TMS for staging and predicting functional decline in frontotemporal dementia.

Abstract Objective To evaluate if transcranial magnetic stimulation (TMS) measures correlate with disease severity and predict functional decline in frontotemporal dementia (FTD) phenotypes. Methods Paired-pulse TMS was used to investigate the activity of different intracortical circuits in 171 FTD patients (122 bvFTD, 31 avPPA, 18 svPPA) and 74 healthy controls. Pearson's correlations were used to analyze the association between TMS measures and disease severity, while multiple regression analysis was used to identify the best clinical or neurophysiological measure to predict functional decline at 12 months. Results We observed significant strong correlations between TMS measures [short interval intracortical inhibition-facilitation (SICI-ICF) and long interval intracortical inhibition (LICI)], and disease severity (evaluated with the FTLD-CDR) (all r > 0.5, p SICI-ICF, short interval intracortical facilitation (SICF) and LICI were also significant predictors of functional decline, evaluated as the change in FTLD-CDR scores at 12 months (all p Conclusions The present study has shown that the dysfunction of inhibitory and facilitatory intracortical circuits, evaluated with TMS, correlates with disease severity and progression, accurately predicting functional decline at 12 months, better than any other investigated marker

Generation of induced pluripotent stem cells (iPSC) from an atrial fibrillation patient carrying a KCNA5 p.D322H mutation

Atrial fibrillation (AF) is the most common sustained arrhythmia associated with several cardiac risk factors, but increasing evidences indicated a genetic component. Indeed, genetic variations of the atrial specific KCNA5 gene have been identified in patients with early-onset lone AF. To investigate the molecular mechanisms underlying AF, we reprogrammed to pluripotency polymorphonucleated leukocytes isolated from the blood of a patient carrying a KCNA5 p.D322H mutation, using a commercially available non-integrating system. The generated iPSCs expressed pluripotency markers and differentiated toward cells belonging to the three embryonic germ layers. Moreover, the cells showed a normal karyotype and retained the p.D322H mutation

Cerebello-spinal tDCS in ataxia: a randomized, double-blind, sham-controlled, crossover trial

Objective To investigate whether a 2-week treatment with cerebellar anodal and spinal cathodal transcranial direct current stimulation (tDCS) could reduce symptoms in patients with neurodegenerative ataxia and could modulate cerebello-motor connectivity at the short and long terms. Methods We performed a double-blind, randomized, sham-controlled, crossover trial with cerebello-spinal tDCS (5 d/wk for 2 weeks) in 20 patients with neurodegenerative ataxia. Each patient underwent a clinical evaluation before and after real tDCS or sham stimulation. A follow-up evaluation was performed at 1 and 3 months with a crossover washout period of 3 months. Cerebello-motor connectivity was evaluated with transcranial magnetic stimulation at baseline and at each follow-up. Results Cerebello-spinal tDCS showed a significant improvement in all performance scores (Scale for the Assessment and Rating of Ataxia, International Cooperative Ataxia Rating Scale, 9-Hole Peg Test, 8-m walking time), in motor cortex excitability, and in cerebellar brain inhibition compared to sham stimulation. Conclusions A 2-week treatment with cerebello-spinal tDCS reduces symptoms in patients with ataxia and restores motor cortex inhibition exerted by cerebellar structures. Cerebello-spinal tDCS might represent a promising future therapeutic and rehabilitative approach in patients with neurodegenerative ataxia, still an orphan disorder of any pharmacologic intervention

Sensitivity and specificity of transcranial magnetic stimulation for differential diagnosis of Alzheimer’s disease and frontotemporal dementia

Background: Early and differential diagnosis of Alzheimer’s disease (AD) and Frontotemporal Dementia (FTD) still remains problematic. Cerebrospinal fluid (CSF) biomarkers, PET amyloid imaging and hippocampal atrophy on MRI have shown the highest accuracy in post-mortem studies of AD cases. Notwithstanding, these biomarkers present considerable drawbacks. In this view, transcranial magnetic stimulation (TMS) allows the assessment, non-invasively and in vivo, of specific neurotransmission signatures. Methods: We performed a prospective study on AD and FTD patients, in accordance with the Standards for Reporting of Diagnostic Accuracy. Paired pulse TMS was used to investigate short-interval intracortical inhibition (SICI) and facilitation (ICF), long-interval intracortical inhibition (LICI) and short-afferent latency inhibition (SAI) in order to measure the activity of different intracortical circuits, with the application of current reference standards, to differentiate patients with AD from those with FTD and healthy controls (HC). The primary outcome measures were sensitivity and specificity of TMS measures, derived from receiver operator curve analysis. Results: A total of 175 subjects met inclusion criteria. We diagnosed 79 AD patients, 64 FTD patients and 32 HC. We found that while AD patients are characterized by a specific impairment of SAI, FTD show a remarkable dysfunction of SICI-ICF intracortical circuits. Using the best index incorporating these measurements (SICI-ICF / SAI ratio), TMS differentiated FTD from AD with a sensitivity of 91·8% and specificity of 88·6%, AD from HC with a sensitivity of 84·8%, and specificity of 90·6%, and FTD from HC with a sensitivity of 90·2% and specificity of 78·1%. These results were confirmed also in patients with a mild disease. Conclusions: TMS is a non-invasive procedure which reliably distinguishes AD from FTD and HC and, if these findings are replicated in larger studies, could represent a useful adjunctive diagnostic tool to be used in clinical practice

Long term clinical and neurophysiological effects of cerebellar transcranial direct current stimulation in patients with neurodegenerative ataxia

Neurodegenerative cerebellar ataxias represent a group of disabling disorders for which we currently lack effective therapies. Cerebellar transcranial direct current stimulation (tDCS) is a non-invasive technique, which has been demonstrated to modulate cerebellar excitability and improve symptoms in patients with cerebellar ataxias

Transcranial stimulation in frontotemporal dementia: A randomized, double‐blind, sham‐controlled trial

Introduction: Frontotemporal dementia (FTD) is a progressive disease for which no curative treatment is currently available. We aimed to determine whether transcranial direct current stimulation (tDCS) can modulate intracortical connectivity and improve cognition in symptomatic FTD patients and presymptomatic FTD subjects. Methods: We performed a double-blind, randomized, sham-controlled trial with anodal tDCS or sham stimulation over the left prefrontal cortex in 70 participants (15 presymptomatic and 55 symptomatic FTD). Results: We observed a significant increase of intracortical connectivity (short interval intracortical inhibition and facilitation) and improvement in clinical scores and behavioral disturbances in both symptomatic FTD patients and presymptomatic carriers after real tDCS but not after sham stimulation. Discussion: A 2-weeks' treatment with anodal left prefrontal tDCS improves symptoms and restores intracortical inhibitory and excitatory circuits in both symptomatic FTD patients and presymptomatic carriers. tDCS might represent a promising future therapeutic and rehabilitative approach in patients with FTD. Keywords: clinical trial; frontotemporal dementia; granulin; presymptomatic; short interval intracortical inhibition; transcranial direct current stimulation; transcranial magnetic stimulation

Transcranial stimulation in frontotemporal dementia: A randomized, double-blind, sham-controlled trial

Introduction: Frontotemporal dementia (FTD) is a progressive disease for which no curative treatment is currently available. We aimed to determine whether transcranial direct current stimulation (tDCS) can modulate intracortical connectivity and improve cognition in symptomatic FTD patients and presymptomatic FTD subjects. Methods: We performed a double-blind, randomized, sham-controlled trial with anodal tDCS or sham stimulation over the left prefrontal cortex in 70 participants (15 presymptomatic and 55 symptomatic FTD). Results: We observed a significant increase of intracortical connectivity (short interval intracortical inhibition and facilitation) and improvement in clinical scores and behavioral disturbances in both symptomatic FTD patients and presymptomatic carriers after real tDCS but not after sham stimulation. Discussion: A 2-weeks' treatment with anodal left prefrontal tDCS improves symptoms and restores intracortical inhibitory and excitatory circuits in both symptomatic FTD patients and presymptomatic carriers. tDCS might represent a promising future therapeutic and rehabilitative approach in patients with FTD. Keywords: clinical trial; frontotemporal dementia; granulin; presymptomatic; short interval intracortical inhibition; transcranial direct current stimulation; transcranial magnetic stimulation