Relationship between cortical brain atrophy, delirium, and long-term cognitive decline in older surgical patients.

In older patients, delirium after surgery is associated with long-term cognitive decline (LTCD). The neural substrates of this association are unclear. Neurodegenerative changes associated with dementia are possible contributors. We investigated the relationship between brain atrophy rates in Alzheimer's disease (AD) and cognitive aging signature regions from magnetic resonance imaging before and one year after surgery, LTCD assessed by the general cognitive performance (GCP) score over 6 years post-operatively, and delirium in 117 elective surgery patients without dementia (mean age = 76). The annual change in cortical thickness was 0.2(1.7) % (AD-signature p = 0.09) and 0.4(1.7) % (aging-signature p = 0.01). Greater atrophy was associated with LTCD (AD-signature: beta(CI) = 0.24(0.06-0.42) points of GCP/mm of cortical thickness; p < 0.01, aging-signature: beta(CI) = 0.55(0.07-1.03); p = 0.03). Atrophy rates were not significantly different between participants with and without delirium. We found an interaction with delirium severity in the association between atrophy and LTCD (AD-signature: beta(CI) = 0.04(0.00-0.08), p = 0.04; aging-signature: beta(CI) = 0.08(0.03-0.12), p < 0.01). The rate of cortical atrophy and severity of delirium are independent, synergistic factors determining postoperative cognitive decline in the elderly.

Successful aging after elective surgery II: Study cohort description.

BACKGROUND: The Successful Aging after Elective Surgery (SAGES) II Study was designed to examine the relationship between delirium and Alzheimer's disease and related dementias (AD/ADRD), by capturing novel fluid biomarkers, neuroimaging markers, and neurophysiological measurements. The goal of this paper is to provide the first complete description of the enrolled cohort, which details the baseline characteristics and data completion. We also describe the study modifications necessitated by the COVID-19 pandemic, and lay the foundation for future work using this cohort. METHODS: SAGES II is a prospective observational cohort study of community-dwelling adults age 65 and older undergoing major non-cardiac surgery. Participants were assessed preoperatively, throughout hospitalization, and at 1, 2, 6, 12, and 18 months following discharge to assess cognitive and physical functioning. Since participants were enrolled throughout the COVID-19 pandemic, procedural modifications were designed to reduce missing data and allow for high data quality. RESULTS: About 420 participants were enrolled with a mean (standard deviation) age of 73.4 (5.6) years, including 14% minority participants. Eighty-eight percent of participants had either total knee or hip replacements; the most common surgery was total knee replacement with 210 participants (50%). Despite the challenges posed by the COVID-19 pandemic, which required the use of novel procedures such as video assessments, there were minimal missing interviews during hospitalization and up to 1-month follow-up; nearly 90% of enrolled participants completed interviews through 6-month follow-up. CONCLUSION: While there are many longitudinal studies of older adults, this study is unique in measuring health outcomes following surgery, along with risk factors for delirium through the application of novel biomarkers-including fluid (plasma and cerebrospinal fluid), imaging, and electrophysiological markers. This paper is the first to describe the characteristics of this unique cohort and the data collected, enabling future work using this novel and important resource.

Aptamer-Based Proteomics Measuring Preoperative Cerebrospinal Fluid Protein Alterations Associated with Postoperative Delirium.

Delirium is a common postoperative complication among older patients with many adverse outcomes. Due to a lack of validated biomarkers, prediction and monitoring of delirium by biological testing is not currently feasible. Circulating proteins in cerebrospinal fluid (CSF) may reflect biological processes causing delirium. Our goal was to discover and investigate candidate protein biomarkers in preoperative CSF that were associated with the development of postoperative delirium in older surgical patients. We employed a nested case-control study design coupled with high multiplex affinity proteomics analysis to measure 1305 proteins in preoperative CSF. Twenty-four matched delirium cases and non-delirium controls were selected from the Healthier Postoperative Recovery (HiPOR) cohort, and the associations between preoperative protein levels and postoperative delirium were assessed using t-test statistics with further analysis by systems biology to elucidate delirium pathophysiology. Proteomics analysis identified 32 proteins in preoperative CSF that significantly associate with delirium (t-test p < 0.05). Due to the limited sample size, these proteins did not remain significant by multiple hypothesis testing using the Benjamini-Hochberg correction and q-value method. Three algorithms were applied to separate delirium cases from non-delirium controls. Hierarchical clustering classified 40/48 case-control samples correctly, and principal components analysis separated 43/48. The receiver operating characteristic curve yielded an area under the curve [95% confidence interval] of 0.91 [0.80-0.97]. Systems biology analysis identified several key pathways associated with risk of delirium: inflammation, immune cell migration, apoptosis, angiogenesis, synaptic depression and neuronal cell death. Proteomics analysis of preoperative CSF identified 32 proteins that might discriminate individuals who subsequently develop postoperative delirium from matched control samples. These proteins are potential candidate biomarkers for delirium and may play a role in its pathophysiology.

Successful aging after elective surgery II: Study design and methods.

BACKGROUND: The Successful Aging after Elective Surgery (SAGES) II study was designed to increase knowledge of the pathophysiology and linkages between delirium and dementia. We examine novel biomarkers potentially associated with delirium, including inflammation, Alzheimer's disease (AD) pathology and neurodegeneration, neuroimaging markers, and neurophysiologic markers. The goal of this paper is to describe the study design and methods for the SAGES II study. METHODS: The SAGES II study is a 5-year prospective observational study of 400-420 community dwelling persons, aged 65 years and older, assessed prior to scheduled surgery and followed daily throughout hospitalization to observe for development of delirium and other clinical outcomes. Delirium is measured with the Confusion Assessment Method (CAM), long form, after cognitive testing. Cognitive function is measured with a detailed neuropsychologic test battery, summarized as a weighted composite, the General Cognitive Performance (GCP) score. Other key measures include magnetic resonance imaging (MRI), transcranial magnetic stimulation (TMS)/electroencephalography (EEG), and Amyloid positron emission tomography (PET) imaging. We describe the eligibility criteria, enrollment flow, timing of assessments, and variables collected at baseline and during repeated assessments at 1, 2, 6, 12, and 18 months. RESULTS: This study describes the hospital and surgery-related variables, delirium, long-term cognitive decline, clinical outcomes, and novel biomarkers. In inter-rater reliability assessments, the CAM ratings (weighted kappa = 0.91, 95% confidence interval, CI = 0.74-1.0) in 50 paired assessments and GCP ratings (weighted kappa = 0.99, 95% CI 0.94-1.0) in 25 paired assessments. We describe procedures for data quality assurance and Covid-19 adaptations. CONCLUSIONS: This complex study presents an innovative effort to advance our understanding of the inter-relationship between delirium and dementia via novel biomarkers, collected in the context of major surgery in older adults. Strengths include the integration of MRI, TMS/EEG, PET modalities, and high-quality longitudinal data.

Neurophysiologic predictors of individual risk for post-operative delirium after elective surgery.

BACKGROUND: Post-surgical delirium is associated with increased morbidity, lasting cognitive decline, and loss of functional independence. Within a conceptual framework that delirium is triggered by stressors when vulnerabilities exist in cerebral connectivity and plasticity, we previously suggested that neurophysiologic measures might identify individuals at risk for post-surgical delirium. Here we demonstrate the feasibility of the approach and provide preliminary experimental evidence of the predictive value of such neurophysiologic measures for the risk of delirium in older persons undergoing elective surgery. METHODS: Electroencephalography (EEG) and transcranial magnetic stimulation (TMS) were collected from 23 patients prior to elective surgery. Resting-state EEG spectral power ratio (SPR) served as a measure of integrity of neural circuits. TMS-EEG metrics of plasticity (TMS-plasticity) were used as indicators of brain capacity to respond to stressors. Presence or absence of delirium was assessed using the confusion assessment method (CAM). We included individuals with no baseline clinically relevant cognitive impairment (MoCA scores ≥21) in order to focus on subclinical neurophysiological measures. RESULTS: In patients with no baseline cognitive impairment (N = 20, age = 72 ± 6), 3 developed post-surgical delirium (MoCA = 24 ± 2.6) and 17 did not (controls; MoCA = 25 ± 2.4). Patients who developed delirium had pre-surgical resting-state EEG power ratios outside the 95% confidence interval of controls, and 2/3 had TMS-plasticity measures outside the 95% CI of controls. CONCLUSIONS: Consistent with our proposed conceptual framework, this pilot study suggests that non-invasive and scalable neurophysiologic measures can identify individuals at risk of post-operative delirium. Specifically, abnormalities in resting-state EEG spectral power or TMS-plasticity may indicate sub-clinical risk for post-surgery delirium. Extension and confirmation of these findings in a larger sample is needed to assess the clinical utility of the proposed neurophysiologic markers, and to identify specific connectivity and plasticity targets for therapeutic interventions that might minimize the risk of delirium.

Structural integrity of the anterior mid-cingulate cortex contributes to resilience to delirium in SuperAging.

Despite its devastating clinical and societal impact, approaches to treat delirium in older adults remain elusive, making it important to identify factors that may confer resilience to this syndrome. Here, we investigated a cohort of 93 cognitively normal older patients undergoing elective surgery recruited as part of the Successful Aging after Elective Surgery study. Each participant was classified either as a SuperAger (n = 19) or typically aging older adult (n = 74) based on neuropsychological criteria, where the former was defined as those older adults whose memory function rivals that of young adults. We compared these subgroups to examine the role of preoperative memory function in the incidence and severity of postoperative delirium. We additionally investigated the association between indices of postoperative delirium symptoms and cortical thickness in functional networks implicated in SuperAging based on structural magnetic resonance imaging data that were collected preoperatively. We found that SuperAging confers the real-world benefit of resilience to delirium, as shown by lower (i.e. zero) incidence of postoperative delirium and decreased severity scores compared with typical older adults. Furthermore, greater baseline cortical thickness of the anterior mid-cingulate cortex-a key node of the brain's salience network that is also consistently implicated in SuperAging-predicted lower postoperative delirium severity scores in all patients. Taken together, these findings suggest that baseline memory function in older adults may be a useful predictor of postoperative delirium risk and severity and that superior memory function may contribute to resilience to delirium. In particular, the integrity of the anterior mid-cingulate cortex may be a potential biomarker of resilience to delirium, pointing to this region as a potential target for preventive or therapeutic interventions designed to mitigate the risk or consequences of developing this prevalent clinical syndrome.

Assessment of potential selection bias in neuroimaging studies of postoperative delirium and cognitive decline: lessons from the SAGES study.

Due to cost and participant burden, neuroimaging studies are often performed in relatively small samples of voluntary participants. This may lead to selection bias. It is important to identify factors associated with participation in neuroimaging studies and understand their effect on outcome measures. We investigated the effect of postoperative delirium on long-term (over 48 months) cognitive decline (LTCD) in 560 older surgical patients (≥ 70 years), including a nested MRI cohort (n = 146). We observed a discrepancy in the effect of delirium on cognitive decline as a function of MRI participation. Although overall difference in cognitive decline due to delirium was not greater than what might be expected due to chance (p = .21), in the non-MRI group delirium was associated with a faster pace of LTCD (-0.063, 95% CI -0.094 to -0.032, p < .001); while in the MRI group the effect of delirium was less and not significant (-0.023, 95% CI -0.076, 0.030, p = .39). Since this limits our ability to investigate the neural correlates of delirium and cognitive decline using MRI data, we attempted to mitigate the observed discrepancy using inverse probability weighting for MRI participation. The approach was not successful and the difference of the effect of delirium in slope was essentially unchanged. There was no evidence that the MRI sub-group experienced delirium that differed in severity relative to MRI non-participants. We could not attribute the observed discrepancy to selection bias based on measured factors. It may reflect a power issue due to the smaller MRI subsample or selection bias from unmeasured factors.

Corrigendum: Perivascular Unit: This Must Be the Place. The Anatomical Crossroad Between the Immune, Vascular and Nervous System.

[This corrects the article DOI: 10.3389/fnana.2020.00017.].

The Role of Inflammation after Surgery for Elders (RISE) study: Examination of [11C]PBR28 binding and exploration of its link to post-operative delirium.

Major surgery is associated with a systemic inflammatory cascade that is thought, in some cases, to contribute to transient and/or sustained cognitive decline, possibly through neuroinflammatory mechanisms. However, the relationship between surgery, peripheral and central nervous system inflammation, and post-operative cognitive outcomes remains unclear in humans, primarily owing to limitations of in vivo biomarkers of neuroinflammation which vary in sensitivity, specificity, validity, and reliability. In the present study, [11C]PBR28 positron emission tomography, cerebrospinal fluid (CSF), and blood plasma biomarkers of inflammation were assessed pre-operatively and 1-month post-operatively in a cohort of patients (N = 36; 30 females; ≥70 years old) undergoing major orthopedic surgery under spinal anesthesia. Delirium incidence and severity were evaluated daily during hospitalization. Whole-brain voxel-wise and regions-of-interest analyses were performed to determine the magnitude and spatial extent of changes in [11C]PBR28 uptake following surgery. Results demonstrated that, compared with pre-operative baseline, [11C]PBR28 binding in the brain was globally downregulated at 1 month following major orthopedic surgery, possibly suggesting downregulation of the immune system of the brain. No significant relationship was identified between post-operative delirium and [11C]PBR28 binding, possibly due to a small number (n = 6) of delirium cases in the sample. Additionally, no significant relationships were identified between [11C]PBR28 binding and CSF/plasma biomarkers of inflammation. Collectively, these results contribute to the literature by demonstrating in a sizeable sample the effect of major surgery on neuroimmune activation and preliminary evidence identifying no apparent associations between [11C]PBR28 binding and fluid inflammatory markers or post-operative delirium.

Perivascular Unit: This Must Be the Place. The Anatomical Crossroad Between the Immune, Vascular and Nervous System.

Most neurological disorders seemingly have heterogenous pathogenesis, with overlapping contribution of neuronal, immune and vascular mechanisms of brain injury. The perivascular space in the brain represents a crossroad where those mechanisms interact, as well as a key anatomical component of the recently discovered glymphatic pathway, which is considered to play a crucial role in the clearance of brain waste linked to neurodegenerative diseases. The pathological interplay between neuronal, immune and vascular factors can create an environment that promotes self-perpetration of mechanisms of brain injury across different neurological diseases, including those that are primarily thought of as neurodegenerative, neuroinflammatory or cerebrovascular. Changes of the perivascular space can be monitored in humans in vivo using magnetic resonance imaging (MRI). In the context of glymphatic clearance, MRI-visible enlarged perivascular spaces (EPVS) are considered to reflect glymphatic stasis secondary to the perivascular accumulation of brain debris, although they may also represent an adaptive mechanism of the glymphatic system to clear them. EPVS are also established correlates of dementia and cerebral small vessel disease (SVD) and are considered to reflect brain inflammatory activity. In this review, we describe the "perivascular unit" as a key anatomical and functional substrate for the interaction between neuronal, immune and vascular mechanisms of brain injury, which are shared across different neurological diseases. We will describe the main anatomical, physiological and pathological features of the perivascular unit, highlight potential substrates for the interplay between different noxae and summarize MRI studies of EPVS in cerebrovascular, neuroinflammatory and neurodegenerative disorders.

Older Patients with Alzheimer's Disease-Related Cortical Atrophy Who Develop Post-Operative Delirium May Be at Increased Risk of Long-Term Cognitive Decline After Surgery.

BACKGROUND: Older surgical patients with Alzheimer's disease (AD) dementia and delirium are at increased risk for accelerated long-term cognitive decline. OBJECTIVE: Investigate associations between a probabilistic marker of preclinical AD, delirium, and long-term cognitive decline. METHODS: The Successful Aging after Elective Surgery cohort includes older adults (≥70 years) without dementia who underwent elective surgery. 140 patients underwent preoperative magnetic resonance imaging and had≥6 months cognitive follow-up. Cortical thickness was measured in 'AD-Signature' regions. Delirium was evaluated each postoperative day by the Confusion Assessment Method. Cognitive performance was assessed using a detailed neuropsychological battery at baseline; months 1, 2, and 6; and every 6 months thereafter until 36 months. Using either a General Cognitive Performance composite (GCP) or individual test scores as outcomes, we performed linear mixed effects models to examine main effects of AD-signature atrophy and the interaction of AD-signature atrophy and delirium on slopes of cognitive change from post-operative months 2-36. RESULTS: Reduced baseline AD-signature cortical thickness was associated with greater 36-month cognitive decline in GCP (standardized beta coefficient, ß = -0.030, 95% confidence interval [-0.060, -0.001]). Patients who developed delirium who also had thinner AD signature cortex showed greater decline on a verbal learning test (ß = -0.100 [-0.192, -0.007]). CONCLUSION: Patients with the greatest baseline AD-related cortical atrophy who develop delirium after elective surgery appear to experience the greatest long-term cognitive decline. Thus, atrophy suggestive of preclinical AD and the development of delirium may be high-risk indicators for long-term cognitive decline following surgery.

A novel classification of fatigue in multiple sclerosis based on longitudinal assessments.

BACKGROUND: Magnetic resonance imaging (MRI) studies of multiple sclerosis-related fatigue had limited reproducibility. Temporal fatigue fluctuations have not been considered. OBJECTIVE: To investigate whether a novel group allocation that reflects temporal dynamics of fatigue improves our ability to detect fatigue-associated structural brain abnormalities. METHODS: Patient stratification based on biennial fatigue assessments: sustained fatigue (SF, n = 29, fatigued at the latest ⩾2 assessments), one time-point fatigue (1F, n = 15, fatigued at the latest, but non-fatigued at the penultimate assessment), reversible fatigue (RF, n = 31, non-fatigued at the latest assessment, but reported fatigue previously), and never fatigued (NF, n = 54). Brain parenchymal fraction (BPF) and T2 lesion volume (T2LV) were compared between these groups and were derived using a conventional, single time-point fatigued versus non-fatigued stratification. RESULTS: The SF versus NF stratification yielded improved power. SF (p = 0.005) and RF (p = 0.043) showed significantly higher T2LV than NF. T2LV showed no significant differences in SF versus 1F, SF versus RF, or 1F versus RF. Fatigued versus non-fatigued patients showed significantly higher T2LV (p = 0.030). We found no significant differences in BPF between the groups. CONCLUSION: Taking into account temporal fatigue dynamics increases the statistical power with respect to T2LV and may improve characterization of brain pathological correlates of MS-related fatigue.

Microstructural fronto-striatal and temporo-insular alterations are associated with fatigue in patients with multiple sclerosis independent of white matter lesion load and depression.

BACKGROUND: Fatigue in multiple sclerosis (MS) has been inconsistently associated with disruption of specific brain circuitries. Temporal fluctuations of fatigue have not been considered. OBJECTIVE: The aim of this study was to investigate the association of fatigue with brain diffusion abnormalities, using robust criteria for patient stratification based on longitudinal patterns of fatigue. METHODS: Patient stratification: (1) sustained fatigue (SF, n = 26): latest two Modified Fatigue Impact Scale (MFIS) ⩾ 38; (2) reversible fatigue (RF, n = 25): latest MFIS < 38 and minimum one previous MFIS ⩾ 38; and (3) never fatigued (NF, n = 42): MFIS always < 38 (five assessments minimum). 3T brain magnetic resonance imaging (MRI) was used to perform voxel-wise comparison of fractional anisotropy (FA) between the groups controlling for age, sex, disease duration, physical disability, white matter lesion load (T2LV), and depression. RESULTS: SF and, to a lesser extent, RF patients showed lower FA in multiple brain regions compared to NF patients, independent of age, sex, disease duration, and physical disability. In cingulo-postcommissural-striato-thalamic regions, the differences in FA between SF and NF (but not between RF and NF or SF) patients were independent of T2LV, and in ventromedial prefronto-precommissuro-striatal and temporo-insular areas, independent of T2LV and depression. CONCLUSION: Damage to ventromedial prefronto-precommissuro-striatal and temporo-insular pathways appears to be a specific substrate of SF in MS.

History of fatigue in multiple sclerosis is associated with grey matter atrophy.

Fatigue in multiple sclerosis (MS) has been associated with brain damage with low replicability. Temporal fatigue fluctuations have not been considered. We assessed whether sustained fatigue (SF) associates more strongly with grey matter (GM) changes than reversible fatigue (RF). Patients were stratified into three groups according to historical fatigue levels: SF (n = 30, i.e. patients who reported fatigue at the latest ≥2 assessments), RF (n = 31, i.e. patients not fatigued at the latest assessment, but reported fatigue previously), and never fatigued (NF, n = 37). Groups were compared for brain GM volume using cross-sectional voxel-based and volumetric analyses of 3T T1-weighted MRI. Confounding effects of depression and related medications were also investigated. SF and RF patients showed similar anatomical distribution of GM atrophy. While we robustly replicated the anatomical patterns of GM atrophy described in previous work, we also found an association between hippocampal atrophy and fatigue. Depression showed confounding effects in frontal, parietal, occipital, accumbal and thalamic regions. Assessed treatments showed confounding effects in frontal, parietal and striatal areas. Our results suggest that history of clinically-relevant fatigue in currently non-fatigued patients is associated with GM atrophy, potentially explaining inconsistent findings of previous studies that stratified patients using a single fatigue assessment.

Postoperative Delirium and Postoperative Cognitive Dysfunction: Overlap and Divergence.

BACKGROUND: Postoperative delirium and postoperative cognitive dysfunction share risk factors and may co-occur, but their relationship is not well established. The primary goals of this study were to describe the prevalence of postoperative cognitive dysfunction and to investigate its association with in-hospital delirium. The authors hypothesized that delirium would be a significant risk factor for postoperative cognitive dysfunction during follow-up. METHODS: This study used data from an observational study of cognitive outcomes after major noncardiac surgery, the Successful Aging after Elective Surgery study. Postoperative delirium was evaluated each hospital day with confusion assessment method-based interviews supplemented by chart reviews. Postoperative cognitive dysfunction was determined using methods adapted from the International Study of Postoperative Cognitive Dysfunction. Associations between delirium and postoperative cognitive dysfunction were examined at 1, 2, and 6 months. RESULTS: One hundred thirty-four of 560 participants (24%) developed delirium during hospitalization. Slightly fewer than half (47%, 256 of 548) met the International Study of Postoperative Cognitive Dysfunction-defined threshold for postoperative cognitive dysfunction at 1 month, but this proportion decreased at 2 months (23%, 123 of 536) and 6 months (16%, 85 of 528). At each follow-up, the level of agreement between delirium and postoperative cognitive dysfunction was poor (kappa less than .08) and correlations were small (r less than .16). The relative risk of postoperative cognitive dysfunction was significantly elevated for patients with a history of postoperative delirium at 1 month (relative risk = 1.34; 95% CI, 1.07-1.67), but not 2 months (relative risk = 1.08; 95% CI, 0.72-1.64), or 6 months (relative risk = 1.21; 95% CI, 0.71-2.09). CONCLUSIONS: Delirium significantly increased the risk of postoperative cognitive dysfunction in the first postoperative month; this relationship did not hold in longer-term follow-up. At each evaluation, postoperative cognitive dysfunction was more common among patients without delirium. Postoperative delirium and postoperative cognitive dysfunction may be distinct manifestations of perioperative neurocognitive deficits.

Evidence of axonal damage in cerebellar peduncles without T2-lesions in multiple sclerosis.

BACKGROUND AND AIM: Cerebellar peduncles (CP) can be probed by diffusion tensor imaging (DTI) to evaluate the integrity of cerebellar afferent and efferent networks. Damage to the CP in multiple sclerosis (MS) could lead to serious cognitive and mobility impairment. The aim of this study was to investigate the extent and the clinical impact of CP damage in MS. METHODS: Sixty-eight MS patients were included in this study along with 27 healthy controls (HC) and underwent an MRI on a 1.5T including T1, T2, FLAIR and DTI. Using DTI, the microstructural integrity within the CP regions (superior (SCP), inferior (ICP) and middle (MCP)) was probed while controlling for focal T2-lesions presence or absence. A general linear model was performed to test for associations between clinical scores and DTI metrics for each CP. RESULTS: Significantly decreased fractional anisotropy (FA) and increased radial diffusivity (RD) were found in the CP of all MS patients compared to those of HC, but to a lesser extent in non-lesioned CP than those with lesions. Axial diffusivity (AD) was significantly and similarly increased in both non-lesioned and lesioned CP, but only in the SCP and ICP. Expanded disability status scale (EDSS) significantly correlated with MCP's FA (p < 0.05) and RD (p < 0.05), while MS functional composite (MSFC) significantly correlated with SCP's FA (p < 0.01) and RD (p < 0.01). CONCLUSION: The diffusion changes (FA and RD) measured in lesioned CP are probably directly related to the presence of inflammatory and/or demyelinating lesions. In contrast, the microstructural alterations reflected by AD increase in non-lesioned CP may result either from remote effects of cerebral white matter injury (diaschisis) or primary axonal degeneration, that are associated with cognitive, sensory and motor impairments of MS patients.

Longitudinal microstructural changes of cerebral white matter and their association with mobility performance in older persons.

Mobility impairment in older persons is associated with brain white matter hyperintensities (WMH), a common finding in magnetic resonance images and one established imaging biomarker of small vessel disease. The contribution of possible microstructural abnormalities within normal-appearing white matter (NAWM) to mobility, however, remains unclear. We used diffusion tensor imaging (DTI) measures, i.e. fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD), to assess microstructural changes within supratentorial NAWM and WMH sub-compartments, and to investigate their association with changes in mobility performance, i.e. Tinetti assessment and the 2.5-meters walk time test. We analyzed baseline (N = 86, age ≥75 years) and 4-year (N = 41) follow-up data. Results from cross-sectional analysis on baseline data showed significant correlation between WMH volume and NAWM-FA (r = -0.33, p = 0.002), NAWM-AD (r = 0.32, p = 0.003) and NAWM-RD (r = 0.39, p = 0.0002). Our longitudinal analysis showed that after 4-years, FA and AD decreased and RD increased within NAWM. In regional tract-based analysis decrease in NAWM-FA and increase in NAWM-RD within the genu of the corpus callosum correlated with slower walk time independent of age, gender and WMH burden. In conclusion, global DTI indices of microstructural integrity indicate that significant changes occur in the supratentorial NAWM over four years. The observed changes likely reflect white matter deterioration resulting from aging as well as accrual of cerebrovascular injury associated with small vessel disease. The observed association between mobility scores and regional measures of NAWM microstructural integrity within the corpus callosum suggests that subtle changes within this structure may contribute to mobility impairment.

Changes to the septo-fornical area might play a role in the pathogenesis of anxiety in multiple sclerosis.

BACKGROUND: Reports on the relationships between white matter lesion load (WMLL) and fatigue and anxiety in multiple sclerosis (MS) are inconsistent. OBJECTIVE: To investigate the association of total and tract-specific WMLL with fatigue and anxiety. METHODS: Total and regional T2 WMLL was assessed for 19 tracts in 48 MS patients (30 females). ICBM-DTI-81 Atlas-based parcellation was combined with WMLL segmentation of T2-weighted magnetic resonance imaging (MRI). Fatigue, anxiety, and depression were assessed using Fatigue Impact Scale, State Trait Anxiety Inventory, and Beck Depression Inventory, respectively. RESULTS: Fatigue, anxiety, and depression showed significant inter-correlation. We found no association between fatigue and total or regional WMLLs, whereas anxiety was associated with total and regional WMLLs in nine tracts. After adjusting for total WMLL, age, and depression, only the column and body of the fornix (CBF) remained significantly associated with anxiety. Post hoc analyses showed no CBF lesions on T1-weighted MRI and suggested, but could not confirm, that the septum pellucidum might play a role in the pathogenesis of anxiety. CONCLUSION: Our results suggest that anxiety in MS patients may have a neuropathological substrate in the septo-fornical area, which requires further validation using larger sample size and ultra-high-field MRI in targeted prospective studies.

Evaluating the Association between Enlarged Perivascular Spaces and Disease Worsening in Multiple Sclerosis.

BACKGROUND AND PURPOSE: Enlarged perivascular spaces (EPVSs) have been associated with relapses and brain atrophy in multiple sclerosis (MS). We investigated the association of EPVS with clinical and MRI features of disease worsening in a well-characterized cohort of relapsing-remitting MS patients prospectively followed for up to 10 years. METHODS: Baseline EPVSs were scored on 1.5T MRI in 30 converters to moderate-severe disability, and 30 nonconverters matched for baseline characteristics. RESULTS: EPVS scores were not significantly different between converters and nonconverters, nor associated with accrual of lesions or brain atrophy. CONCLUSIONS: Our preliminary findings from a relatively small study sample argue against a potential use of EPVS as early indicator of risk for disease worsening in relapsing-remitting MS patients in a clinical setting. Although the small sample size and clinical 1.5T MRI may have limited our ability to detect a significant effect, we provided estimates of the association of EPVS with clinical and MRI indicators of disease worsening in a well-characterized cohort of MS patients.