Perioperative Extracellular Brain Free-Water Changes for Older Adults Electing Total Knee Arthroplasty with General versus Spinal Anesthesia: A Pilot Study.

BACKGROUND: Recent research shows that older adults electing to undergo total knee arthroplasty with general anesthesia have a pre- to postoperative acute increase in molecular free-water within their cerebral white matter. It is unknown if this change is similar for individuals who elect spinal anesthesia methods. OBJECTIVE: To explore white matter microstructural changes in a pilot sample of older adults undergoing total knee arthroplasty and receiving general or spinal anesthesia. METHODS: We assessed acute perioperative changes in brain white matter free-water in a limited number of older adults electing total knee arthroplasty under spinal anesthesia (n = 5) and matched groups of older adults who received general anesthesia (n = 5) or had no surgery (n = 5). Patterns of free-water changes were also compared in the larger group of older adults electing total knee arthroplasty under general anesthesia (n = 61) and older adults with chronic knee pain who received no surgical intervention (n = 65). RESULTS: Our pilot results suggest older adults receiving general anesthesia had pre- to post-surgery free-water increases extensively throughout their white matter whereas those receiving spinal anesthesia appeared to have less consistent free-water increases. CONCLUSIONS: Our pilot results possibly suggest different patterns of perioperative brain white matter free-water changes based on anesthetic approach. We recommend future, larger studies to further examine the effects of anesthetic approach on perioperative brain free-water. The results of our study have potential implications for acute and chronic cognitive changes, perioperative complications, neurodegenerative processes including Alzheimer's disease, and understanding neuroinflammation.

Free Water Fraction Predicts Cognitive Decline for Individuals with Idiopathic Parkinson's disease.

INTRODUCTION: Free water fraction (FWF) is considered a metric of microstructural integrity and may be useful in predicting cognitive decline in idiopathic Parkinson's Disease (PD). We sought to determine if higher FWF within the dorsal portion of the caudate nucleus and basal nucleus of Meynert, two regions associated with cognitive decline in PD, predict change in cognition over a two-year span. Due to the existence of cognitive and neurophysiological subgroups within PD, we statistically categorized participants based on FWF in these regions. METHODS: At baseline, participants completed a research cognitive protocol followed by MRI structural and diffusion metrics. We used k-means cluster analysis with average FWF values from bilateral basal nucleus of Meynert and dorsal caudate to create data-driven FWF clusters for baseline. Two-year reliable change indices were calculated for metrics of language, visuospatial, memory, cognitive flexibility, and reasoning domains. Reliable change scores were compared between the clusters and non-PD peers. RESULTS: Baseline participants included 174 participants (112 PD, 62 non-PD). Cluster analysis yielded three clusters: low FWF in both regions of interest (ROIs), high FWF in both ROIs, and moderate FWF in both ROIs. Reliable change analyses were completed on 93 participants (67 PD, 26 non-PD). After controlling for age and education, the High FWF cluster declined more than non-PD peers in every domain except memory. CONCLUSION: Individuals with high FWF in regions associated with cognitive decline in PD show significant decline across several cognitive domains compared to non-PD peers. Future research should include FWF in additional cortical regions.

The functional connectivity and neuropsychology underlying mental planning operations: data from the digital clock drawing test.

We examined the construct of mental planning by quantifying digital clock drawing digit placement accuracy in command and copy conditions, and by investigating its underlying neuropsychological correlates and functional connectivity. We hypothesized greater digit misplacement would associate with attention, abstract reasoning, and visuospatial function, as well as functional connectivity from a major source of acetylcholine throughout the brain: the basal nucleus of Meynert (BNM). Participants (n = 201) included non-demented older adults who completed all metrics within 24 h of one another. A participant subset met research criteria for mild cognitive impairment (MCI; n = 28) and was compared to non-MCI participants on digit misplacement accuracy and expected functional connectivity differences. Digit misplacement and a comparison dissociate variable of total completion time were acquired for command and copy conditions. a priori fMRI seeds were the bilateral BNM. Command digit misplacement is negatively associated with semantics, visuospatial, visuoconstructional, and reasoning (p's < 0.01) and negatively associated with connectivity from the BNM to the anterior cingulate cortex (ACC; p = 0.001). Individuals with MCI had more misplacement and less BNM-ACC connectivity (p = 0.007). Total completion time involved posterior and cerebellar associations only. Findings suggest clock drawing digit placement accuracy may be a unique metric of mental planning and provide insight into neurodegenerative disease.

Evaluation of early microstructural changes in the R6/1 mouse model of Huntington's disease by ultra-high field diffusion MR imaging.

Diffusion MRI (dMRI) has been able to detect early structural changes related to neurological symptoms present in Huntington's disease (HD). However, there is still a knowledge gap to interpret the biological significance at early neuropathological stages. The purpose of this study is two-fold: (i) establish if the combination of Ultra-High Field Diffusion MRI (UHFD-MRI) techniques can add a more comprehensive analysis of the early microstructural changes observed in HD, and (ii) evaluate if early changes in dMRI microstructural parameters can be linked to cellular biomarkers of neuroinflammation. Ultra-high field magnet (16.7T), diffusion tensor imaging (DTI), and neurite orientation dispersion and density imaging (NODDI) techniques were applied to fixed ex-vivo brains of a preclinical model of HD (R6/1 mice). Fractional anisotropy (FA) was decreased in deep and superficial grey matter (GM) as well as white matter (WM) brain regions with well-known early HD microstructure and connectivity pathology. NODDI parameters associated with the intracellular and extracellular compartment, such as intracellular ventricular fraction (ICVF), orientation dispersion index (ODI), and isotropic volume fractions (IsoVF) were altered in R6/1 mice GM. Further, histological studies in these areas showed that glia cell markers associated with neuroinflammation (GFAP & Iba1) were consistent with the dMRI findings. dMRI can be used to extract non-invasive information of neuropathological events present in the early stages of HD. The combination of multiple imaging techniques represents a better approach to understand the neuropathological process allowing the early diagnosis and neuromonitoring of patients affected by HD.

Statistically Defined Parkinson's Disease Executive and Memory Cognitive Phenotypes: Demographic, Behavioral, and Structural Neuroimaging Comparisons.

BACKGROUND: Some individuals with Parkinson's disease (PD) experience working memory and inhibitory difficulties, others learning and memory difficulties, while some only minimal to no cognitive deficits for many years. OBJECTIVE: To statistically derive PD executive and memory phenotypes, and compare PD phenotypes on disease and demographic variables, vascular risk factors, and specific neuroimaging variables with known associations to executive and memory function relative to non-PD peers. METHODS: Non-demented individuals with PD (n = 116) and non-PD peers (n = 62) were recruited to complete neuropsychology measures, blood draw, and structural magnetic resonance imaging. Tests representing the cognitive domains of interest (4 executive function, 3 memory) were included in a k-means cluster analysis comprised of the PD participants. Resulting clusters were compared demographic and disease-related variables, vascular risk markers, gray/white regions of interest, and white matter connectivity between known regions involved in executive and memory functions (dorsolateral prefrontal cortices to caudate nuclei; entorhinal cortices to hippocampi). RESULTS: Clusters showed: 1) PD Executive, n = 25; 2) PD Memory, n = 35; 3) PD Cognitively Well; n = 56. Even after disease variable corrections, PD Executive had less subcortical gray matter, white matter, and fewer bilateral dorsolateral-prefrontal cortex to caudate nucleus connections; PD Memory showed bilaterally reduced entorhinal-hippocampal connections. PD Cognitively Well showed only reduced putamen volume and right entorhinal cortex to hippocampi connections relative to non-PD peers. Groups did not statistically differ on cortical integrity measures or cerebrovascular disease markers. CONCLUSION: PD cognitive phenotypes showed different structural gray and white matter patterns. We discuss data relative to phenotype demographics, cognitive patterns, and structural brain profiles.

Medial Pontomedullary Stroke Mimicking Severe Bell's Palsy: A Case Report.

INTRODUCTION: Patients with acute unilateral upper and lower facial palsy frequently present to the emergency department fearing they have had a stroke, but many cases are benign Bell's palsy. CASE REPORT: We present a rare case of a medial pontomedullary junction stroke causing upper and lower hemifacial paralysis associated with severe dysphagia and contralateral face and arm numbness. CONCLUSION: Although rare, pontine infarct must be considered in patients who present with both upper and lower facial weakness. Unusual neurologic symptoms (namely diplopia, vertigo, or dysphagia) and signs (namely gaze palsy, nystagmus, or contralateral motor or sensory deficits) should prompt evaluation for stroke.

Acute Finger Ischemia in an Elderly Male without Risk Factors for Hypercoagulability.

Literature on ulnar artery thrombosis and acute finger ischemia is scant and usually related to underlying hypercoagulable or occlusive states, such as atrial fibrillation, thrombangiitis obliterans, vasospasm, trauma, and neurovascular compression at the root of the upper limb. An elderly hypertensive male without an underlying hypercoagulable state, and in otherwise good health, presented to our emergency department with acute multi-finger ischemia, and ulnar artery and palmar arch thromboses. Given his innocuous history, this case demonstrates the importance of maintaining acute arterial thrombosis on the differential for hand pain despite the obvious propensity toward mechanical injuries in the extremities.

Assessing neuraxial microstructural changes in a transgenic mouse model of early stage Amyotrophic Lateral Sclerosis by ultra-high field MRI and diffusion tensor metrics.

OBJECTIVE: Cell structural changes are one of the main features observed during the development of amyotrophic lateral sclerosis (ALS). In this work, we propose the use of diffusion tensor imaging (DTI) metrics to assess specific ultrastructural changes in the central nervous system during the early neurodegenerative stages of ALS. METHODS: Ultra-high field MRI and DTI data at 17.6T were obtained from fixed, excised mouse brains, and spinal cords from ALS (G93A-SOD1) mice. RESULTS: Changes in fractional anisotropy (FA) and linear, planar, and spherical anisotropy ratios (CL, CP, and CS, respectively) of the diffusion eigenvalues were measured in white matter (WM) and gray matter (GM) areas associated with early axonal degenerative processes (in both the brain and the spinal cord). Specifically, in WM structures (corpus callosum, corticospinal tract, and spinal cord funiculi) as the disease progressed, FA, CL, and CP values decreased, whereas CS values increased. In GM structures (prefrontal cortex, hippocampus, and central spinal cord) FA and CP decreased, whereas the CL and CS values were unchanged or slightly smaller. Histological studies of a fluorescent mice model (YFP, G93A-SOD1 mouse) corroborated the early alterations in neuronal morphology and axonal connectivity measured by DTI. CONCLUSIONS: Changes in diffusion tensor shape were observed in this animal model at the early, nonsymptomatic stages of ALS. Further studies of CL, CP, and CS as imaging biomarkers should be undertaken to refine this neuroimaging tool for future clinical use in the detection of the early stages of ALS.

Steal Phenomenon with Tonsillar Arteriovenous Malformation.

Cranial vascular malformations can cause symptoms of headache, stroke, transient ischemic attack, or other cerebrovascular disorders due to steal phenomenon. Subclavian steal phenomenon is a localized change in cerebral perfusion from a cranial arteriovenous malformation (AVM). We present the only recorded case of a tonsillar AVM causing a transient ischemic attack due to steal phenomenon.

Better Brain and Cognition Prior to Surgery Is Associated With Elevated Postoperative Brain Extracellular Free-Water in Older Adults.

For adults age 65 and older, the brain shows acute functional connectivity decreases after total knee arthroplasty with the severity of change predicted by preoperative cognitive function and brain disease burden. The extent of acute structural microstructural brain changes acutely after surgery remains unknown within the literature. For the current study, we report on the severity of acute post-surgery microstructural brain changes as measured by diffusion imaging and free-water analysis. Participants who underwent total knee arthroplasty under general anesthesia and non-surgery peers were part of a federally funded prospective cohort investigation involving participants. Recruitment occurred between 2013 and 2017. Data were collected in outpatient and inpatient settings within a university-affiliated medical center. A total of 232 TKA patients were referred by the study surgeon and contacted for study inclusion. Of these, 78 met inclusion and exclusion criteria and completed assessment. Five participants were excluded due to anesthetic protocol changes (spinal instead of general) with an additional 12 excluded for imaging-related complications. The total included sample size was 61. A total of 127 non-surgery participants were screened with 66 enrolled. One non-surgery participant was excluded for an imaging-related complication. Total knee arthroplasty and general anesthetic protocols were standardized. Participants received preoperative neurocognitive assessment and brain magnetic resonance imaging, with repeat imaging 48 h after surgery or pseudo surgery. Free-water analyses were performed using diffusion weighted images and tract-based spatial statistics with baseline cognitive data used to predict free-water changes. Surgery participants had widespread increases in white matter free-water. Surgery participants with higher cognitive functions as measured by immediate memory and less evidence of brain atrophy and disease (i.e., brain integrity) had greater free-water increase. Non-surgery peers had no free-water change. We interpret the surgery group's free-water change as indicating widespread brain white matter glial response, with greater change indicative of better brain response to the acute surgery/anesthesia experience.

Unveiling early cortical and subcortical neuronal degeneration in ALS mice by ultra-high field diffusion MRI.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease primarily characterized by the progressive impairment of motor functions. However, a significant portion of affected patients develops severe cognitive dysfunction, developing a widespread white (WM) and gray matter (GM) microstructural impairment. The objective of this study is to determine if Gaussian and non-Gaussian diffusion models gathered by ultra-high field diffusion MRI (UHFD-MRI) are an appropriate tool to detect early structural changes in brain white and gray matter in a preclinical model of ALS. ALS brains (G93A-SOD1mice) were scanned in a 16.7 T magnet. Diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) have shown presymptomatic decrease in axonal organization by Fractional Anisotropy (FA) and neurite content by Intracellular Volume Fraction (ICVF) across deep WM (corpus callosum) as well as superficial (cortex) and deep (hippocampus) GM. Additional diffusion kurtosis imaging (DKI) analysis demonstrated broader and earlier GM reductions in mean kurtosis (MK), possibly related to the decrease in neuronal complexity. Histological validation was obtained by an ALS fluorescent mice reporter (YFP, G93A-SOD1 mice). The combination of DTI, NODDI, and DKI models have proved to provide a more complete assessment of the early microstructural changes in the ALS brain, particularly in areas associated with high cognitive functions. This comprehensive approach should be considered as a valuable tool for the early detection of neuroimaging markers.

WW domains provide a platform for the assembly of multiprotein networks.

WW domains are protein modules that mediate protein-protein interactions through recognition of proline-rich peptide motifs and phosphorylated serine/threonine-proline sites. To pursue the functional properties of WW domains, we employed mass spectrometry to identify 148 proteins that associate with 10 human WW domains. Many of these proteins represent novel WW domain-binding partners and are components of multiprotein complexes involved in molecular processes, such as transcription, RNA processing, and cytoskeletal regulation. We validated one complex in detail, showing that WW domains of the AIP4 E3 protein-ubiquitin ligase bind directly to a PPXY motif in the p68 subunit of pre-mRNA cleavage and polyadenylation factor Im in a manner that promotes p68 ubiquitylation. The tested WW domains fall into three broad groups on the basis of hierarchical clustering with respect to their associated proteins; each such cluster of bound proteins displayed a distinct set of WW domain-binding motifs. We also found that separate WW domains from the same protein or closely related proteins can have different specificities for protein ligands and also demonstrated that a single polypeptide can bind multiple classes of WW domains through separate proline-rich motifs. These data suggest that WW domains provide a versatile platform to link individual proteins into physiologically important networks.

Ultra-High Field Diffusion MRI Reveals Early Axonal Pathology in Spinal Cord of ALS mice.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a disease characterized by a progressive degeneration of motor neurons leading to paralysis. Our previous MRI diffusion tensor imaging studies detected early white matter changes in the spinal cords of mice carrying the G93A-SOD1 mutation. Here, we extend those studies using ultra-high field MRI (17.6 T) and fluorescent microscopy to investigate the appearance of early structural and connectivity changes in the spinal cords of ALS mice. METHODS: The spinal cords from presymptomatic and symptomatic mice (80 to 120 days of age) were scanned (ex-vivo) using diffusion-weighted MRI. The fractional anisotropy (FA), axial (AD) and radial (RD) diffusivities were calculated for axial slices from the thoracic, cervical and lumbar regions of the spinal cords. The diffusion parameters were compared with fluorescence microscopy and membrane cellular markers from the same tissue regions. RESULTS: At early stages of the disease (day 80) in the lumbar region, we found, a 19% decrease in FA, a 9% decrease in AD and a 35% increase in RD. Similar changes were observed in cervical and thoracic spinal cord regions. Differences between control and ALS mice groups at the symptomatic stages (day 120) were larger. Quantitative fluorescence microscopy at 80 days, demonstrated a 22% reduction in axonal area and a 22% increase in axonal density. Tractography and quantitative connectome analyses measured by edge weights showed a 52% decrease in the lumbar regions of the spinal cords of this ALS mice group. A significant increase in ADC (23.3%) in the ALS mice group was related to an increase in aquaporin markers. CONCLUSIONS: These findings suggest that the combination of ultra-high field diffusion MRI with fluorescent ALS mice reporters is a useful approach to detect and characterize presymptomatic white matter micro-ultrastructural changes and axonal connectivity anomalies in ALS.

Hematocrit and left ventricular mass: the Framingham Heart study.

OBJECTIVES: The goal of this study was to investigate the relationship between hematocrit (Hct) and left ventricular mass index (LVMI) and LV hypertrophy (LVH) in subjects without known hypertension or cardiovascular disease in the Framingham Heart study. BACKGROUND: Anemia may be an independent risk factor for cardiovascular disease in the general population. One potential explanation for this finding could be an association between Hct with LVMI or LVH. METHODS: Linear and logistic regression analyses were used to evaluate the association between Hct with LVMI and LVH. All analyses were stratified by gender and further according to menopausal status in women. RESULTS: There were 1,376 men and 1,769 women who met the inclusion criteria. The mean Hct and LVMI were 46.5% and 41.9%, and 127.3 and 95.8 g/m, respectively, in men and women. After adjustment for confounders, each 3% lower Hct was associated with a 2.6 g/m higher mean LVMI in men, and a 1.8 g/m higher mean LVMI in postmenopausal women (p < 0.05). There was a significant quadratic relationship between Hct and LVMI in premenopausal women (p < 0.01). Subjects in the lowest quartile of Hct (compared with the rest of the sample) had an adjusted odds ratio of LVH of 2.0 (95% confidence interval [CI] 1.3 to 3.0) in men and 1.4 (95% CI 0.8 to 2.4) in postmenopausal women. CONCLUSIONS: In a sample without known hypertension or cardiovascular disease, a lower Hct is associated with echocardiographically determined LVH in men and a small but significantly higher LVMI in men and postmenopausal women. The clinical importance of these findings remains unknown.

Kidney disease as a risk factor for recurrent cardiovascular disease and mortality.

BACKGROUND: Chronic kidney disease (CKD) is highly prevalent in the United States and is an independent risk factor for adverse cardiovascular disease (CVD) and all-cause mortality outcomes in patients with acute coronary syndromes. Few studies have evaluated the effect of CKD on cardiovascular events in a diverse community-based population with underlying CVD. METHODS: Data for subjects with preexisting CVD were pooled from 4 publicly available, community-based, longitudinal studies: Atherosclerosis Risk in Communities, Cardiovascular Health Study, Framingham Heart Study, and Framingham Offspring Study. CKD was defined as an estimated glomerular filtration rate less than 60 mL/min/1.73 m2 (<1 mL/s/1.73 m2). The primary study outcome was a composite of myocardial infarction (MI), fatal coronary heart disease (CHD), stroke, and all-cause mortality. The secondary outcome included only MI and fatal CHD. RESULTS: A total of 4,278 subjects satisfied inclusion criteria, and 759 subjects (17.7%) had CKD. Mean follow-up was 86 months. The primary and secondary outcomes were observed in 1,703 (39.8%) and 857 subjects (20.0%), respectively. Incidence rates for the primary and secondary outcomes were greater in persons with CKD compared with those without CKD (62.5% versus 34.9% and 30.6% versus 17.8%, respectively). Adjusted hazard ratios for the primary and secondary outcomes were 1.35 (95% confidence interval [CI], 1.21 to 1.52) and 1.32 (95% CI, 1.12 to 1.55), respectively. CONCLUSION: The presence of CKD in a community-based population with preexisting CVD is associated with an increased risk for recurrent CVD outcomes. This increased risk persists after adjustment for traditional CVD risk factors.