Whole-brain Volume Research Articles

The association of menopausal hormone levels with progression-related biomarkers in multiple sclerosis

BackgroundMultiple sclerosis (MS) progression coincides temporally with menopause. However, it remains unclear whether the changes in disease course are related to the changes in reproductive hormone concentrations. We assessed the association of menopausal hormonal levels with progression-related biomarkers of MS and evaluated the changes in serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) levels during menopausal hormone therapy (MHT) in a prospective baseline-controlled design. MethodsThe baseline serum estradiol, follicle stimulating hormone, and luteinizing hormone levels were measured from menopausal women with MS (n = 16) and healthy controls (HC, n = 15). SNfL and sGFAP were measured by single-molecule array. The associations of hormone levels with sNfL and sGFAP, and with Expanded Disability Status Scale (EDSS) and lesion load and whole brain volumes (WBV) in MRI were analyzed with Spearman's rank correlation and age-adjusted linear regression model. Changes in sNfL and sGFAP during one-year treatment with estradiol hemihydrate combined with cyclic dydrogesterone were assessed with Wilcoxon Signed Ranks Test. ResultsIn MS group, baseline estradiol had a positive correlation with WBV in MRI and an inverse correlation with lesion load, sNfL and sGFAP, but no correlation with EDSS. The associations of low estradiol with high sGFAP and low WBV were independent of age. During MHT, there was no significant change in sNfL and sGFAP levels in MS group while in HC, sGFAP slightly decreased at three months but returned to baseline at 12 months. ConclusionOur preliminary findings suggest that low estradiol in menopausal women with MS has an age-independent association with more pronounced brain atrophy and higher sGFAP and thus advanced astrogliosis which could partially explain the more rapid progression of MS after menopause. One year of MHT did not alter the sGFAP or sNfL levels in women with MS.

Impaired cognitive flexibility and disrupted cognitive cerebellum in degenerative cerebellar ataxias.

There is a clinically unmet need for a neuropsychological tool that reflects the pathophysiology of cognitive dysfunction in cerebellar degeneration. We investigated cognitive flexibility in degenerative cerebellar ataxia patients and aim to identify the pathophysiological correlates of cognitive dysfunction in relation to cerebellar cognitive circuits. We prospectively enrolled degenerative cerebellar ataxia patients with age-matched healthy controls who underwent 3 T 3D and resting-state functional MRI. All 56 participants were evaluated with the Scale for Assessment and Rating of Ataxia and neuropsychological tests including the Wisconsin Card Sorting Test, Trail Making Test, Montreal Cognitive Assessment and Mini-Mental State Examination. From MRI scans, we analysed the correlation of whole-brain volume and cortico-cerebellar functional connectivity with the Wisconsin Card Sorting Test performances. A total of 52 participants (29 ataxia patients and 23 healthy controls) were enrolled in this study. The Wisconsin Card Sorting Test scores (total error percentage, perseverative error percentage, non-perseverative error percentage and categories completed), Trail Making Test A and Montreal Cognitive Assessment were significantly impaired in ataxia patients (P < 0.05) compared to age-matched healthy controls. The Wisconsin Card Sorting Test error scores showed a significant correlation with the ataxia score (P < 0.05) controlling for age and sex. In volumetric analysis, the cerebellar right crus I, II, VIIb and VIII atrophy correlated with non-perseverative error percentage in the ataxia group. In functional connectivity analysis, the connectivity between crus I, II and VIIb of the cerebellum and bilateral superior parietal and superior temporal gyrus was significantly altered in ataxia patients. The functional connectivity between left crus II and VIIb of the cerebellum and dorsolateral prefrontal and superior frontal/parietal cortices showed a positive correlation with perseverative error percentage. The connectivity between left crus VIIb and pontine nucleus/middle cerebellar peduncle showed a significant negative correlation with non-perseverative error percentage in the ataxia group. The impaired cognitive flexibility represented by the Wisconsin Card Sorting Test was significantly impaired in degenerative cerebellar ataxia patients and correlated with disease severity. The Wisconsin Card Sorting Test performance reflects hypoactivity of the cognitive cerebellum and disrupted cortico-cerebellar connectivity in non-demented patients with degenerative cerebellar ataxia.

Is vestibular function related to human hippocampal volume?

Recent studies implicate the effect of vestibular loss on cognitive decline, including hippocampal volume loss. As hippocampal atrophy is an important biomarker of Alzheimer's disease, exploring vestibular dysfunction as a risk factor for dementia and its role in hippocampal atrophy is of interest. To replicate previous literature on whole-brain and hippocampal volume in semicircular canal dysfunction (bilateral vestibulopathy; BV) and explore the association between otolith function and hippocampal volume. Hippocampal and whole-brain MRI volumes were compared in adults aged between 55 and 83 years. Participants with BV (n = 16) were compared to controls individually matched on age, sex, and hearing status (n = 16). Otolith influence on hippocampal volume in preserved semicircular canal function was evaluated (n = 34). Whole-brain and targeted hippocampal approaches using volumetric and surface-based measures yielded no significant differences when comparing BV to controls. Binary support vector machines were unable to classify inner ear health status above chance level. Otolith parameters were not associated with hippocampal volume in preserved semicircular canal function. No significant differences in whole-brain or hippocampal volume were found when comparing BV participants with healthy controls. Saccular parameters in subjects with preserved semicircular canal function were not associated with hippocampal volume changes.

White matter network underlying semantic processing: evidence from stroke patients.

The hub-and-spoke theory of semantic representation fractionates the neural underpinning of semantic knowledge into two essential components: the sensorimotor modality-specific regions and a crucially important semantic hub region. Our previous study in patients with semantic dementia has found that the hub region is located in the left fusiform gyrus. However, because this region is located within the brain damage in patients with semantic dementia, it is not clear whether the semantic deficit is caused by structural damage to the hub region itself or by its disconnection from other brain regions. Stroke patients do not have any damage to the left fusiform gyrus, but exhibit amodal and modality-specific deficits in semantic processing. Therefore, in this study, we validated the semantic hub region from a brain network perspective in 79 stroke patients and explored the white matter connections associated with it. First, we collected data of diffusion-weighted imaging and behavioural performance on general semantic tasks and modality-specific semantic tasks (assessing object knowledge on form, colour, motion, sound, manipulation and function). We then used correlation and regression analyses to examine the association between the nodal degree values of brain regions in the whole-brain structural network and general semantic performance in the stroke patients. The results revealed that the connectivity of the left fusiform gyrus significantly predicted general semantic performance, indicating that this region is the semantic hub. To identify the semantic-relevant connections of the semantic hub, we then correlated the white matter integrity values of each tract connected to the left fusiform gyrus separately with performance on general and modality-specific semantic processing. We found that the hub region accomplished general semantic processing through white matter connections with the left superior temporal pole, middle temporal gyrus, inferior temporal gyrus and hippocampus. The connectivity between the hub region and the left hippocampus, superior temporal pole, middle temporal gyrus, inferior temporal gyrus and parahippocampal gyrus was differentially involved in object form, colour, motion, sound, manipulation and function processing. After statistically removing the effects of potential confounding variables (i.e. whole-brain lesion volume, lesion volume of regions of interest and performance on non-semantic control tasks), the observed effects remained significant. Together, our findings support the role of the left fusiform gyrus as a semantic hub region in stroke patients and reveal its crucial connectivity in the network. This study provides new insights and evidence for the neuroanatomical organization of semantic memory in the human brain.

Abstract 70: Rich-Club Behaviour and Analyses in the Human Brain Connectome as Novel Early Biomarkers of Cognitive Decline

Introduction: Transient ischemic attack (TIA) patients have an increased risk of early dementia, but the mechanism is unclear. One potential mechanism is the damaging effects of microvascular disease on brain networks. Rich club is a phenomenon where highly connected nodes form a “rich club” amongst themselves, thus playing an important role in global brain network communication. In this study we aim to determine 1) whether the prominence of the rich club effect declines greater in TIA patients than controls over time, and 2) the relationship of rich club prominence with cognition. Methods: TIA patients (n=47) and controls (n=43) underwent DTI imaging and cognitive assessment at baseline, 1-year, 3-year, and 5-year. Whole-brain tractography utilizing constrained spherical deconvolution was performed to construct whole-brain connectomes for both groups at all available timepoints. The maximum normalized rich club coefficient (Φ max ) was used as an indicator of the prominence of the rich club effect. Independent-sample T-tests were used to compare Φ max cross-sectionally, while a linear mixed effect (LME) model was used to examine the longitudinal change in Φ max in TIA patients vs. controls, while controlling for covariates including age, sex, WMH volume, whole-brain volume, and peak width of skeletonized mean diffusivity. Results: TIA patients had a mean age of 63.94 ( SD =8.62) and 20 females. Controls had a mean age of 60.73 (8.16) and 29 females. The prominence of the rich club was not significantly different between TIA patients and controls at baseline or 1-year ( p &gt;0.05). However, TIA patients showed a significantly less prominent rich club at 3-year and 5-year compared to controls ( p =0.047 and 0.018, respectively). TIA patients exhibited a significantly greater decrease in rich club prominence over time, relative to controls ( p =0.023), after accounting for covariates. Longitudinal LME models showed no association between changes in rich club prominence and changes in cognition ( p &gt;0.05 for all cognitive domains). Conclusion: In this study, we show a decrease in rich club prominence in TIA patients compared to controls which might identify their increased risk of cognitive impairment, and the potential benefits of aggressive vascular risk reduction.

The effect of estradiol add-back: a longitudinal MRI study in prostate cancer patients.

We investigated the effect of estradiol add-back therapy (EAT) on brain activation related to cognitive function and affect in addition to putative changes in gray and white matter volume in testosterone depleted participants with prostate cancer. We conducted a randomized controlled, double-blinded trial in which 40 patients received 0.9 mg of transdermal estradiol per day for 6 months or matched placebo. Anatomical MRI and three functional MRI (fMRI) scans were obtained for the emotion recognition task, verbal memory task, and visuospatial memory task. Activation in corresponding cognitive and affective brain networks was demonstrated for all tasks. Longitudinally, there was no difference in brain activation, reaction time, or accuracy in response to the fMRI tasks between the EAT group and placebo group at 6 months. In addition, there was no detectable change in whole-brain gray or white matter volume or in hippocampal volume between the two groups after 6 months. This study supports earlier findings that EAT does not improve verbal memory or affect and has no immediate effect on hippocampal volume in testosterone depleted patients with prostate cancer.

Thalamic atrophy and dysconnectivity are associated with cognitive impairment in a multi-center, clinical routine, real-word study of people with relapsing-remitting multiple sclerosis

BackgroundPrior research has established a link between thalamic pathology and cognitive impairment (CI) in people with multiple sclerosis (pwMS). However, the translation of these findings to pwMS in everyday clinical settings has been insufficient. ObjectiveTo assess which global and/or thalamic imaging biomarkers can be used to identify pwMS at risk for CI and cognitive worsening (CW) in a real-world setting. MethodsThis was an international, multi-center (11 centers), longitudinal, retrospective, real-word study of people with relapsing-remitting MS (pwRRMS). Brain MRI exams acquired at baseline and follow-up were collected. Cognitive status was evaluated using the Symbol Digit Modalities Test (SDMT). Thalamic volume (TV) measurement was performed on T2-FLAIR, as well as on T1-WI, when available. Thalamic dysconnectivity, T2-lesion volume (T2-LV), and volumes of gray matter (GM), whole brain (WB) and lateral ventricles (LVV) were also assessed. Results332 pwMS were followed for an average of 2.8 years. At baseline, T2-LV, LVV, TV and thalamic dysconnectivity on T2-FLAIR (p < 0.016), and WB, GM and TV volumes on T1-WI (p < 0.039) were significantly worse in 90 (27.1 %) CI vs. 242 (62.9 %) non-CI pwRRMS. Greater SDMT decline over the follow-up was associated with lower baseline TV on T2-FLAIR (standardized β = 0.203, p = 0.002) and greater thalamic dysconnectivity (standardized β = -0.14, p = 0.028) in a linear regression model. ConclusionsPwRRMS with thalamic atrophy and worse thalamic dysconnectivity present more frequently with CI and experience greater CW over mid-term follow-up in a real-world setting.

Sex and Gender in Population Neuroscience.

To understand psychiatric and neurological disorders and the structural and functional properties of the human brain, it is essential to consider the roles of sex and gender. In this chapter, I first define sex and gender and describe studies of sex differences in non-human animals. In humans, I describe the sex differences in behavioral and clinical phenotypes and neuroimaging-derived phenotypes, including whole-brain measures, regional subcortical and cortical measures, and structural and functional connectivity. Although structural whole-brain sex differences are large, regional effects (adjusting for whole-brain volumes) are typically much smaller and often fail to replicate. Nevertheless, while an individual neuroimaging feature may have a small effect size, aggregating them in a "maleness/femaleness" score or machine learning multivariate paradigm may prove to be predictive and informative of sex- and gender-related traits. Finally, I conclude by summarizing emerging investigations of gender norms and gender identity and provide methodological recommendations to incorporate sex and gender in population neuroscience research.

Neurofilament and Brain Atrophy and Their Association with Cognition in Multiple Sclerosis: A 10-Year Follow-Up Study

Introduction. Cognitive impairment is an important contributor to disability in multiple sclerosis (MS). Disconnection of neuronal circuits due to axonal injury is probably an important underlying mechanism for this disability. Neurofilament light chain (NfL) is a neuron-specific constituent of axons and has gained increasing attention as a biomarker of axonal injury. Objective. To assess the association between NfL in serum (sNfL) and cerebrospinal fluid (cNfL) and cognitive function over 10 years and compare these associations with volumetric brain magnetic resonance imaging (MRI) measurements. Methods. Newly diagnosed MS patients were followed prospectively with baseline NfL and MRI as well as with clinical and cognitive assessments for up to 10 years. Results. Forty-one patients were included. Baseline sNfL correlated negatively with symbol digit modalities test (SDMT) at baseline (r=−0.45, p=0.005), year 5 (r=−0.41, p=0.017), and at year 10 (r=−0.52, p=0.008). Baseline cNfL correlated with baseline SDMT (r=−0.34, p=0.030) and SDMT at year 10 (r=−0.44, p=0.037). Baseline volumes of whole brain (r=0.476, p=0.002), gray matter (r=0.467, p=0.002), T1 (r=−0.627, p&lt;0.001), and T2 lesion volumes (r=−0.475, p=0.002) correlated significantly with baseline SDMT. Longitudinal analyses showed that both MRI volumes and EDSS were associated with the rate of SDMT decline, whereas sNfL and cNfL were not. Conclusion. NfL levels measured in serum and cerebrospinal fluid were both associated with cognitive functioning in MS patients over a 10-year period from diagnosis. However, MRI volumes correlated strongly in addition to the rate of cognitive decline.

Automatic Quantification of Enlarged Perivascular Space in Patients With Traumatic Brain Injury Using Super-Resolution of T2-Weighted Images.

The perivascular space (PVS) is important to brain waste clearance and brain metabolic homeostasis. Enlarged PVS (ePVS) becomes visible on magnetic resonance imaging (MRI) and is best appreciated on T2-weighted (T2w) images. However, quantification of ePVS is challenging because standard-of-care T1-weighted (T1w) and T2w images are often obtained via two-dimensional (2D) acquisition, whereas accurate quantification of ePVS normally requires high-resolution volumetric three-dimensional (3D) T1w and T2w images. The purpose of this study was to investigate the use of a deep-learning-based super-resolution (SR) technique to improve ePVS quantification from 2D T2w images for application in patients with traumatic brain injury (TBI). We prospectively recruited 26 volunteers (age: 31 ± 12 years, 12 male/14 female) where both 2D T2w and 3D T2w images were acquired along with 3D T1w images to validate the ePVS quantification using SR T2w images. We then applied the SR method to retrospectively acquired 2D T2w images in 41 patients with chronic TBI (age: 41 ± 16 years, 32 male/9 female). ePVS volumes were automatically quantified within the whole-brain white matter and major brain lobes (temporal, parietal, frontal, occipital) in all subjects. Pittsburgh Sleep Quality Index (PSQI) scores were obtained on all patients with TBI. Compared with the silver standard (3D T2w), in the validation study, the SR T2w provided similar whole-brain white matter ePVS volume (r = 0.98, p < 0.0001), and similar age-related ePVS burden increase (r = 0.80, p < 0.0001). In the patient study, patients with TBI with poor sleep showed a higher age-related ePVS burden increase than those with good sleep. Sleep status is a significant interaction factor in the whole brain (p = 0.047) and the frontal lobe (p = 0.027). We demonstrate that images produced by SR of 2D T2w images can be automatically analyzed to produce results comparable to those obtained by 3D T2 volumes. Reliable age-related ePVS burden across the whole-brain white matter was observed in all subjects. Poor sleep, affecting the glymphatic function, may contribute to the accelerated increase of ePVS burden following TBI.

Clinical and radiological correlates of apathy in multiple sclerosis

Background: Although apathy has been associated with fronto-striatal dysfunction in several neurological disorders, its clinical and magnetic resonance imaging (MRI) correlates have been poorly investigated in people with multiple sclerosis (PwMS). Objectives: To evaluate clinical variables and investigate microstructural integrity of fronto-striatal grey matter (GM) and white matter (WM) structures using diffusion tensor imaging (DTI). Methods: A total of 123 PwMS (age: 40.25 ± 11.5; female: 60.9%; relapsing–remitting multiple sclerosis: 75.6%) were prospectively enrolled and underwent neurological and neuropsychological evaluation, including Expanded Disability Status Scale (EDSS), Apathy Evaluation Scale (AES-S), Hospital Anxiety and Depression Scale (HADS), Modified Fatigue Impact Scale (MFIS) and brain 3T-MRI volumes of whole brain, frontal/prefrontal cortex (PFC) and subcortical regions were calculated. DTI-derived metrics were evaluated in the same GM regions and in connecting WM tracts. Results: Apathetic PwMS (32.5%) showed lower education levels, higher HADS, MFIS scores and WM lesions volume than nonapathetic PwMS. Significant differences in DTI metrics were found in middle frontal, anterior cingulate and superior frontal PFC subregions and in caudate nuclei. Significant alterations were found in the right cingulum and left striatal-frontorbital tracts. Conclusions: Apathy in PwMS is associated with higher levels of physical disability, depression, anxiety and fatigue together with lower educational backgrounds. Microstructural damage within frontal cortex, caudate and fronto-striatal WM bundles is a significant pathological substrate of apathy in multiple sclerosis (MS).

Previous pregnancies might mitigate cortical brain differences associated with surgical menopause.

Surgical menopause causes a sharp drop in estrogen levels in middle-aged women, thus preventing the gradual physiological adaptation that is characteristic of the perimenopause. Previous studies suggest that surgical menopause might increase the risk of dementia later in life. In addition, the transition to motherhood entails long-lasting endocrine and neuronal adaptations. We compared differences in whole-brain cortical volume between women who reached menopause by surgery and a group of women who reached spontaneous non-surgical menopause and determined whether these cortical differences were influenced by previous childbearing. Using surface-based neuroimaging techniques, we investigated cortical volume differences in 201 middle-aged women (134 women who experienced non-surgical menopause, 78 of whom were parous women; and 67 women who experienced surgical menopause, 39 of whom were parous women). We found significant atrophy in the frontal and temporal regions in women who experienced surgical menopause. Nulliparous women with surgical menopause showed significant lower cortical volume in the left temporal gyrus extending to the medial temporal lobe cortex, as well as in the precuneus bilaterally compared to parous women with surgical menopause; whereas our results revealed no significant differences between parous women with surgical menopause and both parous and nulliparous women who reached a non-surgical menopause. Furthermore, in the surgical menopause group, we found a negative correlation between cortical volume and age at first pregnancy in the temporal lobe. Our study suggests that the long-term brain remodeling of parity may mitigate the neural impact of the sudden drop in estrogen levels that characterizes surgical menopause.

Correlation between white matter hyperintensity and delusional symptoms in Alzheimer’s disease

BackgroundPatients with Alzheimer’s disease (AD) often exhibit neuropsychiatric symptoms (NPS), particularly delusions. Previous studies have shown an association between white matter hyperintensities (WMH) and specific NPS. This study aims to explore the relationship between WMH volume and delusions in AD patients by comparing the WMH volumes of delusional and non-delusional subgroups.Methods80 AD patients were divided into a delusion group (n = 36) and a non-delusion group (n = 44) based on the Neuropsychiatric Inventory (NPI). The brain cortical volume and WMH volume were quantitatively calculated for all 80 patients, including total WMH volume, periventricular WMH (PVWMH) volume, deep WMH volume, as well as bilateral frontal lobe, temporal lobe, parietal lobe, and occipital lobe WMH volumes. Firstly, we compared the differences in WMH volumes between the delusion group and non-delusion group. Then, within the delusion group, we further categorized patients based on severity scores of their delusional symptoms into mild (1 point), moderate (2 points), or severe groups (3 points). We compared the WMH volumes among these three groups to investigate the role of WMH volume in delusional symptoms.ResultsThere was a significant difference in left occipital lobe WMH volume between the delusion group and non-delusion group(P < 0.05). Within the delusion group itself, there were significant differences in overall WMH volume as well as PVWMH volume among patients with mild or severe levels of delusions(P < 0.05).ConclusionLeft occipital lobe WMH volume may be associated with the occurrence of delusional AD patients, and the total volume of whole-brain WMH and PVWMH volume may affect the degree of severity of delusional symptoms.

Associations between 5‐lipoxygenase activating protein (FLAP) genetic variation rs9551963 and Alzheimer’s disease phenotypes

AbstractBackgroundLeukotrienes are inflammatory mediators, synthesized by 5‐lipoxygenase and its activating protein (FLAP), and their activity may play a role in Alzheimer’s disease (AD). In AD mouse models, inhibition of FLAP improved memory and reduced amyloid (Aβ) deposition. Single nucleotide polymorphisms (SNPs) of ALOX5AP, which encodes FLAP, have been implicated in ischemic stroke in humans. However, there is limited research on the relationship between ALOX5AP and AD. This longitudinal study investigated associations between the ALOX5AP SNP rs9551963 A/C and various AD phenotypes.MethodParticipants from the Alzheimer’s Disease Neuroimaging Initiative (phases GO, 2, and 3) diagnosed with AD, mild cognitive impairment (MCI), or clinically normal cognition (CN) were categorized as minor allele carriers (AC, CC) or non‐carriers (AA) of rs9551963. Mini Mental State Exam (MMSE) and Rey Auditory Verbal Learning Test (RAVLT) % forgetting were selected to assess cognition. Cerebrospinal fluid biomarkers and MRI brain volumetric data were also considered. Interactions between rs9551963 genotype and time (baseline, month 24, and month 48) were measured in mixed models. All models controlled for age, sex, and APOE e4 status; education and baseline intracranial volume were additional controls in cognitive and volumetric analyses respectively.ResultMinor allele carriers in the AD‐MCI Aβ‐positive group had worse decline on the MMSE (F1,297 = 5.33, p = 0.022, n = 521), and smaller volumes of whole brain (F1,146 = 7.13, p = 0.008, n = 408) and hippocampus (F1,132 = 6.38, p = 0.013, n = 377) over time that were not seen in other subgroups. In the AD subgroup, Aβ‐positive carriers had greater increases in RAVLT % forgetting scores (F1,135.5 = 6.19, p = 0.014, n = 158) and greater whole brain volume loss (F1,27.6 = 5.67, p = 0.024, n = 132), over time. These associations were not seen in Aβ‐negative participants.ConclusionMinor allele carriers of the ALOX5AP SNP rs9551963 who were Aβ‐positive showed greater loss of cognitive status and memory, and more hippocampal and whole brain atrophy, over time. These findings suggest a possible effect of leukotriene synthesis in the progression of AD.

Association of urine dicarboxylic acid levels with intracranial volume–normalized brain regions and with white matter hypo‐intensities

AbstractBackgroundNon‐invasive molecules related to AD imaging biomarkers can reveal disease mechanisms and may help in the mass screening of an aging population. Our study aims to determine if urine dicarboxylic acids (DCA) that changed in AD are coupled with brain volume changes.MethodStudy participants (&gt; 65 years) were recruited in an ongoing HMRI Brain aging study, and MRI data were acquired and analyzed using NeuroQuant. The data were normalized to the intracranial volume (icv). DCAs were quantified using gas chromatography/mass spectrometry. We compared DCA and icv‐normalized brain region volumes in two ways: first, we used descriptive statistics to obtain the median (Q2) for short‐chain DCAs (C4+C5), medium‐chain DCAs (C7+C8+C9) and the ratio of short to medium chain DCAs ((C4+C5)/(C7+C8+C9)). Brain regions were then sorted to correspond to less than (&lt;Q2) or greater than the DCA medians (&gt;Q2). Differences were determined using two‐sample t‐tests and Wilcoxon rank‐sum tests with adjustment for multiple comparisons using FDR. Secondly, icv‐normalized brain regions and T1 hypo‐intensity were compared with DCA levels using a two‐tailed student’s t‐test.ResultThere was no significant difference in the DCA levels of participants with low (icv&lt;Q2) or high icv (icv&gt;Q2) (Fig.1A). In contrast, C4+C5 levels were higher, while C7+C8+C9 were lower in participants with higher whole brain volumes (WBV) (Fig. 1B). In addition, hippocampal volumes were greater when participants had a higher urine C4+C5 and lower C7+C8+C9. We identified 19 other icv‐normalized brain regions that were bigger when urine C4+C5 levels were high. In addition, participants with higher white matter hypo‐intensities had lower urine C4+C5 and a higher C7+C8+C9 DCA levels (Table 1).ConclusionThese data suggest that urine lipid composition is linked to icv‐normalized brain volumes. Higher mitochondrial‐associated lipids reflected larger brain volumes, while oxidized lipids indicated lower brain volumes. Thus, urine lipid levels can be used as surrogate biomarkers in clinical trials targeting brain volume changes. We will use a bigger sample size normalized for ApoE genotype, age, and sex to further examine lipids and brain volumes in participants with different cognitive states.

FC34: Cognitive reserve and depressive burden in older adults: variation according to reserve measurement

Objective:Individual differences in the timing of dementia have been attributed to cognitive reserve (CR), thought to reflect lifelong engagement in stimulating experiences, which provide resilience against brain pathology. In older adults, dementia and depression are closely related, and some studies have linked CR with depression risk in old age. It is unclear if different ways of operationalizing CR exhibit similar association with old-age depression. We examined the association of two measures of CR with depressive burden in older adults: activity-based CR, capturing engagement in stimulating activities using proxy variables, and residual-based CR, indicating residual variance in cognition, not explained by the brain status.Methods:We used data on 354 adults aged 60+ from the Swedish National Study on Aging and Care in Kungsholmen, followed for 15 years. Residual-based reserve was computed from a regression predicting episodic memory with a brain-integrity index incorporating six structural neuroimaging markers (white- matter hyperintensities volume, whole-brain gray matter volume, hippocampal volume, lateral ventricular volume, lacunes, and perivascular spaces), age, and sex. Activity-based reserve incorporated education, work complexity, social network, and leisure activities. Depressive burden was captured over the follow- up with the Montgomery-Åsberg Depression Rating Scale and time until clinically relevant level of symptoms (&gt;6) was modelled using Cox proportional hazard models.Results:Preliminary results indicate that, upon minimal adjustment (age, sex, brain integrity status), top tertiles (ref: bottom tertile) of both activity-based (HR: 0.77; 95% CI: 0.61-0.98) and residual-based CR (HR: 0.62; 95% CI: 0.44-0.98) were associated with a lower risk of depressive burden onset over 15 years. Upon further adjustment for anthropometrics, health behaviors, and chronic disease burden, the association of activity-based CR was attenuated, whereas residual-based CR preserved its effect on depressive burden (HR [fully adjusted model]: 0.59; 95% CI: 0.40-0.88). Next steps include evaluating the ability of reserve measures to attenuate the association of brain integrity with depressive burden using interaction analysis.Conclusion:Preliminary findings suggest that CR may be linked with depression development in older adults, although the association may vary depending on measurement of reserve. Association of activity- based reserve may be attributed to somatic disease pathways.

Comparison of Light-Sheet Fluorescence Microscopy and Fast-Confocal Microscopy for Three-Dimensional Imaging of Cleared Mouse Brain.

Whole-brain imaging is important for understanding brain functions through deciphering tissue structures, neuronal circuits, and single-neuron tracing. Thus, many clearing methods have been developed to acquire whole-brain images or images of three-dimensional thick tissues. However, there are several limitations to imaging whole-brain volumes, including long image acquisition times, large volumes of data, and a long post-image process. Based on these limitations, many researchers are unsure about which light microscopy is most suitable for imaging thick tissues. Here, we compared fast-confocal microscopy with light-sheet fluorescence microscopy for whole-brain three-dimensional imaging, which can acquire images the fastest. To compare the two types of microscopies for large-volume imaging, we performed tissue clearing of a whole mouse brain, and changed the sample chamber and low- magnification objective lens and modified the sample holder of a light-sheet fluorescence microscope. We found out that light-sheet fluorescence microscopy using a 2.5× objective lens possesses several advantages, including saving time, large-volume image acquisitions, and high Z-resolution, over fast-confocal microscopy, which uses a 4× objective lens. Therefore, we suggest that light-sheet fluorescence microscopy is suitable for whole mouse brain imaging and for obtaining high-resolution three-dimensional images.

Beyond the language network: Associations between reading, receptive vocabulary, and grey matter volume in 10-year-olds

Most research on the neurostructural basis of language abilities in children stems from small samples and surface-based measures. To complement and expand the existent knowledge, we investigated associations between grey matter volume and language performance in a large sample of 9-to-11-year-old children, using data from the Adolescent Brain Cognitive Development (ABCD) Study (N = 1865) and an alternative measure of grey matter morphology. We estimated whole-brain grey matter volume for one half of the sample (N = 939) and tested for correlations with scores on a picture vocabulary and a letter and word reading test, with and without factoring in general intelligence and total grey matter volume as additional covariates. The initial analyses yielded correlations between grey matter in the right occipital fusiform gyrus, the right lingual gyrus, and the cerebellum for both vocabulary and reading. Employing the significant clusters from the first analyses as regions of interest in the second half of the cohort (N = 926) in correlational and multiple regression analyses suggests the cluster in the right occipital fusiform and lingual gyri to be most robust. Overall, the amount of variance explained by grey matter volume is limited and factoring in additional covariates paints an inconsistent picture. The present findings reinforce existent doubt with respect to explaining individual differences in reading and vocabulary performance based on unique contributions of macrostructural brain features.

58 Cognitive and Brain Reserve Predict a Decline in Adverse Driving Behaviors Among Cognitively Normal Older Adults

Objective:Daily driving behavior is ultimate measure of cognitive functioning requiring multiple cognitive domains working synergistically to complete this complex instrumental activity of daily living. As the world’s population continues to grow and age older, motor vehicle crashes become more frequent. Cognitive and brain reserve are developing constructs that are frequently assessed in aging research. Cognitive reserve preserves functioning in the face of greater loss of brain structure as experienced during cognitive impairment or dementia. This study determined whether cognitive reserve and brain reserve predict changes in adverse driving behaviors in cognitively normal older adults.Participants and Methods:Cognitively normal participants (Clinical Dementia Rating 0) were enrolled from longitudinal studies at the Knight Alzheimer’s Disease Research Center at Washington University. Participants (n=186) were ≥ 65 years of age, required to have Magnetic Resonance Imaging (MRI) data, neuropsychological testing data, as well as one full year of naturalistic driving data prior to the beginning of COVID-19 lockdown in the United States (March 2020). Naturalistic driving behavior data was collected via the Driving Real World In-vehicle Evaluation System (DRIVES). DRIVES variables included idle time, over speeding, aggression, number of trips, including those at day and night. MRI was performed on 3T Tesla using a research imaging protocol based upon ADNI that includes a high-resolution T1 MPRAGE for assessment of brain structures to produce normalized whole brain volume (WBV) and hippocampal volume (HV). WBV and HV were each assessed using tertiles comparing the top 66% with the bottom 33% where the bottom represented increased atrophy. The Word Reading subtest of the Wide Range Achievement Test 4 (WRAT 4) was utilized as a proxy for cognitive reserve. WRAT 4 scores were compared with the top 66% and the bottom 33% where the bottom were poor performers. Linear-mixed-effect models adjusted for age, education, and sex.Results:Participants on average were older (73.7±4.9), college educated (16.6±2.2), and similar sex distribution (males=100, females=86). Analyses showed statistically significant differences in slopes where participants with increased hippocampal and whole brain atrophy were less likely to overspeed (p=0.0035; p=0.0003), drive aggressively (p=0.0016; p&lt;0.0001), and drive during the daytime (p&lt;0.0001; p&lt;0.0001). However, they were more likely to spend more time idling (p=0.0005; p&lt;0.0001) and drive during the nighttime (p=0.003; p=0.0002). Similar findings occurred with the WRAT 4 where participants with lower scores were less likely to overspeed (p=0.0035), drive aggressively (p=0.0024), hard brake (p=0.0180), and drive during the daytime (p&lt;0.0001) while they were more likely to also spend more time idling (p=0.0012) and drive during the nighttime (p=0.0004).Conclusions:Numerous changes in driving behaviors over time were predicted by increased hippocampal and whole brain atrophy as well as lower cognitive reserve scores proxied by the WRAT 4. These changes show that those with lower brain and cognitive reserve are more likely to restrict their driving behavior and adapt their daily behaviors as they age. These results suggest older adults with lower brain and cognitive reserve are more likely to avoid highways where speeding and aggressive maneuvers are more frequent.

Low-dose lithium adjunct to atypical antipsychotic treatment nearly improved cognitive impairment, deteriorated the gray-matter volume, and decreased the interleukin-6 level in drug-naive patients with first schizophrenia symptoms: a follow-up pilot study

This study was conducted to investigate the effects of long-term low-dose lithium adjunct to antipsychotic agent use on the cognitive performance, whole-brain gray-matter volume (GMV), and interleukin-6 (IL-6) level in drug-naive patients with first-episode schizophrenia, and to examine relationships among these factors. In this double-blind randomized controlled study, 50 drug-naive patients with first-episode schizophrenia each took low-dose (250 mg/day) lithium and placebo (of the same shape and taste) adjunct to antipsychotic agents (mean, 644.70 ± 105.58 and 677.00 ± 143.33 mg/day chlorpromazine equivalent, respectively) for 24 weeks. At baseline and after treatment completion, the MATRICS Consensus Cognitive Battery (MCCB) was used to assess cognitive performance, 3-T magnetic resonance imaging was performed to assess structural brain alterations, and serum IL-6 levels were quantified by immunoassay. Treatment effects were assessed within and between patient groups. Relationships among cognitive performance, whole-brain GMVs, and the IL-6 level were investigated by partial correlation analysis. Relative to baseline, patients in the lithium group showed improved working memory, verbal learning, processing speed, and reasoning/problem solving after 24 weeks of treatment; those in the placebo group showed only improved working memory and verbal learning. The composite MCCB score did not differ significantly between groups. The whole-brain GMV reduction was significantly lesser in the lithium group than in the placebo group (0.46% vs. 1.03%; P < 0.001). The GMV and IL-6 reduction ratios correlated with each other in both groups (r = −0.17, P = 0.025). In the lithium group, the whole-brain GMV reduction ratio correlated with the working memory improvement ratio (r = −0.15, P = 0.030) and processing speed (r = −0.14, P = 0.036); the IL-6 reduction ratio correlated with the working memory (r = −0.21, P = 0.043) and verbal learning (r = −0.30, P = 0.031) improvement ratios. In the placebo group, the whole-brain GMV reduction ratio correlated only with the working memory improvement ratio (r = −0.24, P = 0.019); the IL-6 reduction ratio correlated with the working memory (r = −0.17, P = 0.022) and verbal learning (r = −0.15, P = 0.011) improvement ratios. Both treatments implemented in this study nearly improved the cognitive performance of patients with schizophrenia; relative to placebo, low-dose lithium had slightly greater effects on several aspects of cognition. The patterns of correlation among GMV reduction, IL-6 reduction, and cognitive performance improvement differed between groups.