bluuebunny/crossref_metadata_2025 huggingface dataset:
Astrocyte Ca2+ dysregulation and neurovascular coupling deficits in a diet‐based mouse model of small cerebral vessel disease
Authors: Weiss Blaine E. , Sompol Pradoldej M , Gant John C , Lin Ruei‐Lung , Nelson Peter T , Thibault Olivier , Wilcock Donna M. , Norris Christopher M.
Published: December 2023

Background

Mice exposed to a diet deficient in B6/B12 vitamins and enriched in methionine exhibit hyperhomocysteinemia (HHcy) concomitant with many pathologic features of vascular cognitive impairment and dementia: a very common Alzheimer’s disease related dementia. Here, we evaluated the impact of astrocyte Ca2+ dysregulation and astrocytic Ca2+ signaling pathways in the context of functional hyperemia in fully awake mice exposed to HHcy diet.

Method

Adult C57/BL6 mice were fed for 15 weeks with control chow, or chow deficient in vitamins B6/B12 and enriched in methionine (HHcy diet). Spontaneous and evoked (via air puff whisker stimulation) Ca2+ transients in astrocytes of fully awake mice were investigated in barrel cortex using the Ca2+ sensor GCaMP6f (expressed specifically in astrocytes using AAV) and two‐photon imaging. In other experiments, mice were treated with AAV‐Gfa2‐VIVIT to inhibit the Ca2+‐sensitive calcineurin/NFAT pathway in astrocytes, which regulates reactive astrocyte phenotypes. Two‐photon imaging was then used to assess diet and VIVIT effects on functional hyperemia in barrel cortex of fully awake mice.

Result

Ca2+ transients in individual barrel cortex astrocytes were significantly augmented (greater in amplitude, with faster rise/decay kinetics) in mice treated with HHcy diet. However, the functional connectivity in astrocyte networks of HHcy mice was significantly impaired, particularly during engagement of brain activity with whisker stimulation. Compared to control diet mice, HHcy mice also showed impaired functional hyperemia during whisker stimulation characterized by impaired arteriole dilations and reduced red blood cell velocity in nearby capillaries. Inhibition of reactive astrocyte signaling in HHcy diet mice with VIVIT significantly ameliorated these neurovascular coupling deficits.

Conclusion

The results show that astrocyte Ca2+ dysregulation is a major feature of HHcy and contributes to cerebrovascular dysfunction through hyperactivation of the astrocytic CN/NFAT pathway.
Using subject‐specific disease progression as an estimation of the disease time to model longitudinal neurodegeneration in AD
Authors: Shafiee Neda , Collins D Louis
Published: December 2023

Background

When patients with clinically probable‐AD get their diagnosis, it is difficult to determine exactly when the disease started. Moreover, not all subjects progress in the same manner and rate. However, clinical measurements such as cognitive scores can help give an estimation of where in the disease trajectory each patient stands. To address the issue of estimating the time of disease onset, we investigated a new technique that leverages cognitive test scores to estimate a latent timeline that models the subject‐specific disease progression.

Method

We used the work of Kühnel et al. (2021) to model the progression of AD using cognitive scores (ADAS13 and MMSE). This method aligns patients along a continuous latent timeline based on their predicted disease progression. Data included the MRI scans of 677 amyloid‐positive subjects from ADNI. Scan resolution was increased to 0.5mm isotropic voxel‐size by super‐sampling (Manjón et al. 2010) before non‐linear registration to an ADNI‐based unbiased template. The resulting deformation fields were used to compute the Jacobian determinant map for each subject and find mean atrophy for different ROIs. we were then able to plot the changes in different regions of the brain across the estimated disease progression timeline and compare slopes for the two methods.

Result

Assuming a zero time‐shift for normal subjects, the average time‐shift for the eMCI, lMCI, and AD group was 36.8, 87.5, and 128.8 months respectively. Using the latent time‐shift variable to offset the individual baseline scans, we were able to plot the changes in different regions of the brain across the disease timeline. The results for Hippocampus are shown in figure 1, comparing the estimated timeline to the age as the time‐related axes. We saw much sharper slopes (‐0.01 vol/estimated_time vs ‐0.0025 vol/age) when using the individualized time offset.

Conclusion

Calendar time is perhaps not a good measure for disease progression. The new method offers an estimation of a latent timeline that models the subject‐specific disease progression and may better model the longitudinal changes in different brain regions, and in turn, would enable us to better compare the magnitude and speed of degeneration across brain regions.
Factor Analyses and Age Effects in the CCAB At‐Home Computerized Cognitive Test Battery
Authors: Herron Timothy J , Chok Jas M. , Lwi Sandy J. , Schendel Krista , Curran Brian , Geraci Kristin , Blank Michael , Williams Garrett , Hall Kathleen , Woods David L. , Baldo Juliana
Published: December 2023

Background

The California Cognitive Assessment Battery (CCAB; ccabstudy.com) is a remotely monitored, at‐home, computerized behavioral test and questionnaire suite. Here we evaluate the interpretation of 25 tests within the US English version of the CCAB using both an exploratory factor analysis (EFA) of 155 healthy adults and a confirmatory factor analysis (CFA) of 312 healthy older adults participating in a longitudinal study. We also estimated cross‐sectional age gradients for best fitting latent factors [1].

Method

First, one set of “classic” latent factors (from 1 factor to 8 factors) was extracted from the literature [2][3][4] for assignment of CCAB tests into traditional categories. Second, 155 adult participants (age 22‐86 y.o., mn 54, 57% male, education 8‐20 yrs., md 14) participated in a prefinal version of the CCAB. EFA was performed on their primary CCAB results using the ‘psych’ (v. 1.9.12.31‐1) toolbox in R (v. 3.6.3) with 11 different rotations to extract a second set of CFA latent factors. Third, above two sets of latent factors were used in the ‘lavaan’ CFA toolbox (v. 0.6.5‐1) in R and applied to the first timepoint (enrollment and session 1) of CCAB longitudinal data from an older adult group (age 56‐89 y.o., mn 71, 58% male, education 0‐20 yrs., mn 14).

Result

The EFA and CFA model fit characteristics (Fig 1) show moderately good fits for the EFA and best fitting CFA models. The EFA produced reasonable models from 2 factors to 6 factors. The best fitting “classic” CFA along with its latent factor age regressions is shown in Figure 2. The best fitting EFA‐derived CFA along with its latent factor age regressions is shown in Figure 3.

Conclusion

The best‐fit classic CFA results showed moderately good fit, and visual tests of both speed and memory showed steeper cross‐sectional age gradients than did respective verbal response tests. The EFA‐derived latent factors were better fitting than were the classic factors as they were derived from the CCAB itself. In both cases, however, CCAB test speed measures showed steeper cross‐sectional age gradients than did memory measures. Ongoing work will characterize longitudinal latent factor age gradients.
Data harmonization across eight publicly available longitudinal studies of aging, neurodegeneration and dementia
Authors: Low Kevin , Nourollahimoghadam Elnaz , Nir Talia M , Vargas Hernan , Nguyen Uyen , Shetty Ankush , Xiao Cally , Neu Scott C. , Crawford Karen , Thomopoulos Sophia I , Thompson Paul M , Salminen Lauren , Toga Arthur W. , Pappas Ioannis , Jahanshad Neda
Published: December 2023

Background

Large‐scale multi‐study analyses are required to ensure reproducibility, reliability and generalizability in mapping neurodegeneration and risk for ADRD. However, the heterogeneity in data collection paradigms can complicate and confound data pooling; data harmonization is essential. Longitudinal studies add to the complexity of harmonization as a variety of follow‐up time points and time encoding schemes are used. Here, we pool data from 8 publicly available longitudinal neuroimaging studies on neurodegeneration and dementia to highlight differences in: 1) diagnostic categorization of controls, and people with mild cognitive impairment, and dementia; 2) the extent of follow‐up visits across neuroimaging and clinical assessments; and 3) encodings of various meta‐data elements including scanner manufacturer, sex, and handedness. To allow a systematic approach to multi‐study dementia research, we propose an initial ontological framework for longitudinal data archival and retrieval, capable of capturing similar data elements within given themes while ensuring that unique differences across studies are retained.

Method

AIBL, ADNI‐1, ADNI2/GO, ADNI‐3, OASIS‐2, OASIS‐3, PREVENT‐AD, and MIRIAD, were accessed. Study designs, inclusion and exclusion criteria, and downloaded data elements were used to describe diagnostic criteria, imaging data, demographic features, and longitudinal data collection schemes. We create common terms to map data elements across studies, and a consistent naming scheme for longitudinal data.

Result

Figure 1 shows the breakdown of diagnostic labels per cohort, and highlights how different cognitive labels may be assigned to people with the same performance scores, for example, on the Mini Mental State Examination (MMSE). Figure 2 highlights the differences in longitudinal data collection schemes across cohorts, and in labels of commonly collected elements. Using common terms provided an easy way to simultaneously query data across all studies, while retaining a map back to the original terms. Figure 3 showcases our proposed naming scheme for capturing longitudinal data elements using a relational ontological framework. This framework successfully harmonized data across study demographics, timepoints, and imaging properties.

Conclusion

Multi‐study data analyses are becoming common practice thanks to large scale efforts such as ENIGMA and GAAIN. Harmonization of meta‐data across studies will allow for efficient pooling of data for tracking disease progression and related risk over time.
Estimating the time between amyloid and tau‐PET positivity: Implications for Alzheimer’s disease prevention trials
Authors: Moscoso Alexis , Heeman Fiona , Dunås Tora , Schöll Michael
Published: December 2023

Background

Alzheimer’s disease (AD) is characterized by a preclinical stage in which abnormal accumulation of amyloid‐β (Aβ) leads to phosphorylated tau aggregation. This sequence of events represents the transition between “AD pathologic change” (A+T‐) to the much riskier full AD neuropathology (A+T+, Jack et al. Alzheimers Dement. 2018). Thus, to understand the clinical relevance of the A+T‐ stage in the long term, it is important to understand the temporal course of Aβ and tau. In this study, we used longitudinal Aβ‐ and tau‐positron emission tomography (PET) to estimate the expected time gap between Aβ‐ and tau‐PET positivity, and explored factors that influenced this gap.

Method

We estimated the natural history of amyloid accumulation in AD using longitudinal Aβ‐PET data from 1690 AD‐continuum subjects from the ADNI. Specifically, we fitted a non‐linear mixed effects model (3‐knot spline) and modelled the subject‐specific “age of Aβ positivity” as random effects (Figure 1). An interval‐censored time‐to‐event analysis using “time to amyloid positivity” as time variable was performed on 318 Aβ+ ADNI participants who had available tau‐PET ([18F]flortaucipir) visual reads. Cox proportional hazards regression was used to assess whether age of onset of amyloid positivity, sex, APOE status, and cognitive impairment at follow‐up influenced the onset of tau‐PET positivity relative to Aβ‐positivity.

Result

After ∼11 years from Aβ positivity, 50% of the CU individuals progressed to tau‐PET positivity, while only ∼17% remained tau‐PET negative after 20 years (Figure 2). Among the studied factors, only the presence of cognitive impairment accelerated the onset of visual tau‐PET positivity (HR = 2.52, p<0.001, median tau‐free survival difference ∼6 years) (Figure 3). Both female sex (HR = 1.44, p = 0.16, median tau‐free survival difference∼2.5 years) and presence of the APOE‐ε4 allele (HR = 1.44, p = 0.15, median tau‐free survival difference∼2.5 years) were trend‐level associated to faster onset of tau‐PET positivity.

Conclusion

The time gap between Aβ‐ and tau‐PET positivity typically spans a decade and is highly variable across individuals. This long gap implies that a significant fraction of A+T‐ CU older individuals will never develop tau‐PET positivity and subsequent symptoms in their lifespan, which suggests that these subjects may not benefit from current disease‐modifying therapies for AD.
Increased Genetic Risk for ADHD Potentiates Cognitive Impairment and Brain Hypometabolism in Alzheimer’s Disease Patients
Authors: Leffa Douglas Teixeira , Povala Guilherme , Bellaver Bruna , Lussier Firoza Z , Ferrari‐Souza João Pedro , Ferreira Pamela C.L. , Zalzale Hussein , Aguzzoli Cristiano Schaffer , Rohden Francieli , Soares Carolina , Abbas Sarah , Tissot Cécile , Therriault Joseph , Lopez Oscar L. , Villemagne Victor L , Klunk William E , Cohen Annie , Zimmer Eduardo R. , Karikari Thomas K , Rosa‐Neto Pedro , Rohde Luis Augusto , Molina Brooke , Pascoal Tharick Ali
Published: December 2023

Background

Recent epidemiological studies showed that patients with attention‐deficit/hyperactivity disorder (ADHD) are more likely to be diagnosed with Alzheimer’s Disease (AD). Additionally, increased genetic risk for ADHD, measured with ADHD polygenic risk scores (ADHD‐PRS), was associated with amyloid‐dependent cognitive decline in older adults. However, it is unclear whether higher genetic risk for ADHD is associated with worse cognitive function in patients with AD dementia.

Method

We used data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) to investigate the association between cognitive function (Preclinical Alzheimer Cognitive Composite [PACC], executive function, and memory) and ADHD‐PRS in subjects with AD dementia. Additionally, we tested whether ADHD‐PRS potentiated brain hypometabolism measured with [18F]FDG‐PET. Analyses were controlled by age, sex, years of study, and number of APOE ε4 alleles.

Result

We evaluated baseline data from 264 AD patients (114 women [43.2%], mean [SD] age of 75 [7.6] years). ADHD‐PRS was associated with decreased cognitive function (p‐value = .04, η2 = .01, Figure 1a), more specifically in executive function (p‐value = .04, η2 = .01, Figure 1c). Higher ADHD‐PRS was associated with brain hypometabolism in frontal, parietal, and temporal regions (Figure 2a,b). Brain hypometabolism correlated with worse cognitive function in the following regions: postcentral gyrus (p‐value = .01, η2 = .03), superior parietal gyrus (p‐value = .001, η2 = .07), precentral gyrus (p‐value = .004, η2 = .05), and fusiform gyrus (p‐value<.0001, η2 = .08, Figure 2c,d,e,f). Finally, decreased metabolism in these four regions mediated the effect of ADHD‐PRS on cognitive function (Figure 3).

Conclusion

Findings indicate that a higher genetic risk for ADHD is correlated with impaired cognitive function with small effect sizes. Moreover, the effects of the genetic risk of ADHD on cognitive function were mediated by hypometabolism in frontal, parietal, and temporal brain regions, which could point to a decrease resilience to AD pathology in individuals with ADHD. Clinically, our findings suggest that patients with comorbid ADHD and AD dementia have a more severe disease phenotype, with potential implications for prognosis and treatment.
Bearded capuchin monkey as a model for Alzheimer’s disease (AD) research
Authors: Rodriguez Roberta Diehl , Tavares Maria Clotilde Henriques , Brucki Sonia , Takada Leonel Tadao , Grinberg Lea T. , Otaduy Maria Concepción Gracía , Martin Maria Da Graça Morais , Costa Leite Claudia , Tomaz Carlos , Nitrini Ricardo
Published: December 2023

Background

The absence of a natural animal model is one of the main challenges to research in AD. AD‐type pathology has been described in chimpanzees and other primates’ brains. The bearded capuchin monkey (Sapajus libidinosus) is a New World primate that attracted attention mainly due to its skill in creating and using tools. We evaluated the brains of three captive capuchins (9, 29 and 33 years‐old) who died from natural causes at the Primate Center of University of Brasilia.

Method

Whole brain was fixed in 4% buffered paraformaldehyde within 12 hours of death for three weeks. Structural 7T MRI was acquired in one case before brain slicing. Consecutive coronal sections from the fixed brain were embedded in paraffin, and 5um sections from paraffin blocks were used for staining and immunohistochemistry evaluation. All brain sections were stained with hematoxylin and eosin. Immunohistochemistry with β‐amyloid (4G8), phosphorylated tau (AT8), p62, TDP‐43, α‐synuclein (81A), 68 kDa neurofilament (2F11), GFAP and CD68 antibodies were performed in selected sections to analyze the following areas: frontal cortex, temporal cortex, parietal cortex, occipital cortex, anterior cingulate cortex, hippocampus, amygdala, basal ganglia, thalamus, mesencephalon, pons, medulla oblongata, and cerebellum.

Result

Macroscopic evaluation of the brains showed considerable cortical gyrification. In addition, thick cortical ribbon was observed in the MRI. A complete neuropathological evaluation was available for two cases. Widespread β‐amyloid immunoreactivity was observed in the form of diffuse deposits, core‐space‐corona plaques, perivascular plaques, and amyloid angiopathy. A high frequency of classic neuritic plaques was observed. P‐tau antibody failed to label the dystrophic neurites. However, these lesions were revealed with p62 and neurofilament antibodies. Astrocyte hypertrophy surrounding plaques was observed without microglial activation. Very few hyperphosphorylated tau aggregates resembling neurofibrillary tangles and neuropil threads were found in the temporal and frontal cortex, and Lewy‐type and TDP‐43 pathology were not observed.

Conclusion

In summary, we found β‐amyloid immunoreactivity, classic neuritic plaques surrounded by astrocyte hypertrophy, but only rare P‐tau aggregates. To our knowledge, this is the first evidence reporting brain AD‐like alterations in capuchin monkeys which suggest that this species can be considered an advantageous animal model for AD research.
Biomarkers of synaptic and neuronal dysfunction in relation to mild behavioral impairment: a study of dementia‐free older adults
Authors: Sharif Sergio Fernandez , Guan Dylan X. , Ghahremani Maryam , Leon Rebeca , Smith Eric E. , Ismail Zahinoor
Published: December 2023

Background

Mild behavioral impairment (MBI) represents a high‐risk state for incident cognitive decline and dementia, capturing later‐life emergent and persistent neuropsychiatric symptoms in five domains: 1) decreased motivation; 2) affective dysregulation 3) impulse dyscontrol; 4) social inappropriateness; and 5) psychosis. We examined cross‐sectional associations between MBI and cerebrospinal fluid levels of markers of synaptic/neuronal dysfunction including 1) alpha‐synuclein (α‐syn); 2) growth‐associated protein 43 (GAP‐43); 3) neurogranin (NGRN); 4) synaptosomal‐associated protein 25 (SNAP‐25); 5) visinin‐like protein 1 (VILIP‐1); and 6) chitinase‐3‐like protein 1 (YKL‐40). Longitudinally, we determined associations between these biomarkers and incident MBI or dementia.

Method

Alzheimer’s Disease Neuroimaging Initiative participants with normal cognition and mild cognitive impairment were included (n = 853). MBI scores were derived from the Neuropsychiatric Inventory using a published algorithm. Participants were classified as MBI+ if MBI symptoms were present at ≥2 consecutive visits.

Cross‐sectional associations between MBI total score and each log‐transformed biomarker were modelled using multivariable‐adjusted linear regression. Biomarkers with cross‐sectional associations meeting a pre‐defined p‐value threshold (p<0.1) were then incorporated as exposures into adjusted longitudinal Cox proportional hazard regression models (n = 111) of 1) MBI and 2) dementia as the outcomes, the latter of which also included interactions between MBI status and biomarker levels.

Result

Demographics are summarized in Table 1. Cross‐sectionally, only MBI associations with VILIP‐1 (beta = 3.3%, 95%CI:+0.2% to +6.5%, p = 0.04) and SNAP‐25 (beta = 2.0%, 95%CI:‐0.4% to 6.3%, p = 0.09) met the pre‐defined p‐value for inclusion in Cox models. Longitudinally, higher VILIP‐1 levels were associated with a 3.02‐fold greater rate of incident MBI (95%CI:1.43‐6.40, p = 0.004) and a 3.83‐fold greater rate of incident dementia (95%CI:1.22‐12.03, p = 0.021). The relationship between VILIP‐1 and dementia did not depend on participants having MBI. MBI status predicted incident dementia with an HR = 4.75 (95%CI:2.36‐9.55, p<0.001) and HR = 4.06 (95%CI:2.01‐8.21, p<0.001) after adjusting for VILIP‐1.

Conclusion

Elevated VILIP‐1 levels are associated with greater incidence of MBI and greater incidence of dementia, suggesting that synaptic dysfunction traditionally related to cognitive decline and dementia may also contribute to behavioral changes. Treatments aimed to mitigate MBI symptoms and dementia may explore VILIP‐1—a neuronal calcium‐sensor protein—as a therapeutic target, though more research is needed.
Sex modifies the relationship between cardiorespiratory fitness and insulin resistance
Authors: Edmunds Kyle J , McIntyre Clayton Connor , Breidenbach Bri M , Nelson Alexis R , Lose Sarah R , Bendlin Barbara B , Sager Mark A. , Asthana Sanjay , Johnson Sterling C , Okonkwo Ozioma
Published: December 2023

Background

Cardiorespiratory fitness (CRF) is a protective lifestyle factor against age‐related changes in insulin resistance in adults at‐risk for Alzheimer’s disease (AD); however, this association may differ between males and females. While sex‐dimorphic mechanisms of neurodegeneration and peripheral insulin have been proposed in aging models, it is still unclear whether sex differences exist in the influence of CRF. This study examines whether sex modifies the association between CRF and insulin resistance in a participant sample enriched with risk for AD.

Method

This study included n = 1,131 cognitively unimpaired, nondiabetic participants, where CRF was estimated using a validated equation that incorporates age, sex, BMI, resting heart rate, and self‐reported physical activity. The Homeostatic Model Assessment for Insulin Resistance (HOMA‐IR) quantified insulin resistance using measured plasma glucose levels in mg/dL and insulin in µIU/mL following a 12‐hour fast. Cross‐sectional linear regression models were assembled in a moderation framework to test the interaction between CRF and sex on HOMA‐IR scores using the IBM SPSS PROCESS Macro v3.4. All models controlled for age, education, Apolipoprotein E4 (APOE4) carriage, body mass index (BMI), and familial history of AD. Finally, sex‐stratified analyses were performed to test within‐group associations of CRF and HOMA‐IR.

Result

71.8% of participants had family history of AD and 38.8% were APOE4 carriers. Participants had a mean age of 64.5 ± 7 years and a mean of 16 ± 3 years of education. CRF was negatively associated with HOMA‐IR (β = ‐0.064, SE = 0.03, p = 0.04) and the interaction of CRF and sex was likewise significant (β = ‐0.114, SE = 0.03, p<.001). Stratified models showed that the magnitude of the association between CRF and HOMA‐IR was almost three times as strong among men than women (males: β = ‐0.178, SE = 0.03, p<.001; females: β = ‐0.06, SE = 0.03, p = 0.04).

Conclusion

Among older adults at heightened risk for AD, CRF protects against insulin resistance; however, this association may be stronger in aging males than in females.
A multi‐stage feature selection method to improve classification of Super‐Ager and Cognitive Decliner using Structural brain MRI data – A UK Biobank study
Authors: Parvin Mohammadiarvejeh , Fili Mohammad , Hu Guiping , Willette Auriel A
Published: December 2023

Background

Cognitive aging is described as the age‐related declines in multiple cognitive abilities such as processing speed, memory, and executive function. However, old individuals with cognitive reserve are observed. Moreover, there are older adults aged more than 80 years, called Super‐Agers, who show cognitive abilities at least as good as middle‐aged adults, particularly in memory. Understanding the differences in brain structure between Super‐agers and Cognitive decliners can provide practical knowledge for middle‐aged adults to reserve the cognitive functions as they age and decrease Alzheimer’s Disease risk.

Method

Using the longitudinal cognitive tests of the UK Biobank, principal component analysis (PCA) was applied to combine the performance of the multiple cognitive domains to define the general cognitive ability (GCA) which was used to identify Super‐Ager and Cognitive Decline individuals. GCA 1 scores were extracted by processing speed, verbal and numeric reasoning, prospective memory, and visual declarative memory exams, and GCA 2 scores were extracted by executive function and processing speed exams. Random Forest (RF) classification models with a multi‐stage feature selection method were developed to distinguish Super‐Agers from Cognitive Decliners using the structural Magnetic Resonance (sMRI) features for two GCA 1 and 2 labels individually. Models’ performance and feature importance ranking were analyzed.

Result

RF model achieved AUC of 73% with 54 selected sMRI predictors by GCA 1 labels, and age, education, area of total surface, area of pars orbitalis, mean intensity of thalamus, area of superior frontal were the top six features in classification. Also, RF models achieved AUC of 76% with 42 selected sMRI features by GCA 2 labels, and age, grey‐white contrast in pars triangularis, volume of CA3‐head, grey‐white contrast in pars opercularis, grey‐white contrast in frontal pole, and mean intensity of choroid plexus were the top six features in classification.

Conclusion

our results suggest that using PCA to combine various cognitive domains is an optimal method to analyze GCA in older adults and identify latent cognitive trajectory type. Furthermore, the multi‐stage feature selection model could find the most relevant sMRI features to classify Super‐Agers and Cognitive Decliners.
Cardiorespiratory fitness partially mediates the association between age and insulin resistance in a cohort enriched with risk for Alzheimer’s disease
Authors: Edmunds Kyle J , Breidenbach Bri M , McIntyre Clayton Connor , Lose Sarah R , Bendlin Barbara B , Sager Mark A. , Asthana Sanjay , Johnson Sterling C , Okonkwo Ozioma
Published: December 2023

Background

Age is the cardinal risk factor for Alzheimer’s disease (AD), as well as adverse cardiovascular health and insulin resistance. In the context of promoting cerebrovascular health and resilience to AD, it remains unclear whether cardiorespiratory fitness (CRF)—an important lifestyle factor reflective of habitual exercise—explains age‐related associations in insulin signaling. Understanding how these factors intersect may be crucial for designing effective lifestyle interventions to protect normative brain function in aging. This study examines whether CRF mediates the relationship between age and insulin resistance in a sample enriched with risk for AD.

Method

We included n = 1,131 cognitively unimpaired, nondiabetic participants. CRF was estimated using a validated equation that incorporates age, sex, BMI, resting heart rate, and self‐reported physical activity. The Homeostatic Model Assessment for Insulin Resistance (HOMA‐IR) quantified insulin resistance using measured plasma glucose levels in mg/dL and insulin in µIU/mL following a 12‐hour fast. Cross‐sectional linear regression models were assembled in a mediation framework to test the mechanistic influence of CRF using the IBM SPSS PROCESS Macro v3.4, where indirect effects were estimated using bootstrapping. All models controlled for age, education, Apolipoprotein E4 (APOE4) carriage, body mass index (BMI), and familial history of AD.

Result

71.8% of participants had family history of AD and 38.8% were APOE4 carriers. Participants had a mean age of 64.5 ± 7 years and a mean of 16 ± 3 years of education. Age was significantly associated with estimated CRF [β = ‐0.346; p<0.001] and HOMA‐IR [β = ‐0.036; p<0.01]; CRF was likewise negatively correlated with HOMA‐IR [β = ‐0.106; p<0.001]. Bootstrapping indicated that CRF was a significant partial mediator of the association between age and HOMA‐IR [β = 0.37; 95% CI: 0.19, 0.55].

Conclusion

Age exerts its deleterious influence on peripheral insulin resistance through the degradation of cardiorespiratory fitness among adults at risk for AD.
Cerebral microhemorrhage associations in UK immigrants from the Middle East and North Africa (MENA)
Authors: Haddad Elizabeth , Sheikh‐Bahaei Nasim , Javid Shayan , Jahanshad Neda
Published: December 2023

Background

People from the Middle East and North Africa (MENA) are highly underrepresented in health studies, yet, they are forecasted to contribute the most to increasing projections of dementia over the next 30 years (Nichols, 2022). Cerebral microhemorrhages, or microbleeds (CMBs) in the aging brain have been linked to small vessel disease and neurodegeneration and may provide a proxy for intervention studies to identify those at higher risk for ADRD (Charidimou, 2011). CMBs are related to hemorrhagic amyloid‐related imaging abnormalities (ARIA‐H) reported as adverse events in recent Alzheimer’s clinical trials of amyloid clearing medications (Sperling, 2011). Identifying those at elevated risk for ARIA‐H can help refine inclusion criteria for clinical trials and mitigate risk of complications from these medications. CMBs may be detected by MRI derived susceptibility weighted images (SWI) (Haacke, 2004). We’ve previously reported higher prevalences of metabolic and cardiovascular disorders in MENA compared to other immigrant populations in the UK (Jahanshad, 2022). Using a subset of these individuals with SWI (Miller, 2016), we investigated the effect of these diseases and lifestyle on the presence of CMBs detected on SWI.

Method

185 MENA participants with SWI were included. We used MARS criteria (Gregoire, 2009) to identify CMBs on SWI and validated our findings using other sequences to exclude CMB ‘mimics’ (Figure 1). The number and position of CMBs were reported as well as their classification including ‘definite’, ‘possible’ and ‘total’. The effects of disease and lifestyle were investigated using association rule learning, and Chi‐squared/Fisher’s exact tests were used on the most prominent associations.

Result

10 subjects had at least one definite CMB and 10 more had at least one possible CMB (Table 1). Combinations of male sex, diabetes, obesity, and high waist‐to‐hip ratio were found to have 100% likelihood for having a CMB. The presence of definite CMBs was associated with diabetes (p = 0.017) and overweight BMI (p = 0.017) (Figure 2).

Conclusion

CMBs were associated with male sex, diabetes, and abnormally high anthropometric measures in MENA populations. Future work will test a larger sample and continue to tease apart CMB associations with health markers in those from MENA countries.
Deletion of the adaptor protein p66ShcA prevents the apoptosis of neural stem cells in response to mitogen deprivation
Authors: Powell Andrew M , Betts Dean H , Cumming Robert C
Published: December 2023

Background

Alzheimer’s disease (AD) has been associated with altered hippocampal neurogenesis and the depletion of the neural stem cell (NSC) niche. NSCs rely on cues from their extracellular environment to mediate their survival and maturation. The Shc adaptor family mediates this mitogenic signaling in response to a wide range of growth factors and is necessary for embryonic neurogenesis. A member of this family, p66ShcA has been found to antagonize mitogenic signalling, however its role in neurogenesis has not been established. Moreover, the genetic ablation of p66ShcA, has a been reported to reverse cognitive decline in mouse models of AD, despite its minimal expression in mature neurons.

Method

To evaluate p66ShcA’s role in the fate of NSCs, we generated and characterized a p66ShcA‐null murine NSC line (p66KO‐NSC). The NSCs were characterized by assessing their differentiation competency and viability in response to alterations in epidermal growth factor (EGF) signalling.

Result

The p66KO‐NSCs exhibited enhanced neurogenesis in response to EGF withdrawal, relative to WT NSCs. The pharmacologic inhibition of either EGFR or ERK induced the apoptosis of the WT NSCs via the release of cytochrome C and caspase activation. Surprisingly, the inhibition of EGFR or ERK had a negligible effect on the survival of the p66KO‐NPCs and instead induced their neuronal differentiation.

Conclusion

p66ShcA mediates NSC apoptosis in response to the loss of mitogenic cues. The deletion of p66ShcA increases neurogenesis by facilitating the survival of NSCs during their neuronal differentiation.
A novel humanized Tau‐FAD mice represent a robust model for studying AD‐related dysfunction
Authors: Sambamurti Kumar , Cromwell Ian , Pappolla Miguel A , Kanthasamy Anumantha , Padhi Piyush , Lahiri Debomoy K. , Greig Nigel H , Sarkar Sumit , Padmaraju Vasudevaraju
Published: December 2023

Background

Familial AD (FAD) mice expressing mutant forms of the Amyloid β protein (Aβ) precursor (APP) and presenilin‐1 (PS1) have been key models for AD research. While other studies combined FAD and the Tau protein, none, except 3xTgAD, have been made freely available or characterized well. As APP and Tau are linked in 3xTgAD mice, one cannot evaluate their contribution. This study combined the popular hTau strain lacking mouse Mapt and expressed human wild‐type MAPT with FAD.

Method

We generated HTAP by crossing hTau mice in C57BL6/J (JAX #005491) with FAD mutant APP‐PS1 (MMRRC #034833‐JAX) and HTAP2 with 5xFAD (#032882‐JAX). While hTau hyperphosphorylates Tau at 3 mo, the FAD models deposit Aβ after 5 mo. We compared mouse spatial memory with either a radial arm water maze or a Barnes maze. We also compared the levels of norepinephrine in the hippocampus, cortex, and striatum of HTAP2 with the parental C57BL6/J mice by HPLC analysis

Result

HTAP and HTAP2 mice deposit plaques similar to parental FAD mice and hTau hyperphosphorylated Tau. The combined HTAP mice showed hyperphosphorylated Tau, but the structures appeared distorted. We noted that after 7 months of age, HTAP mice performed poorly in the radial arm water maze compared to wild‐type, FAD, and hTau mice. We observed a similar deficit in HTAP2 in the Barnes Maze. HTAP2 mice showed a significant drop in norepinephrine in all evaluated brain regions, reminiscent of early AD‐related changes.

Conclusion

HTAP/2 mice have exacerbated behavioral deficits, suggesting that it is a more robust model for studying AD‐related dysfunction. However, these mice still perform well in activities of daily living, such as grooming and feeding. Such novel tau mice, which contain the human MAPT gene, would accelerate our ongoing studies on human microRNAs that target human 3'UTR MAPT mRNA without interference from the host Mapt gene. We propose that this system may better represent the behavioral deficits in AD.
Temporal evaluation of imaging and biofluid biomarkers, spatial neuropathology and glial function in the TgF344‐AD rat model
Authors: da Rocha Andreia Silva , Soares Carolina , Machado Luiza Santos , Ferreira Pamela C.L. , Bellaver Bruna , Kunach Peter , Kang Min Su , Souza Diogo O. , Rosa‐Neto Pedro , Green Kim N , Zimmer Eduardo R. ,   MODEL AD
Published: December 2023

Background

The development and characterization of Alzheimer’s disease (AD) animal models is particularly important for the investigation of pathophysiological mechanisms and drug development. The TgF344‐AD rat is a model harboring human APP/PS1 mutations with comprehensive presentation, including age‐dependent development of amyloid‐β (Aβ) plaques, neuronal loss and tau deposits, but not yet fully characterized. In light of this, we evaluated imaging and biofluid biomarkers, spatial neuropathology and glial function in these animals across multiple key ages.

Methods

TgF344‐AD rats and wild‐type littermates were longitudinally evaluated at 3, 6, 9, 12 and 16‐18 months of age. Rats underwent [18F]FDG‐microPET scans and CSF samplings. CSF glial and immune markers (GFAP, S100B, TREM2, IL‐6, TNF‐α, IL‐10) were measured by multiplex immunoassay. A cross‐sectional cohort was used to measure cortical glutamate uptake (ex‐vivo slices) and follow the spatial distribution of Aβ plaques (6E10 antibody) at the same time points.

Results

At 3, 6, 12 and 16‐18mo, no changes in [18F]FDG metabolism were observed. At 9mo, we identified a significant cortical hypermetabolism in the TgF344‐AD rats. CSF GFAP levels were elevated at 6 and 9 months of age, while CSF S100B was decreased at 9mo. The CSF inflammatory markers IL‐6, TNF‐α and IL‐10 were elevated at 16‐18mo. Additionally, the glutamate uptake was increased in the cortex at 9mo and 12mo, and in the hippocampus at 12mo. TREM2 was not altered in any of the ages evaluated. The (Aβ) plaques deposition starts at 6mo in the posterior temporal cortices and hippocampus and spreads slowly to frontal brain regions, reaching a plateau around 16mo.

Conclusion

This work shows that the TgF344‐AD rat model recapitulates the early and transient glucose hypermetabolism seen in AD patients. Our results also indicate an associated early astrocyte response in these animals, with changes in relevant astrocyte biomarkers and function (glutamate uptake). Due to the critical role of astrocytes in brain glucose handling, these findings suggest that astrocyte reactivity could be driving glucose hypermetabolism. In contrast, the neuroinflammatory biomarkers changes identified suggest a strong neuroinflammatory response only at later stages in this rat model, however, further investigations are necessary to better elucidate these findings.
Neighborhood disadvantage is associated with changes in cerebrovascular function among older adults over a 9 year follow‐up period
Authors: Cambronero Francis E. , Zhang Panpan , Gogniat Marissa A. , Liu Dandan , Vytla S. Soumya , Ratangee Brina A. , Roby Dominic V. , Pechman Kimberly R. , Verde Audrey R. , Davis L. Taylor , Landman Bennett A. , Gifford Katherine A. , Hohman Timothy J. , Blennow Kaj , Zetterberg Henrik , Jefferson Angela L.
Published: December 2023

Background

Stressful social environments exert a strong influence on unhealthy aging, both in greater magnitude and independent of individual socioeconomic and lifestyle factors. Neighborhood disadvantage specifically has been linked to accelerated biological aging, cognitive decline, and core Alzheimer’s disease (AD) neuropathology, but little is known about whether neighborhood disadvantage contributes to cerebrovascular dysfunction commonly observed in aging and AD. We examine whether neighborhood disadvantage relates to changes in cerebrovascular outcomes over time, including blood‐brain barrier (BBB) integrity, cerebral blood flow (CBF), and small vessel disease (SVD) biomarkers.

Methods

Vanderbilt Memory and Aging Project participants (n = 296, 73±7 years, 40% female) underwent fasting blood and cerebrospinal fluid (CSF) acquisition serially over a 9‐year follow‐up period (mean follow‐up = 5.5 years). Area Deprivation Index (ADI), representing neighborhood disadvantage, was quantified at baseline based on 17 components [e.g., housing, income, education, and household characteristics (Kind & Buckingham, 2018)]. BBB markers (MMP‐2, MMP‐3, MMP‐9, TIMP‐1, TIMP‐2, PDGFRβ) were quantified from CSF and CSF/plasma albumin ratio was quantified from both CSF and plasma. 3T multimodal MRI images were used to quantify grey matter CBF and SVD markers, including white matter hyperintensities (WMHs), perivascular spaces (PVS), and lacunes. Linear mixed effects regression models related time x ADI to longitudinal BBB, CBF, and SVD outcomes adjusting for age, sex, race/ethnicity, education, cognitive status, Framingham Stroke Risk Profile (minus age), apolipoprotein ε4 status, and follow‐up time. CBF models additionally adjusted for corresponding grey matter volume while SVD models adjusted for T1‐weighted intracranial volume.

Results

Baseline ADI related to increased MMP‐9 (β = 0.03, p‐value = 0.01) and decreased PDGFRβ (β = ‐0.1407, p‐value<0.05) over time but unrelated to longitudinal changes in CBF (p‐values>0.35), SVD (p‐values>0.36), or other BBB outcomes (p‐values>0.07).

Conclusions

Neighborhood socioeconomic disadvantage relates to changes in BBB integrity among older adults over time, particularly molecular markers of barrier disruption and pericyte damage. Findings support the hypothesis that adverse environmental conditions, including low quality housing and community‐wide resource constraints, may contribute to early‐stage cerebrovascular dysfunction beyond individual socioeconomic and lifestyle factors.

Funding

HHMI James H. Gilliam Fellowship for Advanced Study; IIRG‐08‐88733; R01‐AG034962; R01‐AG056534; K24‐AG046373; P20‐AG068
Prompting cognitive assistive technology for multistep tasks in dementia homecare: Testing of mode and sequencing options
Authors: Roberts Emily , Fan Guoliang
Published: December 2023

For people living with dementia, information‐processing capabilities and previously acquired knowledge is generally limited. Daily tasks such as making coffee or teeth brushing may become too difficult to complete independently. People with normal cognitive functioning learn about the environment as they move through it with spatial information obtained sequentially, requiring mental activity to process this successive input into a comprehensive understanding of a task. Without this ability, individuals with dementia in many cases then rely on repetitive cuing for tasks from their family member or caregiver. The approach for this project was the evaluation of task prompting for a wearable cognitive assistive technology for support in cueing on for multi‐step home tasks. Choosing meaningful tasks, and breaking them down in a way that a caregiver would usually provide prompting support is not trivial. The physical or environmental context of the task can also affect the flow of the task, and the personality of the person carrying out the task can influence how methodically the prompts are followed. The testing took place in a lab setting set up to represent a one‐bedroom apartment. A sample of older adults 65+ took part in a series of protocols for eight multi‐step tasks and for each task four delivery modes options (written text, audio, still photo, video) and four sequencing modes (auto‐generated, self‐request, one‐time, step by step) which included: kitchen‐ loading the dishwasher, setting the table and making coffee, bedroom‐ making the bed, folding clothes, bathroom‐ brushing teeth, hand washing and face washing. This pre‐testing of system components was performed in order to reduce marginal risks, increase effectiveness, and maximize benefits for the end‐user population of individuals with dementia who will test the device in future projects and the outcomes from this research will ultimately enable the mode and sequencing of task prompting for this populations' frequently changing needs.
Deep Learning patterns of Aβ accumulation in Alzheimer’s Disease
Authors: Srinivasan Dhivya , Nasrallah Ilya M. , Yang Zhijian , Bilgel Murat , Wen Junhao , Erus Guray , Cui Yuhan , Mamourian Elizabeth , Sotiras Aristeidis , Betthauser Tobey J , Resnick Susan M. , Tosun Duygu , Albert Marilyn S. , Davatzikos Christos ,   for the Alzheimer’s Disease Neuroimaging Initiative,the iSTAGING consortium, & the Preclinical AD consortium
Published: December 2023

Background

Accumulation of amyloid (Aß) plaques is an early pathologic change of Alzheimer’s Disease (AD). However, the mechanisms and pathways by which amyloid spreads across the cerebrum are not fully understood. Deriving distinct dimensions of amyloid deposition and their associations with biomedical factors could be useful to understand how amyloid propagates. In this analysis, we identified two distinct subtypes of progression based on spatiotemporal variations using a recently developed data‐driven, deep learning clustering method called Surreal‐GAN1.

Method

We used data from 482 A+ and 801 A‐ subjects with 18F‐florbetapir PET from the Alzheimer’s Disease Neuroimaging Initiative (ADNI; N = 832) and 11C‐PiB from the Preclinical AD consortium (PAC; N = 451). Standardized uptake value ratio (SUVR) maps (cerebellar GM reference) were transformed to reference space. We derived amyloid status using Gaussian mixture modelling of mean total cortical SUVR for each of 4 sites. We then applied non‐negative matrix factorization2 on the SUVR maps to identify data‐driven common patterns of deposition across the sample. Next, we applied Surreal‐GAN on a total of 1283 subjects to determine the amyloid spatiotemporal subtypes. Correlations with clinical and cognitive variables were evaluated.

Results

Participants were 30%/22% female and had mean age 74.9 (±7.4)/ 67.9(±9.1) years for ADNI and PAC, respectively. We identified 24 components from NMF (Fig 1A) after excluding 6 as non‐target features. Surreal‐GAN showed optimal agreement indices for two patterns. While both patterns shared involvement of posterior cingulate/precuneus and inferior frontal cortex, pattern r1 shows relatively more occipital deposition and pattern r2 shows more frontal deposition (Fig 1B), as seen when comparing strongly r1 vs strongly r2 participants using voxel‐based morphometry (Fig 2). Both were associated with worse global cognitive function and worsening neurodegeneration (Table 1). r1 correlates with white matter hyperintensity volume, a measure of cerebrovascular disease, while pattern r2 is associated with the presence of APOE e4 alleles.

Conclusion

Employing a data‐driven deep learning‐based approach, we derived more than one dissociable pattern of amyloid deposition, potentially differently influenced by vascular disease (r1/occipital) and genetics (r1/frontal). These findings could inform identification of subgroups of individuals who may or may not be responsive to particular clinical intervention.