Search

Background:Differentiation between primary (PLS) and amyotrophic lateral sclerosis (ALS) entails relevant consequences for prognosis and management but is mostly unreliable at early stages. The objectives of the study are: i) to determine the features at onset that could help to differentiate between PLS and ALS; ii) to evaluate the diagnostic performance of an integrated serum biomarker panel; iii) to identify the prognostic factors for patients presenting with an upper motor neuron (UMN)-syndrome.Methods:We selected and retrospectively analyzed the clinical data of patients presenting with UMN-syndrome. At the first evaluation, when available, serum biomarkers were measured using ultrasensitive single molecule array.Results:Study population included 55 PLS and 50 ALS patients. PLS patients presented a longer time to first neurological evaluation (PLS: 35.0 months, IQR: 17.0-38.0; ALS: 12.5 months, IQR: 7.0-21.3; pC9orf72expansion. NfL resulted an independent predictor of final diagnosis (OR: 1.01, 95%CI: 1.00-1.02; p=0.04) and an independent prognostic factor (HR: 1.01, 95%CI: 1.00-1.01; pConclusions:NfL might help to differentiate PLS from ALS patients and to predict prognosis in patients with an UMN-syndrome.

Background and ObjectivesA significant overlap between amyotrophic lateral sclerosis (ALS) and behavioral variant of frontotemporal dementia (bvFTD) has been observed at clinical, genetic, and pathologic levels. Within this continuum of presentations, the presence of mild cognitive or behavioral symptoms in patients with ALS has been consistently reported, although it is unclear whether this is to be considered a distinct phenotype or rather a natural evolution of ALS. Here, we used mathematical modeling of MRI connectomic data to decipher common and divergent neural correlates across the ALS–frontotemporal dementia (FTD) spectrum.MethodsWe included 83 patients with ALS, 35 patients with bvFTD, and 61 healthy controls, who underwent clinical, cognitive, and MRI assessments. Patients with ALS were classified according to the revised Strong criteria into 54 ALS with only motor deficits (ALS-cn), 21 ALS with cognitive or behavioral involvement (ALS-ci/bi), and 8 ALS with bvFTD (ALS-FTD). First, we assessed the functional and structural connectivity patterns across the ALS-FTD spectrum. Second, we investigated whether and where MRI connectivity alterations of patients with ALS with any degree of cognitive impairment (i.e., ALS-ci/bi and ALS-FTD) resembled more the pattern of damage of one (ALS-cn) or the other end (bvFTD) of the spectrum, moving from group-level to single-subject analysis.ResultsAs compared with controls, extensive structural and functional disruption of the frontotemporal and parietal networks characterized bvFTD (bvFTD-like pattern), while a more focal structural damage within the sensorimotor-basal ganglia areas characterized ALS-cn (ALS-cn-like pattern). ALS-ci/bi patients demonstrated an ALS-cn-like pattern of structural damage, diverging from ALS-cn with similar motor impairment for the presence of enhanced functional connectivity within sensorimotor areas and decreased functional connectivity within the bvFTD-like pattern. On the other hand, patients with ALS-FTD resembled both structurally and functionally the bvFTD-like pattern of damage with, in addition, the structural ALS-cn-like damage in the motor areas.DiscussionOur findings suggest a maladaptive role of functional rearrangements in ALS-ci/bi concomitantly with similar structural alterations compared to ALS-cn, supporting the hypothesis that ALS-ci/bi might be considered as a phenotypic variant of ALS, rather than a consequence of disease worsening.

ObjectiveTo investigate structural and functional neural organization in amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), and progressive muscular atrophy (PMA).MethodsA total of 173 patients with sporadic ALS, 38 patients with PLS, 28 patients with PMA, and 79 healthy controls were recruited from 3 Italian centers. Participants underwent clinical, neuropsychological, and brain MRI evaluations. Using graph analysis and connectomics, global and lobar topologic network properties and regional structural and functional brain connectivity were assessed. The association between structural and functional network organization and clinical and cognitive data was investigated.ResultsCompared with healthy controls, patients with ALS and patients with PLS showed altered structural global network properties, as well as local topologic alterations and decreased structural connectivity in sensorimotor, basal ganglia, frontal, and parietal areas. Patients with PMA showed preserved global structure. Patient groups did not show significant alterations of functional network topologic properties relative to controls. Increased local functional connectivity was observed in patients with ALS in the precentral, middle, and superior frontal areas, and in patients with PLS in the sensorimotor, basal ganglia, and temporal networks. In patients with ALS and patients with PLS, structural connectivity alterations correlated with motor impairment, whereas functional connectivity disruption was closely related to executive dysfunction and behavioral disturbances.ConclusionsThis multicenter study showed widespread motor and extramotor network degeneration in ALS and PLS, suggesting that graph analysis and connectomics might represent a powerful approach to detect upper motor neuron degeneration, extramotor brain changes, and network reorganization associated with the disease. Network-based advanced MRI provides an objective in vivo assessment of motor neuron diseases, delivering potential prognostic markers.

Background: Chronic inflammatory demyelinating polyradiculoneuropathy trials have demonstrated the efficacy of IV immunoglobulin vs placebo. However, these trails have not addressed the long-term impact on health-related quality of life (HRQoL). Methods: One hundred seventeen patients in a randomized, double-blind, response-conditional crossover trial received immune globulin IV, 10% caprylate/chromatography purified (IGIV-C [Gamunex®]), or placebo every 3 weeks for up to 24 weeks in the first period (FP). Participants whose inflammatory neuropathy cause and treatment disability score did not improve by ≥1 point received alternate treatment in a 24-week crossover period (CP). In either period, participants who improved and completed treatment were eligible to be randomly reassigned to a blinded 24-week extension phase (EP). HRQoL analyses were conducted using the Short Form-36® (SF-36) and the Rotterdam Handicap Scale (RHS). Results: In the FP, greater improvements in both SF-36 physical and mental component scores were observed with IGIV-C vs placebo, with a significant improvement in the physical component score (difference 4.4 points; 95% confidence interval [CI] 0.7–8.0). Improvements in all SF-36 domains favored IGIV-C vs placebo, with physical functioning, role–physical, social functioning, and mental health reaching significance. Participants receiving IGIV-C experienced a larger improvement in RHS vs those receiving placebo (difference 3.4 points; 95% CI 1.4–5.5; p = 0.001). In the CP, similar general trends were observed. In the EP, mean SF-36 improvements were generally improved or maintained in participants who continued IGIV-C therapy; however, worsening was observed in participants re-randomized to placebo. Conclusions: Long-term therapy with immune globulin IV, 10% caprylate/chromatography purified, improves and maintains health-related quality of life in chronic inflammatory demyelinating polyradiculoneuropathy.

Objective: Recent evidence in animal models suggests that components of the extracellular matrix (ECM) play a primary role in peripheral nerve degeneration and regeneration. Methods: We investigated the expression of several ECM molecules in human sural nerves by immunohistochemistry, Western blot, and reverse transcriptase PCR analysis. To unravel the possible role of these molecules in nerve regeneration, we compared results obtained from nerves with abundant signs of regeneration with those with complete absence of axonal regeneration. The role of some ECM components on neurite extension was further tested in dorsal root ganglion cultures. Results: We observed that the ECM composition significantly differs in regenerating compared with nonregenerating nerves, independently from their etiologic background. Fibronectin was abundantly expressed in regenerating nerves, whereas vitronectin and fibrin(ogen) prevailed in nonregenerating nerves. Whereas fibronectin is secreted by endoneurial cells, in vivo and vitro studies showed that the source of vitronectin and fibrin(ogen) is the bloodstream. Conclusions: These data indicate that nerve regeneration is impaired in the presence of breaches in the blood–nerve barrier or impaired extracellular matrix (ECM) degradation that leads to accumulation of plasma vitronectin and fibrin(ogen). The transformation into mature, fibronectin-enriched ECM is necessary for efficient nerve regeneration in humans.

Cold agglutinin disease (CAD) is characterized by the production of cold agglutinins (CAs), usually IgMk autoantibodies, causing chronic hemolytic anemia and cold induced acrocyanosis (reported in 90% of cases). CAD has traditionally been classified into a primary type (pCAD) and a secondary type accompanied by malignant disease, most often lymphoma. PCAD is considered a stable or slowly progressive disease with good prognosis (median survival: 12.5 years from onset). It has recently been shown that even pCAD frequently associates with an underlying lymphoproliferative disorder characterized by clonal expansion of B cells.1 Peripheral neuropathy (PN) is a rare complication of CAD, with isolated cases reported, but the pathogenetic mechanisms are still object of debate.2–4 ### Case report. A 58-year-old man was admitted to the hospital because of asymmetric motor and sensory impairment of limbs. Three years before he had developed cold-induced acrocyanosis and pCAD had been diagnosed. At that time, two bone marrow biopsies showed no evidence of lymphoma or plasma cell dyscrasia. Six months before admission, the patient developed progressive weakness, sensory loss, and paresthesias in the right foot; 3 months later, the same symptoms appeared in the left foot and the right hand. On admission, neurologic examination showed asymmetric (right>left) weakness in distal muscles of lower limbs and in the right hand, sensory loss with the same distribution, absent tendon reflexes at lower limbs, and hyporeflexia in the arms. Laboratory investigations showed mild anemia (hemoglobin 10 g/dL), …