Alberto Benussi

Mild cognitive impairment in Parkinson's disease is improved by transcranial direct current stimulation combined with physical therapy

Parkinsons disease (PD) is characterized by both motor and cognitive deficits. In PD, physical exercise has been found to improve physical functioning. Recent studies demonstrated that repeated sessions of transcranial direct current stimulation led to an increased performance in cognitive and motor tasks in patients with PD.

Phenotypic Heterogeneity of Monogenic Frontotemporal Dementia

Frontotemporal dementia (FTD) is a genetically and pathologically heterogeneous disorder characterized by personality changes, language impairment, and deficits of executive functions associated with frontal and temporal lobe degeneration. Different phenotypes have been defined on the basis of presenting clinical symptoms, i.e., the behavioral variant of FTD, the agrammatic variant of primary progressive aphasia, and the semantic variant of PPA. Some patients have an associated movement disorder, either parkinsonism, as in progressive supranuclear palsy and corticobasal syndrome, or motor neuron disease (FTD–MND). A family history of dementia is found in 40% of cases of FTD and about 10% have a clear autosomal-dominant inheritance. Genetic studies have identified several genes associated with monogenic FTD: microtubule-associated protein tau, progranulin, TAR DNA-binding protein 43, valosin-containing protein, charged multivesicular body protein 2B, fused in sarcoma, and the hexanucleotide repeat expansion in intron 1 of the chromosome 9 open reading frame 72. Patients often present with an extensive phenotypic variability, even among different members of the same kindred carrying an identical disease mutation. The objective of the present work is to review and evaluate available literature data in order to highlight recent advances in clinical, biological, and neuroimaging features of monogenic frontotemporal lobar degeneration and try to identify different mechanisms underlying the extreme phenotypic heterogeneity that characterizes this disease.

Cerebellar transcranial direct current stimulation in patients with ataxia: A double-blind, randomized, sham-controlled study

Numerous studies have highlighted the possibility of modulating the excitability of cerebellar circuits using transcranial direct current stimulation. The present study investigated whether a single session of cerebellar anodal transcranial direct current stimulation could improve symptoms in patients with ataxia.

Csf p-tau181/tau ratio as biomarker for TDP pathology in frontotemporal dementia

Abstract Our objective was to evaluate the CSF phospho-Tau181/total-Tau (p/t-Tau) ratio to distinguish between the two main forms of frontotemporal lobar degeneration (FTLD): FTLD with TDP-43 (FTLD-TDP) and FTLD with Tau inclusions (FTLD-Tau). CSF p/t-Tau ratio was examined in 79 FTLD patients with predictable neuropathology, i.e. Tau (affected by progressive supranuclear palsy or carriers of mutations within the MAPT gene) or TDP-43 (carriers of mutations within granulin, C9orf72, TARDBP genes or affected by FTD with motor neuron disease). FTLD patients were randomly grouped in a training cohort (n = 39) to assess the best CSF p/t-Tau cut-off score according to ROC analysis, and a validation cohort (n = 40) to evaluate accuracy values of the identified marker. Results showed that, in the training cohort, we found a significantly reduced CSF p/t-Tau ratio in FTLD-TDP relative to FTLD-Tau. ROC analysis for p/t-Tau ratio was 0.873 and cut-off score of 0.136 allowed to differentiate FTLD-TDP and FTLD-Tau with 81.8% sensitivity and 88.2% specificity, respectively. Analysis in the validation cohort showed CSF p/t-Tau ratio < 0.136 to distinguish FTLD-TDP from FTLD-Tau with 83.3% specificity and 63.6% sensitivity, respectively. The positive predictive value of detecting TDP neuropathology was 82.4%. In conclusion, a reduced CSF p/t-Tau ratio represents a viable biomarker to correctly identify TDP pathology in FTLD.

Transcranial magnetic stimulation distinguishes Alzheimer disease from frontotemporal dementia

Objective: To determine whether a transcranial magnetic stimulation (TMS) multiparadigm approach can be used to distinguish Alzheimer disease (AD) from frontotemporal dementia (FTD). Methods: Paired-pulse TMS was used to investigate short-interval intracortical inhibition (SICI) and facilitation (ICF), long-interval intracortical inhibition, and short-latency afferent inhibition (SAI) to measure the activity of different intracortical circuits in patients with AD, patients with FTD, and healthy controls (HC). The primary outcome measures were sensitivity and specificity of TMS measures, derived from receiver operating curve analysis. Results: A total of 175 participants met the inclusion criteria. We diagnosed 79 patients with AD, 64 patients with FTD, and 32 HC. We found that while patients with AD are characterized by a specific impairment of SAI, FTD shows a remarkable dysfunction of SICI-ICF intracortical circuits. With the use of the best indexes, 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 in patients with mild disease. Conclusions: TMS is a noninvasive procedure that reliably distinguishes AD from FTD and HC and, if these findings are replicated in larger studies, could represent a useful additional diagnostic tool for clinical practice. Classification of evidence: This study provides Class III evidence that TMS measures can distinguish patients with AD from those with FTD.

Impaired long-term potentiation-like cortical plasticity in presymptomatic genetic frontotemporal dementia.

Neurophysiological biomarkers were assessed using a TMS multi-paradigm approach in thirteen presymptomatic (n=13 Granulin) and fourteen symptomatic (n=11 Granulin, n=3 C9orf72) subjects with a pathogenic mutation for Frontotemporal Dementia. Intra-cortical facilitation and LTP-like plasticity were impaired in presymptomatic carriers compared to healthy controls more than 15 years before expected symptom onset. In symptomatic carriers, a decrease in short-interval intracortical inhibition compared to presymptomatic carriers was found. In conclusion, these biomarkers could provide the footprints of specific physiopathological processes in the development of this disease and possibly support the diagnosis of autosomal dominant Frontotemporal dementia. This article is protected by copyright. All rights reserved.Neurophysiological biomarkers were assessed using a transcranial magnetic stimulation multiparadigm approach in 13 presymptomatic (n = 13 Granulin) and 14 symptomatic (n = 11 Granulin, n = 3 C9orf72) subjects with a pathogenic mutation for frontotemporal dementia (FTD). Intracortical facilitation and long‐term potentiation–like plasticity were impaired in presymptomatic carriers, compared to healthy controls, more than 15 years before expected symptom onset. In symptomatic carriers, a decrease in short‐interval intracortical inhibition, compared to presymptomatic carriers, was found. In conclusion, these biomarkers could provide the footprints of specific physiopathological processes in the development of this disease and possibly support the diagnosis of autosomal‐dominant FTD. Ann Neurol 2016;80:472–476

Impaired LTP‐like cortical plasticity in presymptomatic genetic FTD

Neurophysiological biomarkers were assessed using a TMS multi-paradigm approach in thirteen presymptomatic (n=13 Granulin) and fourteen symptomatic (n=11 Granulin, n=3 C9orf72) subjects with a pathogenic mutation for Frontotemporal Dementia. Intra-cortical facilitation and LTP-like plasticity were impaired in presymptomatic carriers compared to healthy controls more than 15 years before expected symptom onset. In symptomatic carriers, a decrease in short-interval intracortical inhibition compared to presymptomatic carriers was found. In conclusion, these biomarkers could provide the footprints of specific physiopathological processes in the development of this disease and possibly support the diagnosis of autosomal dominant Frontotemporal dementia. This article is protected by copyright. All rights reserved.Neurophysiological biomarkers were assessed using a transcranial magnetic stimulation multiparadigm approach in 13 presymptomatic (n = 13 Granulin) and 14 symptomatic (n = 11 Granulin, n = 3 C9orf72) subjects with a pathogenic mutation for frontotemporal dementia (FTD). Intracortical facilitation and long‐term potentiation–like plasticity were impaired in presymptomatic carriers, compared to healthy controls, more than 15 years before expected symptom onset. In symptomatic carriers, a decrease in short‐interval intracortical inhibition, compared to presymptomatic carriers, was found. In conclusion, these biomarkers could provide the footprints of specific physiopathological processes in the development of this disease and possibly support the diagnosis of autosomal‐dominant FTD. Ann Neurol 2016;80:472–476

Clinical, Genetic, and Neuroimaging Features of Early Onset Alzheimer Disease: The Challenges of Diagnosis and Treatment

Early Onset Alzheimer Disease (EOAD) is a rare condition, frequently associated with genetic causes. The dissemination of genetic testing along with biomarker determinations have prompted a wider recognition of EOAD in experienced clinical settings. However, despite the great efforts in establishing the contribution of causative genes to EOAD, atypical disease presentation and clinical features still makes its diagnosis and treatment a challenge for the clinicians. This review aims to provide an extensive evaluation of literature data on EOAD, in order to improve understanding and knowledge of EOAD, underscore its significant impact on patients and their caregivers and influence public policies. This would be crucial to define the urgency of evidence-based treatment approaches.

Italian Frontotemporal Dementia Network (FTD Group-SINDEM): sharing clinical and diagnostic procedures in Frontotemporal Dementia in Italy.

In the prospect of improved disease management and future clinical trials in Frontotemporal Dementia, it is desirable to share common diagnostic procedures. To this aim, the Italian FTD Network, under the aegis of the Italian Neurological Society for Dementia, has been established. Currently, 85 Italian Centers involved in dementia care are part of the network. Each Center completed a questionnaire on the local clinical procedures, focused on (1) clinical assessment, (2) use of neuroimaging and genetics; (3) support for patients and caregivers; (4) an opinion about the prevalence of FTD. The analyses of the results documented a comprehensive clinical and instrumental approach to FTD patients and their caregivers in Italy, with about 1,000 newly diagnosed cases per year and 2,500 patients currently followed by the participating Centers. In analogy to other European FTD consortia, future aims will be devoted to collect data on epidemiology of FTD and its subtypes and to provide harmonization of procedures among Centers.

Modulating risky decision-making in Parkinson's disease by transcranial direct current stimulation

Performance on gambling tasks in Parkinsons disease (PD) is of particular interest, as pathological gambling is often associated with dopamine replacement therapy in these patients. We aimed to evaluate the effects of transcranial direct current stimulation (tDCS) over the right dorsolateral prefrontal cortex (DLPFC) in modulating gambling behaviour in PD.