Longitudinal Gray Matter Research Articles

Additive effects of cerebrovascular disease functional connectome phenotype and plasma p-tau181 on longitudinal neurodegeneration and cognitive outcomes.

We investigated the effects of multiple cerebrovascular disease (CeVD) neuroimaging markers on brain functional connectivity (FC), and how such CeVD-related FC changes interact with plasma phosphorylated tau (p-tau)181 (an Alzheimer's disease [AD] marker) to influence downstream neurodegeneration and cognitive changes. Multivariate associations among four CeVD markers and whole-brain FC in 529 participants across the dementia spectrum were examined using partial least squares correlation. Interactive effects of CeVD-related FC patterns and p-tau181 on longitudinal gray matter volume (GMV) and cognitive changes were investigated using linear mixed-effects models. We identified a brain FC phenotype associated with high CeVD burden across all markers. Further, expression of this general CeVD-related FC phenotype and p-tau181 contributed additively, but not synergistically, to baseline and longitudinal GMV and cognitive changes. Our findings suggest that CeVD exerts global effects on the brain connectome and highlight the additive nature of AD and CeVD on neurodegeneration and cognition. Effects of multiple cerebrovascular disease (CeVD) markers on functional connectivity were studied. A global network phenotype linked to high burden across CeVD markers was identified. CeVD phenotype and plasma phosphorylated tau 181 contributed additively to downstream outcomes.

Exploring the links among brain iron accumulation, cognitive performance, and dietary intake in older adults: A longitudinal MRI study

This study evaluated longitudinal brain iron accumulation in older adults, its association with cognition, and the role of specific nutrients in mitigating iron accumulation. MRI-based, quantitative susceptibility mapping estimates of brain iron concentration were acquired from seventy-two healthy older adults (47 women, ages 60–86) at a baseline timepoint (TP1) and a follow-up timepoint (TP2) 2.5–3.0 years later. Dietary intake was evaluated at baseline using a validated questionnaire. Cognitive performance was assessed at TP2 using the uniform data set (Version 3) neuropsychological tests of episodic memory (MEM) and executive function (EF). Voxel-wise, linear mixed-effects models, adjusted for longitudinal gray matter volume alterations, age, and several non-dietary lifestyle factors revealed brain iron accumulation in multiple subcortical and cortical brain regions, which was negatively associated with both MEM and EF performance at T2. However, consumption of specific dietary nutrients at TP1 was associated with reduced brain iron accumulation. Our study provides a map of brain regions showing iron accumulation in older adults over a short 2.5-year follow-up and indicates that certain dietary nutrients may slow brain iron accumulation.

Association of Vascular Risk Factors and Cerebrovascular Pathology With Alzheimer Disease Pathologic Changes in Individuals Without Dementia.

Vascular risk factors (VRFs) and cerebral small vessel disease (cSVD) are common in patients with Alzheimer disease (AD). It remains unclear whether this coexistence reflects shared risk factors or a mechanistic relationship and whether vascular and amyloid pathologies have independent or synergistic influence on subsequent AD pathophysiology in preclinical stages. We investigated links between VRFs, cSVD, and amyloid levels (Aβ1-42) and their combined effect on downstream AD biomarkers, that is, CSF hyperphosphorylated tau (P-tau181), atrophy, and cognition. This retrospective study included nondemented participants (Clinical Dementia Rating < 1) from the European Prevention of Alzheimer's Dementia (EPAD) cohort and assessed VRFs with the Framingham risk score (FRS) and cSVD features on MRI using visual scales and white matter hyperintensity volumes. After preliminary linear analysis, we used structural equation modeling (SEM) to create a "cSVD severity" latent variable and assess the direct and indirect effects of FRS and cSVD severity on Aβ1-42, P-tau181, gray matter volume (baseline and longitudinal), and cognitive performance (baseline and longitudinal). A total cohort of 1,592 participants were evaluated (mean age = 65.5 ± 7.4 years; 56.16% F). We observed positive associations between FRS and all cSVD features (all p < 0.05) and a negative association between FRS and Aβ1-42 (β = -0.04 ± 0.01). All cSVD features were negatively associated with CSF Aβ1-42 (all p < 0.05). Using SEM, the cSVD severity fully mediated the association between FRS and CSF Aβ1-42 (indirect effect: β = -0.03 ± 0.01), also when omitting vascular amyloid-related markers. We observed a significant indirect effect of cSVD severity on P-tau181 (indirect effect: β = 0.12 ± 0.03), baseline and longitudinal gray matter volume (indirect effect: β = -0.10 ± 0.03; β = -0.12 ± 0.05), and baseline cognitive performance (indirect effect: β = -0.16 ± 0.03) through CSF Aβ1-42. In a large nondemented population, our findings suggest that cSVD is a mediator of the relationship between VRFs and CSF Aβ1-42 and affects downstream neurodegeneration and cognitive impairment. We provide evidence of VRFs indirectly affecting the pathogenesis of AD, highlighting the importance of considering cSVD burden in memory clinics for AD risk evaluation and as an early window for intervention. These results stress the role of VRFs and cerebrovascular pathology as key biomarkers for accurate design of anti-amyloid clinical trials and offer new perspectives for patient stratification.

Multivariate associations between psychiatric drug intake and grey matter volume changes in individuals at early stages of psychosis and depression

IntroductionPsychiatric drugs, including antipsychotics and antidepressants, are widely prescribed, even in young and adolescent populations at early or subthreshold disease stages. However, their impact on brain structure remains elusive. Elucidating the relationship between psychotropic medication and structural brain changes could enhance the understanding of the potential benefits and risks associated with such treatment.Objectives Investigation of the associations between psychiatric drug intake and longitudinal grey matter volume (GMV) changes in a transdiagnostic sample of young individuals at early stages of psychosis or depression using an unbiased data-driven approach.Methods The study sample comprised 247 participants (mean [SD] age = 25.06 [6.13] years, 50.61% male), consisting of young, minimally medicated individuals at clinical high-risk states for psychosis, individuals with recent-onset depression or psychosis, and healthy control individuals. Structural magnetic resonance imaging was used to obtain whole-brain voxel-wise GMV for all participants at two timepoints (mean [SD] time between scans = 11.15 [4.93] months). The multivariate sparse partial least squares (SPLS) algorithm (Monteiro et al. JNMEDT 2016; 271:182-194) was embedded in a nested cross-validation framework to identify parsimonious associations between the cumulative intake of psychiatric drugs, including commonly prescribed antipsychotics and antidepressants, and change in GMV between both timepoints, while additionally factoring in age, sex, and diagnosis. Furthermore, we correlated the retrieved SPLS results to personality domains (NEO-FFI) and childhood trauma (CTQ).ResultsSPLS analysis revealed significant associations between the antipsychotic classes of benzamides, butyrophenones and thioxanthenes and longitudinal GMV decreases in cortical regions including the insula, posterior superior temporal sulcus as well as cingulate, postcentral, precentral, orbital and frontal gyri (Figure 1A-C). These brain regions corresponded most closely to the dorsal and ventral attention, somatomotor, salience and default network (Figure 1D). Furthermore, the medication signature was negatively associated with the personality domains extraversion, agreeableness and conscientiousness and positively associated with the CTQ domains emotional and physical neglect.Image:ConclusionsPsychiatric drug intake over a period of one year was linked to distinct GMV reductions in key cortical hubs. These patterns were already visible in young individuals at early or subthreshold stages of mental illness and were further linked to childhood neglect and personality traits. Hence, a better and more in-depth understanding of the structural brain implications of medicating young and adolescent individuals might lead to more cautious, sustainable and targeted treatment strategies.Disclosure of InterestNone Declared

Neural foundation of the diathesis-stress model: longitudinal gray matter volume changes in response to stressful life events in major depressive disorder and healthy controls.

Recurrences of depressive episodes in major depressive disorder (MDD) can be explained by the diathesis-stress model, suggesting that stressful life events (SLEs) can trigger MDD episodes in individuals with pre-existing vulnerabilities. However, the longitudinal neurobiological impact of SLEs on gray matter volume (GMV) in MDD and its interaction with early-life adversity remains unresolved. In 754 participants aged 18-65 years (362 MDD patients; 392 healthy controls; HCs), we assessed longitudinal associations between SLEs (Life Events Questionnaire) and whole-brain GMV changes (3 Tesla MRI) during a 2-year interval, using voxel-based morphometry in SPM12/CAT12. We also explored the potential moderating role of childhood maltreatment (Childhood Trauma Questionnaire) on these associations. Over the 2-year interval, HCs demonstrated significant GMV reductions in the middle frontal, precentral, and postcentral gyri in response to higher levels of SLEs, while MDD patients showed no such GMV changes. Childhood maltreatment did not moderate these associations in either group. However, MDD patients who had at least one depressive episode during the 2-year interval, compared to those who did not, or HCs, showed GMV increases in the middle frontal, precentral, and postcentral gyri associated with an increase in SLEs and childhood maltreatment. Our findings indicate distinct GMV changes in response to SLEs between MDD patients and HCs. GMV decreases in HCs may represent adaptive responses to stress, whereas GMV increases in MDD patients with both childhood maltreatment and a depressive episode during the 2-year interval may indicate maladaptive changes, suggesting a neural foundation for the diathesis-stress model in MDD recurrences.

Partial volume correction in longitudinal tau PET studies: is it really needed?

Background[18F]flortaucipir (FTP) tau PET quantification is known to be affected by non-specific binding in off-target regions. Although partial volume correction (PVC) techniques partially account for this effect, their inclusion may also introduce noise and variability into the quantification process. While the impact of these effects has been studied in cross-sectional designs, the benefits and drawbacks of PVC on longitudinal FTP studies is still under scrutiny. The aim of this work was to study the performance of the most common PVC techniques for longitudinal FTP imaging. MethodsA cohort of 247 individuals from the Alzheimer's Disease Neuroimaging Initiative with concurrent baseline FTP-PET, amyloid-beta (Aβ) PET and structural MRI, as well as with follow-up FTP-PET and MRI were included in the study. FTP-PET scans were corrected for partial volume effects using Meltzer's, a simple and popular analytical PVC, and both the region-based voxel-wise (RBV) and the iterative Yang (iY) corrections. FTP SUVR values and their longitudinal rates of change were calculated for regions of interest (ROI) corresponding to Braak Areas I-VI, for a temporal meta-ROI and for regions typically displaying off-target FTP binding (caudate, putamen, pallidum, thalamus, choroid plexus, hemispheric white matter, cerebellar white matter, and cerebrospinal fluid). The longitudinal correlation between binding in off-target and target ROIs was analysed for the different PVCs. Additionally, group differences in longitudinal FTP SUVR rates of change between Aβ-negative (A-) and Aβ-positive (A+), and between cognitively unimpaired (CU) and cognitively impaired (CI) individuals, were studied. Finally, we compared the ability of different partial-volume-corrected baseline FTP SUVRs to predict longitudinal brain atrophy and cognitive decline. ResultsAmong off-target ROIs, hemispheric white matter showed the highest correlation with longitudinal FTP SUVR rates from cortical target ROIs (R2=0.28–0.82), with CSF coming in second (R2=0.28–0.42). Application of voxel-wise PVC techniques minimized this correlation, with RBV performing best (R2=0.00–0.07 for hemispheric white matter). PVC also increased group differences between CU and CI individuals in FTP SUVR rates of change across all target regions, with RBV again performing best (No PVC: Cohen's d = 0.26–0.66; RBV: Cohen's d = 0.43–0.74). These improvements were not observed for differentiating A- from A+ groups. Additionally, voxel-wise PVC techniques strengthened the correlation between baseline FTP SUVR and longitudinal grey matter atrophy and cognitive decline. ConclusionQuantification of longitudinal FTP SUVR rates of change is affected by signal from off-target regions, especially the hemispheric white matter and the CSF. Voxel-wise PVC techniques significantly reduce this effect. PVC provided a significant but modest benefit for tasks involving the measurement of group-level longitudinal differences. These findings are particularly relevant for the estimations of sample sizes and analysis methodologies of longitudinal group studies.

Serum biomarkers for prognosis and monitoring in asymptomatic Alzheimer’s Disease

AbstractBackgroundPrognostic and monitoring capabilities of blood‐based biomarkers for early cognitive decline, amyloid‐β (Aβ) accumulation and grey matter (GM) loss in the asymptomatic phase of Alzheimer disease require further investigation over extended time periods. This longitudinal study investigated serum glial fibrillary acidic protein (GFAP), neurofilament light (NfL) and Aβ1‐42/Aβ1‐40 as potential prognostic and monitoring biomarkers in cognitively unimpaired (CU) elderly.MethodWe included 184 CU older adults (Table 1) who underwent baseline serum sampling and 2‐yearly neuropsychological assessment for up to 10 years (median: 6 years, Figure 1). A subset (N = 109) underwent serial blood sampling, Aβ‐PET and structural MRI at 2 (N = 73), 3 (N = 34), or 4 (N = 2) time points (time interval: 2‐10 years, median: 6 years). Cognition was evaluated in memory, language and executive functioning domains through conversion of neuropsychological tests scores to standardised z‐scores and subsequent averaging per domain. Aβ‐accumulation and GM loss were analysed in a voxelwise manner using Voxelstats with cluster‐level p RFT&lt;.05 and voxel‐level puncorrected&lt;.001 significance thresholds.[1] Aβ1‐42/Aβ1‐40 was inverted to facilitate biomarker comparison. Linear‐mixed effects models were used to (i) identify the predictive value of serum biomarkers for longitudinal cognitive decline, Aβ‐accumulation and GM loss, (ii) calculate annual serum biomarker rates of change and (iii) investigate associations between longitudinal biomarker changes and longitudinal changes in cognition, Aβ‐PET and GM volume.ResultHigh baseline GFAP and NfL predicted a longitudinal decline in memory (βGFAP*time = ‐0.020, pFDR = 0.03; βNfL*time = ‐0.031, pFDR = 0.002) and language (βGFAP*time = ‐0.025, pFDR&lt;0.001, βNfL*time = ‐0.017, pFDR = 0.04), and longitudinal GM loss within the hippocampus. Low Aβ1‐42/Aβ1‐40 predicted memory decline (βAβ1‐42/Aβ1‐40*time = ‐0.022, pFDR = 0.03) as well as Aβ accumulation within Aβ‐vulnerable regions (Figure 1). Serum GFAP (βtime = 0.022, pFDR&lt;.001) and NfL (βtime = 0.040, pFDR&lt;.001) increased over time. Longitudinal serum NfL increases were associated with a concomitant decline in memory (β∆NfL*time = ‐0.031, pFDR= .004), language (β∆NfL*time = ‐0.022, pFDR= .01) and GM volume (Figure 2). Serum GFAP increases were associated with precuneal Aβ accumulation. Aβ1‐42/Aβ1‐40 decreases were stronger in Aβ‐ subjects (pFDR&lt;.001) and did not associate with Aβ accumulation, nor any other longitudinal marker.ConclusionSerum GFAP, NfL and Aβ1‐42/Aβ1‐40 are prognostic and/or monitoring biomarkers providing complementary information by reflecting different Aβ‐dependent or ‐independent pathophysiological processes.REFERENCE[1] Mathotaarachchi et al. Front Neuroinform 2016.

Healthy Dietary Intake Reduces Longitudinal Brain Iron Accumulation in Older Adults

AbstractBackgroundBrain iron, which tends to accumulate with normal aging, negatively affects cognitive performance. However, the impact of brain iron on cognition appears modifiable. In a recent study from our group [1], we demonstrated that those older adults with high dietary intake of antioxidants, iron chelating nutrients and polyunsaturated fatty acids (Factor 2 in [1]), tended to have lower brain iron and better working memory performance than expected for their age. Here, we extend our previous work by evaluating associations between baseline consumption of Factor 2 nutrients and longitudinal brain iron accumulation, evaluated three years after baseline.MethodsForty‐three, cognitively normal, older adults (26 women, age range 63‐88 years) underwent MRI‐based structural brain imaging and quantitative susceptibility mapping for assessment of brain iron concentration at two time points: baseline (T1) and three years after baseline (T2). Additionally, at T1, nutritional‐intake was assessed via a validated questionnaire. Nutrients were grouped into nutrition factors based on previous literature and factor analysis. Factor 2, comprised vitamin E, lysine, DHA omega‐3 and LA omega‐6, representing antioxidants, iron chelating nutrients and polyunsaturated fatty acids.ResultsVoxelwise, whole‐brain, linear mixed‐effects models (qFDR &lt; 0.05), controlling for longitudinal gray matter volume alterations, age, gender and education, revealed brain iron accumulation within several subcortical and cortical brain regions. Importantly, a significant time point by nutrition interaction was also observed. Specifically, those participants who consumed higher amounts of Factor 2 nutrients at baseline exhibited lower longitudinal brain iron accumulation within the left middle frontal gyrus, left superior parietal lobule, left insular cortex, right inferior temporal cortex, and bilateral hippocampus. Time point by nutrition interactions were not observed for other nutrition factors discussed in [1], such as those comprised of nutrients found in fruits and vegetables, or in green tea.ConclusionOur results indicate that dietary patterns rich in oxidative stress‐reducing antioxidants, iron chelating nutrients and polyunsaturated fatty acids may slow down age‐related, brain iron accumulation in older adults.

Pathophysiological mechanisms of grey matter morphometry changes in preclinical Alzheimer’s disease

AbstractBackgroundThe biological mechanisms underlying structural brain changes in early Alzheimer’s disease (AD) are not well understood. Combining a wide selection of biomarkers of AD pathology, synaptic dysfunction, neuroaxonal injury, and neuroinflammation, and examining their effects on grey matter (GM) changes may provide a deeper understanding of the multifactorial nature of AD. We aimed to identify biological components of key fluid biomarkers predictive of longitudinal GM changes in cognitively unimpaired adults.MethodWe studied 322 cognitively unimpaired individuals from the ALFA+ cohort (Table1) with available longitudinal MRI and cerebrospinal fluid (CSF) biomarkers of β‐amyloid (Aβ42/40), phospho‐tau (p‐tau181), neurogranin, neurofilament light chain (NfL), total‐tau, α‐synuclein, glial fibrillary acidic protein (GFAP), chitinase‐3‐like protein‐1 (YKL‐40), soluble triggering receptor expressed on myeloid cells‐2 (sTREM2), S100 calcium‐binding protein B (S100B), and interleukin‐6 measured using the Roche NeuroToolKit immunoassays. Pairwise longitudinal registration analysis was performed using SPM12 to calculate Jacobian determinant maps. Next, we performed partial least‐squares analysis to determine the optimal number of CSF biomarker components and tested their association with GM volume changes by AT (Amyloid‐Tau) stage.ResultFour distinct biomarker components (C1‐4) were identified (Figure1). C1 was driven by moderate contributions from several biomarkers, particularly markers of core AD pathology and neurodegeneration, which were strongly associated with temporal lobe atrophy in A+T‐ individuals. C2 represented mainly Aβ pathology and, to a lesser extent, axonal damage and astrogliosis that contributed to a decrease in GM volume, especially in the hippocampus in A‐T‐ participants, while showing strong correlations with volume increases in medial frontal regions in A+T+ participants. C3 loading was associated with greater frontoparietal atrophy, especially in A+T+ individuals, and consisted of microglial activation together with Aβ pathology but in the absence of reactive astrogliosis. Lastly, C4, reflecting mostly microglial activation alone, was also strongly associated with frontoparietal atrophy, particularly in A+T+ participants.ConclusionOur results suggest important contributions of Aβ pathology, neuroaxonal damage, and microglial activation to GM morphometry changes in the earliest stages of the AD continuum. Atrophy patterns differed depending on the underlying pathological drivers and on A and T positivity, showing stronger correlations with increasing disease severity; however, volumetric increases were also observed.

Pathophysiological mechanisms of grey matter morphometry changes in preclinical Alzheimer’s disease

AbstractBackgroundThe biological mechanisms underlying structural brain changes in early Alzheimer’s disease (AD) are not well understood. Combining a wide selection of biomarkers of AD pathology, synaptic dysfunction, neuroaxonal injury, and neuroinflammation, and examining their effects on grey matter (GM) changes may provide a deeper understanding of the multifactorial nature of AD. We aimed to identify biological components of key fluid biomarkers predictive of longitudinal GM changes in cognitively unimpaired adults.MethodWe studied 322 cognitively unimpaired individuals from the ALFA+ cohort (Table1) with available longitudinal MRI and cerebrospinal fluid (CSF) biomarkers of ß‐amyloid (Aß42/40), phospho‐tau (p‐tau181), neurogranin, neurofilament light chain (NfL), total‐tau, a‐synuclein, glial fibrillary acidic protein (GFAP), chitinase‐3‐like protein‐1 (YKL‐40), soluble triggering receptor expressed on myeloid cells‐2 (sTREM2), S100 calcium‐binding protein B (S100B), and interleukin‐6 measured using the Roche NeuroToolKit immunoassays. Pairwise longitudinal registration analysis was performed using SPM12 to calculate Jacobian determinant maps. Next, we performed partial least‐squares analysis to determine the optimal number of CSF biomarker components and tested their association with GM volume changes by AT (Amyloid‐Tau) stage.ResultFour distinct biomarker components (C1‐4) were identified (Figure1). C1 was driven by moderate contributions from several biomarkers, particularly markers of core AD pathology and neurodegeneration, which were strongly associated with temporal lobe atrophy in A+T‐ individuals. C2 represented mainly Aß pathology and, to a lesser extent, axonal damage and astrogliosis that contributed to a decrease in GM volume, especially in the hippocampus in A‐T‐ participants, while showing strong correlations with volume increases in medial frontal regions in A+T+ participants. C3 loading was associated with greater frontoparietal atrophy, especially in A+T+ individuals, and consisted of microglial activation together with Aß pathology but in the absence of reactive astrogliosis. Lastly, C4, reflecting mostly microglial activation alone, was also strongly associated with frontoparietal atrophy, particularly in A+T+ participants.ConclusionOur results suggest important contributions of Aß pathology, neuroaxonal damage, and microglial activation to GM morphometry changes in the earliest stages of the AD continuum. Atrophy patterns differed depending on the underlying pathological drivers and on A and T positivity, showing stronger correlations with increasing disease severity; however, volumetric increases were also observed.

Whole-brain gray matter maturation trajectories associated with autistic traits from adolescence to early adulthood.

A growing number of evidence supports a continued distribution of autistic traits in the general population. However, brain maturation trajectories of autistic traits as well as the influence of sex on these trajectories remain largely unknown. We investigated the association of autistic traits in the general population, with longitudinal gray matter (GM) maturation trajectories during the critical period of adolescence. We assessed 709 community-based adolescents (54.7% women) at age 14 and 22. After testing the effect of sex, we used whole-brain voxel-based morphometry to measure longitudinal GM volumes changes associated with autistic traits measured by the Social Responsiveness Scale (SRS) total and sub-scores. In women, we observed that the SRS was associated with slower GM volume decrease globally and in the left parahippocampus and middle temporal gyrus. The social communication sub-score correlated with slower GM volume decrease in the left parahippocampal, superior temporal gyrus, and pallidum; and the social cognition sub-score correlated with slower GM volume decrease in the left middle temporal gyrus, the right ventromedial prefrontal and orbitofrontal cortex. No longitudinal association was found in men. Autistic traits in young women were found to be associated with specific brain trajectories in regions of the social brain and the reward circuit known to be involved in Autism Spectrum Disorder. These findings support both the hypothesis of an earlier GM maturation associated with autistic traits in adolescence and of protective mechanisms in women. They advocate for further studies on brain trajectories associated with autistic traits in women.

Network-Based Spreading of Gray Matter Changes Across Different Stages of Psychosis

Psychotic illness is associated with anatomically distributed gray matter reductions that can worsen with illness progression, but the mechanisms underlying the specific spatial patterning of these changes is unknown. To test the hypothesis that brain network architecture constrains cross-sectional and longitudinal gray matter alterations across different stages of psychotic illness and to identify whether certain brain regions act as putative epicenters from which volume loss spreads. This case-control study included 534 individuals from 4 cohorts, spanning early and late stages of psychotic illness. Early-stage cohorts included patients with antipsychotic-naive first-episode psychosis (n = 59) and a group of patients receiving medications within 3 years of psychosis onset (n = 121). Late-stage cohorts comprised 2 independent samples of people with established schizophrenia (n = 136). Each patient group had a corresponding matched control group (n = 218). A sample of healthy adults (n = 356) was used to derive representative structural and functional brain networks for modeling of network-based spreading processes. Longitudinal illness-related and antipsychotic-related gray matter changes over 3 and 12 months were examined using a triple-blind randomized placebo-control magnetic resonance imaging study of the antipsychotic-naive patients. All data were collected between April 29, 2008, and January 15, 2020, and analyses were performed between March 1, 2021, and January 14, 2023. Coordinated deformation models were used to estimate the extent of gray matter volume (GMV) change in each of 332 parcellated areas by the volume changes observed in areas to which they were structurally or functionally coupled. To identify putative epicenters of volume loss, a network diffusion model was used to simulate the spread of pathology from different seed regions. Correlations between estimated and empirical spatial patterns of GMV alterations were used to quantify model performance. Of 534 included individuals, 354 (66.3%) were men, and the mean (SD) age was 28.4 (7.4) years. In both early and late stages of illness, spatial patterns of cross-sectional volume differences between patients and controls were more accurately estimated by coordinated deformation models constrained by structural, rather than functional, network architecture (r range, >0.46 to <0.57; P < .01). The same model also robustly estimated longitudinal volume changes related to illness (r ≥ 0.52; P < .001) and antipsychotic exposure (r ≥ 0.50; P < .004). Network diffusion modeling consistently identified, across all 4 data sets, the anterior hippocampus as a putative epicenter of pathological spread in psychosis. Epicenters of longitudinal GMV loss were apparent in posterior cortex early in the illness and shifted to the prefrontal cortex with illness progression. These findings highlight a central role for white matter fibers as conduits for the spread of pathology across different stages of psychotic illness, mirroring findings reported in neurodegenerative conditions. The structural connectome thus represents a fundamental constraint on brain changes in psychosis, regardless of whether these changes are caused by illness or medication. Moreover, the anterior hippocampus represents a putative epicenter of early brain pathology from which dysfunction may spread to affect connected areas.

PASSED: Brain atrophy in non-demented individuals in a long-term longitudinal study from two independent cohorts.

Alzheimer's disease (AD) is indicated by a decrease in amyloid beta 42 (Aβ42) level or the Aβ42/Aβ40 ratio, and by increased levels of Tau with phosphorylated threonine at position 181 (pTau181) in cerebrospinal fluid (CSF) years before the onset of clinical symptoms. However, once only pTau181 is increased, cognitive decline in individuals with subjective or mild cognitive impairment is slowed compared to individuals with AD. Instead of a decrease in Aβ42 levels, an increase in Aβ42 was observed in these individuals, leading to the proposal to refer to them as nondemented subjects with increased pTau-levels and Aβ surge with subtle cognitive deterioration (PASSED). In this study, we determined the longitudinal atrophy rates of AD, PASSED, and Biomarker-negative nondemented individuals of two independent cohorts to determine whether these groups can be distinguished by their longitudinal atrophy patterns or rates. Depending on their CSF-levels of pTau 181 (T), total Tau (tTau, N), Aβ42 or ratio of Aβ42/Aβ40 (A), 185 non-demented subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and 62 non-demented subjects from Erlangen AD cohort were assigned to an ATN group (A-T-N-, A-T+N±, A+T-N±and A+T+N±) and underwent T1-weighted structural magnetic resonance imaging (sMRI). Longitudinal grey matter (GM) atrophy patterns were assessed with voxel-based morphometry (VBM) using the cat12 toolbox on spm12 (statistical parametric mapping) of MRI scans from individuals in the ADNI cohort with a mean follow-up of 2 and 5 years, respectively. The annualized atrophy rate for individuals in the Erlangen cohort was determined using region of interest analysis (ROI) in terms of a confirmatory analysis. In the A-T+N± group, VBM did not identify any brain region that showed greater longitudinal atrophy than the A+T+N±, A+T+N± or biomarker negative control group. In contrast, marked longitudinal atrophy in the temporal lobe was evident in the A+T-N± group compared with A+T-N± and biomarker-negative subjects. The ROI in the angular gyrus identified by VBM analysis of the ADNI cohort did not discriminate better than the hippocampal volume and atrophy rate between AD and PASSED in the confirmatory analysis. In this study, nondemented subjects with PASSED did not show a unique longitudinal atrophy pattern in comparison to nondemented subjects with AD. The nonsignificant atrophy rate compared with controls suggests that increased pTau181-levels without concomitant amyloidopathy did not indicate a neurodegenerative disorder.

Age‐dependent effects of the p75 neurotrophin receptor modulator LM11A‐31 on Alzheimer’s disease biomarkers in a 26‐week safety and exploratory endpoint trial

AbstractBackgroundThe p75 neurotrophin receptor (p75NTR) modulates pro‐ and anti‐apoptotic pathways as well as neurite and neuritic spine integrity. This receptor is expressed in cells vulnerable to aging and disease, including basal forebrain cholinergic neurons and hippocampal pyramidal neurons. It is also expressed by glial cells under pathological conditions. Pharmacological modulation of the p75NTR with LM11A‐31 alters both age‐ and disease‐related neuronal dysfunction. For example, LM11A‐31 reverses neuritic pathology in aged mice and reduces amyloid‐induced tau phosphorylation in mouse models of Alzheimer’s disease (AD). In this proof‐of‐concept study, we examined the effects of LM11A‐31 treatment on longitudinal neuroimaging and CSF biomarkers in humans with mild to moderate Alzheimer’s disease. Based on our preclinical work, we hypothesized that age and disease may interact to predict response to LM11A‐31 treatment in humans. Therefore, we additionally conducted subgroup analyses of drug effect in older and younger individuals.MethodParticipants with mild to moderate AD (MMSE score = 18‐26; age 55‐85 years) were enrolled in a 26‐week placebo‐controlled phase 2a safety and exploratory endpoint trial of LM11A‐31. Exploratory outcome measures included structural MRI, CSF AD core biomarkers, and CSF biomarkers related to pathological processes affected in mouse studies including synaptic integrity and inflammation. For placebo and drug, age subgroups were defined using a median‐split: younger (&lt;72 years) and older (&gt; = 72 years).ResultWhole brain structural MRI analyses revealed that 26‐week treatment with LM11A‐31 reduced longitudinal grey matter degeneration in AD‐vulnerable brain regions including the inferior temporal gyrus, insula, frontal operculum and retrosplenial cortex. Furthermore, drug treatment, compared to placebo, prevented longitudinal increases of CSF tau, the presynaptic biomarker SNAP25, and the inflammatory biomarker YKL‐40. Median split analyses demonstrated that drug effects for structural MRI and CSF measures were consistently stronger in younger individuals.ConclusionThis investigation highlights that biomarkers may demonstrate age‐dependency in response to therapeutic interventions in the context of mild‐moderate AD. Our results may inform biomarker selection and design of future studies of LM11A‐31 in human AD.

Tau accumulation and degeneration differ across functional networks in atypical Alzheimer's disease phenotypes

AbstractBackgroundRecent models of Alzheimer's disease (AD) posit that pathogenic tau propagates through interconnected structural networks, suggesting amnestic and non‐amnestic AD (aAD &amp; naAD) phenotypes could reflect differential involvement of functional networks. We tested this hypothesis by contrasting longitudinal grey matter (GM) atrophy and tau accumulation across AD clinical phenotypes in 7 canonical functional networks.MethodsWe analyzed longitudinal 3‐Tesla T1‐weighted MRI from 122 patients [aAD=49; logopenic primary progressive aphasia (lvPPA)=31; posterior cortical atrophy (PCA)=23; behavioral/dysexecutive AD (bvAD)=6; corticobasal syndrome (CBS)=6; mixed naAD=4] with autopsy or CSF evidence of AD pathology and 91 cognitively normal controls (Table 1). Thirty‐one patients (aAD=9; lvPPA=7; PCA=9; bvAD=2; CBS=3; naAD=1) had longitudinal flortaucipir PET (FTP‐PET) data. We computed baseline values and annualized change for GM volume and FTP‐PET standardized uptake value ratios (SUVRs) in the 100‐label, 7‐network parcellation of Schaefer et al. (2018). Linear mixed effects models (α=0.05, corrected) adjusting for MMSE assessed group differences in atrophy and tau accumulation.ResultsAll groups exhibited significant baseline and longitudinal atrophy vs. controls in multiple networks (Figs. 1‐2). Differences in longitudinal atrophy rate (Fig. 2) were observed in the dorsal attention network [PCA&gt;lvPPA, t(371)=3.1, p&lt;0.04], salience network [PCA&gt;aAD, t(371)=3.1, p&lt;0.04], and limbic network [CBS&gt;aAD, t(371)=3.3, p&lt;0.02; CBS&gt;bvAD, t(371)=3.7, p&lt;0.006]. PCA patients exhibited FTP‐PET SUVR increases in all networks (all p&lt;0.02), while aAD patients displayed increases in all networks except visual and limbic (all others p&lt;0.0001). LvPPA patients exhibited net SUVR increases only in the somatomotor network [t(97)=3.5, p&lt;0.001]. At baseline, lvPPA patients had left &gt; right atrophy in all networks [all t&gt;3.7, p&lt;0.0002]; right &gt; left atrophy was observed in the visual network for PCA and CBS; the salience network for PCA and bvAD; and in the dorsal attention, frontoparietal control, and default mode networks for bvAD [all t&gt;3.0, p&lt;0.03]. In longitudinal analyses, no hemispheric differences were found in rates of GM volume loss or FTP‐PET change.ConclusionAD clinical variants exhibited GM atrophy and tau accumulation in partially overlapping networks. Investigating early‐stage disease will be crucial for assessing whether disease spread through canonical functional networks can explain anatomic differences in aAD and naAD phenotypes.

First-time fathers show longitudinal gray matter cortical volume reductions: evidence from two international samples.

Emerging evidence points to the transition to parenthood as a critical window for adult neural plasticity. Studying fathers offers a unique opportunity to explore how parenting experience can shape the human brain when pregnancy is not directly experienced. Yet very few studies have examined the neuroanatomic adaptations of men transitioning into fatherhood. The present study reports on an international collaboration between two laboratories, one in Spain and the other in California (United States), that have prospectively collected structural neuroimaging data in 20 expectant fathers before and after the birth of their first child. The Spanish sample also included a control group of 17 childless men. We tested whether the transition into fatherhood entailed anatomical changes in brain cortical volume, thickness, and area, and subcortical volumes. We found overlapping trends of cortical volume reductions within the default mode network and visual networks and preservation of subcortical structures across both samples of first-time fathers, which persisted after controlling for fathers' and children's age at the postnatal scan. This study provides convergent evidence for cortical structural changes in fathers, supporting the possibility that the transition to fatherhood may represent a meaningful window of experience-induced structural neuroplasticity in males.

Functional connectivity to the premotor cortex maps onto longitudinal brain neurodegeneration in progressive apraxia of speech

Primary progressive apraxia of speech (PPAOS) is a neurodegenerative motor speech disorder affecting the ability to produce speech. If agrammatic aphasia is present, it can be referred to as the non-fluent/agrammatic variant of primary progressive aphasia (nfvPPA). We investigated whether resting-state functional MRI (rs-fMRI) connectivity from disease “epicenters” correlated with longitudinal gray matter atrophy and hypometabolism in nfvPPA and PPAOS. Eighteen nfvPPA and 23 PPAOS patients underwent clinical assessment, structural MRI, rs-fMRI, and [18F] fluorodeoxyglucose (FDG)-PET at baseline and ∼2 years follow-up. Rates of neurodegeneration in nfvPPA and PPAOS correlated with functional connectivity to the premotor, motor, and frontal cortex. Connectivity to the caudate and thalamus was more strongly associated with rates of hypometabolism than atrophy. Connectivity to the left Broca's area was more strongly associated with rates of atrophy and hypometabolism in nfvPPA. Finally, functional connectivity to a network of regions, and not to a single epicenter, correlated with rates of neurodegeneration in PPAOS and nfvPPA, suggesting similar biological mechanisms driving disease progression, with regional differences related to language.

Longitudinal grey matter and metabolic contributions to cognitive changes in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis is characterized by rapidly evolving cognitive and brain impairments. While previous work revealed structural and functional alterations associated with cognitive decline in patients suffering from amyotrophic lateral sclerosis, the relationships between anatomo-functional changes and both disease’s progression and the evolution of cognitive performance remain largely unexplored. Here, we took advantage of repeated multi-modal acquisitions in patients with amyotrophic lateral sclerosis over 1 year to assess the longitudinal sequence of grey matter atrophy, glucose metabolism and cognitive changes. Results revealed metabolic and structural changes over frontal, thalamic and temporal regions. Both cortical hypermetabolism and hypometabolism (right temporal gyrus and right angular gyrus, respectively) were associated with cognitive performance and thalamic hypometabolism during the follow-up testing session. Furthermore, the inferior frontal gyrus atrophy mediated the relation between early hypometabolism in this region and the subsequent decline of the theory of mind abilities. Marked volume loss was associated with larger hypometabolism and impaired cognitive performance. To our knowledge, this is the first study to longitudinally examine both grey matter volume and metabolic alteration patterns in patients with amyotrophic lateral sclerosis, over a mean follow-up time of 1 year. We identify how changes of the inferior frontal gyrus critically underly later cognitive performance, shedding new light on its high prognostic significance for amyotrophic lateral sclerosis-related changes. These results have important implications for our understanding of structural and functional changes associated with amyotrophic lateral sclerosis and how they underly cognitive impairments.

Combined Effects of Synaptic and Axonal Integrity on Longitudinal Gray Matter Atrophy in Cognitively Unimpaired Adults.

Synaptic dysfunction and degeneration is a predominant feature of brain aging, and synaptic preservation buffers against Alzheimer disease (AD) protein-related brain atrophy. We tested whether CSF synaptic protein concentrations similarly moderate the effects of axonal injury, indexed by CSF neurofilament light [NfL]), on brain atrophy in clinically normal adults. Clinically normal older adults enrolled in the observational Hillblom Aging Network study at the UCSF Memory and Aging Center completed baseline lumbar puncture and longitudinal brain MRI (mean scan [follow-up] = 2.6 [3.7 years]). CSF was assayed for synaptic proteins (synaptotagmin-1, synaptosomal-associated protein 25 [SNAP-25], neurogranin, growth-associated protein 43 [GAP-43]), axonal injury (NfL), and core AD biomarkers (ptau181/Aβ42 ratio; reflecting AD proteinopathy). Ten bilateral temporoparietal gray matter region of interest (ROIs) shown to be sensitive to clinical AD were summed to generate a composite temporoparietal ROI. Linear mixed-effects models tested statistical moderation of baseline synaptic proteins on baseline NfL-related temporoparietal trajectories, controlling for ptau181/Aβ42 ratios. Forty-six clinically normal older adults (mean age = 70 years; 43% female) were included. Synaptic proteins exhibited small to medium correlations with NfL (r range: 0.10-0.36). Higher baseline NfL, but not ptau181/Aβ42 ratios, predicted steeper temporoparietal atrophy (NfL × time: β = -0.08, p < 0.001; ptau181/Aβ42 × time: β = -0.02, p = 0.31). SNAP-25, neurogranin, and GAP-43 significantly moderated NfL-related atrophy trajectories (-0.07 ≤ β's ≥ -0.06, p's < 0.05) such that NfL was associated with temporoparietal atrophy at high (more abnormal) but not low (more normal) synaptic protein concentrations. At high NfL concentrations, atrophy trajectories were 1.5-4.5 times weaker when synaptic protein concentrations were low (β range: -0.21 to -0.07) than high (β range: -0.33 to -0.30). The association between baseline CSF NfL and longitudinal temporoparietal atrophy is accelerated by synaptic dysfunction and buffered by synaptic integrity. Beyond AD proteins, concurrent examination of in vivo axonal and synaptic biomarkers may improve detection of neural alterations that precede overt structural changes in AD-sensitive brain regions.

Alcohol and cannabis co-use and longitudinal gray matter volumetric changes in early and late adolescence.

Previous studies have characterized the impact of substance use on cerebral structure and function in adolescents. Yet, the great majority of prior studies employed a small sample, presented cross-sectional findings, and omitted potential sex differences. Using data based on 724 adolescents (370 females) curated from the NCANDA study, we investigated how gray matter volumes (GMVs) decline longitudinally as a result of alcohol and cannabis use. The impacts of alcohol and cannabis co-use and how these vary across assigned sex at birth and age were examined. Brain imaging data comprised the GMVs of 34 regions of interest and the results were evaluated with a Bonferroni correction. Mixed-effects modeling showed faster volumetric declines in the caudal middle frontal cortex, fusiform, inferior frontal, superior temporal (STG), and supramarginal (SMG) gyri, at -0.046 to -0.138 cm3 /year in individuals with prior-year alcohol and cannabis co-use, but not those engaged in alcohol or cannabis use only. These findings cannot be explained by more severe alcohol use among co-users. Further, alcohol and cannabis co-use in early versus late adolescence predicted faster volumetric decline in the STG and SMG across assigned sex at birth. Findings highlight the longitudinal impact of alcohol and cannabis co-use on brain development, especially among youth reporting early adolescent onset of use. The volumetric decline was noted in cortical regions in support of attention, memory, executive control, and social cognition, suggesting the pervasive effect of alcohol and cannabis co-use on brain development.