Association Between Insulin-Like Growth Factor-1 and Social Cognition in Huntington's Disease.

Background: Insulin-like growth factor 1 (IGF-1) seems to be involved in the neural circuits associated with social cognition and brain structure. Objectives: To investigate the association of IGF-1 levels with social cognition and brain structure in Huntington's disease (HD). Methods: We evaluated social cognition using the Ekman test in 22 HD patients and 19 matched controls. Brain structure was assessed using standard volume-based voxel-based morphometry and surface-based cortical thickness pipeline. We analyzed the association of IGF-1 levels with social cognition and brain structure using adjusted regression analysis. Results: Social cognition was worse in HD patients (P < 0.001), on antidopaminergic drugs (P = 0.02), and with lower IGF-1 levels (P = 0.04). In neuroimaging analyses, lower IGF-1 levels were associated with social cognition impairment and atrophy mainly in frontotemporal regions (P < 0.05 corrected). Conclusions: In HD, abnormal IGF-1 function seems to be associated with brain atrophy leading to clinical deficits in social cognition.

Polymorphisms in the oxytocin receptor and their association with apathy and impaired social cognition in Huntington's disease.

BACKGROUND: Huntington's disease (HD) is a neurodegenerative disorder characterized by cognitive, motor, and neuropsychiatric manifestations. Oxytocin is a neuropeptide studied for its role as a neuromodulator regulating multiple behaviors linked to social cognition. Genetic variation of oxytocin receptor (OXTR) might interact in the etiology and development of several impaired social behaviors. Our aim was to study OXTR polymorphisms and their relationship with apathy and social cognition in HD. METHODS: OXTR was sequenced in 21 cases and 22 controls. We assessed apathy, anxiety, depression, and irritability (Hospital Anxiety and Depression Scale-Snaith Irritability scale, HADS-SIS) and social cognition (Ekman 60 faces test), motor symptoms and functionality with the total functional capacity (TFC), and the Unified HD rating Scale (UHDRS). RESULTS: We identified ten variants in OXTR. Three variants were classified as possibly damaging (p.Arg40Gly) or probably damaging (p.Leu46Pro, p.Thr102Asn). Subjects carrying the wild-type genotype of the synonymous variant p.Val45 showed a significantly lower score in the HADS-SIS scale, related to lower irritability (p = 0.013). The only subject carrying the heterozygous genotype of the synonymous variant p.Leu62 showed a significantly higher score on Ekman scale, compared to wild-type (p = 0.049); however, this finding was not confirmed after bootstrapping. CONCLUSION: Variations in OXTR could have a relevant role in the correct development of social and cognitive functions. Future approaches will include the molecular study of p.Arg40Gly, p.Leu46Pro, and p.Thr102Asn to confirm their pathogenicity, as well as the validation of the influence of p.Val45 and p.Leu62 variants for their involvement in irritability and social cognition in HD.

Clinical manifestations of homozygote allele carriers in Huntington disease.

OBJECTIVE: Because patients homozygous for Huntington disease (HD) receive the gain-of-function mutation in a double dose, one would expect a more toxic effect in homozygotes than in heterozygotes. Our aim was to investigate the phenotypic differences between homozygotes with both alleles ≥36 CAG repeats and heterozygotes with 1 allele ≥36 CAG repeats. METHODS: This was an international, longitudinal, case-control study (European Huntington's Disease Network Registry database). Baseline and longitudinal total functional capacity, motor, cognitive, and behavioral scores of the Unified Huntington's Disease Rating Scale (UHDRS) were compared between homozygotes and heterozygotes. Four-year follow-up data were analyzed using longitudinal mixed-effects models. To estimate the association of age at onset with the length of the shorter and larger allele in homozygotes and heterozygotes, regression analysis was applied. RESULTS: Of 10,921 participants with HD (5,777 female [52.9%] and 5,138 male [47.0%]) with a mean age of 55.1 ± 14.1 years, 28 homozygotes (0.3%) and 10,893 (99.7%) heterozygotes were identified. After correcting for multiple comparisons, homozygotes and heterozygotes had similar age at onset and UHDRS scores and disease progression. In the multivariate linear regression analysis, the longer allele was the most contributing factor to decreased age at HD onset in the homozygotes (p < 0.0001) and heterozygotes (p < 0.0001). CONCLUSIONS: CAG repeat expansion on both alleles of the HTT gene is infrequent. Age at onset, HD phenotype, and disease progression do not significantly differ between homozygotes and heterozygotes, indicating similar effect on the mutant protein. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that age at onset, the motor phenotype and rate of motor decline, and symptoms and signs progression is similar in homozygotes compared to heterozygotes.

Vertebrectomía total en bloque en tumores vertebrales: consideraciones técnicas y detalles quirúrgicos / Total en bloc spondylectomy for spinal tumours: Technical aspects and surgical details

Objetivo: Describir detalles quirúrgicos específicos y comentar algunas lecciones aprendidas, a partir de una serie de pacientes con tumores vertebrales a los que se les practicó una vertebrectomía total en bloque (VTB). Métodos: Presentamos una serie retrospectiva de casos. Se analizan variables clínicas, técnicas y de resultado. Resultados: Se intervinieron 10 pacientes (2000-2016) mediante VTB por tumor primario vertebral (osteosarcoma, condrosarcoma, fibrosarcoma y cordoma) o secundario (pulmón, mama, tiroides, esófago y meningioma). Según la clasificación de Tomita, 2 pacientes presentaban lesiones intracompartimentales y el resto extracompartimentales. Todos los pacientes mejoraron del dolor tras la cirugía. Nueve pacientes conservaron la capacidad de caminar en el postoperatorio y uno desarrolló paraplejía. Seis pacientes precisaron reoperaciones por desbridamiento de la herida quirúrgica, recidiva o revisión de la fijación. Otras complicaciones fueron neumotórax, derrame pleural y trombosis venosa. Cuatro pacientes sobreviven (tras 4 meses y hasta 15 años). El resto fallecieron por progresión del tumor primario (de 6,5 meses a 12 años). Se realiza una descripción detallada de los pasos quirúrgicos, consejos y dificultades de la técnica. Se comentan ciertas modificaciones de la técnica y otras cuestiones relativas a la resección. El respeto a ciertas consideraciones (selección de los candidatos, disección vertebral cuidadosa, control estricto del sangrado, manejo cuidadoso de la médula y mantenimiento del concepto de resección radical en todo momento) es clave para realizar con éxito esta intervención. Conclusión: La VTB es una intervención paradigmática en la que el concepto de resección radical implica efectividad funcional y mejora la supervivencia en pacientes seleccionados portadores de tumores vertebrales. Esta experiencia preliminar nos permite destacar algunas de sus características relevantes, especialmente aquellas dirigidas a simplificar la técnica y hacerla más segura

Objective: To describe the specific surgical details and report the lessons learned with a series of patients suffering from spinal tumours that underwent total en bloc spondylectomy (TES). Methods: A retrospective case series review is presented, together with an analysis of the clinical and technical variables, as well as the outcomes. Results: A total of 10 patients underwent TES (2000-2016) for primary (osteosarcoma, chondrosarcoma, fibrosarcoma and chordoma) and secondary spinal tumours (lung, breast, thyroid, oesophagus, and meningioma metastases). According to the Tomita classification, 2 patients had intra-compartmental tumours, and the rest presented as extra-compartmental. All patients experienced an improvement in their pain level after surgery. Nine patients preserved ambulation post-operatively and one patient developed paraplegia. Six patients needed subsequent operations for wound debridement, tumour recurrence, or revision of the fixation. Other complications included pneumothorax, pleural effusion and venous thrombosis. Four patients remain alive (4 months to 15 years follow-up). The rest died due to primary tumour progression (6.5 months to 12 years). A detailed description of the surgical steps, tips, and pitfalls is provided. Modifications of the technique and adjuncts to resection are commented on. Observation of some considerations (selection of candidates, careful blunt vertebral dissection, strict blood loss control, careful handling of the spinal cord, and maintenance of the radical resection concept at all stages) is key for a successful operative performance. Conclusion: TES is a paradigmatic operation, in which the concept of radical resection provides functional effectiveness and improves survival in selected patients suffering from spinal tumours. Our preliminary experience allows us to highlight some specific and relevant features, especially those favouring a simpler and safer operation

[Total en bloc spondylectomy for spinal tumours: Technical aspects and surgical details]. / Vertebrectomía total en bloque en tumores vertebrales: consideraciones técnicas y detalles quirúrgicos.

OBJECTIVE: To describe the specific surgical details and report the lessons learned with a series of patients suffering from spinal tumours that underwent total en bloc spondylectomy (TES). METHODS: A retrospective case series review is presented, together with an analysis of the clinical and technical variables, as well as the outcomes. RESULTS: A total of 10 patients underwent TES (2000-2016) for primary (osteosarcoma, chondrosarcoma, fibrosarcoma and chordoma) and secondary spinal tumours (lung, breast, thyroid, oesophagus, and meningioma metastases). According to the Tomita classification, 2 patients had intra-compartmental tumours, and the rest presented as extra-compartmental. All patients experienced an improvement in their pain level after surgery. Nine patients preserved ambulation post-operatively and one patient developed paraplegia. Six patients needed subsequent operations for wound debridement, tumour recurrence, or revision of the fixation. Other complications included pneumothorax, pleural effusion and venous thrombosis. Four patients remain alive (4 months to 15 years follow-up). The rest died due to primary tumour progression (6.5 months to 12 years). A detailed description of the surgical steps, tips, and pitfalls is provided. Modifications of the technique and adjuncts to resection are commented on. Observation of some considerations (selection of candidates, careful blunt vertebral dissection, strict blood loss control, careful handling of the spinal cord, and maintenance of the radical resection concept at all stages) is key for a successful operative performance. CONCLUSION: TES is a paradigmatic operation, in which the concept of radical resection provides functional effectiveness and improves survival in selected patients suffering from spinal tumours. Our preliminary experience allows us to highlight some specific and relevant features, especially those favouring a simpler and safer operation.

Spinal cord herniation repair with microstaples: case report.

Idiopathic spinal cord herniation (ISCH) is a relatively rare and frequently misdiagnosed condition. It preferentially affects women and causes progressive thoracic myelopathy that presents as a Brown-Séquard syndrome or as spastic paraparesis. Although its etiology and pathogenesis are controversial, ISCH is characterized by the presence of an anterior dural defect that allows the incarceration of a segment of the cord. Typically, a C-shaped ventral displacement and kinking of the cord are visible on sagittal MRI. Surgery aimed at stopping or reversing myelopathic symptoms is usually recommended for symptomatic patients. Surgical options include reduction of the hernia and direct suturing, or enlargement of the dural defect, with or without patching. Suturing under the cord in a very tight space can be troublesome and may lead to neurological deterioration. The authors present the case of a symptomatic ISCH in which nonpenetrating titanium microstaples were used to close the dural defect after cord reduction. The patient experienced a good outcome, and the follow-up MRI study showed adequate cord repositioning and stability of the suture. The use of microstaples, which allows for an easier and faster dural closure than conventional suturing, is a novel technical adjunct that has not been previously reported for this condition. In addition, microstaples produce minimal metallic artifact that does not hinder the quality of follow-up MR images.

Clinical manifestations of intermediate allele carriers in Huntington disease.

OBJECTIVE: There is controversy about the clinical consequences of intermediate alleles (IAs) in Huntington disease (HD). The main objective of this study was to establish the clinical manifestations of IA carriers for a prospective, international, European HD registry. METHODS: We assessed a cohort of participants at risk with <36 CAG repeats of the huntingtin (HTT) gene. Outcome measures were the Unified Huntington's Disease Rating Scale (UHDRS) motor, cognitive, and behavior domains, Total Functional Capacity (TFC), and quality of life (Short Form-36 [SF-36]). This cohort was subdivided into IA carriers (27-35 CAG) and controls (<27 CAG) and younger vs older participants. IA carriers and controls were compared for sociodemographic, environmental, and outcome measures. We used regression analysis to estimate the association of age and CAG repeats on the UHDRS scores. RESULTS: Of 12,190 participants, 657 (5.38%) with <36 CAG repeats were identified: 76 IA carriers (11.56%) and 581 controls (88.44%). After correcting for multiple comparisons, at baseline, we found no significant differences between IA carriers and controls for total UHDRS motor, SF-36, behavioral, cognitive, or TFC scores. However, older participants with IAs had higher chorea scores compared to controls (p = 0.001). Linear regression analysis showed that aging was the most contributing factor to increased UHDRS motor scores (p = 0.002). On the other hand, 1-year follow-up data analysis showed IA carriers had greater cognitive decline compared to controls (p = 0.002). CONCLUSIONS: Although aging worsened the UHDRS scores independently of the genetic status, IAs might confer a late-onset abnormal motor and cognitive phenotype. These results might have important implications for genetic counseling. CLINICALTRIALSGOV IDENTIFIER: NCT01590589.

Energy Balance in Huntington's Disease.

INTRODUCTION: Little is known about the energy needs in Huntington's disease (HD). The aims of this study are to analyze and compare the total energy expenditure (TEE) and energy balance (EB) in a representative sample of HD patients with healthy controls. METHODS: This is an observational, case-control single-center study. Food caloric energy intake (EI) and TEE were considered for estimating EB. A dietary recall questionnaire was used to assess the EI. TEE was computed as the sum of resting energy expenditure (REE), measured by indirect calorimetry and physical activity (PA) monitored by an actigraph. RESULTS: A total of 22 patients were included (36% men, mean age 50.3 ± 15.6 years, motor Unified Huntington's Disease Scale 27.9 ± 23.7, total functional capacity 11.0 (7.0-13.0), EI 38.6 ± 10.0 kcal/kg, PA 5.3 (3.0-7.4) kcal/kg, REE 30.9 ± 6.4 kcal/kg, TEE 2,023.4 (1,592.0-2,226.5) kcal/day) and 18 controls (50% men, mean age 47.4 ± 13.8 years, EI 38.6 ± 10.3 kcal/kg, PA 8.4 (5.0-13.8) kcal/kg, REE 30.8 ± 6.6 kcal/kg, TEE 2,281.0 (2,057.3-2,855.3) kcal/day). TEE was significantly lower in patients compared to controls (p = 0.03). PA was lower in patients compared to controls (p = 0.02). CONCLUSIONS: Although patients with HD appeared to have lower energy expenditure, mainly due to decreased voluntary PA, they were still able to maintain their energy needs with an adequate food intake. © 2015 S. Karger AG, Basel.

Body composition analysis as an indirect marker of skeletal muscle mass in Huntington's disease.

BACKGROUND: Skeletal muscle wasting is likely to play an important role in the Huntington's disease (HD) pathogenesis. Our aim was to analyze the body composition, and specifically fat-free mass (FFM), as an indirect marker of skeletal muscle in patients with HD, and its association with HD severity and energy balance. METHODS: Cross-sectional, case-control study. Body composition was analyzed using bioelectrical impedance. Information was collected as regards of the anthropometrics, disease severity [Unified Huntington Disease Rating (UHDRS) and Total functional capacity (TFC) scores], CAG repeats, protein catabolism, energy intake and energy expenditure. RESULTS: Twenty two patients with HD [mean age 50.3±15.6, mean UHDRS of 27.9±23.7, median TFC of 11 (IQR: 7; 13); median body mass index 23.6 (IQR: 26.8; 22.5)], and 18 controls were included. Both groups were similar in terms of age, gender, body mass index, body composition, physical activity level, and protein catabolism. FFM was correlated with energy intake (r=0.73, p<0.001), resting energy expenditure (r=0.64, p=0.001) and physical activity (r=0.54, p=0.003), but not with CAG repeats, or HD severity. CONCLUSIONS: Our results do not support the presence of significant muscle wasting in patients with early-moderate Huntington's disease. However, to prevent muscle wasting in HD, dietary strategies, in addition to physical exercise, should be further investigated.