Peripheral sTREM2-Related Inflammatory Activity Alterations in Early-Stage Alzheimer's Disease.

Alzheimer's disease (AD) has been linked to multiple immune system-related genetic variants. Triggering receptor expressed on myeloid cells 2 (TREM2) genetic variants are risk factors for AD and other neurodegenerative diseases. In addition, soluble TREM2 (sTREM2) isoform is elevated in cerebrospinal fluid in the early stages of AD and is associated with slower cognitive decline in a disease stage-dependent manner. Multiple studies have reported an altered peripheral immune response in AD. However, less is known about the relationship between peripheral sTREM2 and an altered peripheral immune response in AD. The objective of this study was to explore the relationship between human plasma sTREM2 and inflammatory activity in AD. The hypothesis of this exploratory study was that sTREM2-related inflammatory activity differs by AD stage. We observed different patterns of inflammatory activity across AD stages that implicate early-stage alterations in peripheral sTREM2-related inflammatory activity in AD. Notably, fractalkine showed a significant relationship with sTREM2 across different analyses in the control groups that was lost in later AD-related stages with high levels in mild cognitive impairment. Although multiple other inflammatory factors either differed significantly between groups or were significantly correlated with sTREM2 within specific groups, three inflammatory factors (fibroblast growth factor-2, GM-CSF, and IL-1ß) are notable because they exhibited both lower levels in AD, compared with mild cognitive impairment, and a change in the relationship with sTREM2. This evidence provides important support to the hypothesis that sTREM2-related inflammatory activity alterations are AD stage specific and provides critical information for therapeutic strategies focused on the immune response.

ATN cerebrospinal fluid biomarkers in dementia with Lewy bodies: Initial results from the United States Dementia with Lewy Bodies Consortium.

INTRODUCTION: The National Institute on Aging - Alzheimer's Association (NIA-AA) ATN research framework proposes to use biomarkers for amyloid (A), tau (T), and neurodegeneration (N) to stage individuals with AD pathological features and track changes longitudinally. The overall aim was to utilize this framework to characterize pre-mortem ATN status longitudinally in a clinically diagnosed cohort of dementia with Lewy bodies (DLB) and to correlate it with the post mortem diagnosis. METHODS: The cohort was subtyped by cerebrospinal fluid (CSF) ATN category. A subcohort had longitudinal data, and a subgroup was neuropathologically evaluated. RESULTS: We observed a significant difference in Aß42/40 after 12 months in the A+T- group. Post mortem neuropathologic analyses indicated that most of the p-Tau 181 positive (T+) cases also had a high Braak stage. DISCUSSION: This suggests that DLB patients who are A+ but T- may need to be monitored to determine whether they remain A+ or ever progress to T positivity. HIGHLIGHTS: Some A+T- DLB subjects transition from A+ to negative after 12-months. Clinically diagnosed DLB with LBP-AD (A+T+) maintain their positivity. Clinically diagnosed DLB with LBP-AD (A+T+) maintain their positivity. Monitoring of the A+T- sub-type of DLB may be necessary.

Cooling vest improves surgeons' thermal comfort without affecting cognitive performance: a randomised cross-over trial.

OBJECTIVES: Surgeons become uncomfortable while performing surgery because heat transfer and evaporative cooling are restricted by insulating surgical gowns. Consequently, perceptions of thermal discomfort during surgery may impair cognitive performance. We, therefore, aimed to evaluate surgeons' thermal comfort, cognitive performance, core and mean skin temperatures, perceptions of sweat-soaked clothing, fatigue and exertion with and without a CoolSource cooling vest (Cardinal Health, Dublin, Ohio, USA). METHODS: Thirty orthopaedic surgeons participated in a randomised cross-over trial, each performing four total-joint arthroplasties with randomisation to one of four treatment sequences. The effects of cooling versus no cooling were measured using a repeated-measures linear model accounting for within-subject correlations. RESULTS: The cooling vest improved thermal comfort by a mean (95% CI) of -2.1 (-2.7 to -1.6) points on a 0-10 scale, p<0.001, with no evidence of treatment-by-period interaction (p=0.94). In contrast, cooling had no perceptible effect on cognition, with an estimated mean difference (95% CI) in Cleveland Clinic Cognitive Battery (C3B) Processing Speed Test score of 0.03 (95% CI -2.44 to 2.51), p=0.98, or in C3B Visual Memory Test score with difference of 0.88 (95% CI -2.25 to 4.01), p=0.57. Core temperature was not lower with the cooling vest, with mean difference (95% CI) of -0.13 (-0.33°C to 0.07°C), p=0.19, while mean skin temperature was lower, with mean difference of -0.23 (95% CI -0.40°C to -0.06°C) lower, p=0.011. The cooling vest significantly reduced surgeons' perceptions of sweat-soaked clothing, fatigue and exertion. CONCLUSIONS: A cooling vest worn during surgery lowered core and skin temperatures, improved thermal comfort, and decreased perceptions of sweating and fatigue, but did not improve cognition. Thermal discomfort during major orthopaedic surgery is thus largely preventable, but cooling does not affect cognition. TRIAL REGISTRATION NUMBER: NCT04511208.

Necessity of technicians for computerized neuropsychological assessment devices in multiple sclerosis.

OBJECTIVE: Determine the influence of technician supervision on computer-administered cognitive tests in multiple sclerosis (MS). METHODS: Eighty MS patients underwent assessment using the CogState Brief Battery (CSBB) and the Cleveland Clinic Cognitive Battery (C3B). Each was administered twice, once with a technician guiding assessment, and once with technician-absent. Twenty-eight healthy controls were also evaluated. RESULTS: The influence of technician guidance was not statistically significant for group means on either test. For CSBB, administration problems were more common in the technician-absent condition. CONCLUSION: In this MS sample, reliable and valid test results were obtained from computer-assisted cognitive testing without technician guidance.

Episodic Memory and Hippocampal Volume Predict 5-Year Mild Cognitive Impairment Conversion in Healthy Apolipoprotein ε4 Carriers.

OBJECTIVE: The Apolipoprotein (APOE) ε4 allele increases the risk for mild cognitive impairment (MCI) and dementia, but not all carriers develop MCI/dementia. The purpose of this exploratory study was to determine if early and subtle preclinical signs of cognitive dysfunction and medial temporal lobe atrophy are observed in cognitively intact ε4 carriers who subsequently develop MCI. METHODS: Twenty-nine healthy, cognitively intact ε4 carriers (ε3/ε4 heterozygotes; ages 65-85) underwent neuropsychological testing and MRI-based measurements of medial temporal volumes over a 5-year follow-up interval; data were converted to z-scores based on a non-carrier group consisting of 17 ε3/ε3 homozygotes. RESULTS: At follow-up, 11 ε4 carriers (38%) converted to a diagnosis of MCI. At study entry, the MCI converters had significantly lower scores on the Mini-Mental State Examination, Rey Auditory Verbal Learning Test (RAVLT) Trials 1-5, and RAVLT Immediate Recall compared to non-converters. MCI converters also had smaller MRI volumes in the left subiculum than non-converters. Follow-up logistic regressions revealed that left subiculum volumes and RAVLT Trials 1-5 scores were significant predictors of MCI conversion. CONCLUSIONS: Results from this exploratory study suggest that ε4 carriers who convert to MCI exhibit subtle cognitive and volumetric differences years prior to diagnosis.

The role of the thalamus and hippocampus in episodic memory performance in patients with multiple sclerosis.

BACKGROUND: Episodic memory loss is one of the most common cognitive symptoms in patients with multiple sclerosis (MS), but the pathophysiology of this symptom remains unclear. Both the hippocampus and thalamus have been implicated in episodic memory and show regional atrophy in patients with MS. OBJECTIVE: In this work, we used functional magnetic resonance imaging (fMRI) during a verbal episodic memory task, lesion load, and volumetric measures of the hippocampus and thalamus to assess the relative contributions to verbal and visual-spatial episodic memory. METHODS: Functional activation, lesion load, and volumetric measures from 32 patients with MS and 16 healthy controls were used in a predictive analysis of episodic memory function. RESULTS: After adjusting for disease duration, immediate recall performance on a visual-spatial episodic memory task was significantly predicted by hippocampal volume ( p < 0.003). Delayed recall on the same task was significantly predicted by volume of the left thalamus ( p < 0.003). For both memory measures, functional activation of the thalamus during encoding was more predictive than that of volume measures ( p < 0.002). CONCLUSION: Our results suggest that functional activation may be useful as a predictive measure of episodic memory loss in patients with MS.

An iPad-based Measure of Processing Speed in Older Adults Hospitalized for Heart Failure.

BACKGROUND: In older adults hospitalized with heart failure (HF), cognitive impairment is associated with increased hospital readmission and mortality risk. There is no consensus on an objective, scalable method of cognitive screening in this population. OBJECTIVE: The aim of this project was to determine the feasibility, test-retest reliability, and convergent validity of the Processing Speed Test (PST), a test of information processing, attention, and working memory administered on an iPad in older adults hospitalized with HF. METHODS: Patients hospitalized with HF (n = 30) and age-, sex-, and education-matched controls (n = 30) participated in the study. To determine test-retest reliability, the PST was administered on an iPad on 2 occasions, separated by 12 to 48 hours. The Symbol Digit Modalities Test was administered at the first testing time point to determine convergent validity. RESULTS: Test-retest reliability of the PST was 0.80 and 0.92 in individuals with HF and controls, respectively. Convergent validity was 0.72 and 0.90 for individuals with HF and controls, respectively. Time to complete the PST was similar for both individuals with HF and controls (<5 minutes). CONCLUSION: The iPad-based deployment of the PST was a feasible, reliable, and valid cognitive screen for older adults hospitalized with HF. Using a tablet-based self-administered cognitive screen in older adults with HF provides a method of cognitive assessment that is amenable to widespread clinical utilization.

Processing speed test: Validation of a self-administered, iPad®-based tool for screening cognitive dysfunction in a clinic setting.

BACKGROUND: Cognitive dysfunction is common in multiple sclerosis (MS) patients and has important consequences for daily activities, yet, unlike motor function, is not routinely assessed in the clinic setting. We developed the Processing Speed Test (PST), a self-administered iPad®-based tool to measure MS-related deficits in processing speed. OBJECTIVE: To determine whether the PST is valid for screening cognitive dysfunction by comparing it to the paper-and-pencil Symbol Digit Modalities Test (SDMT). METHODS: We assessed PST test-retest reliability, sensitivity of PST and SDMT in discriminating MS patients from healthy controls (HC), convergent validity between PST and SDMT, correlations between T2 lesion load and PST and SDMT, and PST performance with and without technician present during administration. RESULTS: PST had excellent test-retest reliability, was highly correlated with SDMT, was slightly more sensitive than SDMT in discriminating MS from HC groups, and correlated better with cerebral T2 lesion load than did SDMT. Finally, PST performance was no different with or without a technician in the testing environment. CONCLUSION: PST has advantages over SDMT because of its efficient administration, scoring, and potential for medical record or research database integration. PST is a practical tool for routine screening of processing speed deficits in the MS clinic.

Neuropsychology of Multiple Sclerosis: Looking Back and Moving Forward.

The neuropsychological aspects of multiple sclerosis (MS) have evolved over the past three decades. What was once thought to be a rare occurrence, cognitive dysfunction is now viewed as one of the most disabling symptoms of the disease, with devastating effects on patients' quality of life. This selective review will highlight major innovations and scientific discoveries in the areas of neuropathology, neuroimaging, diagnosis, and treatment that pertain to our understanding of the neuropsychological aspects of MS. Specifically, we focus on the recent discovery that MS produces pathogical lesions of gray matter (GM) that have consequences for cognitive functions. Methods for imaging these GM lesions in MS are discussed along with multimodal imaging studies that integrate structural and functional imaging methods to provide a better understanding of the relationship between cognitive test performance and functional reserve. Innovations in the screening and comprehensive assessment of cognitive disorders are presented along with recent research that examines cognitive dysfunction in pediatric MS. Results of innovative outcome studies in cognitive rehabilitation are discussed. Finally, we highlight trends for potential future innovations over the next decade. (JINS, 2017, 23, 832-842).

Interactive effects of physical activity and APOE-ε4 on white matter tract diffusivity in healthy elders.

Older adult apolipoprotein-E epsilon 4 (APOE-ε4) allele carriers vary considerably in the expression of clinical symptoms of Alzheimer's disease (AD), suggesting that lifestyle or other factors may offer protection from AD-related neurodegeneration. We recently reported that physically active APOE-ε4 allele carriers exhibit a stable cognitive trajectory and protection from hippocampal atrophy over 18months compared to sedentary ε4 allele carriers. The aim of this study was to examine the interactions between genetic risk for AD and physical activity (PA) on white matter (WM) tract integrity, using diffusion tensor imaging (DTI) MRI, in this cohort of healthy older adults (ages of 65 to 89). Four groups were compared based on the presence or absence of an APOE-ε4 allele (High Risk; Low Risk) and self-reported frequency and intensity of leisure time physical activity (PA) (High PA; Low PA). As predicted, greater levels of PA were associated with greater fractional anisotropy (FA) and lower radial diffusivity in healthy older adults who did not possess the APOE-ε4 allele. However, the effects of PA were reversed in older adults who were at increased genetic risk for AD, resulting in significant interactions between PA and genetic risk in several WM tracts. In the High Risk-Low PA participants, who had exhibited episodic memory decline over the previous 18-months, radial diffusivity was lower and fractional anisotropy was higher, compared to the High Risk-High PA participants. In WM tracts that subserve learning and memory processes, radial diffusivity (DR) was negatively correlated with episodic memory performance in physically inactive APOE-ε4 carriers, whereas DR was positively correlated with episodic memory performance in physically active APOE-ε4 carriers and the two Low Risk groups. The common model of demyelination-induced increase in radial diffusivity cannot directly explain these results. Rather, we hypothesize that PA may protect APOE-ε4 allele carriers from selective neurodegeneration of individual fiber populations at locations of crossing fibers within projection and association WM fiber tracts.

Cross-sectional and longitudinal multimodal structural imaging in prodromal Huntington's disease.

OBJECTIVES: Diffusivity in white-matter tracts is abnormal throughout the brain in cross-sectional studies of prodromal Huntington's disease. To date, longitudinal changes have not been observed. The present study investigated cross-sectional and longitudinal changes in white-matter diffusivity in relationship to the phase of prodromal Huntington's progression, and compared them with changes in brain volumes and clinical variables that track disease progression. METHODS: Diffusion MRI profiles were studied for 2 years in 37 gene-negative controls and 64 prodromal Huntington's disease participants in varied phases of disease progression. To estimate the relative importance of diffusivity metrics in the prodromal phase, group effects were rank ordered relative to those obtained from analyses of brain volumes, motor, cognitive, and sensory variables. RESULTS: First, at baseline diffusivity was abnormal throughout all tracts, especially as individuals approached a manifest Huntington's disease diagnosis. Baseline diffusivity metrics in 6 tracts and basal ganglia volumes best distinguished among the groups. Second, group differences in longitudinal change in diffusivity were localized to the superior fronto-occipital fasciculus, most prominently in individuals closer to a diagnosis. Group differences were also observed in longitudinal changes of most brain volumes, but not clinical variables. Last, increases in motor symptoms across time were associated with greater changes in the superior fronto-occipital fasciculus diffusivity and corpus callosum, cerebrospinal fluid, and lateral ventricle volumes. CONCLUSIONS: These novel findings provide new insights into changes within 2 years in different facets of brain structure and their clinical relevance to changes in symptomatology that is decisive for a manifest Huntington's diagnosis. © 2016 International Parkinson and Movement Disorder Society.

Modern Methods for Interrogating the Human Connectome.

OBJECTIVES: Connectionist theories of brain function took hold with the seminal contributions of Norman Geschwind a half century ago. Modern neuroimaging techniques have expanded the scientific interest in the study of brain connectivity to include the intact as well as disordered brain. METHODS: In this review, we describe the most common techniques used to measure functional and structural connectivity, including resting state functional MRI, diffusion MRI, and electroencephalography and magnetoencephalography coherence. We also review the most common analytical approaches used for examining brain interconnectivity associated with these various imaging methods. RESULTS: This review presents a critical analysis of the assumptions, as well as methodological limitations, of each imaging and analysis approach. CONCLUSIONS: The overall goal of this review is to provide the reader with an introduction to evaluating the scientific methods underlying investigations that probe the human connectome.

Diffusion Tensor Imaging Predictors of Episodic Memory Decline in Healthy Elders at Genetic Risk for Alzheimer's Disease.

OBJECTIVES: White matter (WM) integrity within the mesial temporal lobe (MTL) is important for episodic memory (EM) functioning. The current study investigated the ability of diffusion tensor imaging (DTI) in MTL WM tracts to predict 3-year changes in EM performance in healthy elders at disproportionately higher genetic risk for Alzheimer's disease (AD). METHODS: Fifty-one cognitively intact elders (52% with family history (FH) of dementia and 33% possessing an Apolipoprotein E ε4 allelle) were administered the Rey Auditory Verbal Learning Test (RAVLT) at study entry and at 3-year follow-up. DTI scanning, conducted at study entry, examined fractional anisotropy and mean, radial and axial diffusion within three MTL WM tracts: uncinate fasciculus (UNC), cingulate-hippocampal (CHG), and fornix-stria terminalis (FxS). Correlations were performed between residualized change scores computed from RAVLT trials 1-5, immediate recall, and delayed recall scores and baseline DTI measures; MTL gray matter (GM) and WM volumes; demographics; and AD genetic and metabolic risk factors. RESULTS: Higher MTL mean and axial diffusivity at baseline significantly predicted 3-year changes in EM, whereas baseline MTL GM and WM volumes, FH, and metabolic risk factors did not. Both ε4 status and DTI correlated with change in immediate recall. CONCLUSIONS: Longitudinal EM changes in cognitively intact, healthy elders can be predicted by disruption of the MTL WM microstructure. These results are derived from a sample with a disproportionately higher genetic risk for AD, suggesting that the observed WM disruption in MTL pathways may be related to early neuropathological changes associated with the preclinical stage of AD. (JINS, 2016, 22, 1005-1015).

Network topology and functional connectivity disturbances precede the onset of Huntington's disease.

Cognitive, motor and psychiatric changes in prodromal Huntington's disease have nurtured the emergent need for early interventions. Preventive clinical trials for Huntington's disease, however, are limited by a shortage of suitable measures that could serve as surrogate outcomes. Measures of intrinsic functional connectivity from resting-state functional magnetic resonance imaging are of keen interest. Yet recent studies suggest circumscribed abnormalities in resting-state functional magnetic resonance imaging connectivity in prodromal Huntington's disease, despite the spectrum of behavioural changes preceding a manifest diagnosis. The present study used two complementary analytical approaches to examine whole-brain resting-state functional magnetic resonance imaging connectivity in prodromal Huntington's disease. Network topology was studied using graph theory and simple functional connectivity amongst brain regions was explored using the network-based statistic. Participants consisted of gene-negative controls (n = 16) and prodromal Huntington's disease individuals (n = 48) with various stages of disease progression to examine the influence of disease burden on intrinsic connectivity. Graph theory analyses showed that global network interconnectivity approximated a random network topology as proximity to diagnosis neared and this was associated with decreased connectivity amongst highly-connected rich-club network hubs, which integrate processing from diverse brain regions. However, functional segregation within the global network (average clustering) was preserved. Functional segregation was also largely maintained at the local level, except for the notable decrease in the diversity of anterior insula intermodular-interconnections (participation coefficient), irrespective of disease burden. In contrast, network-based statistic analyses revealed patterns of weakened frontostriatal connections and strengthened frontal-posterior connections that evolved as disease burden increased. These disturbances were often related to long-range connections involving peripheral nodes and interhemispheric connections. A strong association was found between weaker connectivity and decreased rich-club organization, indicating that whole-brain simple connectivity partially expressed disturbances in the communication of highly-connected hubs. However, network topology and network-based statistic connectivity metrics did not correlate with key markers of executive dysfunction (Stroop Test, Trail Making Test) in prodromal Huntington's disease, which instead were related to whole-brain connectivity disturbances in nodes (right inferior parietal, right thalamus, left anterior cingulate) that exhibited multiple aberrant connections and that mediate executive control. Altogether, our results show for the first time a largely disease burden-dependent functional reorganization of whole-brain networks in prodromal Huntington's disease. Both analytic approaches provided a unique window into brain reorganization that was not related to brain atrophy or motor symptoms. Longitudinal studies currently in progress will chart the course of functional changes to determine the most sensitive markers of disease progression.

Genetic risk for Alzheimer's disease alters the five-year trajectory of semantic memory activation in cognitively intact elders.

Healthy aging is associated with cognitive declines typically accompanied by increased task-related brain activity in comparison to younger counterparts. The Scaffolding Theory of Aging and Cognition (STAC) (Park and Reuter-Lorenz, 2009; Reuter-Lorenz and Park, 2014) posits that compensatory brain processes are responsible for maintaining normal cognitive performance in older adults, despite accumulation of aging-related neural damage. Cross-sectional studies indicate that cognitively intact elders at genetic risk for Alzheimer's disease (AD) demonstrate patterns of increased brain activity compared to low risk elders, suggesting that compensation represents an early response to AD-associated pathology. Whether this compensatory response persists or declines with the onset of cognitive impairment can only be addressed using a longitudinal design. The current prospective, 5-year longitudinal study examined brain activation in APOE ε4 carriers (N=24) and non-carriers (N=21). All participants, ages 65-85 and cognitively intact at study entry, underwent task-activated fMRI, structural MRI, and neuropsychological assessments at baseline, 18, and 57 months. fMRI activation was measured in response to a semantic memory task requiring participants to discriminate famous from non-famous names. Results indicated that the trajectory of change in brain activation while performing this semantic memory task differed between APOE ε4 carriers and non-carriers. The APOE ε4 group exhibited greater activation than the Low Risk group at baseline, but they subsequently showed a progressive decline in activation during the follow-up periods with corresponding emergence of episodic memory loss and hippocampal atrophy. In contrast, the non-carriers demonstrated a gradual increase in activation over the 5-year period. Our results are consistent with the STAC model by demonstrating that compensation varies with the severity of underlying neural damage and can be exhausted with the onset of cognitive symptoms and increased structural brain pathology. Our fMRI results could not be attributed to changes in task performance, group differences in cerebral perfusion, or regional cortical atrophy.

The relationship between cognitive function and high-resolution diffusion tensor MRI of the cingulum bundle in multiple sclerosis.

BACKGROUND: Imaging can provide noninvasive neural markers of disease progression in multiple sclerosis (MS) that are related to behavioral and cognitive symptoms. Past work suggests that diffusion tensor imaging (DTI) provides a measure of white matter pathology, including demyelination and axonal counts. OBJECTIVES: In the current study, the authors investigate the relationship of DTI measures in the cingulum bundle to common deficits in MS, including episodic memory, working memory, and information processing speed. METHODS: Fifty-seven patients with MS and 17 age- and education-matched controls underwent high-spatial resolution diffusion scans and cognitive testing. Probabilistic tracking was used to generate tracks from the posterior cingulate cortex to the entorhinal cortex. RESULTS: Radial and axial diffusivity values were significantly different between patients and controls (p < 0.031), and in patients bilateral diffusion measures were significantly related to measures of episodic memory and speed of processing (p < 0.033). CONCLUSIONS: The tractography-based measures of posterior cingulum integrity reported here support further development of DTI as a viable measure of axonal integrity and cognitive function in patients with MS.

Diffusion weighted imaging of prefrontal cortex in prodromal Huntington's disease.

Huntington's disease (HD) is a devastating neurodegenerative disease with no effective disease-modifying treatments. There is considerable interest in finding reliable indicators of disease progression to judge the efficacy of novel treatments that slow or stop disease onset before debilitating signs appear. Diffusion-weighted imaging (DWI) may provide a reliable marker of disease progression by characterizing diffusivity changes in white matter (WM) in individuals with prodromal HD. The prefrontal cortex (PFC) may play a role in HD progression due to its prominent striatal connections and documented role in executive function. This study uses DWI to characterize diffusivity in specific regions of PFC WM defined by FreeSurfer in 53 prodromal HD participants and 34 controls. Prodromal HD individuals were separated into three CAG-Age Product (CAP) groups (16 low, 22 medium, 15 high) that indexed baseline progression. Statistically significant increases in mean diffusivity (MD) and radial diffusivity (RD) among CAP groups relative to controls were seen in inferior and lateral PFC regions. For MD and RD, differences among controls and HD participants tracked with baseline disease progression. The smallest difference was for the low group and the largest for the high group. Significant correlations between Trail Making Test B (TMTB) and mean fractional anisotropy (FA) and/or RD paralleled group differences in mean MD and/or RD in several right hemisphere regions. The gradient of effects that tracked with CAP group suggests DWI may provide markers of disease progression in future longitudinal studies as increasing diffusivity abnormalities in the lateral PFC of prodromal HD individuals.

High-resolution diffusion tensor imaging of the fornix predicts memory function in multiple sclerosis.

Background: Cognitive dysfunction is a known symptom of multiple sclerosis (MS), with memory recognized as a frequently impacted domain. Here, we used high-resolution MRI at 7 tesla to build on cross-sectional work by evaluating the longitudinal relationship of diffusion tensor imaging (DTI) measures of the fornix to episodic memory performance. Methods: A sample of 80 people with multiple sclerosis (mean age 51.9 ± 8.1 years; 24% male) underwent baseline clinical evaluation, neuropsychological assessment, and MRI. Sixty-four participants had follow-up neuropsychological testing after 1-2 years. Linear regression was used to assess the relationship of baseline imaging measures to follow-up episodic memory performance, measured using the Selective Reminding Test and Brief Visuospatial Memory Test. A reduced prediction model included cognitive function at baseline, age, sex, and disease course. Results: Radial (ß = -0.222, p < 0.026; likelihood ratio test (LRT) p < 0.018), axial (ß = -0.270, p < 0.005; LRT p < 0.003), and mean (ß = -0.242, p < 0.0139; LRT p < 0.009) diffusivity of the fornix significantly added to the model, with follow-up analysis indicating that a longer prediction interval may increase accuracy. Conclusion: These results suggest that fornix DTI has predictive value specific to memory function in MS and warrants additional investigation in the drive to develop predictors of disease progression.

Multi-shell diffusion MRI of the fornix as a biomarker for cognition in Alzheimer's disease.

BACKGROUND AND PURPOSE: A substantial fraction of those who had Alzheimer's Disease (AD) pathology on autopsy did not have dementia in life. While biomarkers for AD pathology are well-developed, biomarkers specific to cognitive domains affected by early AD are lagging. Diffusion MRI (dMRI) of the fornix is a candidate biomarker for early AD-related cognitive changes but is susceptible to bias due to partial volume averaging (PVA) with cerebrospinal fluid. The purpose of this work is to leverage multi-shell dMRI to correct for PVA and to evaluate PVA-corrected dMRI measures in fornix as a biomarker for cognition in AD. METHODS: Thirty-three participants in the Cleveland Alzheimer's Disease Research Center (CADRC) (19 with normal cognition (NC), 10 with mild cognitive impairment (MCI), 4 with dementia due to AD) were enrolled in this study. Multi-shell dMRI was acquired, and voxelwise fits were performed with two models: 1) diffusion tensor imaging (DTI) that was corrected for PVA and 2) neurite orientation dispersion and density imaging (NODDI). Values of tissue integrity in fornix were correlated with neuropsychological scores taken from the Uniform Data Set (UDS), including the UDS Global Composite 5 score (UDSGC5). RESULTS: Statistically significant correlations were found between the UDSGC5 and PVA-corrected measure of mean diffusivity (MDc, r = -0.35, p < 0.05) from DTI and the intracelluar volume fraction (ficvf, r = 0.37, p < 0.04) from NODDI. A sensitivity analysis showed that the relationship to MDc was driven by episodic memory, which is often affected early in AD, and language. CONCLUSION: This cross-sectional study suggests that multi-shell dMRI of the fornix that has been corrected for PVA is a potential biomarker for early cognitive domain changes in AD. A longitudinal study will be necessary to determine if the imaging measure can predict cognitive decline.