bluuebunny/crossref_metadata_2025 huggingface dataset:
Longitudinal PET imaging identifies earliest stages of Aβ accumulation in Down syndrome
Authors: Zammit Matthew D. , Tudorascu Dana L. , Laymon Charles M. , Cohen Ann D. , Zaman Shahid , Ances Beau M. , Hartley Sigan L. , Johnson Sterling C. , Stone Charles K. , Mathis Chester A. , Klunk William E. , Handen Benjamin L. , Christian Bradley T.
Published: February 2022

Background

Adults with Down syndrome (DS) are genetically predisposed to Alzheimer’s disease (AD) and accumulate beta‐amyloid plaques (Aβ) early in life. Our previous work in this population comparing centiloids and amyloid load (AβL) identified an amyloid‐positive cutoff of 20 AβL. The aim of this study was to evaluate longitudinal AβL change across DS groups based on Aβ status.

Method

175 adults with DS (age=39.8 (8.64) years) were recruited through the Alzheimer’s Biomarker Consortium ‐ Down Syndrome study. Of the 175 adults, N=79 underwent up to four longitudinal [C‐11]PiB scans (2.64 (0.71) years apart). Longitudinal Aβ change was calculated for each individual using AβL. Cluster analysis identified a group of A‐ individuals with significant Aβ increase at subthreshold detection levels, and was used to inform a subthreshold A+ cutoff. Rates of AβL change were compared across groups of A‐ (AβL < 13.3), subthreshold A+ (13.3 < AβL < 20) and A+ (AβL > 20) DS. Average SUVr images were then generated across all participants for each group and SUVrs were extracted to evaluate regional Aβ burden.

Result

The A‐ group showed longitudinal change of 0.32 (0.66) AβL/year, while the subthreshold A+ and A+ groups showed change of 2.60 (1.11) and 3.22 (1.26) AβL/year, respectively (Figure 1). AβL change was statistically different across all groups (ANCOVA F = 76.7, p < .0001) while adjusting for imaging site. Post hoc Student’s t‐tests revealed that the subthreshold A+ and A+ groups had significantly greater AβL change compared to the A‐ group (Bonferroni‐adjusted p < .0001). No significant difference in AβL change was observed between the subthreshold A+ and A+ groups. Figure 2 displays the average SUVr images for each Aβ group. Relative to the A‐ group, the subthreshold A+ group showed greater regional Aβ burden (Table 1).

Conclusion

DS adults with a subthreshold A+ classification showed indistinguishable rates of Aβ change compared to those who are conventionally A+, suggesting that longitudinal PET imaging can identify significant Aβ change early during AD progression. These longitudinal findings can inform sample size estimates for AD clinical trials aimed at early intervention in this population.
Association between the Harvard automated phone task and Alzheimer’s disease pathology in clinically normal older adults
Authors: Gonzalez Christopher , Premnath Pranitha Y. , Kuppe Madeline K. , Fitzpatrick Colleen D. , Properzi Michael J. , Becker Alex , Johnson Keith A. , Rentz Dorene M. , Gatchel Jennifer R. , Vannini Patrizia , Amariglio Rebecca E. , Marshall Gad A.
Published: February 2022

Background

With the advent of prevention trials in preclinical Alzheimer’s disease (AD), evaluating novel and sensitive methods to measure instrumental activities of daily living (IADL) is becoming increasingly important in order to detect these clinically meaningful changes at the earliest stages of disease. The objective of the current exploratory study was to examine the cross‐sectional relationship between a phone performance‐based IADL test, the Harvard Automated Phone Task (APT), and regional cerebral tau and cortical amyloid burden in clinically normal (CN) older adults.

Method

Thirty‐one CN participants (mean age 70.0 (SD 4.8), 70% female) underwent flortaucipir (FTP) tau and Pittsburgh Compound B (PiB) amyloid positron emission tomography (PET). IADL were assessed using the 3 Harvard APT tasks: refilling a prescription (APT‐Script), calling the health insurance company to select a new primary care physician (APT‐PCP), and making a bank account transfer and payment (APT‐Bank). Linear regression models were used in the primary analyses to determine the associations between each APT task rate (correct responses/time) as the dependent variable and cortical amyloid aggregate, entorhinal cortex, inferior temporal, or precuneus tau as predictors of interest in separate analyses. In secondary analyses, models were repeated with an interaction between cortical amyloid and regional tau. Analyses included age, sex, and education as covariates.

Result

A significant association was found between the APT‐Script rate and entorhinal cortex tau (β=‐0.08, 95% CI=‐0.14, ‐0.21, t value=‐2.78, p=0.01). No significant associations were found between other APT tasks and amyloid and tau regions. Additionally, no significant associations were found with the interaction between amyloid and tau regions.

Conclusion

Our preliminary findings suggest an association between a region of early tau accumulation in CN adults, the entorhinal cortex, and a real‐life IADL test. Moreover, APT‐Script task was more normally distributed, and had overall larger variability compared to the other two tasks, suggesting that it may be a more sensitive IADL measurement in CN individuals. Further analyses should explore this relationship in larger samples and longitudinally in order to determine whether the Harvard APT can serve as a reliable IADL outcome measure for preclinical AD prevention trials and ultimately in the clinic setting.
Neuropsychological correlates of plasma NfL in adults with Down syndrome
Authors: Carmona‐Iragui Maria , Videla Laura , Benejam Bessy , Valldeneu Sílvia , Barroeta Isabel , Altuna Miren , Fernandez Susana , Garzón Diana , Padilla Concepción , Iulita M. Florencia , Bejanin Alexandre , Alcolea Daniel , Blesa Rafael , Lleó Alberto , Fortea Juan
Published: February 2022

Background

The diagnosis of symptomatic Alzheimer’s disease (AD) in Down syndrome (DS) is challenging, mainly because the variability in cognitive performance associated with the different levels of intellectual disability. Plasma NfL levels are a promising biomarker of axonal damage with good diagnostic and prognostic performance, but its impact on cognitive performance has not been assessed. We aimed to explore this association between NfL levels and both baseline cognitive performance and the longitudinal cognitive decline.

Method

Prospective longitudinal cohort study. We included adults with DS from the Down Alzheimer Barcelona Neuroimaging Initiative cohort with mild and moderate levels of intellectual disability (ID) who had available plasma and a neuropsychological evaluation (Cambridge Cognitive Examination for Older Adults with Down's syndrome [CAMCOG‐DS] and/or modified Cued Recall Test [mCRT]). Plasma NfL levels were determined by Simoa SR‐XTM. We performed correlation analysis between baseline NfL levels and cognitive scores and linear mixed models to account for longitudinal cognitive measures. Age, sex and cognitive status (asymptomatic, prodromal AD, AD dementia) were considered as co‐variables in the analysis. The analyses were stratified in mild and moderate ID separately.

Result

We selected 378 individuals (mean age: 43.1 [sd 10.9], 46.6% female): 287 had CAMCOG‐DS scores and 224 had mCRT scores. We observed a significant correlation between baseline NfL levels and both CAMCOG‐DS and mCRT (R2=0.18 and R2=0.30, respectively, both p<0.001) (Figure). This correlation remained significant after stratification by ID (R2=0.17 and R2=0.19 for mild ID, R2=0.19 and R2=0.32 for moderate ID, all p<0.001). There was a significant association between longitudinal cognitive scores and baseline NfL levels (β=‐0.0035, p=0.011 for CAMCOG‐DS; β=‐0.015, p<0.001 for mCRT).

Conclusion

Cognitive performance is inversely correlated to plasma NfL levels in adults with DS. This study supports the potential role of plasma NfL levels to identify and track AD‐related cognitive decline in DS.
Exploring the ATN classification system using brain morphology
Authors: Heinzinger Nils , Maass Anne , Yakupov Renat , Schütze Hartmut , Spottke Annika , Ramirez Alfredo , Schneider Anja , Metzger Coraline D. , Laske Christoph , Bittner Daniel , Brosseron Frederic , Priller Josef , Wiltfang Jens , Buerger Katharina , Fließbach Klaus , Heneka Michael T. , Peters Oliver , Speck Oliver , Nestor Peter J. , Teipel Stefan J. , Pross Verena , Glanz Wenzel , Wagner Michael , Jessen Frank , Düzel Emrah , Ziegler Gabriel
Published: February 2022

Background

The NIA‐AA proposed ATN (Amyloid/Tau/Neurodegeneration) as a classification system for AD pathology. The Amyloid Cascade Hypothesis (ACH) implies a sequence across ATN groups that patients might undergo during transition from healthy towards AD: A‐T‐N‐→A+T‐N‐→A+T+N‐→A+T+N+. Here we assess the evidence for monotonic brain volume decline for this particular (Amyloid‐conversion first, Tau‐conversion second, N‐conversion last; therefore ‘ATN’) and alternative progressions (ANT, TAN, TNA, NAT, NTA) using Voxel‐based Morphometry (VBM) of brain anatomy in a large MRI sample.

Method

We used the DELCODE cohort of 437 subjects (49% female) which underwent lumbar puncture, MRI scanning and neuropsychological assessment. ATN classification was performed using (A+/‐) CSF‐Abeta42over40, (T+/‐) CSF‐phospho‐Tau, and (N+/‐) adjusted hippocampal volume. We compared voxel‐based model evidence for monotonic decline of gray matter volume across various sequences over ATN groups accounting for age, sex, education, TIV and WMH. The evidence of each progression was assessed using the Bayesian Information Criterion on voxel‐ and ROI‐level. First, face validity of the ACH transition trajectory A‐T‐N‐→A+T‐N‐→A+T+N‐→A+T+N+ for VBM was compared against 23 biologically less plausible (permuted) sequences among AD‐continuum ATN groups. Then we evaluated the evidence for 6 brain volume progressions from A‐T‐N‐ towards A+T+N+ (ATN, ANT, TAN, TNA, NAT, NTA) including also non‐AD continuum ATN groups.

Result

The ACH‐based progression A‐T‐N‐→A+T‐N‐→A+T+N‐→A+T+N+ is in line with cognitive decline and clinical diagnosis (Figure 1&2). It also has highest evidence in 9% of the gray matter voxels (especially MTL; Figure 3&4). Many (especially cortical) regions were compatible with alternative non‐monotonic volume progressions (‘AP 1’: 16%, ‘AP 2’: 14%; see Figure 3) over ACH progression sequence, compatible with early amyloid‐related tissue expansion or sampling effects due to brain‐reserve (Figure 5). Volume decline in 65% of voxels was more compatible with ATN/ANT progression (A flips first) when compared to alternative sequences (TAN, TNA, NAT, NTA).

Conclusion

Early Amyloid status conversion (before Tau and Neurodegeneration) is compatible with brain volume loss observed during AD progression. The ATN classification and the ACH are compatible with monotonic progress of MTL atrophy.
Neural correlates of executive functions in people with amnestic mild cognitive impairment
Authors: Lejko Nena , Tumati Shankar , Opmeer Esther M. , Marsman Jan‐Bernard C. , Reesink Fransje E. , De Deyn Peter Paul , Aleman André , Ćurčić‐Blake Branislava
Published: February 2022

Background

People with amnestic mild cognitive impairment (aMCI) often experience difficulties in cognitive domains other than memory, including executive functioning. Though these deficits are well documented, their neural correlates remain unknown. The aim of this study was to: (1) identify differences in brain activity and connectivity during planning in people with aMCI and cognitively healthy older adults, and (2) find whether planning‐related activity and connectivity are associated with cognitive performance.

Method

Twenty‐five people with aMCI (67.6 ± 5.2 y, 6 F, 3 left‐handed) and 15 cognitively healthy older adults (66.4 ± 4.3 y, 5 F, all right‐handed) performed a visuospatial planning task (Tower of London; ToL) during functional magnetic resonance imaging (fMRI). Task‐related brain activation and connectivity were compared between the two groups and regressed against measures of executive functions (Digit Symbol Substitution Test, DSST; Trail Making Test difference score, TMT B‐A) and delayed recall (Rey Auditory Verbal Learning). All fMRI analyses were controlled for scores on the Geriatric Depression Scale, the Apathy Evaluation Scale, the DSST, and the TMT B‐A, and corrected for multiple comparisons at cluster‐level.

Result

As expected, people with aMCI had significantly poorer delayed recall than cognitively healthy older adults (F = 15.8, p < 0.0001). They also scored worse on the DSST (F = 5.5, p = 0.025) and the TMT B‐A (U = 77.5, p = 0.012), and were less accurate on the ToL task (F = 10.7, p = 0.002).

During planning, people with aMCI had less activation in two clusters, both located in the precentral gyrus (p = 0.013 and p = 0.047). Across all participants, better performance on the DSST was associated with stronger anti‐correlation between a seed in the left middle frontal gyrus and a cluster in bilateral frontal poles (p = 0.012).

Conclusion

Impaired planning in people with aMCI appears to be underpinned by less activation in areas associated with sequence planning and visuospatial attention. Interestingly, more negative connectivity between the left middle frontal gyrus and frontal areas involved in working memory and task flexibility was associated with better performance on a task of executive functions.
7T locus coeruleus imaging correlates of apathy and cognition in patients with Parkinson’s disease and progressive supranuclear palsy
Authors: Ye Rong , O'Callaghan Claire , Rua Catarina , Hezemans Frank H. , Holland Negin , Malpetti Maura , Jones P. Simon , Passamonti Luca , Rowe James B.
Published: February 2022

Background

Apathy is a common neuropsychiatric feature of both Parkinson’s disease and progressive supranuclear palsy (PSP) (Aarsland, et al., 2001). Early neuropathology in the locus coeruleus (LC) and consequent noradrenergic deficiency are proposed to be key contributors to the pathogenesis of apathy (Passamonti et al., 2018). Here we test the hypothesis that in vivo LC integrity measured by ultra‐high field 7T‐MRI is predictive of apathy in Parkinson’s disease and PSP.

Method

Sixty‐three participants aged 50‐80 years were recruited: 25 people with idiopathic Parkinson’s disease, 14 patients with PSP Richardson’s syndrome and 24 age‐ and sex‐matched healthy controls (HC). Patients underwent clinical assessments for apathy, impulsivity, global cognition, motor severity, mood and sleep (Figure 2A&B). The LC was measured in vivo using a sensitive magnetisation transfer (MT) weighted sequence with ultra‐high 7T‐MRI (0.1mm3 voxels). The contrast‐to‐noise ratio of an atlas‐based signal was used to estimate the LC structural integrity (Ye et al., 2021). The LC integrity was correlated with clinical assessments. To estimate the spatial extent of the correlation within LC, voxelwise analyses used FSL randomise for localising the group differences and the clinical correlations.

Result

Reduced LC integrity was observed along the rostrocaudal axis for both PD and PSP patients, most prominently in the caudal subregion (Figure 1A‐D). This was confirmed by significant voxelwise comparisons between the patient groups and controls (HC>PD, right caudal LC, 37 voxels; HC>PSP, bilateral caudal LC, 206 voxels; FWE‐corrected p<0.05), Figures 1E&F. Patients with PSP and PD showed similar levels of LC degeneration relative to controls, but this was more spatially widespread in PSP. The variability of LC integrity in both disease groups was associated with ACER, MoCA and apathy (Figure 2C&D). Distinctive spatial patterns were identified for the correlations, with the caudal LC consistently associated with cognitive impairment and apathy.

Conclusion

Reduced LC integrity was confirmed in both PD and PSP using in vivo 7T‐MRI. LC degeneration, particularly in the caudal subregion, was associated with apathy and cognitive impairment. Our results suggest, noradrenergic therapies may be beneficial in targeting cognitive and behavioural features of Parkinson’s disease and PSP.
Effect of APOE4 and APOE2 genotype on white matter microstructure
Authors: Nir Talia M. , Nabulsi Leila , Lawrence Katherine E. , Villalon‐Reina Julio E. , Abaryan Zvart , Gari Iyad Ba , Zhu Alyssa H. , Haddad Elizabeth , Muir Alexandra M. , Thompson Paul M. , Jahanshad Neda
Published: February 2022

Background

The apolipoprotein E4 (APOE4) genotype is a major risk factor for late‐onset Alzheimer’s disease (AD). APOE2, on the other hand, has a protective effect. While there is evidence supporting an association between APOE genotype and white matter (WM) microstructure, findings have been inconsistent. Studies assessing AD risk in WM microstructure have largely used diffusion tensor imaging (DTI), but more recent diffusion MRI models may offer additional sensitivity to microstructural properties. Here, we characterized the effects of APOE4 and APOE2 genotypes on WM microstructure in a large, population‐based sample of adults from the UK Biobank.

Method

Diffusion MRI data from 17,896 UK Biobank participants (age range: 45‐80 years; Fig 1a) were analyzed. Ten diffusion measures were derived from 4 models: 1) DTI, 2) the tensor distribution function (TDF), 3) mean apparent propagator MRI (MAPMRI), and 4) neurite orientation dispersion and density imaging (NODDI). Each measure was averaged across voxels within 25 WM regions (Fig 1c). Linear regressions were used to compare regional measures between individuals with an E3E3 genotype and E4 (E3E4+E4E4) or E2 (E2E3+E2E2) carriers, adjusting for age, sex, age‐by‐sex interaction, education, parents with dementia, and the first four genetic ancestry principal components. E4 or E2 carrier‐by‐age interactions were also tested, covarying for APOE genotype. FDR (q=0.05) was used to correct for multiple comparisons across 25 regions.

Result

Compared to E3E3 carriers, E4 carriers showed widespread, yet subtle WM differences (Fig 2). The largest effects were detected with signal‐based model measures that reflect increased mean diffusivity (higher DTI‐MD, higher MSD, lower TDF‐FA). Significant E4‐by‐age interactions were detected with NODDI‐ISOVF, with E4 carriers showing a greater age‐related increase in ISOVF (Fig 3). Compared to E3E3 carriers, E2 carriers showed higher NODDI‐ICVF throughout the WM; differences were not detected with other measures. No significant E2‐by‐age interactions were detected (Fig 4).

Conclusion

APOE4 carriers showed microstructural WM differences in measures reflecting less restricted diffusion, which could indicate neuronal loss or inflammation, particularly in posterior WM. Age‐dependent APOE4 effects were only detected with multi‐compartment diffusion measures. Greater neuronal density in APOE2 carriers may suggest a protective effect in WM, which was also detectable only with a multi‐compartment model.
Sex‐specific cerebral blood flow trajectories in mouse models of Alzheimer’s disease
Authors: Zhao Yifan , Jin Tao , Fitz Nicholas F. , Koldamova Radosveta , Vazquez Alberto L. , Iordanova Bistra
Published: February 2022

Background

Alzheimer’s disease (AD) therapies targeting the aggregation of amyloid‐beta during the late stages have been largely unsuccessful. Growing evidence indicates that cerebral blood flow (CBF) plays a key role during the early AD stages by limiting the energy supply to the brain and impairing the clearance of harmful metabolites1. Recent studies suggest that CBF can be used as a predictor of AD2. Despite the CBF potential as a biomarker, its sex‐specific changes during AD progression are still poorly characterized. In the present study we quantify CBF trajectories in male and female mouse model of AD across lifespan. We also measure the tissue plaques and the vascular deposits in the form of cerebral amyloid angiopathy (CAA) to assess their relationship with CBF.

Method

We used 9.4T MRI of APPswe.PSEN1dE9 mice (12 male,10 female, 6‐24 months) and matched controls (n=15). We quantified CBF (qCBF) using T1‐weighted mapping (TE=12ms, TR=10 sec, 9 inversion times between 15‐8000ms and continuous arterial spin labeling (CASL) with TE=0.32ms and TR=2625ms with a label offset 12mm, duration 2.4s. Both had 64×64 matrix with 210 μm/voxel. We computed qCBF as previously described.3 Smooth muscle actin (SMA) and X34 staining was performed on free floating sections. Two‐way ANOVA was used to evaluate the age and sex effects on parenchymal plaques, CAA and qCBF.

Result

We found CBF to be significantly reduced in AD mice compared to controls (Fig 1, t‐test p=0.00017). Two‐way ANOVA showed a significance in the effects of sex and AD as factors on CBF (p=0.015) and an impact of both sex and age on the tissue plaque accumulation (Fig 2A), CAA was affected by age, with trend for higher CAA in females (Fig 2B), particularly after 13 months when qCBF declined.

Conclusion

When interpreting blood flow as AD biomarker both age and sex should be taken into consideration. The accumulation of tissue and vascular plaques appears to occur at different rates and depends both on age and sex. Further studies are needed on the CAA and CBF interaction and the sex‐specific vascular contributions to AD onset and progression. 1.Kisler et al. (2017). 2.Iturria‐Medina et al. (2015). 3.Zhang et al. (1992).
Association of Hispanic/Latino background and brain structure in Hispanics/Latinos from the SOL‐INCA MRI study
Authors: DeCarli Charles S. , Tarraf Wassim , Gonzalez Kevin A , Stickel Ariana M , Fletcher Evan M , Knaack Alexander , Maillard Pauline , Gallo Linda C , Daviglus Martha L , Testai Fenando D , Isasi Carmen R , Schneiderman Neil , Sofer Tamar , Fornage Myriam , Gonzalez Hector M
Published: February 2022

Background

The Hispanic Community Health Study/Study of Latinos (HCHS/SOL) is a representative, community‐based study of Hispanics and Latinos across the US that seeks to understand health disparities within this heterogeneous population. The Study of Latinos ‐ Investigation of Neurocognitive Aging MRI (SOL‐INCA MRI) is an ancillary MRI study to HCHS/SOL focused on the genetic influence and cognitive impact of age‐ and disease‐related brain measures. Brain structure undergoes substantial development and remodeling from birth through adulthood. Intracranial volume is a measure of maximum brain development, which is under substantial genetic and environmental influences, and is an independent marker of cognitive resilience. We report the influence of self‐described background on intracranial volume, brain tissue and cortical thickness measures for 1388 individuals studied to date.

Method

Hispanics and Latinos (ages 35.9‐85.2 years; 66% female) underwent MRI and analysis at the Imaging of Dementia and Aging (IDeA) laboratory using previously published methods. MRI outcomes of interest included supratentorial intracranial volume (TCV), image segmentation into white matter, gray matter, total brain, and regional cortical thickness. Background was categorized as Cuban, Central American, Dominican, Mexican, Puerto Rican and South American. We performed association analysis using linear regression models accounting for sex, height, background, and their interactions.

Result

Height was positively associated with TCV. Women had significantly smaller TCV than men (Table 1). TCV did not vary significantly with age. After adjusting for age, gender, height, and interactions, TCV measures varied significantly by background, and were greatest for Dominicans. Cuban’s and Mexican’s TCV measures were significantly smaller than Dominican’s (Figure 1). Cerebral gray matter volume as a residual of TCV was also significantly greater for Dominicans as compared to all other backgrounds (Table 2). Residuals of brain, gray and white matter varied significantly across backgrounds (Figure 2). Finally, cortical thickness measures varied significantly by background and brain region, being greatest for both Dominicans and Puerto Ricans (Figure 3).

Conclusion

Brain development results from multiple factors including gene, environment, and gene‐environment interactions. Investigating the genetic and environmental causes of the heterogeneity of brain measures in SOL‐INCA‐MRI are likely to lead to discoveries related to both brain development and possibly brain aging.
Investigating the effects of antihypertensive medication use in AD patients using multi‐modal neuroimaging
Authors: Dake Manmohi D , Marco Matteo , Soininen Hilkka , Venneri Annalena
Published: February 2022

Background

Hypertension is a known risk factor for Alzheimer’s disease (AD). Both conditions cause significant irreversible damage to cerebral constituents that can result in a more severe AD phenotype. Although there are no effective treatments available for AD, hypertension is a modifiable risk factor and its detrimental effects can be alleviated with antihypertensive drug treatments and through primary prevention.

Method

Patients with mild to moderate AD (N = 133) were divided into two groups to examine differences in cerebral constituents and cognitive function in patients who were medicated (n = 71) and unmedicated (n = 62) for hypertension. Within the medicated patient group, a post hoc analysis was conducted to examine differences in patients based on the class of antihypertensive treatment. We used multi‐modal neuroimaging to explore these differences in cerebral blood flow (CBF), white matter integrity, grey matter volume (GMV) and vascular burden.

Result

No differences were detected between the medicated and unmedicated AD patients in the multi‐modal comparisons, although the medicated group showed a slightly better cognitive profile than the unmedicated group, despite having a higher burden of cardiovascular comorbidities and similar blood pressure readings to the unmedicated group. In the post hoc analysis, AD patients who were on beta‐blockers only, presented with higher GMV, CBF and neuropsychological scores and also a lower vascular burden compared to AD patients on other classes of antihypertensive treatment or a combination of the two. In the post hoc analysis of the unmedicated AD patient subgroup, variability in pulse pressure (the difference between systolic and diastolic blood pressure) was linked with lower CBF in subcortical structures.

Conclusion

The use of antihypertensive treatment in AD could mitigate progression of damage to cerebral constituents related to chronically elevated blood pressure. The class of antihypertensive treatment used has varied effects on cerebral constituents in AD patients, pointing towards the need for future longitudinal studies exploring these effects. Evidence from this study also suggests that implementation of antihypertensive treatment could be beneficial in AD patients with uncontrolled hypertension. Measures to promote early identification of comorbidities and targeted interventions could thus help reduce AD severity in patients.
A case with early onset Alzheimer’s disease with amyloid uptake not only in cerebrum but also in cerebellum
Authors: Lee Sunju , Jo Sungyang , Kim Hyung‐Ji , Lee Jae‐Hong
Published: February 2022

Background

Amyloid positron emission tomography (PET) imaging is appropriate for patients with atypical presentation, unusually rapid course and very early onset of dementia. Standardized uptake value ratios (SUVr) are used for relative quantification of 18F‐florbetaben (18F‐FBB) PET scans and cerebellar cortex can be used as reference region for quantification. Previous study showed that 18F‐FBB PET demonstrated a diffuse cortical uptake and in particular an intense uptake in the basal ganglia in familial Alzheimer’s disease with presenilin‐1(PS‐1) mutation.

Method

This report describes the case of a young woman with early‐onset familial Alzheimer’s disease(EOfAD), who has atypical pattern of uptake on amyloid PET.

Result

A 37‐year‐old woman with a college level educational background was brought in by her family for further evaluation of cognitive impairment, personality and behavioral changes. At age 30 years of age, the patient presented memory impairment and she had difficulty serving guests in bakery. Patient had positive family history of early onset dementia; her father, grand mother, and two sisters of grand mother. (Fig. 1 Pedigree showing autosomal dominant inheritance trait of early‐onset dementia. (nn/nn) Age at onset/age at death). She had an initial Mini‐Mental State Examination score of 22/30 (time disorientation, dyscalculia, poor delayed recall). Neuropsychological assessment showed global cerebral dysfunction and revealed dementia with psychiatric symptoms. Brain magnetic resonance imaging showed no significant abnormality. On genetic testing, homozygotes for the apolipoprotein E ε3 allele and a PS‐1 mutation (c.616G>A , p.G602S) was identified. 18F‐FBB PET revealed diffusely increased amyloid deposition including not only bilateral frontal, parietal, posterior cingulate gyrus/precuneus, anterior striatum but also bilateral cerebellar cortex. (Fig. 2 18F‐florbetaben PET, at age 37)

Conclusion

This will be the first case report of EOfAD with increased bilateral cerebellar cortical uptake on 18F‐ FBB PET, we present the case to increase awareness of this unusual entity.
Progression in WMH volume is accompanied by higher gray matter loss: One‐year follow‐up MRI study in TATA Longitudinal Study on Aging Cohort of India
Authors: Tiwari Vivek , Rao Naren P. , M.L. Abhishek , Ravindranath Vijayalakshmi
Published: February 2022

Background

Small vessel disease pathologies such as white matter hyperintensity (WMH) and loss in neuroanatomical volumes with aging have been investigated across various cross‐ sectional and longitudinal‐aging studies in different parts of world. However, it is yet not extensively investigated whether the changes in WMH kinetics over the period impacts the neuroanatomical health? Here, we have measured changes in WMH and neuroanatomic‐volumes, in an ongoing longitudinal study on aging in India called TATA longitudinal study on aging (TLSA), at the baseline and one‐year‐follow‐up visit. The TLSA‐study is a prospective, community‐based, cohort study that comprises of cognitively healthy, educated, and multilingual individuals of both genders aged ≥45 years. The subjects are recruited from urban‐Bangalore, a large metropolitan city in southern India.

Method

MRI measurements were conducted on 3T whole‐body‐scanner. MRI study performed close to the first clinical and cognitive‐examination is termed as baseline visit (V0), while MRI close to one‐year follow‐up is termed as V1. T2w‐FLAIR, 3D‐MPRAGE and DWI MRI were performed at both V0‐ and V1‐visits. WMH was quantified using T2w‐FLAIR and MPRAGE‐T1w images. Anatomical volumes were determined using Freesurfer. The volumes were normalized to the total‐intracranial‐volume. Changes in WMH and anatomic volume were calculated as (Volume at V1 – Volume at V0).

Result

Changes in WMH and neuroanatomic volumes were evaluated for 128‐subjects who had MRI at both the visits, V0 and V1. Quantification of change in WMH (Delta‐WMH) in the TLSA‐subjects revealed that 65% of the subjects showed progression in WMH‐volume while another 35% did not show WMH‐progression. This indicated that there is a subset of cohorts that showed progression in WMH volume (+0.5‐7.9 ml) while another subset of subjects had no change in WMH over the period. Segmentation of neuroanatomical‐volume showed that the subset of the cohort that showed WNH‐progression over the one‐year period had significantly larger reduction in gray‐matter and increase in CSF volume at V1 compared to another subset that did not had changes in WMH.

Conclusion

Progression in WMH may be associated with increased vascular insult to the brain resulting in substantial gray‐matter loss and ventricular increase. Increase in WMH volume may fasten the neuroanatomic deteriorations with aging.
The experiences of apathy in people with dementia and mild cognitive impairment and their carers: A qualitative interview study
Authors: Burgon Clare , Goldberg Sarah , van der Wardt Veronika , Harwood Rowan H
Published: February 2022

Background

Apathy, defined as reduced goal‐directed activity, social engagement and emotion, is highly prevalent in dementia and Mild Cognitive Impairment (MCI), and has important consequences for the individuals that experience it and those who care for them. However, the lived experiences of this population is not well understood. This study aimed to explore how people with dementia and MCI and their carers experience apathy.

Method

People with early dementia and MCI living in four geographical areas of England were invited to take part in a qualitative interview. All participants had capacity to give informed consent. In‐depth semi‐structured interviews were conducted with fourteen people with dementia or MCI and carer dyads, and two participants without a carer present. Patient’s mean age was 76 years, Montreal Cognitive Assessment score was 20, and five were female. Interviews, conducted in the participant’s homes, lasted between 38 and 115 minutes, were audio‐recorded and transcribed verbatim. Reflexive thematic analysis was used to analyse the data.

Result

Findings were organised into two connected themes: ‘The struggle of everyday life is not worth it’ and ‘Threatened identity: changing sense of self and place in the world’. Participants’ everyday lives required more effort and were a “struggle” due to cognitive and physical impairments. This could make the effort to engage, act, and maintain interest not worth it, resulting in apparent apathy. Motivation to stay engaged despite difficulty was influenced by the accessibility of opportunities, and support from others. Participants views of their (past) autonomous and competent self were challenged by the changes they experienced. Participants sometimes focused on their present capabilities, and did what they were still able, whilst others found changes difficult to accept and withdrew from situations which challenged their sense of self.

Conclusion

Apathy is experienced as a response to the everyday difficulties participants faced, which could be exacerbated by lack of support and opportunities. This is in contrast to the popular view of apathy as a symptom of neurodegenerative changes that occur in dementia. Our findings echo those of qualitative research in people with Parkinson’s Disease (Simpson et al., 2014).
Dementia with Lewy bodies subtypes identified by cluster analysis on structural MRI
Authors: Inguanzo Anna , Poulakis Konstantinos , Mohanty Rosaleena , Schwarz Christopher G. , Przybelski Scott A. , Lemstra Afina W. , van de Beek Marleen , van der Flier Wiesje M , Barkhof Frederik , Blanc Frédéric , de Sousa Paulo Loureiro , Philippi Nathalie , Cretin Benjamin , Demuynck Catherine , Nedelska Zuzana , Hort Jakub , Segura Barbara , Junqué Carme , Oppedal Ketil , Aarsland Dag , Westman Eric , Kantarci Kejal , Ferreira Daniel
Published: February 2022

Background

Dementia with Lewy bodies (DLB) is a neurodegenerative disorder that presents with a variety of clinical symptoms. Part of the clinical heterogeneity within DLB has been related to the atrophy/sparing of the hippocampus. We extended that previous research by investigating whether different atrophy patterns exist in DLB, beyond and above the atrophy/sparing of the hippocampus, and whether those patterns contribute to the clinical heterogeneity in DLB. We aimed to identify DLB atrophy subtypes using a hypothesis‐free data‐driven clustering approach based on regional gray matter (GM) volumes and characterize the resulting subtypes across key measures.

Method

We included data from three centers of the European DLB consortium. A high‐resolution 3D T1‐weigthed magnetization prepared rapid gradient echo (MPRAGE) sequence was acquired for 97 DLB patients. Eighty‐four cortical regions and 12 subcortical regions from Mayo Clinic Adult Lifespan Template (https://www.nitrc.org/projects/mcalt/) atlases were obtained. Clusters of DLB patients were then determined using the random forest method. Between‐group differences in key demographic, clinical, MRI volumes and cerebrospinal fluid biomarkers (CSF) (amyloid‐beta, phosphorylated‐tau) were performed for clusters characterization.

Result

We identified three subtypes of DLB patients, with distinct patterns of GM volumes and differences in several clinical and demographic measures. Cluster 1 (C1) included 32 DLB patients (33%), cluster 2 (C2) included 29 DLB patients (30%), and cluster 3 (C3) included 36 DLB patients (37%). The clusters differed in age, with C1 being significantly older (72±8.6) than C3 (66±9.5) (F=3.93, p=0.02). C1 was characterized by lower volumes in fronto‐temporal regions and had a higher frequency of visual hallucinations (68%, vs. C2 35%). C2 showed lower volumes in occipital regions. C3 had higher GM volumes overall compared with the other two clusters and presented with a higher frequency of cognitive fluctuations (91%, vs. C1 67%). There were no differences between groups in CSF biomarkers. These results were independent of cluster differences in age and global GM volume.

Conclusion

There are distinct patterns of brain atrophy in patients with DLB. These patterns seem to differentially contribute to the frequencies of visual hallucinations and cognitive fluctuations, independently of differences in age and global GM volume across subtypes.
The influence of known pathogenic gene mutation and ApoEε4 on neuropsychological evaluation and imaging markers in preclinical stage of familial Alzheimer’s disease
Authors: Quan Meina , Jia Longfei , Tang Yi , Wang Qi , Zhao Tan , Qiu Qiongqiong , Yang Jianwei , Wang Wei , Qin Qi , Wang Yan , Li Wenwen , Xu Hui , Gong Min , Li Fangyu , Li Tingting , Cao Shuman , Li Xinyue , Wang Qigeng , Lu Jie , Jia Jianping
Published: February 2022

Background

In the preclinical stage of familial Alzheimer's disease (FAD), there have been changes in multi‐dimensional indicators, such as pathology, neuropsychology and imaging. This study explored the effects of known pathogenic gene mutation and ApoE on neuropsychology and imaging markers before the appearance of FAD symptoms.

Method

102 cases of asymptomatic mutation non‐carriers (26 cases of ApoEε4) and 38 cases of asymptomatic mutation carriers (17 APP, 21 PS1) in FAD families were assessed by a series of neuropsychological scales, including mini mental state scale (MMSE), auditory verbal learning test (AVLT), etc. MRI images were collected. The volume of representative brain regions was obtained, including subregions of striatum, hippocampus, rostral middle frontal gyrus (rMFG), and posterior cingulate cortex (PCC). Diffusion indices and functional connectivity (FC) of neural pathways (striatum subregions to rMFG, hippocampus to PCC) were also obtained. The neuropsychological scores and imaging indexes were compared between groups, and the imaging indexes with group differences were further correlated with neuropsychological scores.

Result

Compared with asymptomatic mutation non‐carriers, APP group showed a trend increase in delayed recall score in AVLT (P = 0.08), significantly increased cued recall score, and increased radial diffusivity (RD) of bilateral caudate‐rMFG pathway (fig 1, P's < 0.05). In asymptomatic mutation non‐carriers, compared with APOEε4 non‐carriers, APOEε4 carriers showed increased right hippocampal volume, decreased fractional anisotropy (FA) of bilateral hippocampus‐PCC pathway, and increased FC of left caudate‐rMFG pathway (fig 2, P's < 0.05). The RD of right caudate‐rMFG pathway in PS1 group was positively correlated with MMSE total score (r = 0.749). The FC of left caudate‐rMFG pathway was negatively correlated with MMSE total score (fig 3, r = ‐ 0.623, P’s < 0.05).

Conclusion

There are neuropsychological and imaging changes in the early stage of FAD, which are affected by the known pathogenic gene mutation and ApoEε4. APP mutation affected memory domain in cognitive function and the structural connectivity of fronto‐striatal pathway. ApoEε4 mainly affected the structural connectivity of hippocampus‐PCC pathway. The hippocampal volume and the functional connectivity of fronto‐striatal pathway increased compensatively. The overall cognitive function is differently related to the structural and functional connectivity of fronto‐striatal pathway in APP, PS1 and ApoEε4.
How animacy processing is affected in early stages of AD
Authors: Marefat Haniye , Ebrahiminia Fatemeh , Khanbagi Mahdiyeh , Karimi Hamed , Modarres Mohammad Hadi , Kalafatis Chris , Vahabi Zahra , Khaligh‐Razavi Seyed‐Mahdi
Published: February 2022

Background

Previous studies have shown that cognitive impairment in early stages of Alzheimer’s disease (AD) is not limited to memory; other cognitive domains are also disrupted including impairment in visual processing (Boucart, Bubbico et al. 2014). Additionally, it is shown that in healthy human subjects, images are categorized by their animacy status (i.e. animate vs. inanimate) in the higher‐level visual areas (Kriegeskorte, Mur et al. 2008). Here we used fMRI to investigate the spatial patterns of animacy processing in the brain of patients with mild cognitive impairment (MCI)/AD in comparison to healthy controls(HC).

Method

We recruited 20 HCs, 15 MCIs and 10 mild‐ADs. Participants completed the Integrated Cognitive Assessment (ICA) test (Khaligh‐Razavi, Habibi et al. 2019) in the fMRI scanner. ICA is a rapid visual‐categorization task, in which participants indicate whether a presented image contains an animal or not, as fast and accurately as they can. In addition to the conventional univariate analysis –looking at the mean brain responses– we used multivariate‐pattern‐analysis (MVPA) to investigate differences in patterns of brain activity between the three groups. In MVPA, we trained a linear classifier for each brain area, to do animal/non‐animal categorization based on the patterns of brain responses to the images.

Result

In some of the key brain regions, such as R‐parahippocampus and R‐fusiform, overlapping with early tau‐pathology (Braak, Alafuzoff et al. 2006), both HC and MCI showed a significantly higher level of mean brain activity in response to all images compared to the AD group (p‐value<0.0001). Additionally, looking at the patterns of brain activity in the L‐fusiform, HC and MCI could be discriminated based on their MVPA responses(p‐value<0.0015), while there was no univariate difference between the two groups.

Conclusion

We demonstrated HC and MCI/AD can be differentiated not only based on univariate analysis, but also by multivariate measures, i.e. patterns of brain responses to images. Moreover, we showed that the rapid visual categorization task used in this study could engage key brain areas affected by tau pathology in early stages of the disease. This highlights the potential application of such task for earlier detection of the disease, ideally before the onset of memory symptoms.
Subtyping mild cognitive impairment based on imaging and CSF biomarker levels
Authors: Dadar Mahsa , Shafiee Neda , Collins Louis , Camicioli Richard , Duchesne Simon
Published: February 2022

Background

Individuals with mild cognitive impairment (MCI) have variable clinical outcomes, with a proportion converting to dementia in a short follow‐up period. Subtyping MCI subjects based on biomarker levels can provide additional insights on why some individuals progress faster, aiding clinical treatment strategy and facilitating cohort enrichment for clinical trials.

Method

Data included 562 individuals with MCI from the Alzheimer's Disease Neuroimaging Initiative (ADNI) project with baseline MRI, CSF amyloid beta (Aβ), t‐tau, and p‐tau data and a minimum of one‐year follow‐up information on clinical diagnosis. White matter hyperintensities (WMHs) were segmented using a previously validated random forests classifier (Dadar et al. 2017). SNIPE (Scoring by Nonlocal Image Patch Estimator) was used to measure Alzheimer’s‐disease‐like atrophy patterns in the hippocampi (HC) and entorhinal cortex (EC) (Coupé et al. 2019). CSF Aβ, p‐tau and t‐tau levels were obtained from project files. Agglomerative hierarchical clustering as used to cluster the data based on baseline age, education, APOE4 status, CSF Aβ, p‐tau and t‐tau levels, WMH load, and HC and EC grading scores. We then investigated differences in baseline ADAS13 cognitive scores as well as rate of conversion to dementia between different subtypes.

Result

Figure 1 shows the clustering dendrogram, splitting the data into three subtypes of 152, 200, and 210 participants, respectively. Figure 2 compares biomarker values across subtypes. Baseline ADAS13 scores and conversion rates were significantly different across all subtypes (p<0.0001). Subtype 1 had the oldest subjects with largest WMH loads (p<0.0001), with a conversion rate of 30.2%. Subtype 2 had the highest conversion rate (70.0%), with significantly lower CSF Aβ and EC grading scores, and higher CSF p‐tau and t‐tau values (p<0.0001). Subtype 3 had the lowest conversion rate (15.2%), with significantly higher HC and EC grading scores and lower age and WMH loads than the other two subtypes (p<0.0001).

Conclusion

Biomarker‐based subtyping of MCI subjects led to three distinct groups with significantly different clinical outcomes: 1) older individuals with cerebrovascular pathology and moderate conversion rates, 2) individuals with abnormal CSF biomarker levels, hippocampal and entorhinal atrophy, and high conversion rates, and 3) younger individuals without abnormal biomarker levels and low conversion rates.
Longitudinal assessment of [18F]FDG‐PET in the TgF344‐AD rat
Authors: da Rocha Andreia Silva , Ferreira Pamela C.L. , Bellaver Bruna , Peixoto Guilherme G. Schu , Venturin Gianina Teribele , Greggio Samuel , da Costa Jaderson Costa , Souza Diogo O. , Zimmer Eduardo R.
Published: February 2022

Background

The development and characterization of biomarkers abnormalities in Alzheimer’s disease (AD) animal models is particularly important for the investigation of pathophysiological mechanisms and drug development. With this is mind, here, we aimed at characterizing the brain glucose metabolism, indexed by [18F]FDG‐microPET, of the TgF344‐AD rat, a model harboring human APP/PS1 mutations. We hypothesized early hypometabolism ‐ due to astrocyte reactivity and microglial activation ‐ followed by hypometabolism in later stages – due to neurodegeneration.

Method

Hemizygous TgF344‐AD rats and their sex‐matched wild type littermates (n=16) were evaluated in three time points: 3, 6 and 9 months of age. Rats underwent [18F]FDG‐microPET for brain glucose metabolism analysis (SUVr, using the pons as reference region). Locomotor activity and spatial memory were assessed using Open‐Field and and Y‐maze tests, respectively.

Result

TgF344‐AD animals showed no differences in [18F]FDG‐microPET analysis in any of the ages analyzed (Figure A). On the other hand, a decline on their performance in the Y‐maze task was identified at the 9 months time point (p = 0.0132), suggesting a decline in their spatial memory at this age (Figure B). No differences were identified on the parameters analyzed in the Open Field task.

Conclusion

This study is the first to investigate the in vivo brain glucose metabolism in the TgF344‐AD rat model. Our preliminary results suggest that, in comparison to age and sex‐matched littermates, this APP/PS1 rat model does not present relevant changes in the brain glucose metabolism at early stages, even in the presence of detectable cognitive decline.