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ObjectiveHippocampal volume is a sensitive marker of neurodegeneration and a well-established predictor of age-related cognitive impairment. Recently, free-water (FW) magnetic resonance imaging (MRI) has shown associations with pathology in Alzheimer’s disease (AD), but it is still unclear whether these metrics are associated with measures of cognitive impairment. Here, we investigate whether FW and FW-corrected fractional anisotropy (FAT) within medial temporal lobe white matter tracts (cingulum, fornix, uncinate fasciculus, inferior longitudinal fasciculus, and tapetum) provides meaningful contribution to cognition and cognitive decline beyond hippocampal volume.Participants and MethodsVanderbilt Memory & Aging Project participants (n=319, 73±7 years, 59% male) with normal cognition and mild cognitive impairment (40% of cohort) underwent baseline brain MRI, including structural MRI to quantify hippocampal volume, diffusion MRI to quantify medial temporal lobe white matter tract FW and FAT, and longitudinal neuropsychological assessment with a mean follow-up of 3.5 years. Linear regressions were conducted to determine how hippocampal volume and white matter tract FW and FAT interact with baseline memory and executive function performances. Competitive model analyses determined the unique variance provided by white matter tract FW and FAT beyond that of hippocampal volume and other comorbidities. Linear mixed-effects models were conducted to determine how baseline hippocampal volume and white matter tract FW and FAT interact to explain longitudinal change in memory and executive function performances.ResultsFW in the inferior longitudinal fasciculus, tapetum, uncinate fasciculus, and cingulum were robustly associated with baseline memory and executive function. Further, competitive model analysis showed that tract FW contributed unique variance beyond other comorbidities and hippocampal volume for memory (ΔRadj2 range: 0.82-2.00%) and executive function (ΔRadj2 range: 0.88-1.87%). Longitudinal analyses demonstrated significant interactions of hippocampal volume and FAT in the inferior longitudinal fasciculus (p=0.02), tapetum (p=0.02), uncinate fasciculus (p=0.02), and cingulum (p=0.002) with decline in memory. For decline in executive function, we found significant interactions of hippocampal volume and FAT in inferior longitudinal fasciculus (p=0.03), tapetum (p=0.02), uncinate fasciculus (p=0.02), and fornix (p=0.02), as well as cingulum (p=0.02) and fornix (p=0.02) FW.ConclusionsOur results highlight novel associations between FW and FAT measures of medial temporal lobe tract microstructure and cognitive performance such that individuals with smaller hippocampal volumes and lower tract microstructure experience greater cognitive decline. These results suggest that white matter has a unique role in cognitive decline and, therefore, could be used to provide better disease staging, allowing for more precise disease monitoring in AD.

BackgroundStudies have investigated white matter microstructure in relation to late-life cognitive impairments, with fractional anisotropy (FA) and mean diffusivity (MD) measures thought to capture demyelination and axonal degradation. However, new post-processing methods allow isolation of free water (FW), which captures extracellular fluid contributions such as atrophy and neuroinflammation, from tissue components. FW also appears to be highly relevant to late-life cognitive impairment. Here, we evaluated whether executive functions are associated with FW, and FA and MD corrected for FW (FAFWcorr and MDFWcorr).MethodWe examined 489 non-demented men in the Vietnam Era Twin Study of Aging (VETSA) at mean age 68. Two latent factors capturing 'common executive function' and 'working-memory specific' processes were estimated based on 6 tasks. Analyses focused on 11 cortical white matter tracts across three metrics: FW, FAFWcorr, and MDFWcorr.ResultsBetter 'common executive function' was associated with lower FW across 9 of the 11 tracts. There were no significant associations with intracellular metrics after false discovery rate correction. Effects also appeared driven by individuals with MCI (13.7% of the sample). Working memory-specific tasks showed some associations with FAFWcorr, including the triangularis portion of the inferior frontal gyrus. There was no evidence that cognitive reserve (i.e., general cognitive ability assessed in early adulthood) moderated these associations between executive function and FW or FA.DiscussionExecutive function abilities in early old age are associated primarily with extracellular fluid (FW) as opposed to white matter (FAFWcorr or MDFWcorr). Moderation analyses suggested cognitive reserve does not play a strong role in these associations, at least in this sample of non-demented men.

Understanding the architecture of transcallosal connections would allow for more specific assessments of neurodegeneration across many fields of neuroscience, neurology, and psychiatry. To map these connections, we conducted probabilistic tractography in 100 Human Connectome Project subjects in 32 cortical areas using novel post-processing algorithms to create a spatially precise Trancallosal Tract Template (TCATT). We found robust transcallosal tracts in all 32 regions, and a topographical analysis in the corpus callosum largely agreed with well-established subdivisions of the corpus callosum. We then obtained diffusion MRI data from a cohort of patients with Alzheimer’s disease (AD) and another with progressive supranuclear palsy (PSP) and used a two-compartment model to calculate free-water corrected fractional anisotropy (FA(T)) and free-water (FW) within the TCATT. These metrics were used to determine between-group differences and to determine which subset of tracts was best associated with cognitive function (Montreal Cognitive Assessment (MoCA)). In AD, we found robust between-group differences in FW (31/32 TCATT tracts) in the absence of between-group differences in FA(T). FW in the inferior temporal gyrus TCATT tract was most associated with MoCA scores in AD. In PSP, there were widespread differences in both FA(T) and FW, and MoCA was predicted by FA(T) in the inferior frontal pars triangularis, preSMA, and medial frontal gyrus TCATT tracts as well as FW in the inferior frontal pars opercularis TCATT tract. The TCATT improves spatial localization of corpus callosum measurements to enhance the evaluation of treatment effects, as well as the monitoring of brain microstructure in relation to cognitive dysfunction and disease progression. Here, we have shown its direct relevance in capturing between-group differences and associating it with the MoCA in AD and PSP.

Introduction When using free-water diffusion imaging or positron emission tomography (PET), it is established that substania nigra microstructure and presynaptic dopamine activity are impaired in early PD. It is not well understood if these two forms of degeneration are redundant, or if they each provide a unique contribution to the clinical motor and cognitive symptoms. Methods A total of 129 PD and 75 control individuals underwent motor and cognitive evaluations, and in vivo [11C]dihydrotetrabenazine (DTBZ) monoaminergic brain PET imaging and diffusion imaging. Correlations between free-water in the substantia nigra and striatal PET measures were analyzed. Unbiased multiple regression using a backward elimination method was performed between clinical severity and all imaging measures. Results Inverse correlations were found between free-water in posterior substantia nigra and DTBZ binding in putamen and caudate. Multiple regression revealed that increased free-water in the posterior substantia nigra, decreased DTBZ binding in putamen, and age were predictors of higher Hoehn and Yahr stage, MDS-UPDRS III scores, and posture and gait sub-scores. Increased posterior substantia nigra free-water alone was associated tremor scores. Free-water in caudate and putamen did not predict measures of motor performance. Decreased DTBZ binding in caudate, increased free-water in caudate and posterior substantia nigra were associated with higher dementia ratings. Conclusions These findings suggest that free-water in the posterior substantia nigra and presynaptic dopamine imaging in striatum are uniquely associated with the clinical symptoms of PD, indicating that each imaging modality may be measuring a unique mechanism relevant to nigrostriatal degeneration.

Advanced diffusion imaging which accounts for complex tissue properties, such as crossing fibers and extracellular fluid, may detect longitudinal changes in widespread pathology in atypical Parkinsonian syndromes. We implemented fixel-based analysis, Neurite Orientation and Density Imaging (NODDI), and free-water imaging in Parkinson's disease (PD), multiple system atrophy (MSAp), progressive supranuclear palsy (PSP), and controls longitudinally over one year. Further, we used these three advanced diffusion imaging techniques to investigate longitudinal progression-related effects in key white matter tracts and gray matter regions in PD and two common atypical Parkinsonian disorders. Fixel-based analysis and free-water imaging revealed longitudinal declines in a greater number of descending sensorimotor tracts in MSAp and PSP compared to PD. In contrast, only the primary motor descending sensorimotor tract had progressive decline over one year, measured by fiber density (FD), in PD compared to that in controls. PSP was characterized by longitudinal impairment in multiple transcallosal tracts (primary motor, dorsal and ventral premotor, pre-supplementary motor, and supplementary motor area) as measured by FD, whereas there were no transcallosal tracts with longitudinal FD impairment in MSAp and PD. In addition, free-water (FW) and FW-corrected fractional anisotropy (FAt) in gray matter regions showed longitudinal changes over one year in regions that have previously shown cross-sectional impairment in MSAp (putamen) and PSP (substantia nigra, putamen, subthalamic nucleus, red nucleus, and pedunculopontine nucleus). NODDI did not detect any longitudinal white matter tract progression effects and there were few effects in gray matter regions across Parkinsonian disorders. All three imaging methods were associated with change in clinical disease severity across all three Parkinsonian syndromes. These results identify novel extra-nigral and extra-striatal longitudinal progression effects in atypical Parkinsonian disorders through the application of multiple diffusion methods that are related to clinical disease progression. Moreover, the findings suggest that fixel-based analysis and free-water imaging are both particularly sensitive to these longitudinal changes in atypical Parkinsonian disorders.

Limited experimental data exist comparing the mechanical response of the tibial cortex between fixed and rotating platform (RP) total knee arthroplasty (TKA), particularly in the revision setting. We asked if RP-TKA significantly affects tibiofemoral torque and cortical stain response in both the primary and revision settings. Fixed and RP tibial trays were implanted into analogue tibias and biomechanically tested under axial and torsional loading. Torque and strain response were analyzed using digital image correlation. Fixed bearing designs exhibited 13.8 times greater torque (P0.01), and 69% (P0.01) higher cortical strain than RP designs. Strain response was similar in the primary and revision cohorts. The decrease in torque transfer could act as a safeguard to reduce stress, micromotion and torsional fatigue in scenario of poor bone stock.

The goal in the current study was to examine the analgesic effects of a pinch grip-force production task and a working memory task when pain-eliciting thermal stimulation was delivered simultaneously to the left or right hand during task performance. Control conditions for visual distraction and thermal stimulation were included, and force performance measures and working memory performance measures were collected and analyzed. Our experiments revealed 3 novel findings. First, we showed that accurate isometric force contractions elicit an analgesic effect when pain-eliciting thermal stimulation was delivered during task performance. Second, the magnitude of the analgesic effect was not different when the pain-eliciting stimulus was delivered to the left or right hand during the force task or the working memory task. Third, we found no correlation between analgesia scores during the force task and the working memory task. Our findings have clinical implications for rehabilitation settings because they suggest that acute force production by one limb influences pain perception that is simultaneously experienced in another limb. From a theoretical perspective, we interpret our findings on force and memory driven analgesia in the context of a centralized pain inhibitory response. Perspective This article shows that force production and working memory have analgesic effects irrespective of which side of the body pain is experienced on. Analgesia scores were not correlated, however, suggesting that some individuals experience more pain relief from a force task as compared to a working memory task and vice versa.

With increased precision in alignment offered by new generations of instrumentation and customized guides, this study was designed to establish a biomechanically-based target alignment for the balance of tibial loading in order to diminish the likelihood of pain and subsidence related to mechanical overload post-UKA. Sixty composite tibias were implanted with Oxford UKA tibial components with varied sagittal slope, resection depth, rotation and medial shift using patient matched instrumentation. Digital image correlation and strain gage analysis was conducted in static loading to evaluate strain distribution as a result of component alignment. In this model, minimal distal resection and most lateral positioning, neutral component rotation, and 3° of slope (from mechanical axis) exhibited the most balanced strain response to loading following UKA.