bluuebunny/crossref_metadata_2025 huggingface dataset:
Retinal biomarkers predict future cognitive performance in progranulin‐haploinsufficient frontotemporal dementia
Authors: Oertel Frederike Cosima , Younes Kyan , Cobigo Yann , Keihani Azeen , Fonseca Corrina , Bennett Daniel J , Abdelhak Ahmed , Saias Alexandra , Montes Shivany Condor , Chen Robert Y , Cordano Christian , Green Ari J , Elahi Fanny M
Published: February 2022

Background

Progranulin (GRN) haploinsufficiency caused by heterozygous mutations in the GRN gene is a common cause of early‐onset familial frontotemporal dementia (FTD). Our group previously described neuronal ceroid lipofuscinosis‐like features in the retinae of asymptomatic and mildly symptomatic heterozygous GRN mutation carriers (GRN‐carriers). However, additional intraretinal changes, their clinical relevance and utility as biomarkers remain unexplored. We aimed to describe the distinct retinal disease pattern in GRN‐carriers and to investigate the association of retinal change with subsequent brain atrophy and cognitive decline.

Method

We applied optical coherence tomography (OCT) and scanning laser ophthalmoscopy at baseline in 23 GRN‐carriers (age [years, mean+SD]: 62±11, gender [male, N(%)]: 11(48), mean Clinical Dementia Rating (CDR) = 0.5; CDR = 0.0 for 9 subjects) and 85 healthy controls (HCs) (age: 69±15, gender: 42(49)), investigating qualitative and quantitative retinal changes. Linear mixed‐effect models (LME) were used to study the relationships at a group‐level between OCT findings and longitudinal assessments (follow‐up time [months, median(min‐max)]: 28(12‐73)) of cognitive performance including lexical fluency (LF), semantic fluency (SF) and emotion naming (EN). MRI analyses are pending.

Result

Eight eyes (17%) of five GRN‐carriers (22%) had drusen‐like depositions detectable on OCT. Quantifying macular layers, GRN‐carriers had a thicker outer plexiform layer (OPL: 0.33±0.05mm3, p<0.001), thinner outer nuclear layer (ONL: 0.66±0.07mm3, p = 0.019) and thinner retinal pigment epithelium (RPE: 0.15±0.02mm3, p = 0.039) compared with HC (OPL: 0.30±0.03mm3, ONL: 0.69±0.07mm3, RPE: 0.16±0.01mm3), but no differences in inner retinal layers (confirmed excluding eyes with drusen). The OPL/ONL‐ratio was higher in GRN‐carriers (0.51±0.13) than HC (OPL/ONL‐ratio: 0.44+0.08, B = 0.079, p<0.001). GRN‐carriers with OPL/ONL‐ratio>median at baseline had a faster annualized decline of LF (‐2.60±5.62, B = 0.273, p = 0.002), SF (‐5.70±9.76, B = 0.213, p = 0.035) and EN (0.44±1.24, B = 0.066, p = 0.040) during follow‐up compared to subjects with OPL/ONL‐ratio<median (LF: 4.25±3.50; SF: 0.00±4.32, EN: 2.00±1.83).

Conclusion

GRN‐haploinsufficiency is associated with retinal phenotypes, including drusen and outer retinal layer thinning, suggestive of photoreceptor degeneration. OPL/ONL‐ratio predicted FTD associated cognitive worsening ‐ and thereby might have potential as biomarker of disease progression in clinical trials.
White matter tract integrity, but not amyloid burden, is related to cognition in cognitively normal older adults
Authors: Pettigrew Corinne , Soldan Anja , Alm Kylie H. , Bakker Arnold , Zhu Yuxin , Wang Mei‐Cheng , Kutten Kwame , Bilgel Murat , Miller Michael I. , Faria Andreia , Mori Susumu , Albert Marilyn S.
Published: February 2022

Background

The increased focus on preclinical Alzheimer’s disease (AD) necessitates an understanding of how general biomarkers of neuronal injury and AD‐specific biomarkers differentially contribute to the cognitive performance in cognitively normal individuals. It has been suggested that alterations in limbic white matter (WM) tracts may precede both gray matter atrophy and clinical impairment (Teipel et al., 2016). However, few studies have evaluated whether limbic tract alterations are associated with cognitive performance in individuals with normal cognition. To address this gap, this cross‐sectional, multi‐modal imaging study examined whether measures of WM tract integrity, using diffusion tensor imaging (DTI) (including fornix, hippocampal cingulum, and uncinate fasciculus), were related to cognitive performance, independent of cortical amyloid burden in cognitively normal individuals.

Method

Analyses included 130 cognitively normal participants from the BIOCARD Study (Table 1) who completed cognitive assessments, diffusion‐weighted MR and 11C‐PiB PET imaging during their annual visit. Cognitive performance was captured by cognitive composite scores reflecting verbal episodic memory, executive function, and visuospatial processing. WM tract integrity was measured by fractional anisotropy (FA) and radial diffusivity (RD) in the 3 above‐mentioned ROIs. PiB PET amyloid positivity was derived from cortical distribution volume ratios (cDVR) using cerebellar gray matter as the reference.

Linear regressions (covarying age, sex, and education) were used to test 4 a priori cognition‐WM associations. The following relationships were examined: episodic memory and fornix and hippocampal cingulum integrity; executive function and uncinate fasciculus integrity; visuospatial processing and hippocampal cingulum integrity.

Result

In the linear regression models (Table 2), lower hippocampal cingulum FA and greater hippocampal cingulum RD were each associated with better episodic memory performance. Additionally, lower uncinate fasciculus RD (but not FA) was associated with better executive function performance. In contrast, amyloid positivity (i.e., cDVR > 1.06) was unrelated to any of the cognitive composite scores (all ps > .35).

Conclusion

Measures of WM tract integrity account for variability in cognitive performance among cognitively normal individuals, and this association is independent of amyloid burden. Additional analyses are needed to determine whether these microstructural measures reflect general, age‐related markers of neuronal injury vs. alterations related to preclinical AD.
Subcortical brain trajectories in later life between sexes and APOE genotypes: A UK Biobank study of individuals of self‐identified Indian ancestry
Authors: Muir Alexandra M , Ching Christopher , Santhalingam Vigneshwaran , Abaryan Zvart , Zhu Alyssa H , John John P , Venkatasubramanian Ganesan , Thomopoulos Sophia I , Jahanshad Neda , Thompson Paul M
Published: February 2022

Background

In the UK, individuals with Indian ancestry show lower rates of dementia compared to other ethnicities. Most dementia studies mainly examine individuals of European ancestry and/or higher socioeconomic status, making it unclear if effects generalize to other populations. Here we map age trends in subcortical brain morphometry in later life and investigate the modulating effects of sex and APOE genotype in people of self‐identified (SI) Indian ancestry.

Method

T1‐weighted MRI scans from mostly healthy individuals with SI‐Indian ancestry from the UK Biobank (; N = 297; born in India = 43.1%) were processed using FreeSurfer v7.1 to derive bilaterally averaged hippocampus, thalamus, putamen, pallidum, amygdala, caudate, nucleus accumbens, and ventricle volumes. SI‐ancestry groups were confirmed with the first three genetic principal components ()4. Sex‐stratified normative centile reference curves (nomograms) of standardized residuals corrected for intracranial volume (ICV) and scanner were plotted for each structure. Linear mixed models were used to investigate a sex‐by‐age interaction adjusted for scanner and ICV. APOE ε4 carriers and non‐carriers were compared. All results were corrected for multiple comparisons.

Result

Nomograms () show a similar pattern for SI‐Indian and SI‐European ancestry groups (N= 35,608). All subcortical volumes generally declined significantly with increasing age, except for the ventricles which increased as expected (; Cohen’s d: 0.12 ‐ 0.93). No subcortical region showed a significant age by sex interaction (). Subcortical volumes did not differ between carriers and non‐carriers ().

Conclusion

Nomograms and statistical analysis of subcortical brain volume trajectories showed similar patterns between SI‐Indian and SI‐European groups. In the current sample, we detected no sex by age interaction for any subcortical volume nor detrimental effect of APOE ε4 allele, likely due to lack of power. Larger samples of SI‐Indian ancestry individuals along with analyses accounting for life expectancy, short survival with dementia, and risk/protective factors compared with populations of higher prevalence will be valuable to assess whether differential subcortical trajectories may account for lower rates of AD in India compared to other countries.
Findings from an Asian post‐stroke cognitive impairment intervention programme
Authors: Wong Fennie , Ng Sheng Chun , Chua Esther Vanessa , Kandiah Nagaendran
Published: February 2022

Background

Singapore sees more than 7,000 ischemic stroke cases yearly, with majority having physical and cognitive sequelae. Previous reports demonstrate that Post‐stroke cognitive impairment (PSCI) occurs in 37.3% of stroke patients at the National Neuroscience Institute (NNI, Singapore) within 6 months post‐stroke. The severity of rising PSCI rates prompted the implementation of the NNI Stroke Memory Rehabilitation Programme (SMaRT) for ischaemic stroke patients with mild physical impairments. This study aims to evaluate the outcomes of the SMaRT programme on PSCI and post‐stroke coping over a 6‐month period.

Method

The SMaRT programme is a 8‐week group‐based post‐stroke cognitive rehabilitation programme focusing on healthy living habits, memory models, memory strategies and emotion regulation strategies. Patients with clinically diagnosed ischaemic strokes, mild functional and cognitive issues (modified Rankin Scale score≤3 and Mini Mental‐State Examination score≥20) were recruited from April 2018 to September 2020. Assessments were administered at baseline, 8 weeks and 6 months post‐SMaRT, measuring global cognition (Montreal Cognitive Assessment, Visual Cognitive Assessment Tool), visuospatial function/attention (Trail Making Test‐A), emotional coping (Geriatric Depression Scale‐15), daily functioning (Nottingham Extended Activities of Daily Living (NEADL)), subjective quality of life (Dementia Quality of Life (DemQOL)). Paired samples t‐tests compared scores between the three timepoints, adjusting for type I errors with Bonferroni correction.

Result

137 subjects (N males=90 (65.7.%); mean age=63.49 years, SD=9.38, mean years of education=9.50, SD=3.79) underwent SMaRT. Comparing week‐8 to baseline, there was significant improvement in global cognition (MoCA, VCAT: p<.001), emotional coping (GDS, p<.001), daily functions (NEADL, p<.001), subjective quality of life (DemQOL: p=.008). Significant improvement was also observed comparing month‐6 to baseline scores in global cognition (MoCA, VCAT: p<.001), emotional coping (GDS, p<.001), daily functions (NEADL, p<.001), subjective quality of life (DemQOL: p<.001). In both analyses, decreasing trends in TMT‐A (seconds) were observed and approached significance.

Conclusion

The SMaRT programme is effective in mitigating post‐stroke cognitive impairment, particularly in global cognition. Additionally, SMaRT improved mood, daily functioning and subjective quality of life, suggesting its ability to instill positivity and confidence in stroke patients. These suggest a group‐based structured cognitive rehabilitation programme is likely to benefit stroke patients and reduces incidence of PSCI.
The effects of concurrent cognitive and meta‐cognitive training on neuropsychiatric symptoms of people living with younger onset dementia: Protocol for a pilot trial
Authors: Sabates Julieta M , Loi Samantha M , Lautenschlager Nicola T , Brodtmann Amy , Bahar‐Fuchs Alex
Published: February 2022

Background

Neuropsychiatric symptoms (NPS) are behavioural and psychological disturbances frequent in people with dementia that have been linked with lower quality of life, lower cognitive functioning and greater caregiver distress, especially for caregivers of people with younger‐onset dementia (YOD) (1).

Several drug and non‐drug treatments targeting NPS have been investigated in recent years. However, to the best of our knowledge, no treatment has been developed that concurrently targets and trains cognitive and meta‐cognitive processes which are implicated in the expression of NPS. The aim of this pilot trial is to investigate the effects on NPS of a mobile application‐based intervention simultaneously training both processes by incorporating elements of cognitive training and cognitive‐behavioural therapy.

Method

Twenty participants with YOD will be randomised to the training group or to a control group. Participants in the experimental condition will train at home three times a week for four weeks with remote therapist support. NPS, cognitive, psychological and caregiver outcomes will be assessed before and immediately after the intervention.

Result

The mobile application is in the design stage and further studies are underway to incorporate the views of people with YOD and their care‐partners, as well as clinicians, to the design. Recruitment of participants is expected in the second half of 2021.

Conclusion

Findings from this trial will further our understanding of the utility of concurrently targeting cognitive and meta‐cognitive processes in people with YOD when treating NPS and will inform a revision of the application. We believe that results from this study will have important implications for the management and treatment of NPS in the ever‐growing field of interventions utilising technology. 1 Baillon, S., Gasper, A., Wilson‐Morkeh, F., Pritchard, M., Jesu, A. and Velayudhan, L., 2019. Prevalence and Severity of Neuropsychiatric Symptoms in Early‐ Versus Late‐Onset Alzheimer’s Disease. American Journal of Alzheimer's Disease & Other Dementias®, 34(7‐8), pp.433‐438.
Tau PET as a prognostic marker in preclinical and prodromal Alzheimer’s disease
Authors: Ossenkoppele Rik , Mattsson Niklas , Smith Ruben , Groot Colin , Cho Hanna , La Joie Renaud , Baker Suzanne L. , Borroni Edilio , Klein Gregory , Pontecorvo Michael J. , Devous Michael D. , Jagust William J. , Lyoo Chul Hyoung , Rabinovici Gil D. , Hansson Oskar
Published: February 2022

Background

Tau PET tracers have proven useful for diagnostic purposes, but their prognostic utility for predicting future cognitive changes over time is unclear. We aimed to examine the prognostic accuracy of [18F]flortaucipir and [18F]RO948 (tau) PET in individuals across the Alzheimer’s disease (AD) spectrum.

Method

We included 673 cognitively unimpaired individuals (CU, 277/673 amyloid‐β+), 443 participants with mild cognitive impairment (MCI, 279/443 amyloid‐β+) and 315 amyloid‐β+ participants with AD dementia. Amyloid‐β status was determined by PET and/or CSF. The participants underwent [18F]flortaucipir (n=1135, discovery cohort) or [18F]RO948 (n=296, replication cohort) PET, T1‐weighted MRI and repeated Mini‐Mental State Examination (MMSE). Baseline [18F]flortaucipir/[18F]RO948 PET standardized uptake value ratios (SUVR) within in a temporal region‐of‐interest (ROI)and an MRI‐based AD‐signature cortical thickness ROI were used to predict longitudinal changes of MMSE using linear mixed effect models. Additionally, we performed mediation analyses to test whether associations between baseline tau PET and cognitive change were mediated by baseline MRI measures, and examined whether age, sex and APOE genotype modified the association between baseline tau PET and cognitive change.

Result

Tau PET in a temporal ROI predicted changes in MMSE, and associations were stronger than for AD‐signature cortical thickness across all participants (R2: 0.34 vs 0.24, bootstrapped p‐value for difference: <0.001), in amyloid‐β+ MCI (R2: 0.27 vs 0.13, p<0.001) and in amyloid‐β+ CU (R2: 0.14 vs 0.04, p<0.001, Figure‐1). AD signature cortical thickness only modestly mediated the association between tau PET and MMSE scores over time in amyloid‐β+ AD dementia (34.2%[95%CI: 16.8%‐59.0%] of the total effect, p<0.001) and in amyloid‐β+ MCI (11.6%[0‐25.0%], p=0.044), but not in amyloid‐β+ CU (p=0.848, Figure‐2). Age (T=‐2.24, p=0.025), but not sex (T=0.95, p=0.341) or APOE genotype (T=1.32, p=0.188), modified the association between baseline tau PET and cognitive change, such that older individuals showed faster cognitive decline at similar tau PET levels (Figure‐3). Most results were replicated in the [18F]RO948 PET cohort.

Conclusion

Tau PET is a promising tool for predicting future cognitive change and could support the prognostic process in preclinical(i.e. amyloid‐β+ CU) and prodromal (i.e. amyloid‐β+ MCI) stages of Alzheimer’s disease.
Self‐reported history of estrogen hormone therapy differentiates rates of amyloid accumulation (PiB‐PET) relative to males: Findings from the Harvard Aging Brain Study
Authors: Rubinstein Zoe B. , Buckley Rachel F. , Scott Matthew R. , Manning Lyssa K. , Mayblyum Danielle V. , Thibault Emma G. , Jacobs Heidi I.L. , Farrell Michelle E. , Properzi Michael J. , Rabin Jennifer S. , Chhatwal Jasmeer P. , Lois Cristina , Rentz Dorene , Price Julie C. , Schultz Aaron P. , Sperling Reisa A. , Johnson Keith A.
Published: February 2022

Background

Women’s Health Initiative Memory Study (WHIMS) findings suggest that hormone therapy increases risk of dementia. Conversely, evidence from the Kronos Early Estrogen Prevention Study (KEEPS) implicates estrogen hormone therapy (HT) as protective against ß‐amyloid (Aß) burden. We sought to explore if self‐reported HT use is associated with rates of Aß accumulation in an observational sample of clinically‐unimpaired older adults.

Method

134 participants (Age=73yrs±5.8) underwent at least three timepoints of Pittsburgh compound‐B (PiB)‐PET scans over an average of 9.7 years. Longitudinal PiB‐PET was examined as aggregate neocortical DVR (composite reference region: whole cerebellum + eroded white matter). Concurrent with baseline PiB‐PET, female participants self‐reported if they ever took HT. Participants were thus identified as: females who never used HT (HT‐:n=36), females who have ever taken HT to any extent (HT+:n=42), and males (M:n=56). We examined the relationship between these three groups and longitudinal PiB‐PET using linear mixed models, adjusting for baseline age, and with random slopes and intercepts. Post‐hoc analyses adjusted for APOEε4 status and examined interactions between HT and baseline PiB‐PET on change in PiB‐PET from baseline.

Result

While we found no significant sex (male/female) difference in PiB‐PET accumulation (t=1.5,p>0.05,Fig 1A), we observed significant HT group differences with HT‐ exhibiting approximately half the PiB‐PET rate of change than M (t=2.3,p=0.02) and HT+ (t=1.8,p=0.07; Fig 1B). There was no significant slope difference between M and HT+ (t=0.32,p=0.75). These differences survived after covarying for APOEε4. A three‐way interaction with baseline PiB‐PET revealed a greater slope difference between HT‐ and M (t=2.1,p=0.04) in those with higher baseline PiB‐PET relative to lower baseline PiB‐PET (Fig 2).

Conclusion

HT‐ showed significantly slower rates of Aß accumulation than males and a trend‐level slower rate compared to HT+; these differences appear heightened with greater baseline Aß burden. With similar ages across HT groups (p=0.20), these differences did not appear to be a function of chronological age. It remains unclear whether the introduction of estrogen, a mediating commonality, or collider bias is driving these results. Our findings, in conjunction with other studies, suggest the relationship between HT and Aß is complicated and necessitates examination of HT type and duration.
Preclinical Alzheimer disease pathology partially mediates the relationship between cortical thickness and cognitive control
Authors: McKay Nicole S. , Dincer Aylin , Mehrotra Vidushri , Aschenbrenner Andrew J. , Balota David A. , Hornbeck Russ C. , Morris John C. , Benzinger Tammie L.S. , Gordon Brian A.
Published: February 2022

Background

Previous research has shown that with age and disease, the integrity of grey matter structures decline. One such measure of grey matter integrity is cortical thickness, where lower values represent thinning of the cortical surface. Given that cognitive performance tends to decline with age, we were interested in investigating whether performance on attention‐based tasks was related to cortical thickness measured using magnetic resonance imaging (MRI) in an unimpaired older adult cohort. Further, although often unmeasured in studies of cognitive aging, many older adults will present with Alzheimer Disease (AD) pathologies such as beta‐amyloid (Aβ) deposition, despite being asymptomatic. Therefore, we were also interested in quantifying how much of the behavior‐structure relationship seen in older adult cohorts is driven by preclinical AD.

Method

511 cognitively unimpaired (CDR™=0) older adults (Age: M=68.2, SE=0.38) enrolled in studies at the Knight Alzheimer Disease Research Center, were included in these analyses. All participants completed an MRI and several cognitive assessments (Stroop, Simon, and CVOE); a subset of individuals (n=396) also underwent Aβ‐positron emission tomography (PET). A spatial cortical map highlighting regions where cortical thickness and cognition were related was created (Figure 1). This map was entered into subsequent analyses as our MRI variable. We used an established attentional control composite as our behavioral measure of interest. Linear models were conducted to elucidate the relationship between cortical thickness and cognition, and a mediation analysis was performed to examine whether Aβ deposition impacted this relationship.

Result

Using vertex‐wise general linear models, we found that reduced cortical thickness in temporal, medial‐ and lateral‐parietal, and dorsolateral prefrontal cortex, predicted worse performance on an attention task composite (Figure 2). Interestingly, mediation analysis showed that levels of Aβ partially account for the observed relationship between cortical thickness and attentional control (Figure 3).

Conclusion

These results demonstrate that behavioral variability seen in older adult populations reflects corresponding changes in brain anatomy, specifically cortical thickness. Furthermore, our results support the hypothesis that preclinical AD, as measured by Aβ deposition, is partially driving what would otherwise be considered general aging in a cognitively normal older adult population.
Cognitive Health After MenoPause (CHAMP) Study: A study of the health of the cholinergic system and risk factors for future cognitive decline in postmenopausal women aged 50‐70
Authors: Conley Alexander C , Shokouhi Sepideh , Dumas Julie , Newhouse Paul A
Published: February 2022

Background

Menopause is associated with changes in hormone balances, and also to cognition in some women. These changes have been proposed to lead to an increased risk of developing Alzheimer’s disease (AD). However, there is not a clear understanding of how these changes are linked to neurodegeneration. One theory of what may be driving cognitive changes may be linked to how estrogen depletion affects cholinergic system activity. Preclinical studies have shown that estrogen is necessary for normal cholinergic functioning and its withdrawal leads to cholinergic dysfunction and cognitive impairment. And previous studies in postmenopausal women have shown that anticholinergic blockade is effective at modulating activity when performing working memory tasks.

Method

The CHAMP study will determine whether menopause‐related cognitive changes correlate with both cholinergic functional integrity and established AD biomarkers in a sample of 120 healthy postmenopausal women aged 50‐70 years. Using an anticholinergic challenge model, this study will examine cognitive performance on memory tasks using fMRI. The present study will collect established AD biomarkers of amyloid and tau levels in both blood and CSF samples, as well as through amyloid PET imaging, and markers of neurodegeneration including medial temporal lobe volume through structure MRI. In addition, the study will also collect genomic markers of impairment, such as APOE and COMT genotypes.

Result

We predict that women with poor compensation following menopause will be more sensitive to anticholinergic blockade, and will show decreased working memory performance, reduced brain activation, and decreased basal forebrain cholinergic system volume.

Conclusion

In addition, we predict that these cholinergic markers will also be related to menopausal factors associated with poor cognition and biomarkers that are related to AD.
The association of blood pressure variability with white matter integrity and cognitive impairment in cerebral amyloid angiopathy
Authors: Sveikata Lukas , Zotin Maria Clara Zanon , Schoemaker Dorothee , Perosa Valentina , Etherton Mark , Ma Yuan , Charidimou Andreas , Greenberg Steven M. , Viswanathan Anand
Published: February 2022

Background

Emerging evidence suggests that blood pressure variability (BPV) may contribute to small vessel disease (SVD) progression and cognitive impairment beyond the deleterious effects of elevated blood pressure, but the mechanisms remain largely unknown. This study investigates if BPV is associated with white matter (WM) microstructural integrity and the slope of cognitive decline in elderly individuals with cerebral amyloid angiopathy (CAA), a well characterized type of SVD.

Method

We recruited 94 non‐demented individuals (73.3 ± 7.0 y, 40 F, MMSE 27.7 ± 1.5) from a memory‐clinic cohort with and without possible/probable CAA with available neuropsychological evaluation and 3.0 T research MRI. Visit‐to‐visit BPV was assessed using the coefficient of variation derived from the serial outpatient BP measures during a 5‐year interval. A novel diffusion tensor imaging marker – peak width of skeletonized mean diffusivity (PSMD) – was used to evaluate the WM integrity. Using linear regression models, we evaluated the association of PSMD with BPV, adjusted for standard cardiovascular risk factors.

Result

We found a significant association between loss of WM integrity and high systolic BPV (β = 0.37, P < 0.001), but not mean BP. The association remained significant after adjusting for age, antihypertensive medication usage, diabetes, smoking, and body mass index. Furthermore, the association of BPV with WM integrity was stronger when CAA was present (P for interaction = 0.018). Higher BPV at baseline was associated with worse executive function in CAA patients at 2‐year follow‐up (β = ‐0.53, P = 0.003), adjusted for baseline function.

Conclusion

Our findings show that visit‐to‐visit BP fluctuations are associated with loss of WM microstructural integrity and cognitive decline. The association between BP variability and WM integrity might in part be driven by CAA pathology. Further studies are warranted to disentangle the relationship between BP fluctuations, microvascular injury, and cognitive impairment in older adults.
Sequential early cognitive changes sensitive to rising beta‐amyloid and tau pathology in preclinical AD
Authors: Farrell Michelle E. , Papp Kate V. , Buckley Rachel F. , Jacobs Heidi I.L. , Schultz Aaron P , Properzi Michael J , Vannini Patrizia , Hanseeuw Bernard , Rentz Dorene M. , Johnson Keith A. , Sperling Reisa A.
Published: February 2022

Background

AD clinical trials are increasingly looking towards intervention at the earliest stage of preclinical AD, when beta‐amyloid (Aβ) is emerging and tau pathology remains restricted to the MTL. While some evidence suggests subtle cognitive changes start at this early stage, it is unclear what cognitive measures may be most sensitive to emerging pathology and whether they reflect Aβ, tau or both.

Method

143 clinically‐normal adults with longitudinal PIB‐PET, FTP‐PET and cognitive data (median follow‐up: 7.68(1.17) years) were included from the Harvard Aging Brain Study (HABS). Analyses focused first on those initially PIB‐ (<Centiloid (CL) 20), then were expanded to those initially <CL 40, approximately where neocortical tau proliferation accelerates. Linear mixed effects (LME) models first assessed the neocortical PIB slope*time effect on each cognitive task across the full time‐course. FTP was introduced later (∼Year 3), so LME models assessing combined PIB+FTP effects on cognition (Year3+) were divided into prior effects (PIB slope‐Year0‐3, Year3‐FTP level) and concurrent effects (PIB slope‐Y3+, FTP slope‐Y3+). Both entorhinal (ERC) and inferior temporal (IT) FTP were tested. ROC curve analyses assessed sensitivity/specificity of each task and composite measures to PIB slope.

Result

In PIB slope models across the full time‐course (Fig 1), rising PIB was robustly associated with declining processing speed (DSST, Trails A) in those <CL20 and expanded to include memory encoding (FCsrt‐FR, SRT‐tr, LM‐immed) in the <CL40 group. In the combined PIB+FTP models under CL20 (Fig 2), rising PIB slope associated with declining DSST, FCsrt‐FR, and SRT‐tr, while the only FTP effect was between rising ERC FTP and declining FCsrt‐FR. Expanding up to CL40, IT FTP became dominant and related to most cognitive tasks, but independent effects of PIB slope remained for DSST and the encoding measures. A composite measure (DSST, Trails A, FCsrt‐FR, LM‐immed) demonstrated high sensitivity and specificity (SE=.85, SP=.88, Fig 3) to PIB slope, performing better than any individual task and the PACC.

Conclusion

Measures of processing speed and memory encoding were most sensitive to emerging Aβ and tau pathology, and may help to determine whether anti‐Aβ therapies administered at the first signs of Aβ and tau might preserve cognitive function.
Abnormal metabolic brain network in behavioral variant of frontotemporal dementia
Authors: Rus Tomaž , Ležaić Luka , Emeršič Andreja , Kramberger Milica G. , Pirtošek Zvezdan , Eidelberg David , Trost Maja
Published: February 2022

Background

The increasing number of patients with neurodegenerative dementia is a major public health issue. While clinical features of neurodegenerative disorders causing dementia are overlapping, accurate diagnosis is a prerequisite for an effective drug development. Besides the need for a better biomarker of Alzheimer’s disease (AD), development of non‐AD biomarkers is necessary. Behavioral variant of frontotemporal dementia (bvFTD) is the second most common neurodegenerative dementia in patients younger than 65 years. The aim of our study was to identify and validate bvFTD specific metabolic brain pattern using voxel‐based spatial covariance analysis according to the scaled subprofile model (SSM/PCA) on a new cohort of European patients and to study its biologic significance.

Method

20 patients with clinical diagnosis of bvFTD and 20 age‐matched normal controls (NC) underwent metabolic imaging with FDG PET. CSF results were available for 10/20 bvFTD patients and potential AD was excluded based on the biomarker profile. Using SSM/PCA, we identified a significant bvFTD‐related metabolic pattern termed bFDRP‐Slov. The stability of voxel weights on this pattern was evaluated using bootstrap resampling. For validation, pattern expression values were computed in an independent testing set comprised of 25 bvFTD and 22 NC subjects. The specificity of the pattern for bvFTD was assessed by computing values in patients with other causes of dementia: 26 with AD and 16 with sporadic Creutzfeldt‐Jakob disease (sCJD). bFDRP expression was correlated with disease duration and with MMSE.

Result

The bFDRP was characterized by pronounced metabolic reduction in the medial frontal cortex, middle and inferior frontal gyri, anterior cingulum, insula, bilateral caudate and thalamus. bvFDRP expression values discriminated bvFTD patients from their counterparts with AD, sCJD and NC (p<0.0001; one‐way ANOVA). The expression of this pattern was abnormally elevated in bvFTD patients in the identification and validation cohorts (p<0.0001). bvFTD patients’ pattern expression of values did not correlate disease duration or MMSE.

Conclusion

bFDRP is a promising metabolic network biomarker of the disorder, consistent with previously identified disease pattern. Further research is needed to study its clinical significance. Identification of multiple neurodegenerative brain networks may be critical as the combination of different patterns can improve diagnostic accuracy.
Age of amyloid onset, but not amyloid accumulation rate, differs across APOE‐e4 carriers vs. non‐carriers in three cohorts and three methods
Authors: Betthauser Tobey J. , Bilgel Murat , Koscik Rebecca L. , Jedynak Bruno Michel , An Yang , Jonaitis Erin M , Christian Bradley T. , Engelman Corinne D. , Asthana Sanjay , Wong Dean F. , Albert Marilyn S. , Resnick Susan M. , Johnson Sterling C.
Published: February 2022

Background

New methods have recently been developed to model longitudinal amyloid biomarkers in AD. This work compares three methods in three different cohorts, and investigates associations of APOE‐e4 status with amyloid onset age and amyloid accumulation rates.

Method

Participants from ADNI (N=1213), BLSA (N=205) and WRAP (N=272) with available amyloid PET imaging and APOE genotype were included in the study (Table 1). Amyloid (A) burden was quantified using established methods (ADNI: BAI processed SUVR, WM reference region; BLSA: SRTM‐LRSC DVR, PVC, cerebellum GM reference region; WRAP: graphical analysis DVR, cerebellum GM reference region). Group‐based trajectory modeling (GBTM), ordinary differential equation‐Gaussian process (ODE‐GP) and sampled iterative local linear approximation (SILLA) methods were used to model longitudinal amyloid accumulation, estimate A+ onset age, and align amyloid values by years A+ for each cohort. Forward and backward SUVR/DVR prediction, estimated age of A+ onset, and associations of DVR/SUVR residuals with age, time from reference scan, and SUVR/DVR, were compared for each model and cohort. The impact of APOE genotype on A+ onset and amyloid PET accumulation trajectories was investigated using discrete rate sample, Kaplan‐Meier curves, and accelerated failure time models.

Result

All methods produced similar amyloid vs. years A+ curves for each cohort (Figure 1) with most notable discrepancies occurring in the A‐ range. DVR/SUVR prediction performance was similar across methods and was better for retrospective vs. prospective prediction. Amyloid accumulation rates and trajectories were similar for APOE‐e4+ and APOE‐e4‐ genotypes (Figure 2). Kaplan‐Meier curves were different between the APOE groups (log‐rank test, p<0.005 for each test; Figure 3), with the e4+ group exhibiting earlier A+ onset ages compared to e4‐ (Table 2) for all methods and cohorts.

Conclusion

This work demonstrates similar performance of three novel methods for modeling longitudinal amyloid PET burden and estimating individualized A+ onset age. Results suggest that APOE‐e4 status affects the A+ onset age, but not the rate of amyloid PET accumulation. Ongoing work is investigating potential differences in amyloid accumulation trajectories and A+ onset age between APOE genotypes (e.g. e3e3, e3e4, e4e4,...) and is investigating relationships between A+ onset, APOE genotype and onset of cognitive impairment.
Alterations in white matter integrity in cognitively stable Down syndrome correlate with plasma neurofilament light chain: Evidence of early myelin breakdown
Authors: Rosas H. Diana , Hasimoglu Yasemin , Mercaldo Nathaniel , Lai Florence , Petersen Melissa , Brickman Adam M. , Keator David , Yassa Michael A. , Lott Ira T , Silverman Wayne , Schupf Nicole , O'Bryant Sid
Published: February 2022

Background

Alterations in white matter (WM) integrity occur in adults with DS during the early stage of dementia. These changes may be documented by diffusion tensor imaging wherein increases in radial diffusivity (RD), a marker of dysmyelination or myelin breakdown, occur in commissural and limbic pathways in DS. Neurofilament light chain (NfL) is a support protein within large, myelinated axons specifically within the cerebral white matter and is released into blood following axonal damage and is increased in DS. In this study, we evaluated the association between plasma NfL concentrations and RD.

Method

Thirty cognitively stable adults with DS from the Alzheimer Disease in Down Syndrome (part of the ABC‐DS) study, (18 M, 12 F: mean age 47.1 years SD 5.2 years), underwent DTI and plasma NfL concentration measurements. Plasma NfL was assayed using the Simoa platform. Diffusion MRI connectometry was conducted using q‐space diffeomorphic reconstruction and a multiple regression model to assess the associations between plasma NfL and white matter radial diffusivity (RD). The Spearman correlation coefficient, and its 95% confidence interval (CI), was used to quantify the monotonic association between plasma NfL and RD.

Result

Consistent with our hypothesis, we found positive associations between plasma NfL and RD increases, in several WM higher order association tracts, including the corpus callosum (0.46, 95% CI 0.11‐0.70, p=0.012), the cingulum bundle (L: 0.62, 0.34‐0.80, p<0.001; R: 0.54 0.23‐0.76, p=0.002) and the uncinate fasciculus (L: 0.17, ‐0.20‐0.50, p=0.367; R: 0.51, 0.18‐0.73, p=0.004).

Conclusion

Our findings support an important link between alterations in WM myelin integrity, particularly of higher order association areas, and axonal degeneration in cognitively stable adults with Down syndrome. These findings support an important role of WM alterations in adults with DS who are at risk for and who develop AD earlier than in sporadic AD cases. WM might provide an important and novel target for intervention. Additional research is needed to understand the underlying neuropathological processes, including the potential contribution of neuronal dysfunction and/or loss to our findings. Acknowledgements: NIH grant U01AG051412. We are grateful to our participants, families, the agencies serving individuals with ID, and our dedicated staff.
Evaluating the properties of intrinsic functional brain networks vulnerable to Alzheimer’s disease during development through connectomics analysis: Preliminary findings from the PRANK study
Authors: Phipps Connor J. , Sexton Jennifer N. , Behm Lillian , DeCesare Thomas A. , Heller Abi M. , Maerlender Arthur C. , Phatak Vaishali S. , Cramer Justin A. , Blair James , Murman Daniel L. , Warren David E.
Published: February 2022

Background

The organization of the brain’s intrinsic functional networks changes during healthy lifespan development, but pathologies such as Alzheimer’s disease (AD) alter the normative trends in functional network organization. Similarly, cognitive abilities such as memory change across the lifespan, but AD pathology causes memory deficits relative to normative expectations. While AD‐related changes in memory and brain networks are often observed in older adults, it is possible that vulnerability to AD is established through differences in early‐life brain and cognitive development including the periadolescent epoch. Here, we used a cross‐sectional approach to study the organization of AD‐vulnerable brain networks and memory in healthy periadolescent children. Data were drawn from the Polygenic Risk of Alzheimer’s Disease in Nebraska Kids (PRANK) study. The goal of our research is to evaluate whether early‐life functional brain development may create vulnerabilities to late‐onset AD.

Method

To better understand the relationship between network properties of the brain and hippocampal‐dependent memory, we studied cognitive and brain measures in a preliminary sample of periadolescent children (N=40) and healthy young adults (N=10) from the PRANK study. Cognitive assessment included a standardized paired associates learning task (CANTAB), a task that requires hippocampal‐dependent relational memory. Brain structure and function were assessed with MRI protocols adapted from the Human Connectome Project. Resting‐state fMRI data was used to measure resting state functional connectivity which supported our investigation of brain network properties. Analysis focused primarily on the measurement of whole‐brain network properties.

Result

We observed differences in brain variables between the PRANK participants and the dataset of healthy young adults. Between‐group differences were observed in modularity scores and other graph theoretical measures of network organization. We also observed relationship between the functional network properties of periadolescent children and their cognitive performance on the CANTAB task.

Conclusion

Our ongoing study measures the association of brain variables, cognitive performance, and AD polygenic risk score in periadolescent children. Our preliminary analysis of brain and cognitive measures illustrate functional network properties of the periadolescent brain with a focus on associations with cognitive performance. Future directions include examining the association between AD polygenic risk score and the same network properties.
Stroke and cardiovascular disease risk exacerbate brain aging among middle‐age and older Hispanics/Latinos: Preliminary findings from the Study of Latinos‐Investigation of Neurocognitive Aging‐MRI (SOL‐INCA‐MRI)
Authors: Stickel Ariana M. , Tarraf Wassim , Gonzalez Kevin A. , Paredes Alejandra Morlett , Zeng Donglin , Cai Jianwen , Isasi Carmen R. , Kaplan Robert , Lipton Richard B. , Daviglus Martha L. , Testai Fenando D. , Lamar Melissa , Gallo Linda C. , Talavera Gregory A. , Gellman Marc D. , Ramos Alberto R. , Gonzalez Hector M. , DeCarli Charles S.
Published: February 2022

Background

Hispanics/Latinos have high prevalence of cardiovascular disease (CVD) risk factors which increases risk for stroke. However, the downstream impacts of CVD risk and stroke on brain structure in aging Hispanics/Latinos remains largely unknown. We compared Hispanic/Latino brain aging by CVD risk and stroke.

Method

Hispanics/Latinos (nunweighted=1,156, 50‐85 years) from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) underwent magnetic resonance imaging (MRI) as part of the Study of Latinos ‐ Investigation of Neurocognitive Aging‐MRI (SOL‐INCA‐MRI) ancillary study. Outcomes included global (gray matter, total brain) and regional (lobar cortices, hippocampal) brain, lateral ventricle (log‐transformed), and total white matter hyperintensity (WMH; log‐transformed) volumes residualized for total cranial volume. Ten‐year CVD risk at visit 2 (before MRI) was determined by Framingham Risk Score and recoded into three groups (Low (<10%), Medium (10‐<20%) and High (20+%)). Stroke (yes, no) was based on self‐report of ≥1 strokes or transient ischemic attacks at visit 1 and/or 2. Linear regression models tested 1) whether CVD risk or presence of stroke modified the relationship between age and MRI outcomes, and 2) whether CVD risk or stroke related brain aging differed by sex. All models adjusted for height and Hispanic/Latino background.

Result

Sample was 64.3± 7.1 years old on average (nunweighted=798 women). High CVD risk was inversely associated with total brain (standardized beta β=–0.26; p<0.001), total gray (β=‐0.23; p=0.006), frontal (β = ‐0.33; p<0.001) and parietal cortical gray (β =‐0.28; p=0.002) matter volumes and positively associated with (log) lateral ventricle (β log=0.23; p=0.006) and (log) WMH (βlog =0.42; p<0.001) volumes. Stroke/TIA (nunweighted=48) showed a similar profile of associations but only the associations with (log) lateral ventricle (βlog=0.27; p=0.049) and (log) WMH (βlog=0.44; p=0.001) reached significance. Accelerated brain aging (age slope modification) through CVD risk and stroke was evident for total brain volume but less so for other MRI outcomes, and equivalently so across sexes.

Conclusion

Among Hispanics/Latinos, CVD risk and stroke are associated with poorer brain health across brain MRI indicators. Additionally, CVD risk and stroke may accelerate overall brain aging for both Hispanic/Latino men and women as determined by total brain volumes.
Characterizing machine learning studies on ADRD caregivers’ social media posts: A systematic review
Authors: Zou Ning , Wang Zhendong , luo Zhimeng , Xie Bo , He Daqing , Hilsabeck Robin C , Aguirre Alyssa B
Published: February 2022

Background

Social media have increasingly been used by ADRD caregivers to share and seek information. An emerging trend in the literature is using machine learning (ML) methods to understand caregivers’ information behaviors on social media. To date no systematic review exists on what ML methods have been used, what the findings are, and what needs to be improved in order to better understand ADRD caregivers’ information behaviors on social media. This systematic review addresses these gaps in the literature.

Method

Following the PRISMA guidelines, during October and November 2020, we performed three rounds of screening. First, we searched predetermined keywords in ACM Digital Library, IEEE Xplore Digital Library, and PubMed. This step generated 324 results. After removing 92 articles that were not peer‐reviewed journal/conference proceedings and 2 duplicate articles, 230 results remained. Next, we screened the titles and abstracts of the 230 articles using predetermined inclusion/exclusion criteria; 200 articles were excluded, and 30 remained. Finally, we screened the full text of the 30 articles to ensure that they met the inclusion/exclusion criteria; 12 articles were excluded, leaving a final sample of 18 studies for analysis.

Result

All 18 studies covered at least two of the three focal areas: ADRD, ML, and social media; only 6 covered all three areas. Study aims of these 18 studies were in two groups: 1) 4 papers focused on characterizing ADRD caregivers’ behaviors on social media; and 2) 14 papers aimed to build ML models to predict ADRD related activities. Twitter was the data source for 14 studies; other sources included Reddit, Youtube, Weibo, and AskaPatient. The key features for modeling ADRD related activities included semantic representations of post content, positive/negative sentiments, and network structures representing posting/answering activities.

Conclusion

ML provides promising tools for extracting useful information from large amounts of social media posts about ADRD caregivers’ information behaviors. Research in this area is still at its infancy, and much more attention is needed to understand how ML methods can be best utilized. Due to the interdisciplinary nature of the task, effective collaborations leveraging expertise from health sciences, information science and social sciences will be critical.