SPG10 is a rare cause of spastic paraplegia in European families

Background: SPG10 is an autosomal dominant form of hereditary spastic paraplegia (HSP), which is caused by mutations in the neural kinesin heavy chain KIF5A gene, the neuronal motor of fast anterograde axonal transport. Only four mutations have been identified to date.Objective: To determine the frequency of SPG10 in European families with HSP and to specify the SPG10 phenotype.Patients and methods: 80 index patients from families with autosomal dominant HSP were investigated for SPG10 mutations by direct sequencing of the KIF5A motor domain. Additionally, the whole gene was sequenced in 20 of these families.Results: Three novel KIF5A mutations were detected in German families, including one missense mutation (c.759G>T, p.K253N), one in frame deletion (c.768_770delCAA, p.N256del) and one splice site mutation (c.217G>A). Onset of gait disturbance varied from infancy to 30 years of age. All patients presented clinically with pure HSP, but a subclinical sensory--motor neuropathy was detected by neurophysiology studies.Conclusions: SPG10 accounts for approximately 3% of European autosomal dominant HSP families. All mutations affect the motor domain of kinesin and thus most likely impair axonal transport. Clinically, SPG10 is characterised by spastic paraplegia with mostly subclinical peripheral neuropathy

The Escape Problem in a Classical Field Theory With Two Coupled Fields

We introduce and analyze a system of two coupled partial differential equations with external noise. The equations are constructed to model transitions of monovalent metallic nanowires with non-axisymmetric intermediate or end states, but also have more general applicability. They provide a rare example of a system for which an exact solution of nonuniform stationary states can be found. We find a transition in activation behavior as the interval length on which the fields are defined is varied. We discuss several applications to physical problems.Comment: 24 page

Quantum Suppression of the Rayleigh Instability in Nanowires

A linear stability analysis of metallic nanowires is performed in the free-electron model using quantum chaos techniques. It is found that the classical instability of a long wire under surface tension can be completely suppressed by electronic shell effects, leading to stable cylindrical configurations whose electrical conductance is a magic number 1, 3, 5, 6,... times the quantum of conductance. Our results are quantitatively consistent with recent experiments with alkali metal nanowires.Comment: 10 pages, 5 eps figures, updated and expanded, accepted for publication in "Nonlinearity

Deep Brain Stimulation for Parkinson's Disease with Early Motor Complications:A UK Cost-Effectiveness Analysis

International audienceBackground: Parkinson’s disease (PD) is a debilitating illness associated with considerable impairment of quality of life and substantial costs to health care systems. Deep brain stimulation (DBS) is an established surgical treatment option for some patients with advanced PD. The EARLYSTIM trial has recently demonstrated its clinical benefit also in patients with early motor complications. We sought to evaluate the cost-effectiveness of DBS, compared to best medical therapy (BMT), among PD patients with early onset of motor complications, from a United Kingdom (UK) payer perspective.Methods: We developed a Markov model to represent the progression of PD as rated using the Unified Parkinson's Disease Rating Scale (UPDRS) over time in patients with early PD. Evidence sources were a systematic review of clinical evidence; data from the EARLYSTIM study; and a UK Clinical Practice Research Datalink (CPRD) dataset including DBS patients. A mapping algorithm was developed to generate utility values based on UPDRS data for each intervention. The cost-effectiveness was expressed as the incremental cost per quality-adjusted life-year (QALY). One-way and probabilistic sensitivity analyses were undertaken to explore the effect of parameter uncertainty.Results: Over a 15-year time horizon, DBS was predicted to lead to additional mean cost per patient of £26,799 compared with BMT (£73,077/patient versus £46,278/patient) and an additional mean 1.35 QALYs (6.69 QALYs versus 5.35 QALYs), resulting in an incremental cost-effectiveness ratio of £19,887 per QALY gained with a 99% probability of DBS being cost-effective at a threshold of £30,000/QALY. One-way sensitivity analyses suggested that the results were not significantly impacted by plausible changes in the input parameter values.Conclusion: These results indicate that DBS is a cost-effective intervention in PD patients with early motor complications when compared with existing interventions, offering additional health benefits at acceptable incremental cost. This supports the extended use of DBS among patients with early onset of motor complications

Longitudinal Diffusion Tensor Imaging Resembles Patterns of Pathology Progression in Behavioral Variant Frontotemporal Dementia (bvFTD)

Objective: Recently, the characteristic longitudinal distribution pattern of the underlying phosphorylated TDP-43 (pTDP-43) pathology in the behavioral variant of frontotemporal dementia (bvFTD) excluding Pick's disease (PiD) across specific brain regions was described. The aim of the present study was to investigate whether in vivo investigations of bvFTD patients by use of diffusion tensor imaging (DTI) were consistent with these proposed patterns of progression. Methods: Sixty-two bvFTD patients and 47 controls underwent DTI in a multicenter study design. Of these, 49 bvFTD patients and 34 controls had a follow-up scan after ~12 months. Cross-sectional and longitudinal alterations were assessed by a two-fold analysis, i.e., voxelwise comparison of fractional anisotropy (FA) maps and a tract of interest-based (TOI) approach, which identifies tract structures that could be assigned to brain regions associated with disease progression. Results: Whole brain-based spatial statistics showed white matter alterations predominantly in the frontal lobes cross-sectionally and longitudinally. The TOIs of bvFTD neuroimaging stages 1 and 2 (uncinate fascicle—bvFTD pattern I; corticostriatal pathway—bvFTD pattern II) showed highly significant differences between bvFTD patients and controls. The corticospinal tract-associated TOI (bvFTD pattern III) did not differ between groups, whereas the differences in the optic radiation (bvFTD pattern IV) reached significance. The findings in the corticospinal tract were due to a “dichotomous” behavior of FA changes there. Conclusion: Longitudinal TOI analysis demonstrated a pattern of white matter pathways alterations consistent with patterns of pTDP-43 pathology

Observation of Supershell Structure in Alkali Metal Nanowires

Nanowires are formed by indenting and subsequently retracting two pieces of sodium metal. Their cross-section gradually reduces upon retraction and the diameters can be obtained from the conductance. In previous work we have demonstrated that when one constructs a histogram of diameters from large numbers of indentation-retraction cycles, such histograms show a periodic pattern of stable nanowire diameters due to shell structure in the conductance modes. Here, we report the observation of a modulation of this periodic pattern, in agreement with predictions of a supershell structure.Comment: Phys. Rev. Lett., in prin

Friedel phases and phases of transmission amplitudes in quantum scattering systems

We illustrate the relation between the scattering phase appearing in the Friedel sum rule and the phase of the transmission amplitude for quantum scatterers connected to two one-dimensional leads. Transmission zero points cause abrupt phase changes $\pm\pi$ of the phase of the transmission amplitude. In contrast the Friedel phase is a continuous function of energy. We investigate these scattering phases for simple scattering problems and illustrate the behavior of these models by following the path of the transmission amplitude in the complex plane as a function of energy. We verify the Friedel sum rule for these models by direct calculation of the scattering phases and by direct calculation of the density of states.Comment: 12 pages, 12 figure

Cerebellar Integrity in the Amyotrophic Lateral Sclerosis - Frontotemporal Dementia Continuum

Amyotrophic lateral sclerosis (ALS) and behavioural variant frontotemporal dementia (bvFTD) are multisystem neurodegenerative disorders that manifest overlapping cognitive, neuropsychiatric and motor features. The cerebellum has long been known to be crucial for intact motor function although emerging evidence over the past decade has attributed cognitive and neuropsychiatric processes to this structure. The current study set out i) to establish the integrity of cerebellar subregions in the amyotrophic lateral sclerosis-behavioural variant frontotemporal dementia spectrum (ALS-bvFTD) and ii) determine whether specific cerebellar atrophy regions are associated with cognitive, neuropsychiatric and motor symptoms in the patients. Seventy-eight patients diagnosed with ALS, ALS-bvFTD, behavioural variant frontotemporal dementia (bvFTD), most without C9ORF72 gene abnormalities, and healthy controls were investigated. Participants underwent cognitive, neuropsychiatric and functional evaluation as well as structural imaging using voxel-based morphometry (VBM) to examine the grey matter subregions of the cerebellar lobules, vermis and crus. VBM analyses revealed: i) significant grey matter atrophy in the cerebellum across the whole ALS-bvFTD continuum; ii) atrophy predominantly of the superior cerebellum and crus in bvFTD patients, atrophy of the inferior cerebellum and vermis in ALS patients, while ALS-bvFTD patients had both patterns of atrophy. Post-hoc covariance analyses revealed that cognitive and neuropsychiatric symptoms were particularly associated with atrophy of the crus and superior lobule, while motor symptoms were more associated with atrophy of the inferior lobules. Taken together, these findings indicate an important role of the cerebellum in the ALS-bvFTD disease spectrum, with all three clinical phenotypes demonstrating specific patterns of subregional atrophy that associated with different symptomology

Charge densities and charge noise in mesoscopic conductors

We introduce a hierarchy of density of states to characterize the charge distribution in a mesoscopic conductor. At the bottom of this hierarchy are the partial density of states which represent the contribution to the local density of states if both the incident and the out-going scattering channel is prescribed. The partial density of states play a prominent role in measurements with a scanning tunneling microscope on multiprobe conductors in the presence of current flow. The partial density of states determine the degree of dephasing generated by a weakly coupled voltage probe. In addition the partial density of states determine the frequency-dependent response of mesoscopic conductors in the presence of slowly oscillating voltages applied to the contacts of the sample. The partial density of states permit the formulation of a Friedel sum rule which can be applied locally. We introduce the off-diagonal elements of the partial density of states matrix to describe charge fluctuation processes. This generalization leads to a local Wigner-Smith life-time matrix.Comment: 10 pages, 2 figure

Insensitivity to loss predicts apathy in Huntington's disease

Background Apathy is a deficit in goal‐directed behavior that significantly affects quality of life and function. It is common in Huntington's disease and other disorders affecting corticostriatal pathways. Deficits in processing of reward, altered effort, and executive dysfunction are associated with apathy in other disorders, but the cognitive processes leading to apathy in Huntington's disease remain largely unknown. A previously reported deficit in learning from losses in Huntington's disease raises the possibility of a hitherto unrecognized mechanism leading to apathy. This study's objective was to delineate the cognitive processes associated with apathy in HD. Methods We tested 51 Huntington's disease participants and 26 controls on a battery of novel and established measures to assess the contribution to apathy in Huntington's disease of executive function, reward value, reward‐effort calculations, instrumental learning, and response to reward and loss. Results Huntington's disase participants had deficits in instrumental learning with impaired response to loss, but no evidence to suggest altered reward‐related behavior or effort. We also saw an executive dysfunction contribution to apathy in Huntington's disease. Discussion We report the novel finding that apathy in Huntington's disease is associated with blunted responses to losses and impaired instrumental learning. This association is consistent with the known early degeneration of the indirect pathway and amygdala involvement in apathy in Huntington's disease, but is previously unreported in any disorder. In keeping with the comparative preservation of the ventral striatum and orbitofrontal cortex in Huntington's disease, reward valuation and reward‐effort calculations did not contribute to apathy