0.46 [0.24‐0.99]), Black (OR = 0.53 [0.35‐0.80]), and Hispanic (OR = 0.38 [0.24‐0.61]) older adults with MCI were significantly less likely to perform at/above MMSE cutoff. Regressions in controls revealed a significant race/ethnicity by education interaction with greater magnitude of the association between education and MMSE in Black and Hispanic participants controlling for age, sex, and primary language. Associations between MMSE and CDR‐SB were significantly weaker in Black and Hispanic participants (Figure 1) and participants without high school education after controlling for age, sex, and primary language.

Conclusion

We found that the MMSE has a greater education bias and weaker functional validity among Black and Hispanic older adults. Findings suggest that using an MMSE cutoff may be an inappropriate criterion for assessing disease stage among underrepresented participants. We discuss the implications of findings for the current state of diversity in clinical trials and for clinical diagnostic practice with diverse older adults. Focus points will include the need for culturally fair, sensitive, and psychometrically robust brief cognitive measures and the critical importance of incorporating social determinants of health into clinical and research practices.
How does APOE genotype moderate the relationship between physical activity and Alzheimer’s disease risk? A novel integrative model
Authors: de Frutos Jaisalmer , Sewell Kelsey R , García‐Colomo Alejandra , Markovic Shaun J , Erickson Kirk I. , Brown Belinda M
Published: December 2022

Background

Evidence suggests that physical activity (PA) confers protection against Alzheimer’s disease (AD), while the Apolipoprotein E (APOE) ε4 allele represents the greatest genetic risk factor. Extensive research has thus far failed to establish whether frequent PA can mitigate the increased AD risk associated with APOE ε4. Studies looking at various AD‐related traits (e.g., amyloid beta burden or cortical atrophy) might show diverse results because the biological pathways involved are differentially influenced by PA, APOE ε4 carriage and their interaction. In order to bridge these discrepancies, the aim of this theoretical article is to propose a novel model of how PA and APOE ε4 carriage, independently and in combination, may alter well‐established molecular mechanisms underlying AD pathogenesis.

Method

Available literature was searched to investigate how PA and APOE ε4 carriage, independently and in combination, may alter several molecular pathways involved in AD pathogenesis. The reviewed mechanisms include amyloid beta (Aβ) and tau deposition and clearance, neuronal resilience and neurogenesis, lipid function and cerebrovascular alterations, brain immune response, and glucose metabolism.

Result

We have identified potential pathways through which the beneficial effects of PA might offset some of the detrimental outcomes of APOE ε4 carriage. Nonetheless, PA does not seem to be able to entirely prevent or revert the noxious effects of genetic risk. Our integrative model includes evidence‐based and theoretical synergistic interactions across mechanisms, and a proposal of testable hypotheses for future studies.

Conclusion

PA influences a wide array of molecular targets involved in AD neuropathology. A better understanding of where, when and most importantly, how, PA decreases AD risk in the presence of the APOE ε4 allele is essential to formulate combined therapeutic approaches.
Risk factors for loneliness in family caregivers of people with dementia and enduring mental health conditions during the COVID‐19 pandemic in Latin America
Authors: Leon Tomas , Miranda‐Castillo Claudia , Slachevsky Andrea , Tapia‐Muñoz Thamara , Olavarria Loreto , Castro Loreto , Pinto Alejandra , Chen Yaohua Sophie , Leroi Iracema , Lawlor Brian , Duran‐Aniotz Claudia , Grycuk Emilia , Beber Bárbara Costa , Peres Fernando Aguzzoli , Nubia Carla , Gaitan Pablo , Vilar‐Compte Mireya , O'Sullivan Roger
Published: December 2022

Background

During the COVID‐19 pandemic, loneliness has increased in the general population due to government measures to contain the spread of the disease. In Latin America (LA), caregiving is most often delivered informally by family members Family caregivers often face mental health challenges linked to their caregiving role and their social context. Pandemic‐related social restrictions have been especially detrimental for older people with dementia or other brain health challenges, as well as their family caregivers. We aimed to investigate the associations of loneliness, social isolation and care burden in these family caregivers.

Method

We undertook a cross‐sectional survey of over 300 informal caregivers of people with dementia or enduring mental health problems living in 4 Latin American countries, Mexico, Brazil, Chile, and Peru. We categorized loneliness into 3 groups ‘low’, ‘moderate’ and ‘severe loneliness’. Here, we analyzed factors related to changes in the prevalence of moderate and severe loneliness before and during the pandemic using a longitudinal multinomial logistic regression model.

Result

During the pandemic, there was a significant increase in loneliness prevalence (p<.001) among caregivers in Latin America, with more people having moderate (6.25% pre‐pandemic; 17.67% mid‐pandemic) and severe loneliness (2.78% pre‐pandemic; 15.19% mid‐pandemic). Gender differences in the prevalence of loneliness or higher levels of loneliness among dementia caregivers compared to caregivers of other conditions were not seen. The regression model revealed that the increment in risk for moderate loneliness during the pandemic was related to caregivers' age, level of education, and social contact/isolation. Increased risk for severe loneliness was related to caregivers' social contact during the pandemic and perceived mental health.

Conclusion

Public health interventions regarding COVID‐19 pandemic should consider increased loneliness in Latin‐American caregivers. This population will need both, short and long‐term mental health and practical support. Next steps include gathering more evidence on specific risk factors for loneliness and its impact on caregivers’ physical and mental health.
Toward a statistical foundation for brain signatures of behavioral outcome
Authors: Fletcher Evan M , Gavett Brandon E , Farias Sarah , DeCarli Charles S. , Widaman Keith F. , De Leon Fransia S. , Mungas Dan M.
Published: December 2022

Background

The “brain signature of cognition” concept has garnered interest as a data‐driven, exploratory approach to better understand key brain regions involved in specific cognitive functions, with the potential to maximally characterize brain substrates of clinical outcomes. However, to be a robust brain phenotype, the signature approach requires a statistical foundation showing that model performance replicates across a variety of cohorts. Here, we outline a procedure that provides this foundation for a signature models of episodic memory and extend this to a measure of functional everyday memory.

Method

University of California, Davis (UCD) and ADNI provided imaging and memory data. For cognitive and ECog memory, we derived regional brain gray matter (GM) cortical thickness (CT) measures, testing for replicability (Fig. 1). Signature model generation used two steps in each cohort: 1) Randomly select 40 discovery subsets of size N = 400. In each subset, use voxelwise regression to compute the CT signature regions for outcome at three t‐values of association. 2) Compile frequency maps of region selection across all 40 discovery sets and designate regions with selection frequency >70% as “consensus” signature masks for each cohort. Model validation used regressions of outcomes on consensus masks: 1) Compare adjusted R2 fits of both consensus signature models in 40 discovery sets in each cohort (thus, symmetrically compare same and oppositely generated models). 2) In each full cohort, compare signature model fits with competing models.

Result

Spatial replications produced strongly convergent consensus signature regions derived from UCD and ADNI (Fig. 2). Consensus model fits were highly correlated in 40 random subsets of each cohort (Fig. 3 top) indicating high replicability, with tight (∼80%) ratios of within/outside cohort model fits (Fig. 3 bottom), indicating low bias. In comparisons over each full cohort, signature models outperformed other models with one exception (Fig. 4).

Conclusion

Multiple random model generations, followed by consensus selection of regional brain substrates, produced signature models that both consistently replicated model fits to memory and outperformed other commonly used measures. Results support consensus signature models as robust biomarkers of cognition and everyday function across imaging cohorts with differing demographic composition (see Table).
School‐Based Brain Health Curriculum: Teaching the skill of advocacy through the lens of brain health for middle and high school students
Authors: Felten Kristen M. , Smith Kathleen O'Toole
Published: December 2022

Background

It is estimated that 250,000 children and young adults in the U.S. provide care to family members with dementia, according to the Alzheimer’s Association Facts and Figures from 2015. Research increasingly demonstrates that lifestyle choices throughout life affect later brain health. This knowledge provided the impetus for the Wisconsin Departments of Health Services and Public Instruction to develop the Advocacy for Self or Others: Brain Health curriculum. The purpose of this presentation is to describe the curriculum and discuss implications for the future.

Method

In partnership between these two state agencies, this unit was created to help youth learn the skill of advocating for themselves or another person, an important skill for life and in caregiving. Students in middle or high school will apply this skill to one of eight areas of brain health that were developed for the curriculum. The curriculum intends to reduce the stigma around dementia, promote awareness of brain health strategies, and increase understanding of caregiving for a person with dementia. The unit also includes information on the effect of music on the brain, and how a love of music can be a connection between generations.

Results

The Department of Public Instruction will make the curriculum available on their website, where anyone is welcome to access and use it. Five Wisconsin schools will receive funding to pilot the material to demonstrate student learning and achievement with the material, as well as usability for educators. The units covering brain health material include: Overall Brain Health

• Keeping your Brain Healthy

• Aging and the Brain

• Music and the Brain

• Concussion & Brain Injury Awareness

• Reducing Stigma and Providing Care

Conclusion

It is possible for school systems to become involved in promoting brain health, reducing stigma around dementia through promoting understanding, and supporting students who are providing care at home. Partnerships between experts in curriculum development for youth and content around dementia and brain health can be brought together to offer a new topic to educators for use in health classes, physical education, consumer education, psychology, student health associations, and more.
Research Inclusion Supports Equity (RISE): Building Community and Research Engagement among Sexual and Gender Minority Adults at Risk for Alzheimer’s Disease and Related Dementias
Authors: Wharton Whitney , Anderson Joel G , Verble Danielle D , Likos Kelly D. S. , Flatt Jason D. , Kittle Krystal R.
Published: December 2022

Background

An estimated 2.7 million U.S. older adults self‐identify as a sexual and/or gender minority (SGM; i.e., lesbian, gay, bisexual, transgender, and/or queer), a numbers that will increase to 4 million by 2030. SGM adults age 50+ experience a higher prevalence of chronic disease and disability and poorer mental and physical health. About 27‐45% of SGM adults provide informal care for family and friends, taking on caregiving roles at a higher rate (one in five) than the general population (one in six). Little is known about the health‐ and caregiving‐related needs of SGM adults living with ADRD and SGM caregivers of people with ADRD.

Method

A concerted, national effort to recruit SGM people into ADRD‐related research does not exist. Our recently funded NIA R24 award titled “Research Inclusion Supports Equity (RISE)” will increase research inclusion and engagement of SGM adults living with ADRD or caring for someone living with ADRD to allow for future development of targeted interventions and prevention studies in this under‐resourced community.

Result

We will present the rationale, design, best practices, and progress to date including: 1) our community‐based participatory research protocol for national and SGM‐community‐led engagement and outreach activities, 2) details of our RISE recruitment registry of SGM adults with ADRD and SGM caregivers for people with ADRD), and 3) development of a replicable model for recruitment and retention of SGM adults with ADRD and SGM ADRD caregivers in aging‐related research.

Conclusions

Opportunities for investigator / physician / Center collaboration and utilization of the RISE Research registry will be discussed.
The relationship between plasma matrix metalloproteinase‐9 and cerebrospinal fluid biomarkers of tau is sex‐dependent
Authors: Tsiknia Amaryllis A. , Sundermann Erin E. , Edland Steven D. , Reas Emilie T. , Brewer James B. , Galasko Douglas R. , Banks Sarah J.
Published: December 2022

Background

Matrix metalloproteinase‐9 (MMP‐9) is a proinflammatory, proteolytic enzyme that is dysregulated in Apolipoprotein (APOE) ε4 carriers, patients with mild cognitive impairment (MCI) and Alzheimer’s disease (AD) and has been shown to accelerate tau oligomerization, blood‐brain barrier breakdown and amyloid‐β (Aβ) accumulation. Evidence suggests that MMP‐9 activity may be regulated by sex hormones, yet it is unknown whether the association between plasma MMP‐9 and cerebrospinal fluid (CSF) AD biomarker levels varies by sex.

Method

In 335 ADNI participants (128 women, mean age 74.8±7.4), including 56 cognitively normal adults, 183 MCI patients and 96 AD dementia patients, we examined whether sex modulates total and free plasma MMP‐9 associations with CSF total tau (t‐tau), tau phosphorylated at threonine 181 (p‐tau181) and Aβ42.

Result

Free and total plasma MMP‐9 levels were not associated with sex, age, APOE ε4 status or cardiovascular disease risk (CVDR). Total plasma MMP‐9 levels were higher in AD dementia patients versus MCI patients but did not differ between normal controls and MCI or AD patients. Free and total MMP‐9 levels were not associated with CSF Aβ42 regardless of sex. There was a sex × total plasma MMP‐9 interaction on CSF t‐tau (β=24.7; 95% CI, 82.5 to 355.2; P=0.002) and p‐tau181 (β=24.7; 95% CI, 8.9 to 40.4; P=0.002). Higher total MMP‐9 correlated with higher t‐tau and p‐tau181 levels in women, but with lower levels in men. There was a sex × free plasma MMP‐9 interaction on CSF p‐tau181 (β=19.5; 95% CI, 6.0 to 33.1; P=0.005) and t‐tau (β=147.8; 95% CI, 30.2 to 265.3; P=0.01). Higher free plasma MMP‐9 correlated with lower CSF p‐tau181 and t‐tau in men, but not women. These relationships were independent of age, education, diagnosis, CVDR, and CSF Aβ42 levels, and were likely driven by APOE ε4‐carriers as free or total MMP‐9 levels were not significantly associated with CSF biomarkers among non‐carriers regardless of sex.

Conclusion

Our findings provide preliminary evidence of sex differences in associations between MMP‐9 and CSF tau biomarkers, particularly among APOE ε4‐carriers. Compared to male ε4‐carriers, female ε4‐carriers might be more vulnerable to MMP‐9 activity, possibly promoting higher levels of AD‐related tau pathology.
Understanding the Neuronal Requirement for Glycolysis
Authors: Li Huihui , Shields Lauren , Lo Iris , Rathmell Jeffrey , Heiden Matthew Vander , Nakamura Ken
Published: December 2022

Background

The brain has a high energy demand and consumes large amounts of glucose. In Alzheimer’s disease (AD), glucose uptake is reduced, but the significance of this change for neurodegeneration is unclear. Furthermore, whether or not neurons directly take up glucose has been debated in the field. Indeed, the lactate‐shuttle hypothesis predicts that glucose is primarily metabolized by glia or astrocytes into lactate, which is subsequently delivered to neurons and utilized continuously under aerobic conditions. However, studies utilizing glucose analogs challenge that model, and support direct glucose uptake by neurons. Here, we sought to understand the essential role of the neuronal glucose metabolism, to provide a starting point for new approaches to understand and target metabolic changes in AD.

Method

To interrogate the role of neuronal glucose metabolism, we generated mice with targeted deletion of the dominant glucose transporter (GLUT3), or the enzyme that catalyzes the final step in glycolysis (PKM1), specifically in CA1 and other forebrain neurons from postnatal day 19. Mice were assessed with spatial learning and memory behavioral tests, and glucose metabolism and ATP production were monitored in individual neurons and synapses using a FRET‐based live imaging approach.

Result

Male and female GLUT3 KO mice showed age‐dependent memory deficits beginning at 7 months of age, and PKM1 KO mice showed impaired memory at 12 months of age, although this defect was only present in female mice. GLUT3KO neurons had decreased basal glucose levels and uptake. GLUT3KO synapses also showed significantly reduced basal ATP levels, and their ATP levels were unresponsive to electrical stimulation, which increases neuronal energy demand. In hippocampal neurons, blocking the last step of glycolysis by PKM1 knockout decreased the basal level of ATP production at synapses in cultures prepared from female pups, and resulted in unresponsiveness to electrical stimulation in both female and male cultures.

Conclusion

Our results indicate that to function properly and maintain ATP levels at synapses, neurons require glucose that can be taken up directly and metabolized through glycolysis. Therefore, decreased glucose uptake in AD may contribute to neuronal dysfunction and degeneration.
Image‐based primary age‐related tauopathy as a risk of dementia: a five‐year longitudinal study
Authors: Kim Han‐Kyeol , Lee Jae Hoon , Chun Joong‐Hyun , Ryu Young Hoon , Lyoo Chul Hyoung , Cho Hanna
Published: December 2022

Background

To investigate cognitive and pathological (amyloid and tau) changes of image‐based primary age‐related tauopathy (PART) in a long‐term follow‐up cohort study.

Method

In this study, a total of 108 patients who were both negative in amyloid and tau PET images were enrolled. All participants completed the same two PET scans (18F‐flortaucipir for tau and 18F‐florbetaben for Aβ), and neuropsychological tests at least twice over 5 years. We defined PART+ as those who had a higher standardized uptake value ratio (SUVR) in the entorhinal cortex than the cutoff calculated by the Youden index. We investigated the cognitive and 18F‐florbetaben and 18F‐flortaucipir SUVR changes longitudinally between PART+ and PART‐ participants while adjusting for age, sex, education, and ApoE4.

Result

Compared with PART‐, PART+ participants had more rapid worsening of MMSE (β=‐0.274, p<0.001), CDR‐SB (β=0.081, p<0.001), and memory function (β=‐0.140, p=0.008). No significant differences were observed in the language, visuospatial, frontal‐executive, attention domains, and total cognitive battery score. In PART+ participants, the annual Aβ accumulation rate from whole cortical SUVR was also increased (β=0.016, p=0.003), and a more rapid accumulation rate was observed in Alzheimer’s disease (AD) specific hot meta‐region‐of‐interest (meta‐ROI) SUVR, compared with PART‐ participants (β=0.019, p=0.001). The annual tau accumulation rate of PART+ was higher than PART‐ in the entorhinal cortex (β=0.010, p<0.001), however, no differences were observed in whole cortical SUVR tau.

Conclusion

The PART+ participants showed a rapid cognitive decline in memory function as well as MMSE, and CDR‐SB, than those of PART‐. In addition, amyloid was accumulated at a faster rate in PART+ participants and tau was accumulated more rapidly in the medial temporal area. In conclusion, our longitudinal study suggests that image‐based entorhinal tau defined as a PART+ could be an earlier stage than the preclinical stage of AD.
The Dementia Engagement Modelling Program (DEMP): a novel Australian model of care for aged care residents affected by COVID‐19
Authors: Atee Mustafa , Morris Thomas , Alford Marie
Published: December 2022

Like other countries, aged care homes in Australia have been significantly affected by the COVID‐19 pandemic. To ensure the safety of residents and staff, lockdown, and social restrictions (e.g., limited or no visits from family) have been introduced across Australia. These measures caused tremendous emotional, psychological, and physical burdens on residents, particularly those living with dementia.

In response to the pandemic, the Australian Government has funded the Aged Care COVID‐19 Grief and Trauma support package for older people receiving aged care, their families, and aged care staff. Part of this package is the Dementia Engagement Modelling Program (DEMP), a free national support program developed by Dementia Support Australia, HammondCare to help staff support residents whose wellbeing have been affected by COVID‐19 with tailored engagement strategies. The program represents a first line multimodal support for people living with dementia in residential aged care who may have experienced withdrawal, frustration, or fear and at a greater risk of developing behaviors and psychological symptoms of dementia (BPSD), such as apathy, anxiety, and depression. Through a multidisciplinary team of dedicated consultants, the program delivers best practice, person‐centered engagement strategies to support staff, providing meaningful engagement, comfort, and reassurance to residents living with dementia. DEMP consultants work collaboratively and closely with lifestyle and care staff to develop tailored activities and provide appropriate resources (e.g., brokerage items such as music therapy) for engagement. DEMP will also provide support and coaching to staff for the individual or small groups to ensure that both staff and residents gain the full benefit from the program.

The eligibility criteria for DEMP support include aged care homes that: 1) experienced an outbreak of COVID‐19 or those subject to a precautionary lockdown, and/or 2) sought engagement plans and strategies for residents living with dementia, or those at risk of developing BPSD due to COVID‐19 restrictions.

This descriptive study will discuss the DEMP's model of care, eligibility criteria, activities, and outcomes and provide case examples that can guide meaningful engagement for other aged care residents living in other countries during COVID‐19.
Structural and metabolic brain correlates of excess Aβ accumulation at the earliest AD continuum
Authors: Cacciaglia Raffaele , Milà‐Alomà Marta , Shekari Mahnaz , Operto Grégory , Falcon Carles , Minguillón Carolina , Molinuevo Jose Luis , Zetterberg Henrik , Blennow Kaj , Suárez‐Calvet Marc , Quevenco Frances‐Catherine , Gispert Juan Domingo
Published: December 2022

Background

The discrepancy between the expected and actual level of cerebral amyloid (Aβ) deposition for any given level of soluble Alzheimer’s disease (AD) core biomarkers, has been proposed as a proxy measure of factors promoting fibrillar Aβ accumulation in the brain. However, the impact of these factors on brain structure and function in cognitively unimpaired (CU) individuals has not been reported. Here, we assessed the impact on brain structure and metabolism of the excess cortical Aβ deposition for a given level of CSF pTau/Aβ42 ratio, a marker of pathophysiological progression along the Alzheimer’s continuum. Furthermore, we analyzed whether this association is modulated by the APOE‐ε4 risk allele.

Method

We included 243 CU participants from the ALFA study (mean age=61.68 years) who underwent a lumbar puncture, magnetic resonance imaging (MRI), 18F‐Fluorodeoxyglucose (FDG) and 18F‐Flutemetamol positron emission tomography (PET) scans. CSF Aβ42 and pTau181 were measured with the Elecsys® immunoassay (Roche Diagnostics International Ltd). The centiloid pipeline was applied to Aβ PET and a general linear model (GLM) was implemented to regress out the effects of CSF pTau/Aβ42 ratio from centiloid values. These residualized centiloids (resCent) were used in subsequent GLMs to predict whole‐brain gray matter volume (GMv) as well as metabolism. Statistical significance threshold was set to p<0.005, with a cluster extent correction of 100 voxels.

Result

Negative associations between resCent and GMv were observed in the dorsolateral prefrontal cortex (Fig. 1a), while for FDG, positive associations were found in the inferior frontal and superior temporal gyrus, as well as the anterior cingulate and inferior temporal cortices (Fig. 1b). The associations for GMv were further modulated by the APOE‐ε4 risk allele in a dose‐dependent manner, indicating a lower GMv in ε4‐carriers, in the inferior and middle frontal gyrus, subgenual cingulate cortex and the insula (Fig. 2).

Conclusion

Our results suggest that, factors associated with excessive Aβ deposition are associated with structural and metabolic brain alterations already in the earliest stages of preclinical Alzheimer’s continuum. The associations for GMv were modulated by APOE‐ε4 indicating a higher structural vulnerability to these factors for carriers of the risk allele all along the preclinical stages of AD.
Is cortical grey matter diffusivity an early biomarker for neuronal damage?
Authors: Debatisse Justine , Leng Fangda , Brooks David J , Edison Paul
Published: December 2022

Background

There is growing evidence that pathological changes in Alzheimer’s disease (AD) begin several years before the symptom onset. Neuroimaging approaches can be used to detect microstructural alterations in the early stages of neurodegeneration using diffusion‐weighted MRI. Cortical grey matter mean diffusivity (cMD) is thought to be increased in AD following pathological alterations resulting in disrupted neuronal function, neuronal death and cellular atrophy. We hypothesised that changes in MD could be detected early in the disease progression and that they would be correlated with structural imaging biomarkers.

Method

72 patients (mean age=69.1, SD=9.2) cognitively normal (CN, n=21) and with mild cognitive impairment (MCI, n=51) were included in this study. All participants underwent T1‐weighted MPRAGE MRI, diffusion tensor imaging (DTI) and PET amyloid ([18F]flutemetamol). Regional cortical thickness was measured on T1‐MPRAGE using FreeSurfer v.6.0. DTI data were processed with FSL v.6.0 to compute MD maps. Standard uptake ratio (SUVR) values were calculated in SPM12 to identify the amyloid deposition within cortical regions. Amyloid status (Aβ‐positive/Aβ‐negative) was determined from processed data using a cerebellar gray matter reference to create target‐to‐cerebellar ratio. Subjects were considered positive with an uptake value of greater than mean+2SD of the control subjects. Student's t‐test were used to compare imaging modalities between CN and MCI participants. Pearson’s correlation coefficients were calculated to assess the relationship between imaging modalities.

Result

There was a significantly increased MD in MCI compared to CN participants in hippocampus (p=0.0213) and in medial temporal lobe (p=0.033). There were no significant group differences neither in whole brain mean cortical thickness (p=0.6984) nor in temporal cortical thickness (p=0.0923). Interestingly, when splitting subjects based on their amyloid status, we found that whole brain MD was significantly negatively correlated with whole brain cortical thickness in amyloid negative (CN+MCI amyloid negative, p<0.001) but not in amyloid positive (CN+MCI amyloid positive, p=0.99).

Conclusion

We found that changes in gray matter diffusivity could be detected in the early stages of AD pathology. We also found that there is a direct relationship between MD and structural changes (i.e. cortical thickness) only before amyloid deposition suggesting that MD provides information about early microstructural changes before macrostructural changes.
Resistance, brain and cognitive resilience to ATN in a memory clinic population
Authors: Ribaldi Federica , Quattrocchi Lara , Garibotto Valentina , Tomczyk Szymon , Scheffler Max , Lovblad Karl‐Olof , Fernandez Aldara Vazquez , Chicherio Christian , Blennow Kaj , Frisoni Giovanni B , Altomare Daniele
Published: December 2022

Background

Brain resistance (R) has been defined as the capacity of the brain to preserve its integrity and to sustain normal cognition despite aging. Resilience has been defined as the capacity to sustain a better‐than‐expected brain integrity (brain resilience,BR) or cognitive performance (cognitive resilience,CR) in presence of pathological burden. There is a high variability in the individuals’ R, BR or CR, and it has been demonstrated that individuals with high BR and CR develop symptoms later than those with low CR. The aim of this study was to investigate the association between demographics, clinical features, and blood measures and individual’s R, BR and CR. Moreover, we investigated the cognitive longitudinal trajectories of individuals with low and high R, BR and CR.

Method

166 patients from the Geneva Memory Center cohort (41 controls, 106 MCI, 19 dementia) who underwent amyloid‐PET (A), tau‐PET (T), MRI (N) and clinical and neuropsychological assessment were included. Linear regression models were performed to extract residuals, used as measures of individual R (age predicted by ATN), BR (thickness by AT), and CR (MMSE by ATN). The associations between R, BR, CR and demographics, clinical features, blood measures were investigated using linear models. Moreover, linear mixed models were performed to examine whether longitudinal changes in MMSE scores differed as a function of R, BR or CR.

Result

Mean age was 71 (8), 52% were female, mean years of education was 14 (4). Resistance predicted by ATN was positively associated with plasma NfL (β=0.50,p<0.001) and GFAP (β=0.32,p=0.007). Brain resilience predicted by AT was associated with gender (higher in males) and, yet not significantly, age (β=0.14,p=0.063). Cognitive resilience predicted by ATN was associated with age (β=0.18,p=0.020) and education (β=0.27,p<0.001). Individuals with low cognitive resilience had a lower MMSE scores at baseline but those with higher cognitive resilience showed a faster cognitive decline.

Conclusion

We confirm the expected associations between BR, age and gender, and between CR and age and education, consistent with previous literature findings. The association between R and plasma markers opens novel perspectives for screening and preventive programs while the assessment of the effect of plasma biomarkers on resistance needs further investigation.
Psychosocial risk factors on hippocampal subfield volumes: the Medea‐7T study
Authors: Twait Emma L. , Blom Kim , Koek Huiberdina L. , Zwartbol Maarten H.T. , Ghaznawi Rashid , Hendrikse Jeroen , Biessels Geert Jan , Geerlings Mirjam I.
Published: December 2022

Background

Specific subfields within the hippocampus have shown vulnerability to chronic stress, highlighting the importance of looking regionally within the hippocampus to understand the role of psychosocial risk factors in the development of neurodegenerative diseases. The current study had two aims: to perform a systematic review on psychosocial factors and hippocampal subfield volume and to explore the association of psychosocial factors with hippocampal volume, both total volume and among subfields, using high‐field 7T MRI.

Method

Within the Memory Depression and Aging (Medea)‐7T study, 333 participants without dementia underwent 7T MRI and answered psychosocial questionnaires. Hippocampal subfields were automatically segmented from T2‐weighted images using ASHS software. Generalized linear models accounting for correlated outcomes were used to assess the association between subfields (i.e., entorhinal cortex, subiculum, Cornu Ammonis (CA)1, CA2, CA3, dentate gyrus, and tail) and each psychosocial factor (i.e., depressive symptoms, anxiety symptoms, childhood maltreatment, recent life events, and social support), adjusting for age, sex, and intracranial volume.

Result

Neither depression nor anxiety was associated with specific hippocampal (sub)volumes. Recent life events were associated with greater total volume (B = 0.17, 95% CI: 0.07; 0.27). However, reporting childhood maltreatment was associated with smaller total hippocampal volume (B per standard deviation = ‐0.20, 95% CI: ‐0.31; ‐0.10). Among subfields, high social support was associated with greater volume in the CA3 (B = 0.47, 95% CI: 0.21; 0.73).

Conclusion

This study suggests possible differential effects among hippocampal (sub)volumes and psychosocial factors, specifically reporting childhood maltreatment and social support. The systematic review highlighted inconsistencies in results, highlighting the need for future studies validating these results.