ANTsX neuroimaging-derived structural phenotypes of UK Biobank.

UK Biobank is a large-scale epidemiological resource for investigating prospective correlations between various lifestyle, environmental, and genetic factors with health and disease progression. In addition to individual subject information obtained through surveys and physical examinations, a comprehensive neuroimaging battery consisting of multiple modalities provides imaging-derived phenotypes (IDPs) that can serve as biomarkers in neuroscience research. In this study, we augment the existing set of UK Biobank neuroimaging structural IDPs, obtained from well-established software libraries such as FSL and FreeSurfer, with related measurements acquired through the Advanced Normalization Tools Ecosystem. This includes previously established cortical and subcortical measurements defined, in part, based on the Desikan-Killiany-Tourville atlas. Also included are morphological measurements from two recent developments: medial temporal lobe parcellation of hippocampal and extra-hippocampal regions in addition to cerebellum parcellation and thickness based on the Schmahmann anatomical labeling. Through predictive modeling, we assess the clinical utility of these IDP measurements, individually and in combination, using commonly studied phenotypic correlates including age, fluid intelligence, numeric memory, and several other sociodemographic variables. The predictive accuracy of these IDP-based models, in terms of root-mean-squared-error or area-under-the-curve for continuous and categorical variables, respectively, provides comparative insights between software libraries as well as potential clinical interpretability. Results demonstrate varied performance between package-based IDP sets and their combination, emphasizing the need for careful consideration in their selection and utilization.

Neurofilament light chain concentration mediates the association between regional medial temporal lobe structure and memory in adults with Down syndrome.

INTRODUCTION: Virtually all people with Down syndrome (DS) develop neuropathology associated with Alzheimer's disease (AD). Atrophy of the hippocampus and entorhinal cortex (EC), as well as elevated plasma concentrations of neurofilament light chain (NfL) protein, are markers of neurodegeneration associated with late-onset AD. We hypothesized that hippocampus and EC gray matter loss and increased plasma NfL concentrations are associated with memory in adults with DS. METHODS: T1-weighted structural magnetic resonance imaging (MRI) data were collected from 101 participants with DS. Hippocampus and EC volume, as well as EC subregional cortical thickness, were derived. In a subset of participants, plasma NfL concentrations and modified Cued Recall Test scores were obtained. Partial correlation and mediation were used to test relationships between medial temporal lobe (MTL) atrophy, plasma NfL, and episodic memory. RESULTS: Hippocampus volume, left anterolateral EC (alEC) thickness, and plasma NfL were correlated with each other and were associated with memory. Plasma NfL mediated the relationship between left alEC thickness and memory as well as hippocampus volume and memory. DISCUSSION: The relationship between MTL gray matter and memory is mediated by plasma NfL levels, suggesting a link between neurodegenerative processes underlying axonal injury and frank gray matter loss in key structures supporting episodic memory in people with DS.

ANTsX neuroimaging-derived structural phenotypes of UK Biobank.

UK Biobank is a large-scale epidemiological resource for investigating prospective correlations between various lifestyle, environmental, and genetic factors with health and disease progression. In addition to individual subject information obtained through surveys and physical examinations, a comprehensive neuroimaging battery consisting of multiple modalities provides imaging-derived phenotypes (IDPs) that can serve as biomarkers in neuroscience research. In this study, we augment the existing set of UK Biobank neuroimaging structural IDPs, obtained from well-established software libraries such as FSL and FreeSurfer, with related measurements acquired through the Advanced Normalization Tools Ecosystem. This includes previously established cortical and subcortical measurements defined, in part, based on the Desikan-Killiany-Tourville atlas. Also included are morphological measurements from two recent developments: medial temporal lobe parcellation of hippocampal and extra-hippocampal regions in addition to cerebellum parcellation and thickness based on the Schmahmann anatomical labeling. Through predictive modeling, we assess the clinical utility of these IDP measurements, individually and in combination, using commonly studied phenotypic correlates including age, fluid intelligence, numeric memory, and several other sociodemographic variables. The predictive accuracy of these IDP-based models, in terms of root-mean-squared-error or area-under-the-curve for continuous and categorical variables, respectively, provides comparative insights between software libraries as well as potential clinical interpretability. Results demonstrate varied performance between package-based IDP sets and their combination, emphasizing the need for careful consideration in their selection and utilization.

Pathways linking pulse pressure to dementia in adults with Down syndrome.

Individuals with Down syndrome (DS) are less likely to have hypertension than neurotypical adults. However, whether blood pressure measures are associated with brain health and clinical outcomes in this population has not been studied in detail. Here, we assessed whether pulse pressure is associated with markers of cerebrovascular disease, entorhinal cortical atrophy, and diagnosis of dementia in adults with DS. Participants with DS from the Biomarkers of Alzheimer's Disease in Adults with Down Syndrome study (ADDS; n=195, age=50.6±7.2 years, 44% women, 18% diagnosed with dementia) were included. Higher pulse pressure was associated with greater global, parietal, and occipital WMH volume. Pulse pressure was not related to enlarged PVS, microbleeds, infarcts, entorhinal cortical thickness, or dementia diagnosis. However, in a serial mediation model, we found that pulse pressure was indirectly related to dementia diagnosis through parieto-occipital WMH and, subsequently through entorhinal cortical thickness. Higher pulse pressure may be a risk factor for dementia in people with DS by promoting cerebrovascular disease, which in turn affects neurodegeneration. Pulse pressure is an important determinant of brain health and clinical outcomes in individuals with Down syndrome despite the low likelihood of frank hypertension.

Overnight olfactory enrichment using an odorant diffuser improves memory and modifies the uncinate fasciculus in older adults.

Objective: Cognitive loss in older adults is a growing issue in our society, and there is a need to develop inexpensive, simple, effective in-home treatments. This study was conducted to explore the use of olfactory enrichment at night to improve cognitive ability in healthy older adults. Methods: Male and female older adults (N = 43), age 60-85, were enrolled in the study and randomly assigned to an Olfactory Enriched or Control group. Individuals in the enriched group were exposed to 7 different odorants a week, one per night, for 2 h, using an odorant diffuser. Individuals in the control group had the same experience with de minimis amounts of odorant. Neuropsychological assessments and fMRI scans were administered at the beginning of the study and after 6 months. Results: A statistically significant 226% improvement was observed in the enriched group compared to the control group on the Rey Auditory Verbal Learning Test and improved functioning was observed in the left uncinate fasciculus, as assessed by mean diffusivity. Conclusion: Minimal olfactory enrichment administered at night produces improvements in both cognitive and neural functioning. Thus, olfactory enrichment may provide an effective and low-effort pathway to improved brain health.

Reduced structural connectivity of the medial temporal lobe including the perforant path is associated with aging and verbal memory impairment.

The perforant path, the white matter bundle connecting the entorhinal cortex (ERC) with the hippocampal formation deteriorates with age-related cognitive decline. Previous investigations using diffusion-weighted MRI to quantify perforant path integrity in-vivo have been limited due to image resolution or have quantified the perforant path using methods susceptible to partial volume effects such as the tensor model and without consideration of its 3-dimensional morphology. In this investigation, we use quantitative-anisotropy informed tractography derived from ultra-high resolution diffusion imaging (ZOOMit) to investigate structural connectivity of the perforant path and other medial temporal lobe (MTL) pathways in older adults (63 to 98 years old, n = 51). We show that graph density within the MTL declines with age and is associated with lower delayed recall performance. We also show that older age and poorer delayed recall are associated with reduced streamlines connecting the ERC and dentate gyrus of the hippocampus (the putative perforant path). This work suggest that intra-MTL connectivity may new candidate biomarkers for age-related cognitive decline.

Posterior white matter hyperintensities are associated with reduced medial temporal lobe subregional integrity and long-term memory in older adults.

White matter hyperintensities are a marker of small vessel cerebrovascular disease that are strongly related to cognition in older adults. Similarly, medial temporal lobe atrophy is well-documented in aging and Alzheimer's disease and is associated with memory decline. Here, we assessed the relationship between lobar white matter hyperintensities, medial temporal lobe subregional volumes, and hippocampal memory in older adults. We collected MRI scans in a sample of 139 older adults without dementia (88 females, mean age (SD) = 76.95 (10.61)). Participants were administered the Rey Auditory Verbal Learning Test (RAVLT). Regression analyses tested for associations among medial temporal lobe subregional volumes, regional white matter hyperintensities and memory, while adjusting for age, sex, and education and correcting for multiple comparisons. Increased occipital white matter hyperintensities were related to worse RAVLT delayed recall performance, and to reduced CA1, dentate gyrus, perirhinal cortex (Brodmann area 36), and parahippocampal cortex volumes. These medial temporal lobe subregional volumes were related to delayed recall performance. The association of occipital white matter hyperintensities with delayed recall performance was fully mediated statistically only by perirhinal cortex volume. These results suggest that white matter hyperintensities may be associated with memory decline through their impact on medial temporal lobe atrophy. These findings provide new insights into the role of vascular pathologies in memory loss in older adults and suggest that future studies should further examine the neural mechanisms of these relationships in longitudinal samples.

Entorhinal-Hippocampal Circuit Integrity Is Related to Mnemonic Discrimination and Amyloid-ß Pathology in Older Adults.

Mnemonic discrimination, a cognitive process that relies on hippocampal pattern separation, is one of the first memory domains to decline in aging and preclinical Alzheimer's disease. We tested whether functional connectivity (FC) within the entorhinal-hippocampal circuit, measured with high-resolution resting state fMRI, is associated with mnemonic discrimination and amyloid-ß (Aß) pathology in a sample of 64 cognitively normal human older adults (mean age, 71.3 ± 6.4 years; 67% female). FC was measured between entorhinal-hippocampal circuit nodes with known anatomical connectivity, as well as within cortical memory networks. Aß pathology was measured with 18F-florbetapir-PET, and neurodegeneration was assessed with subregional volume from structural MRI. Participants performed both object and spatial versions of a mnemonic discrimination task outside of the scanner and were classified into low-performing and high-performing groups on each task using a median split. Low object mnemonic discrimination performance was specifically associated with increased FC between anterolateral entorhinal cortex (alEC) and dentate gyrus (DG)/CA3, supporting the importance of this connection to object memory. This hyperconnectivity between alEC and DG/CA3 was related to Aß pathology and decreased entorhinal cortex volume. In contrast, spatial mnemonic discrimination was not associated with altered FC. Aß was further associated with dysfunction within hippocampal subfields, particularly with decreased FC between CA1 and subiculum as well as reduced volume in these regions. Our findings suggest that Aß may indirectly lead to memory impairment through entorhinal-hippocampal circuit dysfunction and neurodegeneration and provide a mechanism for increased vulnerability of object mnemonic discrimination.SIGNIFICANCE STATEMENT Mnemonic discrimination is a critical episodic memory process that is performed in the dentate gyrus (DG) and CA3 subfield of the hippocampus, relying on input from entorhinal cortex. Mnemonic discrimination is particularly vulnerable to decline in older adults; however, the mechanisms behind this vulnerability are still unknown. We demonstrate that object mnemonic discrimination impairment is related to hyperconnectivity between the anterolateral entorhinal cortex and DG/CA3. This hyperconnectivity was associated with amyloid-ß pathology and neurodegeneration in entorhinal cortex, suggesting aberrantly increased network activity is a pathological process. Our findings provide a mechanistic explanation of the vulnerability of object compared to spatial mnemonic discrimination in older adults and has translational implications for choice of outcome measures in clinical trials for Alzheimer's disease.

Why do mothers never stop grieving for their deceased children? Enduring alterations of brain connectivity and function.

A child's death is a profound loss for mothers and affects hundreds of thousands of women. Mothers report inconsolable and progressive grief that is distinct from depression and impacts daily emotions and functions. The brain mechanisms responsible for this relatively common and profound mental health problem are unclear, hampering its clinical recognition and care. In an initial exploration of this condition, we used resting state functional MRI (fMRI) scans to examine functional connectivity in key circuits, and task-based fMRI to examine brain network activity in grieving mothers in response to pictures of their deceased child and as well as recognizable deceased celebrities and unfamiliar individuals. We compared nine mothers who had lost an adult child and aged-matched control mothers with a living child of a similar age. Additionally, we collected diffusion imaging scans to probe structural connectivity and complemented the imaging studies with neuropsychological assessments. Increased functional activation in Ventral Attention/Salience Networks accompanied by a reduced activation in the medial prefrontal cortex in response to the deceased child's picture robustly distinguished the grieving mothers from controls. Heightened resting-state functional connectivity between the paraventricular thalamic nucleus (PVT) and the amygdala distinguished the grieving mothers from the controls and correlated with subjective grief severity. Structurally, maternal grief and its severity were associated with alterations in corticolimbic white matter tracts. Finally, grieving mothers performed worse than controls on neuropsychological tests of learning, memory, and executive function, linked with grief severity. Reduced activation in cortical regions inhibiting emotions and changes in the PVT circuitry-a region involved in long-term emotional memories and decision making under conflict-distinguish grieving mothers from controls. Notably, the magnitude of neurobiological changes correlates with the subjective severity of grief. Together, these new discoveries delineate a prevalent and under-recognized mental health syndrome and chart a path for its appreciation and care.

Hippocampal dentate gyrus integrity revealed with ultrahigh resolution diffusion imaging predicts memory performance in older adults.

Medial temporal lobe (MTL) atrophy is a core feature of age-related cognitive decline and Alzheimer's disease (AD). While regional volumes and thickness are often used as a proxy for neurodegeneration, they lack the sensitivity to serve as an accurate diagnostic test and indicate advanced neurodegeneration. Here, we used a submillimeter resolution diffusion weighted MRI sequence (ZOOMit) to quantify microstructural properties of hippocampal subfields in older adults (63-98 years old) using tensor derived measures: fractional anisotropy (FA) and mean diffusivity (MD). We demonstrate that the high-resolution sequence, and not a standard resolution sequence, identifies dissociable profiles for CA1, dentate gyrus (DG), and the collateral sulcus. Using ZOOMit, we show that advanced age is associated with increased MD of the CA1 and DG as well as decreased FA of the DG. Increased MD of the DG, reflecting decreased cellular density, mediated the relationship between age and word list recall. Further, increased MD in the DG, but not DG volume, was linked to worse spatial pattern separation. Our results demonstrate that ultrahigh-resolution diffusion imaging enables the detection of microstructural differences in hippocampal subfield integrity and will lead to novel insights into the mechanisms of age-related memory loss.

Obstructive sleep apnea, cerebrovascular disease, and amyloid in older adults with Down syndrome across the Alzheimer's continuum.

We determined the extent to which obstructive sleep apnea (OSA) is associated with increased cerebrovascular disease and amyloid burden, and the relation of the two processes across clinical Alzheimer's disease (AD) diagnostic groups in adults with Down syndrome (DS). Adults with DS from the Biomarkers of Alzheimer's Disease in Down Syndrome (ADDS) study were included given available research MRI (n = 116; 50 ± 8 years; 42% women) and amyloid PET scans (n = 71; 50 ± 7 years; 39% women) at the time of analysis. Participants were characterized as cognitively stable (CS; 64%), with mild cognitive impairment-DS (MCI-DS; 23%), with possible AD dementia (5%), or with definite AD dementia (8%). OSA was determined via medical records and interviews. Models tested the effect of OSA on MRI-derived cerebrovascular biomarkers and PET-derived amyloid burden, and the moderating effect of OSA and AD diagnosis on biomarkers. OSA was reported in 39% of participants, which did not differ by clinical AD diagnostic group. OSA was not associated with cerebrovascular biomarkers but was associated with greater cortical amyloid burden. White matter hyperintensity (WMH) volume (primarily in the parietal lobe), enlarged perivascular spaces, and cortical and striatal amyloid burden were greater across clinical AD diagnostic groups (CS

Probing the proteome to explore potential correlates of increased Alzheimer's-related cerebrovascular disease in adults with Down syndrome.

Cerebrovascular disease is associated with symptoms and pathogenesis of Alzheimer's disease (AD) among adults with Down syndrome (DS). The cause of increased dementia-related cerebrovascular disease in DS is unknown. We explored whether protein markers of neuroinflammation are associated with markers of cerebrovascular disease among adults with DS. Participants from the Alzheimer's disease in Down syndrome (ADDS) study with magnetic resonance imaging (MRI) scans and blood biomarker data were included. Support vector machine (SVM) analyses examined the relationship of blood-based proteomic biomarkers with MRI-defined cerebrovascular disease among participants characterized as having cognitive decline (n = 36, mean age ± SD = 53 ± 6.2) and as being cognitively stable (n = 78, mean age = 49 ± 6.4). Inflammatory and AD markers were associated with cerebrovascular disease, particularly among symptomatic individuals. The pattern suggested relatively greater inflammatory involvement among cognitively stable individuals and greater AD involvement among those with cognitively decline. The findings help to generate hypotheses that both inflammatory and AD markers are implicated in cerebrovascular disease among those with DS and point to potential mechanistic pathways for further examination.

Latent anxiety in clinical depression is associated with worse recognition of emotional stimuli.

BACKGROUND: Major Depressive Disorder, characterized by cognitive affective biases, is a considerable public health challenge. Past work has shown that higher depressive symptoms are associated with augmented memory of negative stimuli. In contrast, anxiety symptoms have been associated with overgeneralization of emotional memories. Given the high comorbidity of depression and anxiety, it is critical to understand how cognitive affective biases are differentially associated with clinical symptoms. METHOD: We used continuous measures of depression (Beck Depression Inventory [BDI-II]) and anxiety (Beck Anxiety Inventory [BAI]) to evaluate an adult sample (N = 79; 18-41 years old, 58 female). Emotional memory discrimination and recognition memory were tested using an emotional discrimination task. We applied exploratory factor analysis to questions from the BAI and BDI-II to uncover latent constructs consisting of negative affect, anhedonia, somatic anxiety, and cognitive anxiety. RESULTS: We report evidence that anxious symptoms were associated with impaired recognition of negative items after accounting for age and sex. Our exploratory factor analysis revealed that impaired negative item recognition is largely associated with somatic and cognitive anxiety factors. LIMITATIONS: Interpretations in a mixed pathology sample, especially given collinearity among factors, may be difficult. CONCLUSIONS: We provide evidence that somatic and cognitive anxiety are related to impaired recognition memory for negative stimuli. Future clinical investigations should uncover the neurobiological basis supporting the link between recognition of negative stimuli and somatic/cognitive symptoms of anxiety.

Altered connectivity of the default mode network in cognitively stable adults with Down syndrome: "Accelerated aging" or a prelude to Alzheimer's disease?

INTRODUCTION: Most individuals with Down syndrome (DS) have the neuropathological changes of Alzheimer's disease (AD) by age 40 and will have developed dementia by age 60. Alterations of the intrinsic connectivity of the default mode network (DMN) are associated with AD in the neurotypical population. In this study, we sought to determine whether, and how, connectivity between the hubs of the DMN were altered in cognitively stable adults with DS who did not have evidence of either mild cognitive impairment or AD. METHODS: Resting state functional MRI scans were collected from 26 healthy adults with DS and 26 healthy age-matched non-DS controls. Nodes comprising the DMN were generated as ROI's (regions of interest) and inter-nodal correlations estimated. RESULTS: Analysis of intra-network connectivity of the DMN revealed anterior-posterior DMN dissociation and hyper- and hypo-connectivity, suggesting "accelerated aging" in DS. DISCUSSION: Disruption of the DMN may serve as a prelude for AD in DS.

Alzheimer-Related Cerebrovascular Disease in Down Syndrome.

OBJECTIVE: Adults with Down syndrome (DS) develop Alzheimer disease (AD) pathology by their 5th decade. Compared with the general population, traditional vascular risks in adults with DS are rare, allowing examination of cerebrovascular disease in this population and insight into its role in AD without the confound of vascular risk factors. We examined in vivo magnetic resonance imaging (MRI)-based biomarkers of cerebrovascular pathology in adults with DS, and determined their cross-sectional relationship with age, beta-amyloid pathology, and mild cognitive impairment or clinical AD diagnostic status. METHODS: Participants from the Biomarkers of Alzheimer's Disease in Down Syndrome study (n = 138, 50 ± 7 years, 39% women) with MRI data and a subset (n = 90) with amyloid positron emission tomography (PET) were included. We derived MRI-based biomarkers of cerebrovascular pathology, including white matter hyperintensities (WMH), infarcts, cerebral microbleeds, and enlarged perivascular spaces (PVS), as well as PET-based biomarkers of amyloid burden. Participants were characterized as cognitively stable (CS), mild cognitive impairment-DS (MCI-DS), possible AD dementia, or definite AD dementia based on in-depth assessments of cognition, function, and health status. RESULTS: There were detectable WMH, enlarged PVS, infarcts, and microbleeds as early as the 5th decade of life. There was a monotonic increase in WMH volume, enlarged PVS, and presence of infarcts across diagnostic groups (CS < MCI-DS < possible AD dementia < definite AD dementia). Higher amyloid burden was associated with a higher likelihood of an infarct. INTERPRETATION: The findings highlight the prevalence of cerebrovascular disease in adults with DS and add to a growing body of evidence that implicates cerebrovascular disease as a core feature of AD and not simply a comorbidity. ANN NEUROL 2020;88:1165-1177.

Retraining speech production and fluency in non-fluent/agrammatic primary progressive aphasia.

The non-fluent/agrammatic variant of primary progressive aphasia (nfvPPA) presents with a gradual decline in grammar and motor speech resulting from selective degeneration of speech-language regions in the brain. There has been considerable progress in identifying treatment approaches to remediate language deficits in other primary progressive aphasia variants; however, interventions for the core deficits in nfvPPA have yet to be systematically investigated. Further, the neural mechanisms that support behavioural restitution in the context of neurodegeneration are not well understood. We examined the immediate and long-term benefits of video implemented script training for aphasia (VISTA) in 10 individuals with nfvPPA. The treatment approach involved repeated rehearsal of individualized scripts via structured treatment with a clinician as well as intensive home practice with an audiovisual model using 'speech entrainment'. We evaluated accuracy of script production as well as overall intelligibility and grammaticality for trained and untrained scripts. These measures and standardized test scores were collected at post-treatment and 3-, 6-, and 12-month follow-up visits. Treatment resulted in significant improvement in production of correct, intelligible scripted words for trained topics, a reduction in grammatical errors for trained topics, and an overall increase in intelligibility for trained as well as untrained topics at post-treatment. Follow-up testing revealed maintenance of gains for trained scripts up to 1 year post-treatment on the primary outcome measure. Performance on untrained scripts and standardized tests remained relatively stable during the follow-up period, indicating that treatment helped to stabilize speech and language despite disease progression. To identify neural predictors of responsiveness to intervention, we examined treatment effect sizes relative to grey matter volumes in regions of interest derived from a previously identified speech production network. Regions of significant atrophy within this network included bilateral inferior frontal cortices and supplementary motor area as well as left striatum. Volumes in a left middle/inferior temporal region of interest were significantly correlated with the magnitude of treatment effects. This region, which was relatively spared anatomically in nfvPPA patients, has been implicated in syntactic production as well as visuo-motor facilitation of speech. This is the first group study to document the benefits of behavioural intervention that targets both linguistic and motoric deficits in nfvPPA. Findings indicate that behavioural intervention may result in lasting and generalized improvement of communicative function in individuals with neurodegenerative disease and that the integrity of spared regions within the speech-language network may be an important predictor of treatment response.

Spectral characteristics of skin sympathetic nerve activity in heat-stressed humans.

Skin sympathetic nerve activity (SSNA) exhibits low- and high-frequency spectral components in normothermic subjects. However, spectral characteristics of SSNA in heat-stressed subjects are unknown. Because the main components of the integrated SSNA during heat stress (sudomotor/vasodilator activities) are different from those during normothermia and cooling (vasoconstrictor activity), we hypothesize that spectral characteristics of SSNA in heat-stressed subjects will be different from those in subjects subjected to normothermia or cooling. In 17 healthy subjects, SSNA, electrocardiogram, arterial blood pressure (via Finapres), respiratory activity, and skin blood flow were recorded during normothermia and heat stress. In 7 of the 17 subjects, these variables were also recorded during cooling. Spectral characteristics of integrated SSNA, R-R interval, beat-by-beat mean blood pressure, skin blood flow variability, and respiratory excursions were assessed. Heat stress and cooling significantly increased total SSNA. SSNA spectral power in the low-frequency (0.03-0.15 Hz), high-frequency (0.15-0.45 Hz), and very-high-frequency (0.45-2.5 Hz) regions was significantly elevated by heat stress and cooling. Interestingly, heat stress caused a greater relative increase of SSNA spectral power within the 0.45- to 2.5-Hz region than in the other spectral ranges; cooling did not show this effect. Differences in the SSNA spectral distribution between normothermia/cooling and heat stress may reflect different characteristics of central modulation of vasoconstrictor and sudomotor/vasodilator activities.