E. Coppi

Cross-validation of biomarkers for the early differential diagnosis and prognosis of dementia in a clinical setting

PurposeThe aim of this study was to evaluate the supportive role of molecular and structural biomarkers (CSF protein levels, FDG PET and MRI) in the early differential diagnosis of dementia in a large sample of patients with neurodegenerative dementia, and in determining the risk of disease progression in subjects with mild cognitive impairment (MCI).MethodsWe evaluated the supportive role of CSF Aβ42, t-Tau, p-Tau levels, conventional brain MRI and visual assessment of FDG PET SPM t-maps in the early diagnosis of dementia and the evaluation of MCI progression.ResultsDiagnosis based on molecular biomarkers showed the best fit with the final diagnosis at a long follow-up. FDG PET SPM t-maps had the highest diagnostic accuracy in Alzheimer’s disease and in the differential diagnosis of non-Alzheimer’s disease dementias. The p-tau/Aβ42 ratio was the only CSF biomarker providing a significant classification rate for Alzheimer’s disease. An Alzheimer’s disease-positive metabolic pattern as shown by FDG PET SPM in MCI was the best predictor of conversion to Alzheimer’s disease.ConclusionIn this clinical setting, FDG PET SPM t-maps and the p-tau/Aβ42 ratio improved clinical diagnostic accuracy, supporting the importance of these biomarkers in the emerging diagnostic criteria for Alzheimer’s disease dementia. FDG PET using SPM t-maps had the highest predictive value by identifying hypometabolic patterns in different neurodegenerative dementias and normal brain metabolism in MCI, confirming its additional crucial exclusionary role.

Excitatory deep repetitive transcranial magnetic stimulation with H-coil as add-on treatment of motor symptoms in Parkinson's disease: an open label, pilot study.

BACKGROUNDnRepetitive transcranial magnetic stimulation (rTMS) has been proposed as a potential treatment for Parkinsons disease (PD). H-coils, inducing deeper and wider magnetic fields compared to traditional coils, may be potentially useful in PD, characterized by widespread, bilateral involvement of cortico-subcortical circuits.nnnOBJECTIVEnTo evaluate the safety of repetitive deep TMS (rDTMS) with H-coil as add-on treatment of motor symptoms in PD.nnnMETHODSnTwenty-seven PD patients (aged 60.1 ± 6.8 y; PD-duration: 6.3 ± 2.8 y; motor-UPDRS: 39.6 ± 10.1) underwent 12 rDTMS sessions over 4 weeks at excitatory (10 Hz) frequency over primary motor (M1) and bilateral prefrontal (PF) regions. Motor UPDRS off therapy was assessed before and after the last rDTMS session, together with safety records at each treatment session.nnnRESULTSnNo drop-outs or adverse events were recorded. Motor UPDRS significantly improved after rDTMS (10.8 points average reduction; P < 0.0001).nnnCONCLUSIONSnHigh-frequency rDTMS might be a safe treatment for PD motor symptoms. Further placebo-controlled, randomized studies are warranted.

Interhemispheric Balance in Parkinson's Disease: A Transcranial Magnetic Stimulation Study

BACKGROUNDnParkinsons disease (PD) is characterized by various changes in motor excitability.nnnOBJECTIVEnTo examine through Transcranial Magnetic Stimulation (TMS) cortical excitability, specifically addressing interhemispheric connections in PD.nnnMETHODSnNineteen PD patients with a predominant involvement of the left hemibody (7 females, age 61.7xa0years,) and 13 controls (6 females, age 61.5xa0years) entered the study. Patients were subdivided into two groups (early and advanced) according to the time from PD diagnosis. Participants underwent evaluation of Resting Motor Threshold (RMT) and ipsilateral Silent Period (iSP), induced by suprathreshold TMS on the ipsilateral-M1, measured as suppression of voluntary EMG activity. Mirror Movements (MM) were EMG-recorded and scored, in three upper limb muscles, during unilateral voluntary hand movement. Patients were studied at baseline (OFF drug) and after acute levodopa challenge (ON).nnnRESULTSnPD patients showed a general reduction in RMT vs controls (Pxa0<xa00.01 for right and left hemisphere) in both drug conditions. Early PD had a significantly lower RMT over the right vs the left hemisphere (Pxa0=xa00.027); this difference was no longer significant after levodopa. In early PD patients, MM were mainly observed in the right arm during voluntary activation of the left, more affected side both in OFF (Pxa0=xa00.033) and in ON (Pxa0=xa00.046). In PD, RMT of the left, less affected M1 was significantly correlated with the right lateralized motor score (Pxa0=xa00.011; Spearmans coefficientxa0=xa0-0.585), as well as with disease duration. In PD patients, a shorter (Pxa0=xa00.039) and smaller (Pxa0=xa00.037) iSP was detected when the stimulus was applied to the worse M1 (right) compared with the contralateral side. This asymmetry was significant only OFF drug. In the PD group iSP-duration from the right, less affected APB was negatively correlated with the MM recorded from the same side during the voluntary movement of the worse side (Spearmans coefficientxa0=xa0-0.498; Pxa0=xa00.035).nnnCONCLUSIONSnIncreased cortical motor excitability in PD, consistent with previous findings, is more evident in the worse hemisphere, particularly in early PD. Asymmetric motor involvement is also associated with excessive involuntary mirroring and defective interhemispheric inhibition, both unfavoring the more affected side. Altogether, these findings suggest that asymmetric motor involvement in PD, particularly in the earlier phases of the disease, affects the interhemispheric balance of cortical excitability, movement lateralization and transcallosal inhibition.

Islet Transplantation Stabilizes Hemostatic Abnormalities and Cerebral Metabolism in Individuals With Type 1 Diabetes

OBJECTIVE Islets after kidney transplantation have been shown to positively affect the quality of life of individuals with type 1 diabetes (T1D) by reducing the burden of diabetes complications, but fewer data are available for islet transplantation alone (ITA). The aim of this study was to assess whether ITA has a positive impact on hemostatic and cerebral abnormalities in individuals with T1D. RESEARCH DESIGN AND METHODS Prothrombotic factors, platelet function/ultrastructure, and cerebral morphology, metabolism, and function have been investigated over a 15-month follow-up period using ELISA/electron microscopy and magnetic resonance imaging, nuclear magnetic resonance spectroscopy, and neuropsychological evaluation (Profile of Mood States test and paced auditory serial addition test) in 22 individuals with T1D who underwent ITA (n = 12) or remained on the waiting list (n = 10). Patients were homogeneous with regard to metabolic criteria, hemostatic parameters, and cerebral morphology/metabolism/function at the time of enrollment on the waiting list. RESULTS At the 15-month follow-up, the group undergoing ITA, but not individuals with T1D who remained on the waiting list, showed 1) improved glucose metabolism; 2) near-normal platelet activation and prothrombotic factor levels; 3) near-normal cerebral metabolism and function; and 4) a near-normal neuropsychological test. CONCLUSIONS ITA, despite immunosuppressive therapy, is associated with a near-normalization of hemostatic and cerebral abnormalities.

Mapping early changes of cortical motor output after subcortical stroke: A transcranial magnetic stimulation study

After acute stroke several changes in cortical excitability occur involving affected (AH) and unaffected hemisphere (UH) but whether they contribute to motor recovery is still controversial. We performed transcranial magnetic stimulation mapping of several upper limb muscles over the two hemispheres in thirteen patients at 4-12 days from subcortical stroke and after 1 month. The occurrence of mirror movements (MMs) on the healthy side during contraction of paretic muscles was measured. At baseline, cortical excitability parameters over the AH decreased in comparison with controls, while excitability over the UH increased correlating with severity of motor deficits of the affected arm at baseline as well as with poor recovery. At follow-up, map parameters of the UH became closer to those of controls independently from recovery, while for the AH the number of responsive sites increased significantly. Ipsilateral motor evoked responses (iMEPs) in the affected arm were never elicited. We observed an early impairment in dexterity of the ipsilesional hand that recovered over-time but persistently differed in comparison with controls. MMs occurrence increased at baseline correlating with reduced cortical excitability of the AH as well as with increased map density over the UH. The acute increased excitability of the UH after stroke has a negative prognostic value on recovery and negatively affects motor performance of the ipsilesional hand. Moreover, the absence of iMEPs and the normalization of motor cortical excitability at follow-up indicate that the UH primary motor area does not contribute to recovery.

Brain Changes within the Visuo-Spatial Attentional Network in Posterior Cortical Atrophy

Posterior cortical atrophy (PCA) is characterized by basic visual and high order visual-spatial dysfunctions. In this study, we investigated long-distance deafferentation processes within the frontal-parietal-occipital network in ten PCA patients using a MRI-PET combined approach. Objective voxel-based [18F]FDG-PET imaging measured metabolic changes in single patients. Comprehensive investigation of diffusion tensor imaging (DTI) metrics and grey-matter density with voxel-based morphometry were obtained in a subgroup of 6 patients. Fractional anisotropy in the superior longitudinal fasciculus correlated with the PET metabolic changes within the inferior parietal and frontal eye field regions. [18F]FDG-PET analysis showed in each PCA case the typical bilateral hypometabolic pattern, involving posterior temporal, parietal, and occipital cortex, with additional hypometabolic foci in the frontal eye fields. Voxel-based morphometry showed right-sided atrophy in the parieto-occipital cortex, as well as a limited temporal involvement. DTI revealed extensive degeneration of the major anterior-posterior connecting fiber bundles and of commissural frontal lobe tracts. Microstructural measures in the superior longitudinal fasciculus were correlated with the PET metabolic changes within the inferior parietal and frontal eye field regions. Our results confirmed the predominant occipital-temporal and occipital-parietal degeneration in PCA patients. [18F]FDG-PET and DTI-MRI combined approaches revealed neurodegeneration effects well beyond the classical posterior cortical involvement, most likely as a consequence of deafferentation processes within the occipital-parietal-frontal network that could be at the basis of visuo-perceptual, visuo-spatial integration and attention deficits in PCA.

Deep Repetitive Transcranial Magnetic Stimulation With H-coil on Lower Limb Motor Function in Chronic Stroke: A Pilot Study

OBJECTIVESnTo assess the efficacy of high-frequency (20 Hz) brain stimulation on lower limb motor function in subjects with chronic (> 6 mo) subcortical stroke.nnnDESIGNnDouble-blind, placebo-controlled crossover study.nnnSETTINGnUniversity hospital.nnnPARTICIPANTSnRight-handed subjects (N=10) affected by a first-ever subcortical stroke in the territory of the middle cerebral artery were included in this study.nnnINTERVENTIONSnRepetitive transcranial magnetic stimulation (rTMS) was delivered with the H-coil, specifically designed to target deeper and larger brains regions. Each subject received both real and sham rTMS in a random sequence. The 2 rTMS cycles (real or sham) were composed of 11 sessions each, administered over 3 weeks and separated by a 4-week washout period.nnnMAIN OUTCOME MEASURESnLower limb functions were assessed by the lower limb Fugl-Meyer scale, the 10-m walk test, and the 6-minute walk test before and 1 day after the end of each treatment period, as well as at a 4-week follow-up.nnnRESULTSnReal rTMS treatment was associated with a significant improvement in lower limb motor function. This effect persisted over time (follow-up) and was significantly greater than that observed with sham stimulation. A significant increase in walking speed was also found after real rTMS, but this effect did not reach statistical significance in comparison with the sham stimulation.nnnCONCLUSIONSnThese data demonstrated that 3 weeks of high-frequency deep rTMS could induce long-term improvements in lower limb functions in the chronic poststroke period, lasting at least 1 month after the end of the treatment.

The Progranulin (GRN) Cys157LysfsX97 Mutation is Associated with Nonfluent Variant of Primary Progressive Aphasia Clinical Phenotype

The progranulin gene (GRN) g.10325_10331delCTGCTGT (relative to nt1 in NG_007886.1), alias Cys157LysfsX97, has been so far reported only once in a patient with frontotemporal dementia. Here, we describe a 63-year old patient carrying the same mutation, presenting with a 3-year history of language disorder, and diagnosed clinically with nonfluent variant of primary progressive aphasia according to current criteria. This patients description expands the spectrum of clinical presentations of frontotemporal lobar degeneration caused by the GRN Cys157LysfsX97 mutation.

Deep magnetic stimulation in a progressive supranuclear palsy patient with speech involvement

In the last few years, several dementia conditions have been recognized as responsible for speech disorders [1]. The underlying pathology is variable and encompasses Alzheimer’s disease (AD) [2] and frontotemporal lobar degeneration, including its variants such as corticobasal degeneration and progressive supranuclear palsy (PSP) [3]. Particularly, beside the classical symmetric parkinsonism and gaze supranuclear palsy, PSP patients may present apraxia of speech (AOS) and progressive nonfluent aphasia (PNFA) [4]. AOS represents a motor speech disorder showing slow speech rate, prolonged intervals between words, decreased articulatory accuracy and sound distortions [4]. PNFA is a language disorder with dysfluent, effortful and agrammatic speech, often accompanied by similar difficulty with writing and comprehension [1]. Regardless of aetiology, AOS and PNFA usually co-occur, eventually leading to a complete mutism. Cortical atrophy predominantly shows a perisylvian distribution [1]. Unfortunately despite the recent advantages in diagnostic accuracy, the therapeutic options for these patients are disappointing. Repetitive TMS (rTMS) is based on the application of transient electromagnetic fields to induce electric currents in the brain and consequently transynaptic depolarization of neurons located in superficial cortical layers. Increased cortical excitability has been reported after high-frequency rTMS (5 Hz or higher), while the opposite after low-frequency (1 Hz) [5]. Evidence is accumulating about a possible beneficial role of high-frequency left prefrontal rTMS on cognitive performances in subjects with dementia [7]. For example, improved naming was observed after stimulation of the dorsolateral prefrontal cortex (DLPF) [6]. This non-invasive technique has also been applied to improve both motor and non-motor symptoms in Parkinson’s disease (PD) [8]. However, one main feature of rTMS applied with traditional focal coils is its relatively narrow and superficial magnetic field, which can be a limiting factor when aiming to target deep or widespread brain regions, as could be the case in neurodegenerative disorders. Deep transcranial magnetic stimulation (DTMS) can be obtained with the H-coil, capable of generating broader and deeper magnetic field than the figure-of-8 coil, without significantly increasing superficial stimulation intensities [9]. The broader and deeper stimulation of H-coils may increase the risk for side effects, [10] however no significant safety concerns have been reported so far with the H2-coil, used in this study [11]. Electronic supplementary material The online version of this article (doi:10.1007/s00415-012-6772-3) contains supplementary material, which is available to authorized users.

P19.19 Effects of high-frequency repetitive transcranial magnetic stimulation (rTMS) applied with H-coil for chronic migraine prophylaxis

Introduction: We investigated the effects of repetitive transcranial magnetic stimulation (rTMS) on corticomotor excitability (CE), motor behavior, and mood in patients with progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Repetitive TMS has not been investigated systematically in PSP or CBD patients. PSP and CBD share bradykinetic-rigid features of Parkinson’s disease. PSP and CBD show a high incidence of frontal dysfunction and depression; CBD is dominated by asymmetric limb apraxia and dystonia. Objectives: We hypothesized that rTMS over primary motor cortex (M1rTMS) would affect CE and motor behavior while rTMS over dorsolateral prefrontal cortex (DLPFC-rTMS) would affect mood. Patients were randomized to receive M1-rTMS, DLPFC-rTMS, or sham-rTMS at 90% motor threshold in 3 sessions with assessments before vs. after stimulation. 5 CBD patients received 1 Hz-rTMS (for dystonia) and 10 PSP patients received 5 Hz-rTMS (for akinesia-rigidity) over M1 contralateral to the more symptomatic limb. All patients received 5 Hz-rTMS over left DLPFC. Methods: CE was assessed with resting motor thresholds (rMT) and motor evoked potential amplitudes (MEP); motor behavior assessed with maximal (MAX) and comfortable (COM) tapping speed; mood assessed with visual analog scales. Results: (1) In PSP, 5 Hz rTMS over M1 did not improve tapping speeds, (2) rTMS over left DLPFC showed a trend towards improvement of overall wellness (p = 0.07, 2-tailed), a protocol comparable with rTMS use for depression, (3) rTMS over M1 in PSP did not significantly modify MEP amplitude. We found no significant differences in rMT in PSP patients vs healthy controls; CBD patients may have higher motor thresholds compared to healthy controls (p = 0.028), but was limited in CBD patients due to high rMT. Conclusions: These preliminary results provide support to further explore high-frequency left DLPFC rTMS for affective symptoms. Higher frequency rTMS over M1 or higher intensity stimulation may be needed to demonstrate changes in CE. Alternative strategies for addressing high rMT in CBD patients may be needed for applying rTMS.