Nathanael D. Hevelone

Age-related alterations in white matter microstructure measured by diffusion tensor imaging

Cerebral white matter (WM) undergoes various degenerative changes with normal aging, including decreases in myelin density and alterations in myelin structure. We acquired whole-head, high-resolution diffusion tensor images (DTI) in 38 participants across the adult age span. Maps of fractional anisotropy (FA), a measure of WM microstructure, were calculated for each participant to determine whether particular fiber systems of the brain are preferentially vulnerable to WM degeneration. Regional FA measures were estimated from nine regions of interest in each hemisphere and from the genu and splenium of the corpus callosum (CC). The results showed significant age-related decline in FA in frontal WM, the posterior limb of the internal capsule (PLIC), and the genu of the CC. In contrast, temporal and posterior WM was relatively preserved. These findings suggest that WM alterations are variable throughout the brain and that particular fiber populations within prefrontal region and PLIC are most vulnerable to age-related degeneration.

Predictors of Abdominal Aortic Aneurysm Sac Enlargement After Endovascular Repair

Background— The majority of infrarenal abdominal aortic aneurysm (AAA) repairs in the United States are performed with endovascular methods. Baseline aortoiliac arterial anatomic characteristics are fundamental criteria for appropriate patient selection for endovascular aortic repair (EVAR) and key determinants of long-term success. We evaluated compliance with anatomic guidelines for EVAR and the relationship between baseline aortoiliac arterial anatomy and post-EVAR AAA sac enlargement. Methods and Results— Patients with pre-EVAR and at least 1 post-EVAR computed tomography scan were identified from the M2S, Inc. imaging database (1999 to 2008). Preoperative baseline aortoiliac anatomic characteristics were reviewed for each patient. Data relating to the specific AAA endovascular device implanted were not available. Therefore, morphological measurements were compared with the most liberal and the most conservative published anatomic guidelines as stated in each manufacturers instructions for use. The primary study outcome was post-EVAR AAA sac enlargement (>5-mm diameter increase). In 10 228 patients undergoing EVAR, 59% had a maximum AAA diameter below the 55-mm threshold at which intervention is recommended over surveillance. Only 42% of patients had anatomy that met the most conservative definition of device instructions for use; 69% met the most liberal definition of device instructions for use. The 5-year post-EVAR rate of AAA sac enlargement was 41%. Independent predictors of AAA sac enlargement included endoleak, age ≥80 years, aortic neck diameter ≥28 mm, aortic neck angle >60°, and common iliac artery diameter >20 mm. Conclusion— In this multicenter observational study, compliance with EVAR device guidelines was low and post-EVAR aneurysm sac enlargement was high, raising concern for long-term risk of aneurysm rupture.

Cerebral cortex and the clinical expression of Huntington's disease: complexity and heterogeneity

The clinical phenotype of Huntingtons disease (HD) is far more complex and variable than depictions of it as a progressive movement disorder dominated by neostriatal pathology represent. The availability of novel neuro-imaging methods has enabled us to evaluate cerebral cortical changes in HD, which we have found to occur early and to be topographically selective. What is less clear, however, is how these changes influence the clinical expression of the disease. In this study, we used a high-resolution surface based analysis of in vivo MRI data to measure cortical thickness in 33 individuals with HD, spanning the spectrum of disease and 22 age- and sex-matched controls. We found close relationships between specific functional and cognitive measures and topologically specific cortical regions. We also found that distinct motor phenotypes were associated with discrete patterns of cortical thinning. The selective topographical associations of cortical thinning with clinical features of HD suggest that we are not simply correlating global worsening with global cortical degeneration. Our results indicate that cortical involvement contributes to important symptoms, including those that have been ascribed primarily to the striatum, and that topologically selective changes in the cortex might explain much of the clinical heterogeneity found in HD. Additionally, a significant association between regional cortical thinning and total functional capacity, currently the leading primary outcome measure used in neuroprotection trials for HD, establishes cortical MRI morphometry as a potential biomarker of disease progression.

Diffusion tensor imaging in presymptomatic and early Huntington's disease: Selective white matter pathology and its relationship to clinical measures.

Atrophy of cortical and subcortical gray matter is apparent in Huntingtons disease (HD) before symptoms manifest. We hypothesized that the white matter (WM) connecting cortical and subcortical regions must also be affected early and that select clinical symptoms were related to systems degeneration. We used diffusion tensor magnetic resonance imaging (DTI) to examine the regional nature of WM abnormalities in early HD, including the preclinical period, and to determine whether regional changes correlated with clinical features. We studied individuals in early stages (HD), presymptomatic individuals known to carry the genetic mutation that causes HD (Pre‐HD), and matched healthy controls. DTI indices of tissue integrity were obtained from several regions of interest, including the corpus callosum (CC), internal capsule (IC), and basal ganglia, were compared across groups by t tests, and were correlated to cognitive and clinical measures. WM alterations were found throughout the CC, in the anterior and posterior limbs of the IC, and in frontal subcortical WM in HD subjects, supporting the selective involvement of the pyramidal tracts in HD; a similar distribution of changes was seen in Pre‐HD subjects, supporting presymptomatic alterations. There was a significant relationship between select DTI measures and cognitive performance. Alterations in diffusion indices were also seen in the striatum that were independent of atrophy. Our findings support that WM alterations occur very early in HD. The distribution of the changes suggests that these changes contribute to the disruption of pyramidal and extrapyramidal circuits and also support a role of compromised cortical circuitry in early cognitive and subtle motor impairment during the preclinical stages of HD.

Regional cortical thinning in preclinical Huntington disease and its relationship to cognition.

The authors studied presymptomatic individuals with the Huntington disease (HD) mutation to determine whether cortical thinning was present. They found thinning that was regionally selective, semi-independent of striatal volume loss, and correlated with cognitive performance. Early, extensive cortical involvement occurs during the preclinical stages of HD.

Suggested objective performance goals and clinical trial design for evaluating catheter-based treatment of critical limb ischemia

OBJECTIVE To develop a set of suggested objective performance goals (OPG) for evaluating new catheter-based treatments in critical limb ischemia (CLI), based on evidence from historical controls. METHODS Randomized, controlled trials of surgical, endovascular, and pharmacologic/biologic treatments for CLI were reviewed according to specified criteria regarding study population and data quality. Line-item data were obtained for selected studies from the sponsor/funding agency. A set of specific outcome measures was defined in accordance with the treatment goals for the CLI population. Risk factors were examined for their influence on key endpoints, and models of stratification based on specific clinical and anatomic variables developed. Sample size estimates were made for single-arm trial designs based on comparison to the suggested OPG. RESULTS Bypass with autogenous vein was considered the established standard, and data compiled from three individual randomized, controlled trials (N = 838) was analyzed. The primary efficacy endpoint was defined as perioperative (30-day) death or any major adverse limb event (amputation or major reintervention) occurring within one year. Results of open surgery controls demonstrated freedom from the primary endpoint in 76.9% (95% confidence interval [CI] 74.0%-79.9%) of patients at one year, with amputation-free survival (AFS) of 76.5% (95% CI 73.7%-79.5). An additional 3% non-inferiority margin was suggested in generating OPG for catheter-based therapies. Defined clinical (age > 80 years and tissue loss) and anatomic (infra-popliteal anatomy or lack of good quality saphenous vein) risk subgroups provided significantly different point estimates and OPG threshold values. CONCLUSIONS For new catheter-based therapies in CLI, OPGs offer a feasible approach for pre-market evaluation using non-randomized trial designs. Such studies should incorporate risk stratification in design and reporting as the CLI population is heterogeneous with respect to baseline variables and expected outcomes. Guidelines for CLI trial design to address consistency in study cohorts, methods of assessment, and endpoint definitions are provided.

Creatine in Huntington disease is safe, tolerable, bioavailable in brain and reduces serum 8OH2′dG

In a randomized, double-blind, placebo-controlled study in 64 subjects with Huntington disease (HD), 8 g/day of creatine administered for 16 weeks was well tolerated and safe. Serum and brain creatine concentrations increased in the creatine-treated group and returned to baseline after washout. Serum 8-hydroxy-2′-deoxyguanosine (8OH2′dG) levels, an indicator of oxidative injury to DNA, were markedly elevated in HD and reduced by creatine treatment.

Age-Related Changes in Prefrontal White Matter Measured by Diffusion Tensor Imaging

Age‐related degeneration of brain white matter (WM) has received a great deal of attention, with recent studies demonstrating that such changes are correlated with cognitive decline and increased risk for the development of age‐related neurodegenerative disease. Past studies have used magnetic resonance imaging (MRI) to measure the volume of normal and abnormal tissue signal as an index of tissue pathology. More recently, diffusion tensor MRI (DTI) has been employed to obtain regional measures of tissue microstructure, such as fractional anisotropy (FA), providing better spatial resolution and potentially more sensitive metrics of tissue damage than traditional volumetric measures. We used DTI to examine the regional basis of age‐related alterations in prefrontal WM. As expected from prior volumetric and DTI studies, prefrontal FA was reduced in older adults (OA) compared to young adults (YA). Although WM volume has been reported to be relatively preserved until late aging, FA was significantly reduced by middle age. Much of prefrontal WM showed reduced FA with increasing age. Ventromedial and deep prefrontal regions showed a somewhat greater reduction compared to other prefrontal areas. Prefrontal WM anisotropy correlated with prefrontal WM volume, but the correlation was significant only when the analysis was limited to participants over age 40. This evidence of widespread and regionally accelerated alterations in prefrontal WM with aging illustrates FAs potential as a microstructural index of volumetric measures.

White matter pathology isolates the hippocampal formation in Alzheimer's disease.

Prior work has demonstrated that the memory dysfunction of Alzheimers disease (AD) is accompanied by marked cortical pathology in medial temporal lobe (MTL) gray matter. In contrast, changes in white matter (WM) of pathways associated with the MTL have rarely been studied. We used diffusion tensor imaging (DTI) to examine regional patterns of WM tissue changes in individuals with AD. Alterations of diffusion properties with AD were found in several regions including parahippocampal WM, and in regions with direct and secondary connections to the MTL. A portion of the changes measured, including effects in the parahippocampal WM, were independent of gray matter degeneration as measured by hippocampal volume. Examination of regional changes in unique diffusion parameters including anisotropy and axial and radial diffusivity demonstrated distinct zones of alterations, potentially stemming from differences in underlying pathology, with a potential myelin specific pathology in the parahippocampal WM. These results demonstrate that deterioration of neocortical connections to the hippocampal formation results in part from the degeneration of critical MTL and associated fiber pathways.

Use, Costs and Comparative Effectiveness of Robotic Assisted, Laparoscopic and Open Urological Surgery

PURPOSE Although robotic assisted laparoscopic surgery has been aggressively marketed and rapidly adopted, there are few comparative effectiveness studies that support its purported advantages compared to open and laparoscopic surgery. We used a population based approach to assess use, costs and outcomes of robotic assisted laparoscopic surgery vs laparoscopic surgery and open surgery for common robotic assisted urological procedures. MATERIALS AND METHODS From the Nationwide Inpatient Sample we identified the most common urological robotic assisted laparoscopic surgery procedures during the last quarter of 2008 as radical prostatectomy, nephrectomy, partial nephrectomy and pyeloplasty. Robotic assisted laparoscopic surgery, laparoscopic surgery and open surgery use, costs and inpatient outcomes were compared using propensity score methods. RESULTS Robotic assisted laparoscopic surgery was performed for 52.7% of radical prostatectomies, 27.3% of pyeloplasties, 11.5% of partial nephrectomies and 2.3% of nephrectomies. For radical prostatectomy robotic assisted laparoscopic surgery was more prevalent than open surgery among white patients in high volume, urban hospitals (all p≤0.015). Geographic variations were found in the use of robotic assisted laparoscopic surgery vs open surgery. Robotic assisted laparoscopic surgery and laparoscopic surgery vs open surgery were associated with shorter length of stay for all procedures, with robotic assisted laparoscopic surgery being the shortest for radical prostatectomy and partial nephrectomy (all p<0.001). For most procedures robotic assisted laparoscopic surgery and laparoscopic surgery vs open surgery resulted in fewer deaths, complications, transfusions and more routine discharges. However, robotic assisted laparoscopic surgery was more costly than laparoscopic surgery and open surgery for most procedures. CONCLUSIONS While robotic assisted and laparoscopic surgery are associated with fewer deaths, complications, transfusions and shorter length of hospital stay compared to open surgery, robotic assisted laparoscopic surgery is more costly than laparoscopic and open surgery. Additional studies are needed to better delineate the comparative and cost-effectiveness of robotic assisted laparoscopic surgery relative to laparoscopic surgery and open surgery.