Frank Schreiber

Sonography of the median nerve in CMT1A, CMT2A, CMTX, and HNPP

Introduction: In this study we compare the ultrasound features in the median nerve in patients with different types of Charcot–Marie–Tooth (CMT) disease and hereditary neuropathies with liability to pressure palsies (HNPP) as a typical entrapment neuropathy. Methods: Median nerve ultrasound and conduction studies were performed in patients with CMT1A (n = 12), MFN2‐associated CMT2A (n = 7), CMTX (n = 5), and HNPP (n = 5), and in controls (n = 28). Results: Median nerve cross‐sectional area (CSA) was significantly increased in CMT1A, whereas, in axonal CMT2A, fascicle diameter (FD) was enlarged. CSA correlated with nerve conduction slowing in CMT1A and with axonal loss, as shown by motor and sensory nerve amplitudes in both CMT1A and CMT2A. A relatively low wrist‐to‐forearm‐ratio (WFR <0.8) or a relatively high WFR (>1.8) appeared to be unlikely in MFN2 and Cx32 mutations of CMT2A and CMTX, respectively. Conclusion: Differences in CSA, FD, and WFR of the median nerve can be helpful in defining subtypes of hereditary neuropathies. Muscle Nerve 47:385‐395, 2013

Comparison of Visual and Quantitative Florbetapir F 18 Positron Emission Tomography Analysis in Predicting Mild Cognitive Impairment Outcomes

IMPORTANCE The applicability of β-amyloid peptide (Aβ) positron emission tomography (PET) as a biomarker in clinical settings to aid in selection of individuals at preclinical and prodromal Alzheimer disease (AD) will depend on the practicality of PET image analysis. In this context, visual-based Aβ PET assessment seems to be the most feasible approach. OBJECTIVES To determine the agreement between visual and quantitative Aβ PET analysis and to assess the ability of both techniques to predict conversion from mild cognitive impairment (MCI) to AD. DESIGN, SETTING, AND PARTICIPANTS A longitudinal study was conducted among the Alzheimers Disease Neuroimaging Initiative (ADNI) sites in the United States and Canada during a 1.6-year mean follow-up period. The study was performed from September 21, 2010, to August 11, 2014; data analysis was conducted from September 21, 2014, to May 26, 2015. Participants included 401 individuals with MCI receiving care at a specialty clinic (219 [54.6%] men; mean [SD] age, 71.6 [7.5] years; 16.2 [2.7] years of education). All participants were studied with florbetapir F 18 [18F] PET. The standardized uptake value ratio (SUVR) positivity threshold was 1.11, and one reader rated all images, with a subset of 125 scans rated by a second reader. MAIN OUTCOMES AND MEASURES Sensitivity and specificity of positive and negative [18F] florbetapir PET categorization, which was estimated with cerebrospinal fluid Aβ1-42 as the reference standard. Risk for conversion to AD was assessed using Cox proportional hazards regression models. RESULTS The frequency of Aβ positivity was 48.9% (196 patients; visual analysis), 55.1% (221 patients; SUVR), and 64.8% (166 patients; cerebrospinal fluid), yielding substantial agreement between visual and SUVR data (κ = 0.74) and between all methods (Fleiss κ = 0.71). For approximately 10% of the 401 participants in whom visual and SUVR data disagreed, interrater reliability was moderate (κ = 0.44), but it was very high if visual and quantitative results agreed (κ = 0.92). Visual analysis had a lower sensitivity (79% vs 85%) but higher specificity (96% vs 90%), respectively, compared with SUVR. The conversion rate was 15.2% within a mean of 1.6 years, and a positive [18F] florbetapir baseline scan was associated with a 6.91-fold (SUVR) or 11.38-fold (visual) greater hazard for AD conversion, which changed only modestly after covariate adjustment for apolipoprotein ε4, concurrent fludeoxyglucose F 18 PET scan, and baseline cognitive status. CONCLUSIONS AND RELEVANCE Visual and SUVR Aβ PET analysis may be equivalently used to determine Aβ status for individuals with MCI participating in clinical trials, and both approaches add significant value for clinical course prognostication.

Simultaneous Occurrence and Interaction of Hypoperfusion and Embolism in a Patient With Severe Middle Cerebral Artery Stenosis

Background and Purpose— The coincidence of hemodynamic and embolic findings in patients with stroke from large artery stenosis has suggested an interaction of both pathologies. This has emerged into the hypothesis of an impaired washout of emboli in the presence of hypoperfusion. We propose an additional link between both pathologies. Summary of Case— A 48-year-old woman presented with a recurrent symptomatic severe left middle cerebral artery stenosis. MRI depicted left hemispheric ischemic infarcts in the deep and subcortical white matter and in the cortical border zone. One-hour transcranial Doppler monitoring detected 64 microembolic signals distal to the arterial stenosis. Monitoring also revealed recurrent thrombus formation at the stenotic plaque with decline of poststenotic flow velocity followed by embolism with abrupt excessive flow velocity increase and subsequent normalization at the initial baseline level. Cerebrovascular reserve in the distribution territory of the stenosed artery as assessed by transcranial Doppler after carbon dioxide stimulation revealed a normal reserve capacity in periods with baseline poststenotic flow velocity and an exhausted reserve capacity when flow velocity was decreased due to stenotic thrombus formation. Conclusion— In our patient, adherent thrombus formation resulted in an increasing severity of the stenosis with subsequent vasodilatation and diminution of flow resistance in the depending vascular distribution territory. MRI suggested that adherent thrombi were predominantly washed into terminal supply and border zone brain regions, ie, into regions with supposed maximum vasodilatation and least flow resistance immediately before thrombus avulsion. Preferred wash-in of emboli into regions with low blood flow resistance might be an additional mechanism besides impaired washout in patients with severe large artery disease.

Peripheral nerve ultrasound in amyotrophic lateral sclerosis phenotypes

Introduction: In this study we sought to determine the cross‐sectional area (CSA) of peripheral nerves in patients with distinct subtypes of amyotrophic lateral sclerosis (ALS). Methods: Ulnar and median nerve ultrasound was performed in 78 ALS patients [classic, n = 21; upper motor neuron dominant (UMND), n = 14; lower motor neuron dominant (LMND), n = 20; bulbar, n = 15; primary lateral sclerosis (PLS), n = 8] and 18 matched healthy controls. Results: Compared with controls, ALS patients had significant, distally pronounced reductions of ulnar CSA (forearm/wrist level) across all disease groups, except for PLS. Median nerve CSA (forearm/wrist level) did not differ between controls and ALS. Conclusion: Ulnar nerve ultrasound in ALS subgroups revealed significant differences in distal CSA values, which suggests it has value as a marker of LMN involvement. Its potential was particularly evident in the UMND and PLS groups, which can be hard to separate clinically, yet their accurate separation has major prognostic implications. Muscle Nerve 51:669–675, 2015

Increased density of GAD65/67 immunoreactive neurons in the posterior subiculum and parahippocampal gyrus in treated patients with chronic schizophrenia.

Abstract Objectives. Alterations of glutamic acid decarboxylase (GAD) play a crucial role in schizophrenic pathology. While GAD has been studied in several brain regions, its expression in the posterior hippocampus formation has not been investigated in schizophrenia. Methods. We studied the brains of 17 patients with chronic schizophrenia and 15 controls. Using the optical dissector method we counted GAD65/67 immunoreactive neurons and pyramidal cells in the posterior hippocampus, subiculum, and parahippocampal gyrus, and measured the cortical thickness in posterior subiculum and parahippocampal gyrus. Patients had received typical neuroleptics for the mean of 20.8 years. Results. In the patients we observed a significant increase of GAD immunoreactive neurons in the subiculum (left/right P = 0.004) and the parahippocampal gyrus (left P = 0.001, right P = 0.006). The hippocampus showed no or only subtle trends towards higher GAD densities. The density of pyramidal neurons and cortical thickness did not differ between the groups. A significant association between GAD density and the duration of illness was found in women with schizophrenia. Conclusions. The current data on GAD65/67 indicates a dysregulation of the GABAergic system in schizophrenia patients that may be associated with cognitive decline. However, a long term effect of neuroleptics on the GABAergic system cannot be excluded.

Impact of lifestyle dimensions on brain pathology and cognition

Single lifestyle factors affect brain biomarkers and cognition. Here, we addressed the covariance of various lifestyle elements and investigated their impact on positron emission tomography-based β-amyloid (Aβ), hippocampal volume, and cognitive function in aged controls. Lower Aβ burden was associated with a lifestyle comprising high cognitive engagement and low vascular risk, particularly in apolipoprotein E ε4 carriers. Although cognitive function was related to high lifetime cognitive engagement and low vascular risk, Aβ load had no relation to current cognitive function. The covariance between high adult socioeconomic status, high education, and low smoking prevalence predicted better cognitive function and this was mediated by larger hippocampal volume. Our data show that lifestyle is a complex construct composed of associated variables, some of which reflect factors operating over the life span and others which may be developmental. These factors affect brain health via different pathways, which may reinforce one another. Our findings moreover support the importance of an intellectually enriched lifestyle accompanied by vascular health on both cognition and presumed cerebral mediators of cognitive function.

Alzheimer Disease Signature Neurodegeneration and APOE Genotype in Mild Cognitive Impairment With Suspected Non–Alzheimer Disease Pathophysiology

Importance There are conflicting results claiming that Alzheimer disease signature neurodegeneration may be more, less, or similarly advanced in individuals with &bgr;-amyloid peptide (A&bgr;)–negative (A&bgr;−) suspected non–Alzheimer disease pathophysiology (SNAP) than in A&bgr;-positive (A&bgr;+) counterparts. Objective To examine patterns of neurodegeneration in individuals with SNAP compared with their A&bgr;+ counterparts. Design, Setting, and Participants A longitudinal cohort study was conducted among individuals with mild cognitive impairment (MCI) and cognitively normal individuals receiving care at Alzheimer’s Disease Neuroimaging Initiative sites in the United States and Canada for a mean follow-up period of 30.5 months from August 1, 2005, to June 30, 2015. Several neurodegeneration biomarkers and longitudinal cognitive function were compared between patients with distinct SNAP (A&bgr;− and neurodegeneration-positive [A&bgr;−N+]) subtypes and their A&bgr;+N+ counterparts. Main Outcomes and Measures Participants were classified according to the results of their florbetapir F-18 (A&bgr;) positron emission tomography and their Alzheimer disease–associated neurodegeneration status (temporoparietal glucose metabolism determined by fluorodeoxyglucose F 18 [FDG]–labeled positron emission tomography and/or hippocampal volume [HV] determined by magnetic resonance imaging: participants with subthreshold HV values were regarded as exhibiting hippocampal volume atrophy [HV+], while subthreshold mean FDG values were considered as FDG hypometabolism [FDG+]). Results The study comprised 265 cognitively normal individuals (135 women and 130 men; mean [SD] age, 75.5 [6.7] years) and 522 patients with MCI (225 women and 297 men; mean [SD] age, 72.6 [7.8] years). A total of 469 individuals with MCI had data on neurodegeneration biomarkers; of these patients, 107 were A&bgr;−N+ (22.8%; 63 FDG+, 82 HV+, and 38 FDG+HV+) and 187 were A&bgr;+N+ (39.9%; 135 FDG+, 147 HV+, and 95 FDG+HV+ cases). A total of 209 cognitively normal participants had data on neurodegeneration biomarkers; of these, 52 were A&bgr;−N+ (24.9%; 30 FDG+, 33 HV+, and 11 FDG+HV+) and 37 were A&bgr;+N+ (17.7%; 22 FDG+, 26 HV+, and 11 FDG+HV+). Compared with their A&bgr;+ counterparts, all patients with MCI SNAP subtypes displayed better preservation of temporoparietal FDG metabolism (mean [SD] FDG: A&bgr;–N+, 1.25 [0.11] vs A&bgr;+N+, 1.19 [0.11]), less severe atrophy of the lateral temporal lobe, and lower mean (SD) cerebrospinal fluid levels of tau (59.2 [32.8] vs 111.3 [56.4]). In MCI with SNAP, sustained glucose metabolism and gray matter volume were associated with disproportionately low APOE &egr;4 (A&bgr;–N+, 18.7% vs A&bgr;+N+, 70.6%) and disproportionately high APOE &egr;2 (18.7% vs 4.8%) carrier prevalence. Slower cognitive decline and lower rates of progression to Alzheimer disease (A&bgr;–N+, 6.5% vs A&bgr;+N+, 32.6%) were also seen in patients with MCI with SNAP subtypes compared with their A&bgr;+ counterparts. In cognitively normal individuals, neurodegeneration biomarkers did not differ between A&bgr;−N+ and A&bgr;+N+ cases. Conclusions and Relevance In MCI with SNAP, low APOE &egr;4 and high APOE &egr;2 carrier prevalence may account for differences in neurodegeneration patterns between A&bgr;−N+ and A&bgr;+N+ cases independent from the neuroimaging biomarker modality used to define neurodegeneration associated with Alzheimer disease.

Vascular basement membrane alterations and β-amyloid accumulations in an animal model of cerebral small vessel disease

Non-amyloid cerebral small vessel disease (CSVD) and cerebral amyloid angiopathy (CAA) may be interrelated through the damaged basement membranes (BMs) and extracellular matrix changes of small vessels, resulting in a failure of β-amyloid (Aβ) transport and degradation. We analyzed BM changes and the pattern of deposition of Aβ in the walls of blood vessels in spontaneously hypertensive stroke-prone rats (SHRSP), a non-transgenic CSVD model. In 45 SHRSP and 38 Wistar rats aged 18 to 32 weeks: (i) the percentage area immunostained for vascular collagen IV and laminin was quantified; (ii) the capillary BM thickness as well as endothelial and pericyte pathological changes were analysed using transmission electron microscopy (TEM); and (iii) the presence of vascular Aβ was assessed. Compared with controls, SHRSP exhibited a significantly higher percentage area immunostained with collagen IV in the striatum and thalamus. SHRSP also revealed an age-dependent increase of the capillary BM thickness and of endothelial vacuoles (caveolae) within subcortical regions. Endogenous Aβ deposits in the walls of small blood vessels were observed in the cortex (with the highest incidence found within fronto-parietal areas), striatum, thalamus and hippocampus. Vascular β-amyloid accumulations were frequently detected at sites of small vessel wall damage. Our data demonstrate changes in the expression of collagen IV and of the ultrastructure of BMs in the small vessels of SHRSP. Alterations are accompanied by vascular deposits of endogenous Aβ. Impaired β-amyloid clearance along perivascular and endothelial pathways and failure of extracellular Aβ degradation may be the key mechanisms connecting non-amyloid CSVD and CAA.

Model-based controller design for antagonistic pairs of fluidic muscles in manipulator motion control

A control structure is presented for manipulators actuated by joints with pairwise antagonistic pneumatic muscles. The used muscles and the resulting behavior of a single manipulator joint featuring antagonistic muscles in a symmetric configuration are characterized. Pneumatic joint actuation results in a hysteretic behavior, it is shown that in this case the hysteresis can be described by a Preisach hysteresis model. The resulting hysteresis model allows the construction of a model-reference following controller, with a model control loop, designed for good tracking performance and a disturbance rejection loop optimized for suppression of disturbances. Experiments confirm the improvement in tracking control as compared to the system solely controlled by a feedback regulator.

On the joint design and hydraulic actuation of octahedron VGT robot manipulators

In this paper, the design for variable geometry truss manipulators, with 3-DOF octahedron-shaped modules and hydraulic actuation is introduced. The main features of the concept are the optimized multiple collocated spherical joints and a structure-integrated supply of the drive fluid for the hydraulic actuators. Based upon the known Spherical Joint Mechanism, design rules are deduced and modified joint elements are presented to provide a larger workspace for a single module. The potential of the resulting module design is demonstrated by the calculation of the workspace, as well as the payload-to-mass ratio. Based upon the presented results, a family of highly maneuverable light-weight hyper-redundant manipulators can be derived.