Cerebellar ataxias are a heterogenous group of degenerative disorders for which we currently lack effective and disease-modifying interventions. The field of non-invasive brain stimulation has made ...much progress in the development of specific stimulation protocols to modulate cerebellar excitability and try to restore the physiological activity of the cerebellum in patients with ataxia. In light of limited evidence-based pharmacologic and non-pharmacologic treatment options for patients with ataxia, several different non-invasive brain stimulation protocols have emerged, particularly employing repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS) techniques. In this review, we summarize the most relevant rTMS and tDCS therapeutic trials and discuss their implications in the care of patients with degenerative ataxias.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Parkinson's disease is characterised neuropathologically by α-synuclein aggregation. Currently, there is no blood test to predict the underlying pathology or distinguish Parkinson's from atypical ...parkinsonian syndromes. We assessed the clinical utility of serum neuronal exosomes as biomarkers across the spectrum of Parkinson's disease, multiple system atrophy and other proteinopathies.
We performed a cross-sectional study of 664 serum samples from the Oxford, Kiel and Brescia cohorts consisting of individuals with rapid eye movement sleep behavioural disorder, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, frontotemporal dementia, progressive supranuclear palsy, corticobasal syndrome and controls. Longitudinal samples were analysed from Parkinson's and control individuals. We developed poly(carboxybetaine-methacrylate) coated beads to isolate L1 cell adhesion molecule (L1CAM)-positive extracellular vesicles with characteristics of exosomes and used mass spectrometry or multiplexed electrochemiluminescence to measure exosomal proteins.
Mean neuron-derived exosomal α-synuclein was increased by twofold in prodromal and clinical Parkinson's disease when compared with multiple system atrophy, controls or other neurodegenerative diseases. With 314 subjects in the training group and 105 in the validation group, exosomal α-synuclein exhibited a consistent performance (AUC=0.86) in separating clinical Parkinson's disease from controls across populations. Exosomal clusterin was elevated in subjects with non-α-synuclein proteinopathies. Combined neuron-derived exosomal α-synuclein and clusterin measurement predicted Parkinson's disease from other proteinopathies with AUC=0.98 and from multiple system atrophy with AUC=0.94. Longitudinal sample analysis showed that exosomal α-synuclein remains stably elevated with Parkinson's disease progression.
Increased α-synuclein egress in serum neuronal exosomes precedes the diagnosis of Parkinson's disease, persists with disease progression and in combination with clusterin predicts and differentiates Parkinson's disease from atypical parkinsonism.
Frontotemporal dementia (FTD) is a heterogeneous clinical and neuropathological disorder characterized by behavioral abnormalities, executive dysfunctions and language deficits. FTD encompasses a ...wide range of different pathological entities, associated with the accumulation of proteins, such as tau and TPD-43. A family history of dementia is found in one third of cases, and several genes causing autosomal dominant inherited disease have been identified. The clinical symptoms are preceded by a prodromal phase, which has been mainly studied in cases carrying pathogenetic mutations. New experimental strategies are emerging, in both prodromal and clinical settings, and outcome markers are needed to test their efficacy. In this complex context, in the last few years, advanced neuroimaging techniques have allowed a better characterization of FTD, supporting clinical diagnosis, improving the comprehension of genetic heterogeneity and the earliest stages of the disease, contributing to a more detailed classification of underlying proteinopathies, and developing new outcome markers on clinical grounds. In this review, we briefly discuss the contribution of brain imaging and the most recent techniques in deciphering the different aspects of FTD.
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Cerebellar ataxias represent a heterogeneous group of disabling disorders characterized by motor and cognitive disturbances, for which no effective treatment is currently available. In this ...randomized, double-blind, sham-controlled trial, followed by an open-label phase, we investigated whether treatment with cerebello-spinal transcranial direct current stimulation (tDCS) could improve both motor and cognitive symptoms in patients with neurodegenerative ataxia at short and long-term. Sixty-one patients were randomized in two groups for the first controlled phase. At baseline (T0), Group 1 received placebo stimulation (sham tDCS) while Group 2 received anodal cerebellar tDCS and cathodal spinal tDCS (real tDCS) for 5 days/week for 2 weeks (T1), with a 12-week (T2) follow-up (randomized, double-blind, sham controlled phase). At the 12-week follow-up (T2), all patients (Group 1 and Group 2) received a second treatment of anodal cerebellar tDCS and cathodal spinal tDCS (real tDCS) for 5 days/week for 2 weeks, with a 14-week (T3), 24-week (T4), 36-week (T5) and 52-week follow-up (T6) (open-label phase). At each time point, a clinical, neuropsychological and neurophysiological evaluation was performed. Cerebellar-motor cortex connectivity was evaluated using transcranial magnetic stimulation. We observed a significant improvement in all motor scores (scale for the assessment and rating of ataxia, international cooperative ataxia rating scale), in cognition (evaluated with the cerebellar cognitive affective syndrome scale), in quality-of-life scores, in motor cortex excitability and in cerebellar inhibition after real tDCS compared to sham stimulation and compared to baseline (T0), both at short and long-term. We observed an addon-effect after two repeated treatments with real tDCS compared to a single treatment with real tDCS. The improvement at motor and cognitive scores correlated with the restoration of cerebellar inhibition evaluated with transcranial magnetic stimulation. Cerebello-spinal tDCS represents a promising therapeutic approach for both motor and cognitive symptoms in patients with neurodegenerative ataxia, a still orphan disorder of any pharmacological intervention.
•This review presents the contribution of TMS to the management of dementia.•TMS can be used as a biomarker of the excitability and function of cerebral cortex in dementia.•Increasing evidence ...supports the beneficial effects of rTMS in Alzheimer’s disease-related dementias at mild/early stage.
Transcranial magnetic stimulation (TMS) is a powerful tool to probe in vivo brain circuits, as it allows to assess several cortical properties such asexcitability, plasticity and connectivity in humans. In the last 20 years, TMS has been applied to patients with dementia, enabling the identification of potential markers of thepathophysiology and predictors of cognitive decline; moreover, applied repetitively, TMS holds promise as a potential therapeutic intervention.
The objective of this paper is to present a comprehensive review of studies that have employed TMS in dementia and to discuss potential clinical applications, from the diagnosis to the treatment.
To provide a technical and theoretical framework, we first present an overview of the basic physiological mechanisms of the application of TMS to assess cortical excitability, excitation and inhibition balance, mechanisms of plasticity and cortico-cortical connectivity in the human brain. We then review the insights gained by TMS techniques into the pathophysiology and predictors of progression and response to treatment in dementias, including Alzheimer’s disease (AD)-related dementias and secondary dementias. We show that while a single TMS measure offers low specificity, the use of a panel of measures and/or neurophysiological index can support the clinical diagnosis and predict progression.
In the last part of the article, we discuss the therapeutic uses of TMS. So far, only repetitive TMS (rTMS) over the left dorsolateral prefrontal cortex and multisite rTMS associated with cognitive training have been shown to be, respectively, possibly (Level C of evidence) and probably (Level B of evidence) effective to improve cognition, apathy, memory, and language in AD patients, especially at a mild/early stage of the disease. The clinical use of this type of treatment warrants the combination of brain imaging techniques and/or electrophysiological tools to elucidate neurobiological effects of neurostimulation and to optimally tailor rTMS treatment protocols in individual patients or specific patient subgroups with dementia or mild cognitive impairment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Objective
Transcranial magnetic stimulation (TMS) has been suggested as a reliable, noninvasive, and inexpensive tool for the diagnosis of neurodegenerative dementias. In this study, we assessed the ...classification performance of TMS parameters in the differential diagnosis of common neurodegenerative disorders, including Alzheimer disease (AD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD).
Methods
We performed a multicenter study enrolling patients referred to 4 dementia centers in Italy, in accordance with the Standards for Reporting of Diagnostic Accuracy. All patients underwent TMS assessment at recruitment (index test), with application of reference clinical criteria, to predict different neurodegenerative disorders. The investigators who performed the index test were masked to the results of the reference test and all other investigations. We trained and tested a random forest classifier using 5‐fold cross‐validation. The primary outcome measures were the classification accuracy, precision, recall, and F1 score of TMS in differentiating each neurodegenerative disorder.
Results
A total of 694 participants were included, namely 273 patients diagnosed as AD, 67 as DLB, and 207 as FTD, and 147 healthy controls (HC). A series of 3 binary classifiers was employed, and the prediction model exhibited high classification accuracy (ranging from 0.89 to 0.92), high precision (0.86–0.92), high recall (0.93–0.98), and high F1 scores (0.89–0.95) in differentiating each neurodegenerative disorder.
Interpretation
TMS is a noninvasive procedure that reliably and selectively distinguishes AD, DLB, FTD, and HC, representing a useful additional screening tool to be used in clinical practice. Ann Neurol 2020;87:394–404
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
To assess whether exposure to non-invasive brain stimulation with transcranial alternating current stimulation at γ frequency (γ-tACS) applied over Pz (an area overlying the medial parietal cortex ...and the precuneus) can improve memory and modulate cholinergic transmission in mild cognitive impairment due to Alzheimer’s disease (MCI-AD).
In this randomized, double-blind, sham controlled, crossover pilot study, participants were assigned to a single 60 min treatment with exposure to γ-tACS over Pz or sham tACS. Each subject underwent a clinical evaluation including assessment of episodic memory pre- and post-γ-tACS or sham stimulation. Indirect measures of cholinergic transmission evaluated using transcranial magnetic stimulation (TMS) pre- and post-γ-tACS or sham tACS were evaluated.
Twenty MCI-AD participants completed the study. No tACS-related side effects were observed, and the intervention was well tolerated in all participants. We observed a significant improvement at the Rey auditory verbal learning (RAVL) test total recall (5.7 95% CI, 4.0 to 7.4, p < 0.001) and long delayed recall scores (1.3 95% CI, 0.4 to 2.1, p = 0.007) after γ-tACS but not after sham tACS. Face-name associations scores improved during γ−tACS (4.3 95% CI, 2.8 to 5.8, p < 0.001) but not after sham tACS. Short latency afferent inhibition, an indirect measure of cholinergic transmission evaluated with TMS, increased only after γ-tACS (0.31 95% CI, 0.24 to 0.38, p < 0.001) but not after sham tACS.
exposure to γ-tACS over Pz showed a significant improvement of memory performances, along with restoration of intracortical connectivity measures of cholinergic neurotransmission, compared to sham tACS.
•Randomized, double-blind, sham controlled, cross-over study of γ-tACS in MCI-AD.•Improvement at the Rey auditory verbal learning after γ-tACS.•Short latency afferent inhibition increased after γ-tACS.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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.
OBJECTIVETo evaluate the statistical parametric mapping (SPM) procedure for fluorodeoxyglucose (FDG)-PET imaging as a possible single-subject marker of progression to dementia in Parkinson disease ...(PD).
METHODSFifty-four consecutive patients with PD without dementia (age at onset of 59.9 ± 10.1 years, disease duration of 5.3 ± 3.4 years) entered the study. The patients underwent an extensive motor and cognitive assessment and a single-subject FDG-PET SPM evaluation at baseline. A 4-year follow-up provided disease progression and dementia diagnosis.
RESULTSThe FDG-PET SPM was evaluated by 2 expert raters allowing the identification of a “typical PD pattern” in 29 patients, whereas 25 patients presented with “atypical patterns,” namely, dementia with Lewy bodies (DLB)-like (n = 12), Alzheimer disease (AD)-like (n = 6), corticobasal syndrome (CBS)-like (n = 5), and frontotemporal dementia (FTD)-like (n = 2). At 4-year follow-up, 13 patients, all showing atypical brain metabolic patterns at baseline, progressed to dementia (PD dementia). The DLB- and AD-like SPM patterns were the best predictor for incident dementia (p < 0.005, sensitivity 85%, specificity 88%), independently from demographics or cognitive baseline classification.
CONCLUSIONSThis study suggests that FDG-PET SPM at the single-subject level might help in identifying patients with PD at risk of developing dementia.
In the last decade, non-invasive blood-based and neurophysiological biomarkers have shown great potential for the discrimination of several neurodegenerative disorders. However, in the clinical ...workup of patients with cognitive impairment, it will be highly unlikely that any biomarker will achieve the highest potential predictive accuracy on its own, owing to the multifactorial nature of Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD).
In this retrospective study, performed on 202 participants, we analysed plasma neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and tau phosphorylated at amino acid 181 (p-Tau
) concentrations, as well as amyloid β42 to 40 ratio (Aβ
/
) ratio, using the ultrasensitive single-molecule array (Simoa) technique, and neurophysiological measures obtained by transcranial magnetic stimulation (TMS), including short-interval intracortical inhibition (SICI), intracortical facilitation (ICF), long-interval intracortical inhibition (LICI), and short-latency afferent inhibition (SAI). We assessed the diagnostic accuracy of combinations of both plasma and neurophysiological biomarkers in the differential diagnosis between healthy ageing, AD, and FTLD.
We observed significant differences in plasma NfL, GFAP, and p-Tau
levels between the groups, but not for the Aβ
/Aβ
ratio. For the evaluation of diagnostic accuracy, we adopted a two-step process which reflects the clinical judgement on clinical grounds. In the first step, the best single biomarker to classify "cases" vs "controls" was NfL (AUC 0.94, p < 0.001), whilst in the second step, the best single biomarker to classify AD vs FTLD was SAI (AUC 0.96, p < 0.001). The combination of multiple biomarkers significantly increased diagnostic accuracy. The best model for classifying "cases" vs "controls" included the predictors p-Tau
, GFAP, NfL, SICI, ICF, and SAI, resulting in an AUC of 0.99 (p < 0.001). For the second step, classifying AD from FTD, the best model included the combination of Aβ
/Aβ
ratio, p-Tau
, SICI, ICF, and SAI, resulting in an AUC of 0.98 (p < 0.001).
The combined assessment of plasma and neurophysiological measures may greatly improve the differential diagnosis of AD and FTLD.
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