bluuebunny/crossref_metadata_2025 huggingface dataset:
Plasma p‐tau181 and nfl as surrogates biomarkers in clinical trials targeting preclinical stage of Alzheimer’s disease
Authors: Ferreira Pamela C.L. , Ferrari‐Souza João Pedro , Tissot Cécile , Bellaver Bruna , Leffa Douglas Teixeira , Povala Guilherme , Lussier Firoza Z , Therriault Joseph , Benedet Andrea Lessa , Ashton Nicholas J. , Cohen Ann D. , Lopez Oscar L. , Tudorascu Dana , Klunk William E , Soucy Jean‐Paul , Gauthier Serge , Villemagne Victor L , Zetterberg Henrik , Blennow Kaj , Rosa‐Neto Pedro , Zimmer Eduardo R. , Karikari Thomas K , Pascoal Tharick A.
Published: December 2023

Background

The preclinical stage of Alzheimer’s disease (AD) is one of the main focuses of clinical trials. Plasma and positron emission tomography (PET) biomarkers have already been proposed to monitor participants’ disease progression in clinical trials targeting cognitively unimpaired (CU) individuals. Although longitudinal changes in plasma phosphorylated tau 181 (p‐tau181) and neurofilament light chain(NfL) correlate with AD progression, it is unknown whether these changes can be used to monitor drug effects in preventive clinical trials. Here, we aimed to evaluate the utility of using changes in plasma p‐tau181 and NfL as surrogate biomarkers for clinical trials targeting preclinical AD.

Method

We access 257 CU older individuals that had available Aß‐PET at baseline, as well as the baseline, up to 24‐month plasma p‐tau181 and NfL measures from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). We calculate the estimated sample size needed to test a 25% drug effect with 80% of power at a 0.05 level on reducing changes in plasma markers.

Result

We demonstrated that therapeutical clinical trials of 24‐month follow‐up using p‐tau181 and NfL would require 78% and 63% smaller sample sizes compared with a 12‐month follow‐up(Figure 1). The use of intermediate levels of Aß(CL20‐40), rather than merely Aß positivity, as an enrichment strategy reduced the sample size by 73% for p‐tau181 and 59% for NfL over 24 months. As demonstrated in Figure 2A the estimated cost of a clinical trial using only plasma biomarkers is lower than using neuroimaging biomarkers for surrogacy(Figure 2A). However, as showed by Figure 2B a trial including all Aß positive individuals, the total estimated cost when considering surrogate biomarkers plus other related assessments are numerically higher using plasma than neuroimaging biomarkers; while trials including only individuals with intermediate Aß levels, the cost was similar using plasma and neuroimaging biomarkers for surrogacy.

Conclusion

Our results suggest that to monitor large scale large‐scale population interventions in CU Aß positive individuals’ plasma p‐tau181/ NfL could potentially be used. Furthermore, using a strategy that has been proposed in recent clinical trials, we demonstrated that the use of intermediate levels of Aß is more cost‐effective than trials using Aß‐positive individuals in clinical.
Moderate alcohol use, total brain volume, and white matter hyperintensities among racially and ethnically diverse middle‐aged adults
Authors: Guzmán Diana S. , Renteria Miguel Arce , Avila Justina F , Turney Indira C , Rossano Samantha , Johnson Aubrey S. , Smith Anna C. , Okafor Amarachukwu , Morales Clarissa , Gu Yian , Manly Jennifer J. , Brickman Adam M. , Lao Patrick J.
Published: December 2023

Background

Moderate alcohol use may provide later life cognitive benefits compared to heavy alcohol use. However, results have been mixed, with reports of both increased and decreased gray and white matter volumes with moderate drinking. Additionally, alcohol use on brain health may differ by sex and race/ethnicity. Understanding the association between brain health and moderate drinking in a representative, community‐based study will provide insight into the reported cognitive benefits. We investigated the relationship between alcohol use and total brain volume (TBV) and white matter hyperintensities (WMH) in a diverse sample of middle‐aged non‐alcohol dependent community‐dwelling adults.

Method

Participants (N = 350; Mage = 54±10 years; 33 Black Men, 38 Black Women, 66 Latinx Men, 166 Latinx Women, 7 White Men, 20 White Women) from the Offspring study of Racial and Ethnic Disparities in Alzheimer’s Disease, a community‐based study in Northern Manhattan, underwent structural (TBV = 1051±106cm3) and vascular (WMH = 3±4cm3) MRI. Alcohol use was assessed by the Alcohol Use Disorder Identification Test–Concise (AUDIT‐C). Individuals likely to be alcohol dependent (AUDIT‐C = 9) were excluded (n = 16). We assessed alcohol use and TBV or WMH, adjusting for age, in the overall group, and stratified by sex/gender groups, racial/ethnic groups, and sex/gender by race/ethnicity groups.

Result

Overall, greater TBV was associated with younger age (‐3.5cm3 [‐4.7, ‐2.3], p = 9E‐10) and greater alcohol use (5.1cm3 [‐6.8, 10.8], p = 0.085). No associations were found within men and women separately. Within race/ethnic groups, greater alcohol use was associated with greater TBV only among Latinx (7.6cm3 [0.1, 15.3], p = 0.055). Within sex/gender by race/ethnicity groups, greater alcohol use was associated with lower TBV among White men (‐36.8cm3 [‐45.0, ‐28.5], p = 1E‐3). There were no associations with WMH.

Conclusion

Moderate alcohol use was not reliably associated with brain health, but the effect was on the order of 1‐2 years of aging, in a diverse sample of middle‐aged non‐alcohol dependent community‐dwelling adults. However, moderate alcohol use may have effects on brain volume within specific sex/gender and race/ethnicity groups with implications for later life cognitive impairment. Future work should explore region specific associations, alcohol use factors (i.e., context of use, alcohol type, duration of use), and its relationship to change over time.
The Influence of Prior Head Injury on Late‐Life Cognition and White Matter Microstructure in Older Adults At‐Risk of Alzheimer’s disease
Authors: Chiu Larissa Kristi , Ai Meishan , Tremblay‐Mercier Jennifer , Villeneuve Sylvia , Geddes Maiya R.
Published: December 2023

Background

The long‐term combined effects of mild traumatic brain injury (mTBI) and APOE e4‐allele carrier status (APOE+/‐), a genetic risk factor of Alzheimer’s disease (AD), on cognition and white matter structural integrity in older adults at‐risk of AD is not fully understood.

Method

To investigate mTBI effects on late‐life neurobehavioural outcomes, a subsample of the PREVENT‐AD cohort was analyzed. Participants were cognitively normal adults over age 55 with a parental or multiple‐sibling history of AD. The mTBI group included individuals who self‐reported at least one prior mTBI with loss of consciousness and/or memory gap (n = 48, 33.3% APOE4+). Rey Auditory Verbal Learning Test measured immediate and delayed memory, Color‐Word Interference Test measured cognitive flexibility and inhibitory control, and Trail Making Test measured processing speed and attention. The control group included demographically‐matched (age, sex, years of education) participants from the same cohort without self‐reported mTBI (n = 62, 29.0% APOE4+). Data were analyzed using 2‐way ANOVAs with weighted means on years of education, corrected for multiple comparisons. To evaluate underlying structural differences in white matter tracts between mTBI and control groups, diffusion tensor imaging (DTI) metrics, including fractional anisotropy, axial and radial diffusivity, using the JHU‐atlas parcellation.

Result

mTBI/APOE4+ individuals performed significantly worse on cognitive outcomes of delayed recall, cognitive flexibility, and inhibitory control compared to controls; however, they performed significantly better on tests of processing speed and visual attention compared to mTBI/APOE4‐ individuals. DTI results showed that the mTBI group, compared to the control group, had significantly decreased axial diffusivity in the left internal capsule, right superior longitudinal fasciculus, and superior frontooccipital fasciculus (SFOF) (p<0.05 uncorrected). Within the mTBI group, significant positive correlation between lower processing speed and decreased axial diffusivity of SFOF, accounting for age and sex.

Conclusion

Our findings suggest that prior mTBI impacts cognitive aging in older adults at‐risk of AD differentially depend on APOE4 status, where APOE4+ individuals with prior mTBI had worse working memory, cognitive flexibility, and inhibitory control but better processing speed outcomes. Lower cognitive outcomes in mTBI individuals may be supported by decreased diffusivity in specific white matter tracts. These results can inform dementia prevention in these individuals.
Sex modulates the role of astrocyte reactivity in preclinical Alzheimer’s disease
Authors: Bellaver Bruna , Povala Guilherme , Ferreira Pamela C.L. , Leffa Douglas Teixeira , Ferrari‐Souza João Pedro , Lussier Firoza Z , Zalzale Hussein , Soares Carolina , Aguzzoli Cristiano Schaffer , Rohden Francieli , Abbas Sarah , Benedet Andrea Lessa , Ashton Nicholas J. , Tissot Cécile , Therriault Joseph , Servaes Stijn , Stevenson Jenna , Rahmouni Nesrine , Lopez Oscar L. , Tudorascu Dana , Villemagne Victor L , Klunk William E , Cohen Ann D. , Gauthier Serge , Zimmer Eduardo R , Zetterberg Henrik , Blennow Kaj , Karikari Thomas K , Rosa‐Neto Pedro , Pascoal Tharick Ali
Published: December 2023

Background

Astrocyte reactivity is a common finding in individuals across the Alzheimer’s disease (AD) continuum. Recently, we demonstrated that individuals with higher levels of plasma glial fibrillary acidic protein (GFAP), a marker of astrocyte reactivity, present a stronger association between amyloid‐ß (Aß) and tau pathologies in preclinical AD. Because cohort studies and clinical trials show sex differences in AD biomarkers, we investigated whether the effects of astrocyte reactivity on the association between Aß and tau differs in men and women

Method

We assessed 1,016 CU individuals from three cohorts with available Aß (plasma/PET), plasma p‐tau181 and GFAP measures. A subset of individuals also has plasma p‐tau217 available (n = 136).Individuals were classified as positive (Ast+) or negative (Ast‐) for astrocyte reactivity using a cutoff based on plasma GFAP of younger Aß‐ individuals.Linear regressions accounting for age and sex were used to evaluate the association between plasma p‐tau epitopes and Aß burden.An interaction between term between Aß*sex was also added to the models.Voxel‐wise associations between biomarkers were tested using linear regressions accounting for age, sex, and adjusting for multiple comparisons.

Result

We found that Aß burden was associated with plasma p‐tau in Ast+ but not in Ast‐ . Men in the Ast+ group presented a much increased association between Aß with plasma p‐tau181 (ß = 0.71,p<0.0001,Fig.1a) or p‐tau217 (ß = 1.23,p = 0.00086,Fig.1b) compared to women. Similarly, a significant interaction between Aß and sex on plasma p‐tau181 (ß = 0.47,p = 0.005,Fig1a) and p‐tau217 (ß = 1.01,p = 0.002,Fig.1b) was observed only in the Ast+ individuals. Voxel‐wise analysis showed the differences in the topographical association between Aß and plasma p‐tau epitopes between men and women. In men but not women, Aß‐PET associates with plasma p‐tau181 (Fig.2) and plasma p‐tau217 (Fig.3) in important AD regions such as precuneus, posterior cingulate and orbitofrontal cortex.

Conclusion

A sex effect was observed in the association between Aß burden and plasma p‐tau epitopes in individuals with increased astrocyte reactivity, with the association being stronger in men than women. The greater effect of Aß on tau phosphorylation in the presence of Ast+ in men than in women may have implications for interpretation of biomarkers in clinical trials testing as anti‐Aß therapies already showed different effects between men and women.
In‐vivo Braak Stage Distribution of Screened and Randomized Participants from Auτonomy, a Phase 2 Anti‐p‐tau Monoclonal Antibody Trial in Early Symptomatic Alzheimer’s Disease
Authors: Saad Ziad S. , Cohen Julie S , Fedgchin Maggie M , Quiceno Mary Ellen , Henley David , Kolb Hartmuth C.
Published: December 2023

Background

Tau PET is the gold standard for in‐vivo quantification of tau neurofibrillary tangles (NFT) which, along with amyloid plaques and neurodegeneration, constitute the pathological hallmarks of Alzheimer’s Disease (AD). The ongoing Autonomy trial (NCT04619420) enrolls participants presenting with mild cognitive impairment (MCI) or mild AD dementia who are tau PET positive. The Janssen plasma p217+tau assay is being used as a pre‐screen for eligibility to proceed to tau PET to reduce participant burden and improve screening efficiency. Using preliminary screening data available to date, we report on the in‐vivo PET‐based Braak stage distribution and compare the outcomes to published, histology‐based Braak staging.

Method

NFT levels were quantified using 18F‐MK‐6240 SUVR in Braak Regions Of Interest (ROI)[1] using cerebellar gray as the reference region. In‐vivo Braak staging (Braakiv) was implemented following the approach by Biel et al.[2], with 18F‐flortaucipir to 18F‐MK‐6240 SUVR threshold conversion from Gogola et al.[3]. Participants with atypical[2] stages were reassigned to the Braak stage corresponding to the highest Braak ROI with average SUVR > 1.4. The screening results reported herein are from the first 355 participants with available biomarker screening data.

Result

Of 355 screened participants, 90% were assigned to typical Braakiv stages. Of the 10% atypical stages, 94% were lacking elevated uptake in Braak 2 ROI. When using the coerced stage assignment, the average Braakiv stage was 3.7 across all screened participants and 3.6 in randomized participants (Figure 1). For the 221 randomized participants, 59% were Braakiv stage 4 or less, and 40% were Braakiv stage 3 or less.

Conclusion

In early Alzheimer’s disease participants who were screened with tau PET in the ongoing Autonomy trial, the average Braakiv stage was consistent with the average histology‐based Braak stage in MCI patients of 3.57 [4]. These results further support the use of tau PET‐based in‐vivo staging[5] as a proxy for histology‐based Braak staging. [1] Schöll et al. Neuron 2016. [2] Biel, D., et al. Alz Res Therapy 2021. [3] Gogola A. et al. J Nucl Med. 2022. [4] Markesbery WR. J Alzheimers Dis. 2010. [5] Therriault, J. et al. Nat Aging 2022
Relationship between white matter lesion coalescence and plasma cystatin C in an ethnically diverse population
Authors: Sudre Carole H , James Sarah‐Naomi , Barnes Jo , Huang Felicia , Direk Kenan , Barkhof Frederik , Jäger H. Rolf , Chaturvedi Nishi , Hughes Alun D
Published: December 2023

Background

Brain and kidney share anatomical similarities in terms of the small vessels serving their irrigation. Previous work have shown associations between markers of cerebral small vessel disease (CSVD) e.g. white matter hyperintensities (WMH) and markers of renal function e.g. cystatin C. Few studies have however investigated the relationship between renal function and more detailed descriptions of lesion shape and distribution

Method

768 individuals from the tri‐ethnic SABRE cohort underwent brain MRI including T1w and FLAIR sequences. WMH were automatically segmented and an overall measure of coalescence was derived from the lesion map ranging from 0 (only punctuate lesions) to 4 (high level of coalescence). Regional coalescence measures according to distance from the ventricles were further derived in 4 equidistant layers. Clinic blood samples were available for 731 individuals (45% female, mean age 71.3 (SD 6.4) years) including from 311 European; 172 African Caribbean; and 248 South Asian ethnicity. Blood measures include plasma cystatin C, a marker of glomerular filtration rate, white blood cell count (WBC) and HbA1c. Associations between cystatin C and coalescence score or lesion volume expressed as percentage of total intracranial volume were investigated using robust linear regression adjusting for age, ethnicity, sex, HbA1c and WBC; all factors known to be associated with cystatin C levels and WMH.

Result

Cystatin C was positively associated with male sex, WBC and HbA1c, and differed across ethnicities being highest in South Asians and lowest in African Caribbeans. After adjusting for potential confounders, cystatin C was positively associated with overall coalescence score (b = 0.026 [0.004;0.047], p = 0.018) despite unconvincing evidence of an association with overall lesion volume (b = 0.003 [‐0.0003; 0.007], p = 0.066). Associations between cystatin C and coalescence score were stronger in the South Asian group (b = 0.066 [0.027;0.105], p interaction = 0.001). Associations between cystatin C and coalescence score were similar across different layers.

Conclusion

Shape patterns of WMH, rather than overall WMH volume, may provide a more sensitive measure to assess the relationship with markers of small vessel disease in the kidneys.
Brain‐age mediates the association between modifiable risk factors and cognitive decline early in the AD continuum
Authors: Cumplido‐Mayoral Irene , Brugulat‐Serrat Anna , Sánchez‐Benavides Gonzalo , Escalante Armand González , Anastasi Federica , Milà‐Alomà Marta , Falcon Carles , Shekari Mahnaz , Cacciaglia Raffaele , Minguillon Carolina , Fauria Karine , Molinuevo Jose Luis , Suarez‐Calvet Marc , Vilaplana Verónica , Gispert Juan Domingo ,   for the ALFA study
Published: December 2023

Background

Neuroimaging‐derived brain‐age is a useful biomarker to study the brain’s biological aging process. Brain‐age has shown cross‐sectional associations with cognitive function and modifiable risk factors for dementia. We aimed to study, in cognitively unimpaired (CU) individuals, the mediating role of brain‐age in the association between modifiable risk factors and cognitive changes, and the impact of AD pathology on this role.

Method

We included 416 CU individuals from the ALFA+ study with available structural MRI, measurements of the global cognitive Preclinical Alzheimer’s Cognitive Composite (PACC) (370 individuals had a follow‐up PACC assessment 3.28±0.27 years later), and lifestyle and cardiovascular risk factors assessments. We computed brain‐age delta as the difference between chronological and predicted brain‐age using a previously pre‐trained machine learning algorithm on structural MRI data. Partial Least Squares Path Modeling (PLS‐PM) was employed to investigate the mediation effect of brain‐age delta between a computed latent variable from modifiable risk factors (cardiovascular, mental health and mood, metabolic/endocrine disease history, and alcohol consumption factors; Table 1) and a latent variable from longitudinal PACC. Statistical bias adjustment was performed to control for the confounding effects of age and sex by using multiple linear regression. The analysis was performed on the whole sample (ALL) and after stratification by amyloid‐ß (Aß) status. Participants were classified as amyloid‐ß positive (Aß+) if CSF Aß42/40<0.071 (Milà‐Alomà et al, 2020). Significance of mediation was examined by 95% confidence interval bootstrap.

Result

The effect of risk factors (latent risk) on longitudinal cognition (latent cognition) was partially mediated by brain‐age delta only in Aß+ individuals (57.286%) (Figure 1C). Higher latent risk was associated with older brain‐age delta (p = 0.003) and older brain‐age delta was associated with worse latent cognition (p = 0.007). Conversely, the indirect effect was not significant in ALL nor in Aß‐ individuals, where brain‐age delta was not significantly associated with latent cognition (Figure 1A‐B). Still, higher latent risk was associated with older brain‐age delta (ALL: p<0.001; Aß‐: p = 0.004) and associated with worse latent cognition (ALL: p = 0.012, Aß‐: p = 0.001).

Conclusion

In CU individuals in the AD continuum, biological brain aging mediates the association between modifiable risk factors and cognitive decline.
Assessing reactive astrogliosis in Parkinson’s brain with astroglial tracers BU99008 and deprenyl
Authors: Rocha Filipa Monteiro , Nordberg Agneta K , Kumar Amit
Published: December 2023

Background

The knowledge regarding the role of reactive astrogliosis in Parkinson’s disease (PD) is still at the surface level, however, a few in vivo PET studies have speculated that reactive astrogliosis could be an early event in PD pathology. Moreover, a direct link between a‐synuclein pathology and astrocytes in PD has been also shown, where astrocytes play a key role in a‐synuclein propagation by shuttling a‐synuclein between neurons and astrocytes. The PET imaging field is advancing very fast and different astrocytic‐tracers are now available, such as 11C‐Deprenyl (DED) (targeting MAO‐B) and 11C‐BU99008 (detect imidazoline‐2‐binding sites (I2Bs)), which we believe is crucial to explore the role of reactive astrogliosis, including astrocytic heterogeneity in PD. Hence, we used a multi‐tracer approach to understand the role of reactive astrogliosis and to validate its reliability as a potential biomarker in PD and related synucleinopathies.

Method

We used specialized postmortem saturation radioligand binding assay and small frozen human brain section autoradiography in PD and controls (CN) brains.

Result

The 3H‐BU99008 and 3H‐DED saturation binding studies in the frontal cortex (FC) brain homogenate (BH) of PD (n = 2‐3) and CN (n = 2) cases demonstrated relatively higher 3H‐DED binding as compared to 3H‐BU99008 with following Bmax (binding‐density) and Kd values: 3H‐BU99008 CNBmax – 59.1fmol/mg, Kd‐ 2.9nM vs. PDBmax – 51.6fmol/mg, 2.3nM; 3H‐DED CNBmax – 190.6fmol/mg, Kd‐ 2.7nM and PDBmax –244.2fmol/mg, Kd‐ 6.7nM. 3H‐BU99008 binding in the Cau in PD was ∼3‐fold higher than in CN. In contrast, the 3H‐DED binding between CN and PD brains in the Cau BH was almost comparable. Interestingly, qualitative, and semi‐quantitative assessment of small frozen brain section autoradiographies showed increased specific binding of 3H‐BU99008 and 3H‐DED in PD (n = 4) frontal & temporal cortices as compared to CN (n = 2‐3). In Cau, 3H‐BU99008 again showed higher binding than CN whereas 3H‐DED binding was comparable to CN, further complementing our saturation data.

Conclusion

The first study to assess reactive astrogliosis signature in postmortem PD brains with astroglial tracers BU99008 and DED. The findings clearly highlight regional differences in BU99008 and DED binding in PD brains and suggest increased reactive astrogliosis at the end stages of the disease warrants further investigation.
Validating noninvasive techniques for 11C‐ER176 PET quantification in controls and Alzheimer’s disease patients
Authors: Rossano Samantha , Talmasov Daniel , Johnson Aubrey S. , Smith Anna C. , Guzmán Diana S. , Okafor Amarachukwu , Kreisl William Charles , De Jager Philip L , Lao Patrick J.
Published: December 2023

Background

Noninvasive yet accurate PET quantification methods are crucial for safe yet meaningful PET studies. [11C]ER176 is a PET radioligand that images neuroinflammation via the 18‐kDa translocator protein (TSPO), which is upregulated in activated microglia and has previously been a PET target in Alzheimer’s disease research. Currently, the gold‐standard method for quantifying ER176 PET is kinetic modeling of the dynamic PET data using the arterial input function (AIF), which is invasive and expensive. The current study explores a pseudo‐reference region (RR) technique to noninvasively quantify ER176 scans to facilitate clinical PET studies.

Method

Dynamic 90‐min [11C]ER176 PET scans were acquired in 11 participants, 5 controls (5M/0F) and 6 patients (3 MCI‐3M/0F; 3 AD‐2M/1F). Arterial blood data were collected throughout the duration of the scan and were used along with the dynamic imaging data to determine regional total volume of distribution (VT) using the two‐tissue compartment model. Standardized Uptake Value Ratio (SUVR) was calculated by normalizing the radioactivity in each region by that of the reference region (cerebellar gray matter). We explored differences across methods (AIF‐derived VT vs. RR‐derived SUVR) and across groups (controls vs. patients).

Result

Within each group, the outcome measures from AIF and RR methods were well correlated (Controls: R2 = 0.986, p < 0.001; Patients: R2 = 0.983, p < 0.001; Figure 1). Both methods showed greater TSPO expression in patients compared to controls, with mean differences in the medial temporal cortex of 14.99% between groups for VT and 10.65% between groups for SUVR, but lower variance for SUVR compared to VT (Figure 2). Both quantification methods showed similar regional patterns of percent differences between groups, corresponding to tau progression along Braak staging (Figure 3).

Conclusion

Results suggest that using the cerebellum, which does not accumulate amyloid plaques or tau aggregates until end‐stage disease, as a reference region for [11C]ER176 may be a valid method for quantifying differences between AD patients and controls compared to gold‐standard methodology. Regional increases in neuroinflammation are more reliable for SUVR than VT in AD‐related regions. Ongoing work includes a larger sample size to further validate noninvasive PET quantification.
Atrophy of posteromedial sulci in aging and Alzheimer’s disease differs by sulcal type and location
Authors: Maboudian Samira A. , Willbrand Ethan H. , Jagust William J. , Weiner Kevin S.
Published: December 2023

Background

Recent work has shown that the morphology of tertiary sulci — small, evolutionarily‐newer sulci that emerge last in gestation — is associated with individual differences in cognitive development and symptoms of neuropsychiatric disorders, but these sulci have not been investigated in aging. Here we extend these findings on tertiary sulci to the aging brain.

Method

We manually defined sulci on cortical surface reconstructions of T1 MRI scans in FreeSurfer and extracted the cortical thickness and mean anterior coordinate of each sulcus. We defined sulci in posteromedial cortex (PMC) in 72 younger adults (YA; age 18‐35) from the Human Connectome Project, 72 cognitively normal older adults (OA; age 65‐90) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), and 72 age‐matched amyloid positive older adults with AD from ADNI: 4,341 sulci total. We used a mixed‐effects ANOVA to examine the effects of group (YA, OA, AD) as a between‐subject variable, and sulcal type (tertiary or non‐tertiary) and hemisphere (left/right) as within‐subject variables on sulcal cortical thickness. We used LASSO regression with nested cross‐validation for feature selection to determine which sulcal measures are most related to ADNI Memory Composite (MEM) scores, and LOOCV linear regression to predict MEM scores from the best model. Because not all sulci are found in all participants, only the most consistent were included in the LASSO models.

Result

In PMC, tertiary sulci show more age‐ and AD‐related thinning compared to non‐tertiary (group x sulcal type interaction p<.0001; Fig. 1). Additionally, atrophy in PMC shows a more anterior bias in aging that is absent in AD (Fig. 2). The best model for predicting ADNI‐MEM scores relies on a subset of mostly posterior sulci, suggesting a posterior shift in atrophy may be more related to cognitive decline (Fig. 3).

Conclusion

This is the first study to investigate tertiary sulci in aging and AD. Results show tertiary sulci in PMC are especially vulnerable to atrophy in aging and that a subset of PMC sulci are particularly associated with memory. The results provide insight into the anatomical specificity of age‐ and AD‐related atrophy in PMC and its association with cognitive decline.
Influence of visible white matter lesions on volumes from automated parcellations
Authors: Sudre Carole H , Carrasco Ferran Prados , James Sarah‐Naomi , Wong Andrew , Malone Ian B , Cash David M , Fox Nick C , Cardoso M Jorge , Schott Jonathan M , Barnes Jo
Published: December 2023

Background

White matter hyperintensities (WMH) are a common occurrence in ageing populations. Their hypointense appearance on T1‐weighted scans is known to affect automated processing and subsequent extraction of volumetric measurements. While lesion infilling with healthy appearing tissue is a common practice in the context of multiple sclerosis, this is not yet the case in studies of neurodegenerative diseases. We investigated the impact of WMH infilling on the volumetric outputs of two automated parcellation pipelines.

Method

T1‐weighted and T2‐FLAIR scans were acquired for 462 individuals in the Insight46 neuroimaging substudy of the MRC National Survey for health and Development (NSHD). WMH were automatically segmented and T1‐weighted scans were subsequently infilled over the lesion masks. Two automated parcellation methods Geodesic Information Flows (GIF) and FastSurfer (FS) were run on the two T1‐weighted scans (original and infilled). Cortex, lateral ventricles, basal ganglia (BG), whole brain and total intracranial volumes (TIV) were derived from the four resulting parcellations. Spearman correlation was used to assess the relationship within and across methods according to infilling status. Correlations were also calculated between the observed volumes or percentage difference (original vs infilled volumes) and the WMH burden expressed as percentage of TIV.

Result

The relationship between parcellated volumes and WMH burden varied across methods and tissues/brain areas. While there was little observable relationship for GIF between brain volume or TIV difference and WMH, this relationship was positive for FS. The relationship with cortical volume difference was in opposite directions for GIF (negative relationship) and FS (positive relationship), indicating a tendency to decrease the estimated volume when WMH were visible for GIF and increase it for FS. For lateral ventricles and basal ganglia, volumetric measurements were higher in the presence of visible WMH for GIF and FS (Figure1). Correlations between FS and GIF were slightly stronger after infilling but correlation with WMH burden were attenuated (Table2).

Conclusion

The impact of presence of visible WMH on T1‐weighted scan varies according to the chosen technique of analysis and strong correlations were observed between the difference in measured volumes and the WMH burden. Infilling should be considered when T1‐weighted derived volumes are studied.
Parental history of memory impairment predicts β‐amyloid burden and positivity in a preclinical population
Authors: Seto Mabel , Hohman Timothy J. , Mormino Elizabeth C. , Papp Kathryn V. , Amariglio Rebecca E. , Rentz Dorene M. , Johnson Keith A. , Schultz Aaron P. , Sperling Reisa A. , Buckley Rachel F. , Yang Hyun‐Sik
Published: December 2023

Background

Alzheimer’s disease (AD) is highly heritable, and previous studies suggest that a maternal family history of AD confers a greater risk for AD than paternal history. Whether the maternal and paternal history of AD dementia impacts AD endophenotypes among cognitively unimpaired individuals is not fully described. We examine the effects of parental history of dementia on brain amyloid levels and both subjective and objective measures of cognition.

Method

Measures of objective and subjective cognition (Preclinical Alzheimer’s Cognitive Composite; Cognitive Function Index), APOE‐e4 genotype, ß‐amyloid (Aß) PET, and self‐reported parental history of memory impairment and AD dementia were obtained from 4,429 cognitively unimpaired individuals screening for the Anti‐Amyloid Treatment in Asymptomatic Alzheimer’s (A4) study (mean(SD); age = 71.2(4.7), %male = 40.7, %Non‐Hispanic White = 87.9). Aß was measured with 18F‐florbetapir‐PET using a mean neocortical composite referenced to whole cerebellum (Aß+threshold:1.11 SUVr). Linear regression models assessed the association between maternal or paternal history with cross‐sectional cortical Aß levels and cognition covarying for the participant’s age, sex, and years of education where relevant.

Result

As previously reported, parental history of memory impairment (one or both parents) was significantly associated with elevated neocortical Aß (p<0.001). The association between Aß and history in both parents remained significant when covarying for APOE‐e4 allele count (p = 0.002). In interaction models, parental history in either one or both parents did not modulate the association between APOE‐e4 and Aß. Mean amyloid levels were elevated in individuals with history in both parents (n = 456, p<0.001) and in those with only maternal family history (n = 1776, p<0.001), compared to those with only paternal history (n = 634) or no family history (n = 1563, Figure 1B). Regression models confirmed this finding: ß = 0.03, p<0.001 in individuals with maternal history, ß = 0.01, p = 0.1 in individuals with paternal history. The results remained consistent for participants whose parents received a clinical diagnosis of AD dementia (ßmaternal = 0.02, pmaternal = 0.01; ßpaternal = 0.02, ppaternal = 0.2). No associations with subjective or objective cognition were observed.

Conclusion

We confirm that self‐reported family history of dementia is associated with elevated brain amyloid independently of APOE‐e4 status in the A4 Study, with evidence that maternal family history has a stronger impact on Aß burden among asymptomatic older individuals.
Characterizing the effects of chemotherapy on the brain of patients with head and neck cancer using FDG PET
Authors: Bishay Steven , Schwartz Trent , Smith David Samuel , Lee Lok Hin , Rosenthal Eben , Hohman Timothy J. , Jefferson Angela L. , Koran Mary Ellen
Published: December 2023

Background

Chemotherapy has known adverse effects on the brain. From small (N<30) studies primarily in breast cancer, we know that post‐chemotherapy brain changes can be detected with 18F ‐fluorodeoxyglucose positron emission tomography (FDG PET), but this has been relatively unexplored in other cancers, and has not been explored in patients with head and neck cancer (HNCa) (Chen, 2018). Patients with HNCa have 2‐3 times the risk of dementia after therapy compared to controls and may be particularly vulnerable given underlying lower levels of education and heavy tobacco and alcohol use (Zer, 2018). We will determine which areas of the brain are most vulnerable to the chemotherapy in HNCa with FDG PET.

Method

Patients with HNCa were identified from Vanderbilt’s Cancer Registry, limited to patients with FDG PET in the last year (2021). Clinical data was mined from the electronic health record. Images were processed with well‐established SPM12 methods (Friston, 1995). A voxel‐wise ANCOVA was performed on FDG PET images before and after chemotherapy, including covariates of age, sex, ethnicity, and time between chemotherapy and follow‐up imaging using conservative family wise error of <0.05 and voxel extent threshold of 10.

Result

68 patients with HNCa met inclusion criteria and all patients received Carboplatin‐based chemotherapy (Table 1). Compared to baseline, 17 clusters met conservative significance thresholds with decreases in glucose metabolism following treatment (Figure 1). These included large regions (46397 1.5mm3 voxels) in the frontal and temporal lobes (pFWE = <0.001). Specifically, there was significantly decreased glucose metabolism in the dorsolateral prefrontal cortex (BA 9), frontoparietal cortex (BA 10), orbital frontal cortex (BA 11), medial and superior temporal gyri (BA 21, 22), dorsal (BA 24), and the subgenual (BA 25), pregenual (BA 32), and rostral (BA 33) anterior cingulate cortex post‐chemotherapy.

Conclusion

To our knowledge, this is the first study to explore the effects of chemotherapy in HNCa, a population particularly vulnerable to these effects. We found that regions in the forebrain and temporal lobes are most vulnerable. Studies like these are important to establish and confirm spatial distributions of these effects which will be crucial for development of diagnostics and monitoring tools for these effects.
Mapping the effects of functional and structural network reorganization on the tau‐cognition relationship in Alzheimer’s disease
Authors: Ottoy Julie , Kang Min Su , de Wael Reinder Vos , Park Bo‐Yong , Bezgin Gleb , Lussier Firoza Z , Rahmouni Nesrine , Stevenson Jenna , Arias Jaime Fernandez , Soucy Jean‐Paul , Gauthier Serge , Bernhardt Boris , Black Sandra E. , Rosa‐Neto Pedro , Goubran Maged
Published: December 2023

Background

Tau pathology can spread through connectivity‐based networks, with certain regions (or epicenters) accumulating more tau than others. Such spatial vulnerabilities may be due to their unique apical position in the cortical hierarchy, which can be elucidated through ‘gradients of connectivity’ (Margulies 2016 PNAS). Prior work showed that the primary gradient of functional connectivity unveils a uni‐to‐transmodal topography of the healthy neocortex which highly correlates with a cognitive gradient of perception‐to‐abstraction. Here, we hypothesized that the gradients of functional/structural connectivity interact with tau to affect cognitive functions in Alzheimer’s disease (AD).

Method

We included 213 participants from TRIAD (103 CN Aß‐, 103 CN Aß+, and 75 CI Aß+) with diffusion‐weighted MRI, resting‐state functional MRI, 18F‐MK6240 tau‐PET, and an extensive cognitive battery. We performed non‐linear dimensionality reduction on the individual functional and structural connectomes, and extracted the first components (‘gradients’) ‐explaining most variance (G1FC and G1SC). First, we compared G1FC_or_SC between diagnostic groups. Second, we investigated the interaction effect of G1FC_or_SC*tauSUVR on cognition (across 9 cognitive domains). Last, we investigated whether the tau‐cognition relationship changed in a topography‐specific manner along the cortical hierarchy, within (equally‐sized) gradient‐derived meta‐ROIs along G1FC_or_SC. Results were compared to Braak‐derived regional associations. Analyses were adjusted for age, sex, APOE, education, and multiple comparisons.

Result

We observed reduced segregation of functional networks in AD compared to controls, with unimodal (lower‐order cognitive) and transmodal (higher‐order cognitive) regions moving closer on G1FC. This may indicate loss of network specialization in AD. Participants who had both higher tau and G1FC alterations had more cognitive impairment (Fig.1A; shown for MMSE/language). This interaction‐effect was less pronounced with G1SC (Fig.1B). Last, tau correlated with cognition in a topography‐specific progressive manner (i.e., along the transmodal‐unimodal G1FC axis and anterior‐posterior G1SC axis) (Fig.1C). Notably, tau correlated with delayed memory progressively along the posterior‐anterior G1SC axis (R2 = 0.93 in all and R2 = 0.95 in A+) and BraakI‐VI axis (R2 = 0.77 in all and R2 = 0.28 in A+).

Conclusion

Our work supports the contribution of connectome‐driven tau distribution on cognitive impairment in AD. Connectome gradients may provide a spatial framework to study tau spreading along the major axes of brain organization underlying specific cognitive domains.
Characterizing the effects of COVID‐19 on the brain using FDG PET imaging before and after COVID‐19 infection
Authors: Bishay Steven , Schwartz Trent , Smith David Samuel , Lee Lok Hin , Reid Sonya , Hohman Timothy J. , Jefferson Angela L. , Warner Jeremy , Koran Mary Ellen
Published: December 2023

Background

Individuals diagnosed with COVID‐19 have been found to have changes in brain structure as well as dramatic neuropsychiatric effects such as dementia, Parkinsonism, and greater likelihood of stroke (Taquet, 2021). Infection has also been shown to result in hypometabolic changes on 18F ‐fluorodeoxyglucose positron emission tomography (FDG PET) when compared to normal controls (Guedj, 2021). This study will seek to determine which brain regions are most affected by COVID‐19 with FDG PET. To our knowledge, we are the first study to compare pre‐ and post‐infection FDG PET imaging within patients. These patients were coincidentally infected with COVID‐19 between standard of care longitudinal FDG PET imaging for cancer.

Method

Patients with COVID‐19 who had FDG PET imaging that included the brain before and after serologic COVID‐19 diagnosis were identified from an internal COVID‐19 registry. Clinical data was mined from the electronic health record. Images were processed with well‐established SPM12 methods (Friston, 1995). A voxel‐wise ANCOVA was performed on FDG PET images before and after COVID‐19 infection, including covariates of age, sex, ethnicity, and time between chemotherapy and follow‐up imaging using p < 0.001 and voxel extent threshold of 10.

Result

29 patients met inclusion criteria (Table 1). Compared to baseline, 4 clusters of voxels were significantly decreased after COVID‐19 infection in the temporal lobes, anterior cingulate gyrus, and superior cerebellum (Table 2). In a post‐hoc analysis, spherical regions of interest (radius = 5 mm) surrounding these clusters were tested for post‐infection hypometabolism. The bilateral temporal lobes, anterior lobe of cerebellum, and right caudate head showed significant decrease in glucose metabolism following COVID‐19 infection (p < 0.05).

Conclusion

Currently, this is the first study to leverage a pre‐COVID‐19 infection FDG PET for comparison to imaging post‐infection. We discovered regions in the temporal lobe, frontal lobe, and cerebellum that showed hypometabolic changes following infection, important for determining spatial localization of the effects of this viral infection.
Assessment of brain oxygen extraction fraction between normal cognition and mild cognitive impairment in an elderly cohort using quantitative BOLD
Authors: Le Linh N. N. , Wheeler Gregory J. , Fletcher Evan , Blockley Nicholas P. , Fan Audrey
Published: December 2023

Background

This study is to quantify oxygen extraction fraction (OEF), an important physiological biomarker for brain hemodynamic impairment, in the elderly cohort using non‐invasive quantitative BOLD (qBOLD) modeling, which is an MRI method for assessment of hemodynamic and metabolic properties.

Method

56 participants (75.4±7.0yo, 37F), including 46 cognitively normal (CN) individuals (75.2±7.3yo, 29F) and 10 mild‐cognitive‐impairment (MCI) patients (76.0±6.1yo, 7F), were recruited from UC Davis Alzheimer’s Disease Research Center cohort. MRI scans were acquired on a 3T scanner (Siemens Tim Trio) with a 32‐channel head coil, including an Asymmetric Spin Echo (ASE) scan (TR/TE, 2800/66ms; 2.3×2.3.x1.3mm3 resolution; FOV, 224mm; 13 values of the spin echo displacement time, from 0 to 52ms) and a T1‐weighted MPRAGE. T1‐weighted images were segmented into regions of interest (ROI), including gray matter (GM), white matter (WM), and cortical lobes (frontal, parietal, occipital, temporal) using FSL FAST. ASE signal curves were preprocessed and fit to two‐compartment qBOLD model with Variational Bayesian framework to estimate deoxygenated blood volume (DBV) and transverse relaxation rate (R2’), which are used to quantify OEF with known physiological constants (Cherukara et al., NeuroImage 2019). Average OEF values were calculated and compared for each ROI between CN and MCI groups using pairwise t‐tests with Bonferroni correction. The correlation between OEF and age were assessed using a linear mixed effects model that accounted for subject clustering.

Result

Compared to CN, reduced DBV and increased OEF were observed throughout most of the brain on the group average level in MCI (Figure 1). In regional analysis, we observed a trend of increased OEF in MCI compared to CN in several ROIs, which was significant in the occipital lobe (p = 0.007) (Figure 2). In Figure 3, OEF was inversely correlated with age in the parietal lobe for CN (p = 0.026). In contrast, there was a positive trend of association between OEF and age for MCI across all regions.

Conclusion

This study showed that age has an association with brain oxygen extraction that are differently affected by normal aging and MCI. Higher brain OEF in MCI individuals may reflect changes in oxygen metabolism because of underlying pathology, including vascular injury and compensation for hypoperfusion.
Functional connectivity of the frontoparietal control network is positively associated with cognition, independent of amyloid and tau burden, in the A4 study
Authors: Boyle Rory , Shirzadi Zahra , Coughlan Gillian T , Properzi Michael J , Chhatwal Jasmeer P. , Buckley Rachel F. , Sperling Reisa A. , Schultz Aaron P.
Published: December 2023

Background

The Anti‐Amyloid in Asymptomatic Alzheimer’s Disease (A4) study is the first secondary prevention trial of an anti‐amyloid therapy, solanezumab, in cognitively unimpaired older adults with elevated amyloid‐beta (Ab)‐PET burden. The inclusion of resting‐state functional connectivity MRI (fcMRI) as a secondary outcome measure is a novelty for clinical trials. Despite promising longitudinal findings, there is mixed evidence for cross‐sectional associations between functional connectivity in the default mode (DMN) and frontoparietal control (FPCN) networks, with Ab, tau, and cognition. Here, in a large cross‐sectional sample, we investigate these associations and assess whether fcMRI accounts for variability in cognition that is not attributable to Ab or tau.

Method

1,641 participants from A4 and the LEARN observational arm with fcMRI passed quality control and had complete data for sociodemographics, cognition, and Ab (Florbetapir)‐PET (Table 1). A subset had tau (Flortaucipir)‐PET (n = 420). Within‐network connectivity estimates of the default mode (DMN) and left and right frontoparietal control networks (FPCN) were obtained using template‐based rotation (Fig. 1). Using hierarchical regressions, we examined the independent associations of functional connectivity with Ab burden (mean cortical standardized uptake value [SUVr]), tau burden (mean of inferior temporal and entorhinal SUVrs), and cognition (Preclinical Alzheimer’s Cognitive Composite), independent of covariates (age, sex, education level, head motion, scanner and, where applicable, Ab and/or tau burden).

Result

Ab and tau burden were not independently associated with DMN or right FPCN connectivity. Higher tau was associated with reduced left FPCN connectivity, independent of Ab. Stronger left and right FPCN connectivity were associated with better cognition, independent of Ab and tau (Table 2). This association was stronger for the left FPCN.

Conclusion

FPCN functional connectivity is associated with better cognition, independent of Ab and tau burden. This association was strongest in the left FPCN and supports evidence that implicates FPCN connectivity in cognitive reserve and resilience. While this association is robust, weak effect sizes suggest that functional connectivity explains a limited amount of variability in cognition after accounting for covariates and AD pathology. Future release of the A4 study longitudinal data will enable quantification of the added value of fcMRI in AD clinical trials.