bluuebunny/crossref_metadata_2025 huggingface dataset:
Harmonizing machine learning imaging biomarkers – CDESH and the case for harmonization in both MR image and low‐dimensional (scalar) output space
Authors: Gunter Jeffrey L. , Cogswell Petrice M , Senjem Matthew L. , Kantarci Kejal , Knopman David S. , Petersen Ronald C. , Graff‐Radford Neill R. , Radford Jonathan Graff , Jack Clifford R.
Published: December 2022

Background

In 2018 we presented the Computational DESH (CDESH) metric (DOI:10.1016/j.nicl.2018.11.015), a machine learning measure of abnormal CSF space patterns commonly observed on MRI in Disproportionately Enlarged Subarachnoid‐space Hydrocephalus (DESH‐type) NPH. We have shown that CDESH positive individuals often have discordant CSF and PET amyloid measures (DOI:10.1016/j.jalz.2019.06.4921). Positive CDESH scores are predictive of cognitive decline (DOI:10.1016/j.neuroimage.2021.117899, DOI: 10.1212/WNL.0000000000008616). The score is calculated from regional CSF volumes in a sulcal atlas and within the ventricles using a support vector machine (SVM). The Mayo Clinic Study of Aging (MCSA) changed scanner platforms (GE to Siemens) and T1‐weighted image resolution (1.2mm x 1.05mm x 1.05mm to 0.8mm isotropic) in 2017. We refer to these as “isotropic” or “anisotropic” scans. Our objective was to assess the dependence of a machine learning method (specifically CDESH) to image input variation and, if necessary, determine what needed corrections.

Method

All data considered is from the MCSA or Mayo Clinic ADRC. The SVM was trained on anisotropic images with laboriously labelled ground truth. We resampled the isotropic data from a crossover study (N=112, typically scanned same‐day with both platforms/resolutions) to match the anisotropic resolution. Two approaches to correction were evaluated (Figure 1). In Figure 2 we compare of the score with and without correction cross‐sectionally in 998 MCSA participants. In Figure 3 we present longitudinal series from 23 participants with multiple scans using the isotropic resolution protocol and at least one prior anisotropic image.

Results

Comparisons of data from the crossover study are presented in Figure 1. Matching voxel resolution to the data used to train the SVM is critical and a subsequent mild linear score adjustment may be warranted. Cross‐sectional comparisons (Figure 2) confirm improvement matching voxel resolution with a possible mild linear score adjustment. After matching voxel resolution CDESH score trajectories (Figure 3) are markedly more stable across this scanner/protocol change.

Conclusion

The SVM‐based CDESH score is sensitive to voxel resolution. Corrections are needed in image processing and possibly in the scalar output score to achieve stability across protocol and scanner changes. The resulting correction supports coherent long timeseries data and longitudinal extension of previous work.
Evaluation of novel data‐driven metrics of amyloid β deposition for longitudinal PET studies
Authors: Bollack Ariane , Cash David M , Markiewicz Pawel J , Wink Alle Meije , Prosser Lloyd , Coath William , Pemberton Hugh , Farrar Gill , Barkhof Frederik
Published: December 2022

Background

Positron emission tomography (PET) provides in vivo quantification of amyloid‐β (Aβ) pathology. The most common method for assessing PET is standardized uptake value ratio (SUVr), which can be affected by physiological and technical factors. Novel, data‐driven metrics have been developed to address these sources of variability. We evaluate cross‐sectional and longitudinal performance of four data driven metrics.

Method

Three cohorts were used for evaluation: Insight 46, a neuroimaging sub‐study of the 1946 British birth cohort, Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing, and a test‐retest flutemetamol dataset (Table 1). Data from participants were included if good quality volumetric MRI and amyloid PET, using florbetapir (Insight 46) or flutemetamol (AIBL and test‐retest data), was available. No partial volume correction was applied. Four data driven metrics were extracted: the Centiloid derived from non‐negative matrix factorisation (CLNMF), the Aβ PET pathology accumulation index (Aβ‐index), amyloid load (Aβ‐load), and amyloid pattern similarity score (AMPSS). These data‐driven metrics were compared to a global composite SUVr, with either a pons (flutametamol) or cerebellar grey matter (florbetapir) reference region, and a Centiloid (CL) score. They were evaluated by measures of repeatability in test‐retest data, associations with non‐displaceable binding potential (BPND, computed from Logan graphical analysis), sample size estimates to detect a 20% slowing in Aβ accumulation with 95% significance and 80% power, and accuracy in predicting the second follow‐up visit.

Result

All metrics show good to excellent reliability. The repeatability is highly influenced by the amyloid burden, the range, and the offset of each metric. (Table 1) All metrics are strongly correlated to the BPND (R
2: 0.8 to 0.94), with SUVr and CL explaining more variance in BPND than the data‐driven metrics. (Figure) Sample size estimates were lowest in CL and CLNMF compared to the SUVr. (Table 2) The Aβ‐index had the best predictive power over ∼3 years while the other metrics were comparable. (Table 3)

Conclusion

Novel data driven metrics provide comparable performance in terms of accuracy and performance to more established quantification methods of Aβ PET tracer uptake, but with additional benefits, such as being MRI‐free, reference region independent, or more robust to change in tracer.
The use of amyloid‐PET in memory clinic patients: AMYPAD Diagnostic and Patient Management Study
Authors: Altomare Daniele , Barkhof Frederik , Caprioglio Camilla , Collij Lyduine E. , Scheltens Philip , van Berckel Bart NM , Alves Isadora Lopes , Berkhof Johannes , van Maurik Ingrid S. , Garibotto Valentina , Moro Christian , Delrieu Julien , Molinuevo Jose Luis , Grau‐Rivera Oriol , Gispert Juan Domingo , Drzezga Alexander , Jessen Frank , Nordberg Agneta K , Walker Zuzana , Demonet Jean‐François , Gismondi Rossella , Farrar Gill , Stephens Andrew W , Frisoni Giovanni B ,   AMYPAD consortium
Published: December 2022

Background

Amyloid‐PET allows the direct assessment of amyloid deposition, one of the main hallmarks of Alzheimer’s disease. However, this technique is currently not or incompletely reimbursed due to lack of randomized controlled studies demonstrating a clinical impact.

Method

AMYPAD‐DPMS is a prospective, multicenter, randomized controlled study. Patients with subjective cognitive decline plus (SCD+), mild cognitive impairment (MCI) or dementia from 8 European memory clinics were randomized into three study arms: ARM1, amyloid‐PET performed early in the diagnostic workup (within 1 month); ARM2, late in the diagnostic workup (after 8±2 months); or ARM3, if and when the managing physician chose to. The primary endpoint was the proportional difference in ARM1 and ARM2 participants in receiving an etiological diagnosis with very high diagnostic confidence (i.e. ≥ 90%) within 3 months. Secondary endpoints included changes in diagnosis and treatment plan.

Result

Participants were recruited from April 16th, 2018, to October 30th, 2020. There were 272 participants in ARM1, 260 ARM2, and 261 ARM3 that underwent both baseline and 3‐month visit. 88% of ARM3 participants underwent amyloid‐PET within 3 months, and the average time from baseline to prescribe amyloid‐PET was 46 (IQR=58) days. After 3 months, 40% (109/272) of ARM1 participants and 37% (97/261) of ARM3 had a diagnosis with very high confidence vs 11% (30/260) in ARM2 (p<0.001). This was consistent across clinical stages (SCD+: 30%, 22%, and 6%, p<0.05; MCI: 42%, 39%, and 9%, p<0.05; dementia: 49%, 49%, and 20%, p<0.05). Changes in diagnosis were more frequent in ARM1 (44%) versus ARM3 (29%, p=0.001) and ARM2 (11%, p<0.001), and in ARM3 versus ARM2 (p<0.001). In participants for whom an etiological diagnosis of AD or non‐AD was confirmed after 3 months, changes in diagnostic confidence were greater in ARM1 (AD: +14%; non‐AD: +12%) and ARM3 (+11%; +10%) vs ARM2 (+1%, +1%; p<0.05).

Conclusion

An amyloid‐PET performed in the early phases of a diagnostic workup is associated with a greater proportion of etiological diagnoses with very high confidence and more frequent changes in diagnosis and higher diagnostic confidence after 3 months. This evidence supports the implementation of this technique early in the diagnostic workup.
Relationship between stress response and mitochondrial respiration in skeletal muscle of apolipoprotein E4 (APOE4) carriers
Authors: Johnson Chelsea N. , Thyfault John P , McCoin Colin S. , Swerdlow Russell H , Wang Xiaowan , John Casey S. , Geiger Paige C , Morris Jill K.
Published: December 2022

Background

Expression of the stress‐inducible chaperone protein, heat shock protein 70 (HSP70/72), is elevated in the Alzheimer’s disease (AD) brain. This may result from mitochondrial stress, as AD mitochondria are characterized by reduced complex IV activity and ATP levels. Further, patients with mild cognitive impairment (MCI) have reduced lipid‐stimulated mitochondrial respiration in skeletal muscle, providing evidence that mitochondrial dysfunction occurs peripherally, manifests early in the disease, and is related to lipid metabolism. Interestingly, the primary genetic risk factor for sporadic AD, the apolipoprotein E4 (APOE4) allele, plays an important role in lipid metabolism. The goal of this study was to characterize the skeletal muscle stress response in APOE4 carriers and the relationship with muscle mitochondrial function.

Method

We analyzed skeletal muscle tissue from previously collected biopsies (vastus lateralis) from 23 older adults (65+) who were cognitively healthy (CH, n=8) or MCI (n=15) and at genetic risk for AD (APOE4 carriers). We measured HSP72 protein levels via Western blot and leveraged previously collected data on APOE4 genotype, mitochondrial respiration (basal, state 3, state 3S, uncoupled), plasma cholesterol and platelet citrate synthase activity, the latter of which is a marker of mitochondrial content. Analyses were controlled for age and sex.

Result

HSP72 expression negatively correlated with basal respiration (R2 = 0.518, p = 0.002), ADP‐stimulated respiration (R2 = 0.775, p = <0.001) and succinate‐stimulated respiration (R2 = 0.405, p = 0.011) in the presence of the lipid, palmitoyl‐carnitine, in skeletal muscle of APOE4 carriers with MCI, but not in CH APOE4 carriers. HSP72 expression negatively correlated with platelet citrate synthase activity (R2 = 0.518, p = 0.002) in APOE4 carriers with MCI, but not in CH APOE4 carriers. HSP72 expression positively correlated with plasma cholesterol in all participants (R2 = 0.182, p = 0.042).

Conclusion

This work supports a potential role for the heat shock response in responding to peripheral mitochondrial dysfunction and elevated cholesterol levels during cognitive decline in APOE4 carriers. Further work is needed to determine if this stress response serves a protective role.
Processing of acoustically degraded speech in primary progressive aphasia and Alzheimer’s disease
Authors: Jiang Jessica , Requena‐Komuro Mai‐Carmen , Benhamou Elia , Johnson Jeremy , Sivasathiaseelan Harri , Chokesuwattanaskul Anthipa , Russell Lucy L , Warren Jason D , Hardy Chris JD
Published: December 2022

Background

In daily life, spoken messages are often “degraded” by competing sounds and vocal idiosyncrasies. Comprehension of degraded speech demands intense computations across distributed neural networks; it is likely to present a particular challenge for patients with neurodegenerative pathologies. However, this issue has not been studied systematically.

Method

Here, we studied the processing of degraded speech signals in a cohort of patients representing all major variant syndromes of primary progressive aphasia (N = 32), in relation to patients with typical Alzheimer’s disease (N = 19) and healthy age‐matched controls (N = 25). As a model paradigm for the degraded ‘noisy’ speech signals of daily life, we used noise‐vocoding: digital division of the speech signal into a variable number of frequency channels constituted from amplitude‐modulated white noise, such that fewer channels convey less spectrotemporal detail and reduce intelligibility. We assessed the impact of noise‐vocoding on the recognition of spoken three‐digit numbers (e.g., ‘five‐hundred‐and‐eighty‐seven’) and used psychometric modelling to ascertain the threshold number of noise‐vocoding ‘channels’ required for intelligibility by each participant.

Result

Compared with healthy controls, all patient groups showed normal comprehension of natural speech; for vocoded speech, patients with semantic variant primary progressive aphasia performed normally whereas other patient groups had a raised noise‐vocoding threshold and this was particularly marked in logopenic aphasia.

Conclusion

Our findings suggest that degraded speech is a promising paradigm for probing real‐world communication difficulties in people with dementia, and for stratifying syndromes and pathologies. Future work should assess the potential of this paradigm for developing new biomarkers and interventions to assess and improve communication function in these diseases.
Cumulative loneliness and subsequent memory function and rate of decline among adults aged ≥50 in the United States, 1996‐2016
Authors: Yu Xuexin , Westrick Ashly C , Kobayashi Lindsay C
Published: December 2022

Background

To investigate the association between the cumulative duration of loneliness and subsequent memory function and rate of decline over a 20‐year period in middle aged and older adults.

Method

Data were from biennial interviews with 9,032 adults aged ≥50 in the population‐based US Health and Retirement Study from 1996‐2016. Loneliness status (yes vs. no) was assessed biennially from 1996‐2004 and its duration over this period was categorized as never, 1 time point, 2 time points, and ≥3 time points. Episodic memory was assessed biennially from 2004‐2016 as a composite of immediate and delayed recall trials combined with proxy‐reported memory. We used multivariable‐adjusted mixed effects regression to estimate the association between loneliness duration and subsequent memory function and decline. Three‐way interaction terms were included to test effect modification by sex and age.

Result

Mean (SD) age at baseline was 64 (9) years, 63% of the sample was female (5,646/9,032), and the median follow‐up time was 10 years, contributing 46,890 observations from 2004‐2016. A total of 1,624 adults (18%) experienced loneliness at one time point, 825 (9%) experienced loneliness at two time points, and 1,069 (12%) experienced loneliness at ≥3 time points. Annual memory decline among non‐lonely adults was 0.08 standard deviation (SD) units (95% CI: ‐0.08, ‐0.07) per year. A longer duration of loneliness was associated with a faster rate of memory decline (1 time point: 0.01 SD additional annual decline, 95% CI: ‐0.01, ‐0.01; 2 time points: 0.02 SD additional annual decline, 95% CI: ‐0.02, ‐0.01; ≥3 time points: 0.03 SD additional annual decline, 95% CI: ‐0.03, ‐0.02; P trend <0.001). The association was stronger among women than men (three‐way interaction P trend <0.001) and adults aged ≥65 years than those aged <65 years (three‐way interaction P trend = 0.01).

Conclusion

Long‐term loneliness may be a salient risk factor for accelerated memory aging, especially among women aged 65 and over. Our findings could help rule out reverse causation between loneliness and memory outcomes, suggesting that loneliness could be part of a preclinical syndrome of Alzheimer’s disease and related dementias.
Relationships between hearing impairment with 7‐year cognition and cognitive change: Results from the Study of Latinos‐ Investigation of Neurocognitive Aging (SOL‐INCA)
Authors: Mendoza Alonzo , Stickel Ariana M , Tarraf Wassim , Kuwayama Sayaka , Kaur Sonya , Paredes Alejandra Morlett , Daviglus Martha L , Testai Fenando D , Zeng Donglin , Isasi Carmen R , Baiduc Rachael R , Dinces Elizabeth , Lee David J , González Hector M
Published: December 2022

Background

Hearing impairment among Hispanics/Latinos has been associated with poorer cognition, potentially increasing mild cognitive impairment (MCI) and dementia risk. We aimed to examine associations between baseline hearing impairment with 1) cognition at visit 2 (7‐years later, on average), 2) 7‐year average change in cognition, and 3) mild cognitive impairment (MCI) at visit 2 among diverse Hispanics/Latinos.

Method

Hispanics/Latinos (n = 6031, average baseline age 56.4‐years) from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) were enrolled in the SOL ‐ Investigation of Neurocognitive Aging (SOL‐INCA) ancillary study. Hearing impairment was defined as a pure tone average (500, 1,000, 2,000, 4,000 Hz) >25 dBHL in the better ear. Cognitive testing was performed at Visit 1 and again an average of 7‐years later. Tests included measures of learning and memory, verbal fluency, and executive functioning and processing speed, and global cognition (a z‐score composite from averaging each test). MCI was calculated based on NIA‐AA criteria. Survey linear regressions were used to separately model the associations between hearing impairment with outcomes of interest, controlling for age, gender, education, Hispanic/Latino background, field center, marital status, depressive symptoms, income, and Framingham cardiovascular disease risk.

Result

Performance at visit 2: In fully adjusted models, hearing impairment at baseline was associated with lower scores in global cognition (B = ‐0.12; SE = 0.03; p<0.0001) evident in learning, memory and verbal fluency, but not executive function or processing speed at visit 2 (7 years later). 7‐year (average) cognitive change: Hearing impairment was associated with significant change (declines) in processing speed (B = ‐0.12; SE = 0.06; p<0.05) but not with change in global cognition or other cognitive domains. MCI: Hearing impairment was not associated with prevalent MCI.

Conclusion

We found that hearing impairment was related to lower cognitive function and increased cognitive decline compared to Hispanics/Latinos with normal hearing. Hearing impairment was not associated with MCI among Hispanics/Latinos, and further longitudinal data are needed to determine if this holds as the cohort continues to age. Future studies should also examine comorbid sensory impairments and type of hearing impairments (noise induced hearing loss, conductive, sensorineural) with cognitive trajectories and MCI risk.
Connections between reproductive health and cognitive aging among women enrolled in the HCHS/SOL and SOL‐INCA
Authors: Stickel Ariana M , Tarraf Wassim , Wu Benson , Sundermann Erin E. , Gallo Linda C , Lamar Melissa , Daviglus Martha L , Zeng Donglin , Thyagarajan Bharat , Isasi Carmen R , Lipton Richard B. , Cordero Christina , Perreira Krista M , González Hector M , Banks Sarah J
Published: December 2022

Background

Lifetime risk for Alzheimer’s disease is higher among women than men, and reproductive health factors may contribute to differential risk. Reproductive health and cognitive aging among Hispanic women/Latinas is understudied, so we examined such relationships in the Hispanic Community Healthy Study/Study of Latinos (HCHS/SOL) and the SOL‐Investigation of Neurocognitive Aging (SOL‐INCA).

Method

The sample included Hispanic/Latina post‐menopausal women (n = 1,903, baseline age 44‐74 years). Exposures included oral contraceptive use, number of live births (parity), number of pregnancies, age at menarche, age at menopause, and reproductive span (years with menses). Outcomes included visit 2 cognitive performance (7‐years after baseline on average), 7‐year cognitive change (reliable change index), and NIA‐AA criteria mild cognitive impairment (MCI) prevalence. Cognitive measures included verbal learning and memory, verbal fluency, executive functioning (Trail B, higher scores = worse performance), and processing speed (Digit Symbol Substitution = DSS; Trail A, higher scores = worse performance), and a global composite (average of all individual z‐scores). Survey linear regressions were used to separately model the associations between reproductive health measures and outcomes, controlling for baseline age, education, language preference, Hispanic/Latina background, field center, income, birthplace, marital status, insurance status, and body mass index.

Result

Performance at visit 2: Oral contraceptive use was associated with higher global cognitive performance (β = 0.129 [SE = 0.043], p<0.01), learning (β = 0.197 [SE = 0.062], p<0.01), and processing speed (βDSS = 0.147 [SE = 0.049], p<0.01 and βTrailA = ‐0.142 [SE = 0.071], p<0.05) than non‐use. Higher parity was associated with worse executive functioning (β = 0.035 [SE = 0.017], p<0.05) and processing speed (βDSS = ‐0.054 [SE = 0.015], p<0.001). 7‐year (average) cognitive change: Oral contraceptive use, higher parity, and higher pregnancies were each protective against change in learning (β = 0.147 [SE = 0.064], β = 0.040 [SE = 0.019], and β = 0.034 [SE = 0.014], respectively; all ps<0.05). Older age at menarche was protective against change in global cognition (β = 0.045 [SE = 0.016], p<0.01), learning (β = 0.035 [SE = 0.017], p<0.05) and memory (β = 0.037 [SE = 0.017], p<0.05). MCI: No exposures were associated with MCI.

Conclusion

Reproductive health was linked to later life cognition among diverse Hispanic/Latina women. Future work should examine potential hormonal (e.g., estrogen) mechanisms. Although not associated with MCI In the present study, reproductive health may be linked to MCI status as the cohort ages and more women transition to MCI or dementia.
Findings from Dialogue with Patients and Families of Persons with Dementia
Authors: Splaine Michael
Published: December 2022

Background

Patient v.Voice in clinical guidelines has become a standard practice in medical and care community.

Method

Focus groups (online) were held with members of the IPA work group on Agitation and Dementia with early stage advisory groups to Alzheimer’s Associations and family caregivers.

Result

Language about agitation was tested, refined, clarified in the overalL IPA guidelines. Many early stage persons also voiced strong opinions about non pharmacological treatments as preferred.

Conclusion

Our work group and documents were enhanced by taking time for consitituency consultation.
Resilience to Alzheimer’s Disease in a pathologicaly confirmed cohort
Authors: Ahangari Narges , Fischer Corinne E. , Schweizer Tom A. , Munoz David G.
Published: December 2022

Background

Why some individuals with significant Alzheimer’s disease(AD) lesions in their brain retain their cognitive abilities while others with the same level of pathology manifest symptoms of dementia remains incompletely understood. The term cognitive resilience refers to this phenomenon. With limited success in pharmacological interventions that prevent the onset of AD pathology, more efforts are aiming toward developing strategies to delay the clinical expression of AD; acetylcholinesterase inhibitors serve as an example, and compounds with similar pharmacodynamics such as nicotine may play a similar role. Here we sought to identify demographic, clinical, genetic, and neuropathological features associated with cognitive resilience in participants with severe AD neuropathology.

Method

Data for this retrospective cohort was collected from the datasets developed by the National Alzheimer’s Coordinating Centre (NACC). Individuals with severe AD pathology and no other primary neuropathology diagnoses who had their last visit within 2 years of their time of death were included. Severe AD pathology definition was based on National Institute on Aging–Reagan (NIA‐Reagan) criteria pathology, i.e., frequent neuritic plaques and Braak & Braak stage V/VI pathology. Cognition was assessed using the Mini‐Mental Status Examination (MMSE) score at their last visit and cases with scores ≥24 were defined as being cognitively intact, and thus resilient. Following bivariate analysis to compare resilient with non‐resilient groups, significantly different variables were adjusted for demographics using logistic regression analysis. Subsequently, statistically significant characteristics were entered in a multivariable model.

Results

We classified 59(9%) individuals as resilient and 595(91%) as non‐resilient. The binary logistic regression model showed that resilient subjects were older (odds ratio[OR] = 1.03;95% confidence interval[CI] = 1–1.07), had more years of education (OR = 1.16;95%CI = 1.04‐1.29), had lower BMI (OR = 0.91;95%CI = 0.85‐0.99), were more likely to be a smoker (OR = 2.78;95% CI = 1.45‐5.34), and were more likely to use an anticoagulant/antiplatelet at last visit compared with subjects with impaired cognition (OR = 1.87;95%CI = 1.01‐3.48).

Conclusions

Our results corroborated previous findings that lower BMI and higher education are associated with AD cognitive resilience, and additionally demonstrated that the level of smoking and usage of anticoagulant/antiplatelet medication have a direct relationship with cognitive resilience to AD severe pathology. Nicotine mimetics could be explored as a potential option for preventing AD clinical expression.
Stress, anxiety and depression in older adults at increased risk for cognitive decline: association with biomarkers and sex/gender differences
Authors: Arenaza‐Urquijo Eider M , Akinci Muge , Palpatzis Eleni , Peña‐Gomez Cleofé , Suárez‐Calvet Marc , Gispert Juan Domingo , Minguillón Carolina , Grau‐Rivera Oriol , Sánchez‐Benavides Gonzalo , Fauria Karine
Published: December 2022

Background

Anxious depressive symptomatology and stress are associated with cognitive decline. Recent evidence suggests a relation between these factors and Alzheimer’s disease (AD) pathophysiology early in the continuum. With the current increases in anxiety, depression and stress due to the Covid19 pandemic ‐ notably in women ‐ unrevealing the biological mechanisms underlying these associations with a sex/gender approach appears fundamental.

Method

We included a total of 1170 participants in a series of observational cohort studies. Participants were cognitively unimpaired with increased risk of AD dementia (family history, APOE ε4, subjective cognitive decline). We investigated stressful life events with a lifespan perspective, stress perception, and changes in anxiety/depression in late life in relation to CSF, PET and MRI biomarkers of AD pathologies, neuroinflammation and brain atrophy. To that end, we performed multiple regression models adjusted by age, sex and education level. We also carried out stratified analyses by sex and explored sex differences in lifestyle and anxious‐behaviors (e.g., eating and sleep patterns).

Result

The accumulation of stressful life events as well as late‐life anxious depressive symptoms were associated with neuroinflammation markers, notably in women. Midlife stress was associated with increased tau and brain atrophy, together with lifetime history of anxiety/depression. In late life, amyloid positivity predicted longitudinal increases in anxiety and depression in the face of stressors, i.e., the covid19 pandemic, in women. Stress perception was not itself associated with any biomarker tested but mediated the increases in anxiety/depression. Women showed higher anxiety/depression and stress‐perception than men. While sex‐differences were identified in eating and sleep patterns, these did not explain the reported associations.

Conclusions

Our results suggest that mental health factors and stress should be tackled from a life‐span and sex/gender perspective in people at risk for cognitive decline (Fig1): midlife stress may enhance tau pathology and brain atrophy. Accumulation of stress and anxiety/depression may enhance neuroinflammation pathways in women as well as brain atrophy. Once amyloid is present, women may be more prone to show increases in anxiety and depression in the face of stressors. Finally, stress‐perception represents an intervenable factor that may prevent increases in anxiety and depression.
Associations between psychological factors, grey matter volume, and resistance and resilience to tau pathology in cognitively unimpaired older adults
Authors: Strikwerda‐Brown Cherie , St‐Onge Frederic , Yakoub Yara , Ozlen Hazal , Binette Alexa Pichet , Breitner John , Villeneuve Sylvia , Group PREVENT‐AD Research
Published: December 2022

Background

Modifiable factors may influence risk for Alzheimer’s disease (AD) via two distinct, though not mutually exclusive, pathways: resistance and resilience to pathology. Whereas cognitive ‘resilience’ is defined as the maintenance of better‐than‐expected cognitive performance in the face of Aβ and tau pathology, ‘resistance’ refers to an absence or delaying of the pathology itself. We explored the potential influence of psychological factors on resistance and resilience to tau pathology in older adults at risk of AD dementia, and whether grey matter volume mediates these relationships.

Method

Measures of psychological factors (including mindfulness, optimism, purpose in life, Big‐5 personality traits, and affective symptoms), longitudinal cognitive assessments, and structural MRI scans were collected in 259 nondemented older adults, along with Aβ‐ and tau‐ positron emission tomography (PET) scans in a subset of 156 individuals. Relationships between psychological factors and entorhinal tau pathology, and between psychological factors and cognitive resilience to entorhinal tau pathology (quantified using the residuals method), were explored, controlling for age, sex, and global Aβ burden. Principal components analysis was then performed to reduce the psychological factors that were associated with resistance/resilience down to their underlying components. Relationships between the psychological components and grey matter volume were explored using voxel‐based morphometry analyses. Finally, the potentially mediating effect of grey matter volume on the relationships between the psychological components and resistance/resilience to pathology were examined.

Result

One principal component was associated with resistance to pathology, comprising mindful acting with awareness, perseverative thinking, conscientiousness, neuroticism, depression, purpose in life, and optimism. Two principal components were associated with resilience to pathology, the first comprising mindful nonjudgment, anxiety, and stress, and the second comprising extraversion and openness. These three principal components were associated with partially distinct patterns of grey matter volume, which overlapped in medial prefrontal and posterior cingulate cortices (Figure 1). Grey matter volume partially mediated the relationship between psychological factors and resistance, but not resilience, to pathology.

Conclusion

Psychological functioning may influence resistance and resilience to AD pathology in cognitively unimpaired older adults. Increased grey matter associated with different combinations of protective psychological factors may assist in the delaying or prevention of AD pathology.
Definitions and characteristics of successful cognitive aging
Authors: Pezzoli Stefania , Giorgio Joseph , Harrison Theresa M. , Martersteck Adam , Jagust William J.
Published: December 2022

Background

Different approaches have been used to define successful agers (SA), but there is currently no consensus on either the definition of SA or the underlying neural mechanisms. The aim of this study was to compare new and existing definitions, to understand whether SA are resistant to atrophy and Alzheimer’s disease pathology or resilient to their effects, and whether this varies by SA definition.

Method

Machine learning algorithms were used to predict age from neuropsychological tests in 184 cognitively normal adults over the age of 70. Differences between cognitive‐predicted age and chronological age (cognitive age gap, CAG) were used as a novel measure of SA, defined as below the 20th percentile (SA‐CAG, n = 37). In the same sample, SA were also defined as individuals performing in the top 20% on composite scores for episodic memory (SA‐EM, n = 37) and non‐memory cognition (SA‐NM, n = 37), and participants with performance comparable to individuals aged 18‐32 years on the California Verbal Learning Test long delay free recall (SA‐CVLT, n = 31). The four definitions were used to compare SA to typical agers (TA, n = 109) in hippocampal volume, anterior cingulate cortex (ACC) thickness, APOE genotype, PET‐measured amyloid (11C‐Pittsburgh compound‐B, PiB) and, in a subsample (n = 114), PET‐measured tau (18F‐Flortaucipir, FTP). All analyses were age and sex adjusted.

Result

SA‐CAG definition showed moderate agreement with SA‐EM (Cohen’s κ = 0.46), SA‐NM (κ = 0.49), but only fair agreement with SA‐CVLT (κ = 0.24). Fair agreement was found between the other definitions (Figure 1). Compared to TA, greater hippocampal volume was found in SA‐CAG (p = 0.005), SA‐EM (p = 0.02), and SA‐CVLT (p = 0.02). Greater ACC thickness was found in SA‐CAG (p = 0.01), SA‐EM (p = 0.02), and SA‐NM (p = 0.004). Lower entorhinal FTP uptake was found in SA‐CAG (p = 0.04), SA‐EM (p = 0.007), and SA‐NM (p = 0.008) (Figure 2). No between‐group differences were detected in the proportion of APOE ε4 carriers and PiB+ participants.

Conclusion

Despite imperfect overlap in SA groups identified by different definitions, common brain features were found in SA‐CAG, SA‐EM, and SA‐NM compared to TA. Greater hippocampal volume, greater ACC thickness and lower entorhinal tau deposition suggests that SA, regardless of its exact definition, may be resistant to tau pathology and its downstream effects.
The association between cognitive reserve, cognition and brain age in Midlife: The CARDIA Study
Authors: Dintica Christina S. , Habes Mohamad , Davatzikos Christos , Sidney Stephen , Yaffe Kristine
Published: December 2022

Background

Cognitive reserve (CR) factors have been suggested to be protective of cognitive function in older adults. Less is known about this relationship in midlife, and whether the protective effect of CR may depend on brain age (relative to chronological age) in midlife. We aimed to investigate whether CR factors are associated with cognition in midlife, independent of brain age.

Methods

As part of the ongoing prospective Coronary Artery Risk Development in Young Adults (CARDIA) study, we identified 612 Black and White participants (mean age 55 SD 3.5) with brain MRI and cognitive testing. We generated a CR composite score from structural equation modeling including four CR‐enhancing factors: education, cognitive activities, occupational cognitive complexity, and adult literacy. Cognitive function was assessed at Year 30 with a composite measure of tests of memory, processing speed, executive function, and language. Brain age was ascertained using a previously validated high dimensional neuroimaging pattern analysis, based on machine learning algorithms, that quantifies individual differences in age‐related atrophy using MRI‐derived structural brain characteristics. We used linear regression to assess the associations between CR composite above or below median (high versus low), brain aging, and cognitive function, adjusting for chronological age, sex, race, intracranial volume, and scanning site.

Results

There was a modest association between the CR composite and brain age; higher CR was associated with lower brain age (β‐0.40, CI: ‐0.67 to ‐0.13). High CR was associated with better performance on all cognitive tests compared to low CR (p<0.001 for all). These associations remained with the inclusion of brain age as a covariate. Having high CR is associated with better cognitive performance regardless of brain age (Figure 1).

Conclusion

Our findings suggest that CR factors are associated with better cognitive function in midlife, and that brain aging and CR are two independent factors that may contribute to cognitive aging in midlife.
A whole‐genome‐sequencing study to identify genetic variants associated with Alzheimer’s disease progression
Authors: Shi Ruyu , Fan Kang‐Hsien , Lopez Oscar L. , Feingold Eleanor , Kamboh M. Ilyas
Published: December 2022

Background

Alzheimer’s disease (AD) is an irreversible neurodegenerative brain disease with varying disease progression rates among individuals. This study aims to identify possible underlying genetic variants associated with AD progression using a whole‐genome sequencing approach.

Method

Whole‐genome sequencing at 30x coverage was performed on 416 late‐onset AD patients (mean baseline age ± sd) = 76.47 ± 6.10) having at least two Mini‐Mental State Examination (MMSE) scores ranged from 0 to 30. Since the study subjects had varying time points of visit and MMSE records, we defined AD progression phenotypes in four ways, including differentially specified progression rates and time to pre‐defined events in genome‐wide association analyses. Genetic association analyses between single‐nucleotide variants (SNVs) and phenotypes were adjusted for baseline age, sex, year of education, baseline MMSE measures, and the first four principal components.

Result

Six novel genome‐wide statistically significant associations (p<5E‐08) were observed in our study. Two associations were detected with the same SNVs on chromosomes 2 (SLC4A10/rs13036052) and 7 (chr7:58053009[Hg38] near ZNF716) with overall progression rates. One genetic variant on chromosome 6 (chr6:3127309[Hg38] near BPHL) was associated with annual progression rate. In addition, three associations were seen on chromosomes 1 (rs199560872), 14 (chr14:9600158[Hg38] near TUNAR), and 18 (rs34718969) with time‐to‐event phenotypes. All top variants were present either in introns or intergenic regions.

Conclusion

Our initial whole‐genome sequencing analyses have identified several independent associations with AD progression, which need to be confirmed in larger sequencing samples.
Depression in young adulthood to midlife and brain aging in midlife: A 30‐year follow‐up of The CARDIA Study
Authors: Dintica Christina S. , Habes Mohamad , Simone Tamar , Schreiner Pamela , Erus Guray , Yaffe Kristine
Published: December 2022

Background

Evidence suggests that depression is a risk factor for dementia in older adults, but the link between depressive symptoms and brain health earlier in life is poorly understood. We aimed to investigate the relationship between depressive symptoms in early adulthood through midlife and brain aging in midlife.

Methods

From the prospective study of Coronary Artery Risk Development in Young Adults, we identified 649 Black and White participants (age 18‐30 at baseline) with brain MRI and cognitive testing 30 years later (mean age 55, SD 3.5). The participants underwent 6 repeated assessments for depressive symptoms measured with the Center for Epidemiological Studies Depression scale (CES‐D) over 30 years. The CES‐D range is 0‐60, a score of 16 points or more is considered depressed. Cumulative exposure of depressive symptoms was estimated by time‐weighted averages (TWA). We used a previously validated high dimensional neuroimaging pattern analysis, based on machine learning algorithms, that quantifies individual differences in age‐related atrophy using MRI‐derived structural brain characteristics. Linear regression was used to test the association between average cumulative depressive symptoms, brain aging, and cognition, adjusted chronological age, sex, race, education, intracranial volume, and scanning site

Results

Every standard deviation (5‐points) higher average cumulative depression symptoms was associated with approximately one‐year greater brain age (Table 1). Participants with higher average cumulative depressive symptoms greater than the clinically significant cutoff of 16 points over the 30 years, had on average 3‐years greater brain age (95% CI: 0.74 to 4.96) compared to below the clinical cutoff. Adjusting for anti‐depressive medication use at any time during the follow‐up, slightly attenuated the association (Table 1).

Conclusion

Higher depressive symptoms across 30 years from early to mid‐adulthood are associated with accelerated brain aging in midlife. This suggests that elevated depressive symptoms in early adulthood can have implications for brain aging as early as in midlife.
Impairment of cerebral CO2 dynamic vasoreactivity in MCI & AD patients: a multi‐center study of cerebral flow regulation
Authors: Marmarelis Vasilis , Billinger Sandra A , Chui Helena C , Joe Elizabeth B , Shin Dae , Cardim Danilo , Hashem Suhaib , Aaron Stacey E , Cullum Munro , Kelly Brendan , Zhang Rong
Published: December 2022

Background

Alzheimer’s Disease Centers in Los Angeles (USC), Dallas (UT‐SWMC) and Kansas City (KUMC) have joined together to study the regulation of cerebral perfusion through analysis of spontaneous time‐series data using a modeling methodology that previously yielded indications of reduced CO2 dynamic vasomotor reactivity (DVR) in amnestic MCI patients. We report initial results from this ongoing multi‐center study that confirm those preliminary findings and, furthermore, elucidate the effects of slow‐paced breathing.

Method

Five‐minute spontaneous changes in arterial blood pressure (ABP), end‐tidal CO2 (etCO2) and cerebral blood flow velocity (CBFV) in middle cerebral arteries were obtained before and after 5‐min session of slow‐paced breathing (8 breaths/minute). Using data from 25 MCI patients, 7 AD patients and 45 age‐matched cognitively normal controls (NC), we obtained predictive models of the dynamic effects of ABP and etCO2 (proxy for blood CO2) upon CBFV via our kernel‐based modeling methodology. These predictive models were used to compute indices (physio‐markers) that quantify the DVR in each participant, as time‐average of the model‐predicted CBFV response to unit‐step change of etCO2 over the first 30 seconds.

Result

The obtained DVR indices were significantly different for the 32 patients (MCI and AD lumped together due to small number of AD) vs. 45 age‐matched controls (p= 0.0099). Notably, the delineation between patients and controls improved (p= 0.0011) after a 5‐min session of slow‐paced breathing. Figure 1 shows the average model‐predicted CBFV response to unit‐step change of etCO2 for 32 MCI/AD patients (red line) and 45 controls (blue line) before and after the 5‐min paced‐breathing session. Note the negative average steady‐state CBFV response of the patients (red) that indicates polarity reversal of the normal CO2 vasomotor reactivity (blue). Better delineation between patients and controls is achieved (p= 2x10‐5) when the DVR indices from the two sessions, before and after slow‐paced breathing, were averaged (see histograms in Figure 2).

Conclusion

Significantly lower DVR indices under resting spontaneous conditions were observed in 32 MCI/AD patients relative to 45 age‐matched controls. This reduction is detected more reliably after 5‐min of slow‐paced breathing. Averaging of the DVR indices obtained before and after slow‐paced breathing improved further this delineation (p= 2x10‐5).
Advanced diffusion‐weighted MRI sensitively detects age and sex effects in 34,423 adults
Authors: Nabulsi Leila , Lawrence Katherine E , Laltoo Emily , Santhalingam Vigneshwaran , Abaryan Zvart , Villalon‐Reina Julio E , Nir Talia M , Gari Iyad Ba , Zhu Alyssa H , Haddad Elizabeth , Muir Alexandra M , Jahanshad Neda , Thompson Paul M
Published: December 2022

Background

Aging and Alzheimer’s disease (AD) are associated with alterations in the brain’s white matter (WM) microstructure. AD also exhibits significant sex differences and, similar to age, sex has also been associated with WM microstructural variability. A comprehensive characterization of how aging and sex impact WM microstructure may thus improve our understanding of processes involved in AD. Here we examined age and sex effects on traditional and advanced measures of WM microstructure in middle‐ to older‐aged adults.

Method

Cross‐sectional diffusion‐weighted MRI (dMRI) scans were analyzed from 34,423 UK Biobank participants (aged 45‐80 years; 53% female) using single‐shell models (DTI, TDF), and advanced multi‐shell models (NODDI, MAP). Metrics were projected to a standard WM skeleton using publicly available ENIGMA protocols, based on TBSS (FSL). Mean values for each dMRI metric were extracted from the whole WM skeleton, and age was modeled using fractional polynomial regressions, co‐varying for years of education, waist/hip ratio, population structure, and the Townsend index. Sex‐stratified centile curves were created for each dMRI metric to provide normative reference charts.

Result

WM microstructure across the brain was significantly associated with participants’ age and sex for all dMRI models (main effects, ps<.001). Increasing age in our cross‐sectional sample was associated with lower anisotropy (DTI‐FA, TDF‐FA), neurite density (NODDI‐ICVF, MAP‐RTOP, MAPMRI‐RTAP), and restriction (MAP‐RTPP) as well as higher diffusivity (DTI‐AxD, DTI‐MD, DTI‐RD), free water (NODDI‐ISOVF), and white matter dispersion (NODDI‐OD) for both males and females (Figures 1 and 2). Some metrics showed a gentle decline until around age 60, followed by a precipitous decline thereafter (e.g., TDF‐FA, NODDI‐ICVF, MAP‐RTAP, Figures 1 and 2). Significant sex differences in aging were most sensitively detected by the advanced dMRI multi‐shell models NODDI and MAPMRI (age‐by‐sex interaction; males showing a steeper trajectory for NODDI‐OD, p<.001, females showing a steeper trajectory for MAPMRI‐RTPP, p<.01, with age).

Conclusion

Participant age and sex are significantly associated with the brain’s WM microstructure; advanced dMRI models displayed the greatest sensitivity, strenghtening previous findings in a smaller UKB sample (15k). Along with our calculated centile curves, we offer an important normative reference to guide future studies of Alzheimer’s disease.
The longevity‐promoting intervention 17α‐Estradiol protects against aging phenotypes in APOE4 mice
Authors: McGill Cassandra J , Christensen Amy , Qian Wenjie , Benayoun Bérénice A. , Pike Christian J.
Published: December 2022

Background

The two primary risk factors for late onset Alzheimer’s Disease (AD) are aging and APOE4 genotype. While the causal relationship between aging and AD is not well defined, shared phenotypes, such as decreased metabolic function and increased inflammation, are strong leads. APOE genotype may be linked to AD phenotype through the regulation of aging processes. The NIA Interventions Testing Program found that 17α‐estradiol (17αE2) treatment can increase male mouse lifespan. Since 17αE2 has been shown to act upon systemic and neural pathways that have also been associated with AD pathology, we propose that 17αE2 may constitute a pleiotropic intervention strategy. Further, because APOE4 is associated with impaired healthspan and lifespan, 17αE2 may preferentially improve outcomes in the context of APOE4 genotype.

Method

To examine the effects at the earliest phases of AD development, we used 10‐month‐old APOE3 or APOE4 targeted replacement male mice maintained for 20 weeks on normal chow in the absence or presence of 14.4 ppm 17αE2. Mice were evaluated on various metabolic, behavioral, and molecular measures.

Result

Our initial results indicate genotype differences in the impact of 17αE2 across multiple outcomes. APOE4 mice were impaired across metabolic measures including body weight, plasma leptin, and hepatic steatosis, and 17αE2 treatment significantly attenuated these metabolic phenotypes. APOE4 mice exhibited an aged phenotype compared to APOE3, notably with higher frailty indices; however, 17αE2 treatment reduced the frailty index more strongly in APOE4 mice compared to APOE3. Interestingly, transcriptomic analysis of isolated microglia from both APOE3 and APOE4 17αE2 treated mice displays a downregulation of genes relating to inflammation and upregulation of those in metabolic pathways.

Conclusion

These data confirm and extend prior findings that APOE4 is linked to progeroid effects both peripherally and neurally, outcomes associated with AD risk. Importantly, although 17αE2 significantly improved a range of measure across genotypes, it showed the strongest effects in the APOE4 genotype.

This research was funded by the Cure Alzheimer’s Fund.