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Purpose: [123I]FP-CIT (DaTSCAN®) single-photon emission computed tomography (SPECT) imaging is widely used to study neurodegenerative parkinsonism, by measuring presynaptic dopamine transporter (DAT) in striatal regions. Beyond DAT, [123I]FP-CIT may be considered for other monoaminergic systems, in particular the serotonin transporter (SERT). Independent component analysis (ICA) implemented in source-based morphometry (SBM) could represent an alternative method to explore monoaminergic pathways, studying the relationship among voxels and grouping them into "neurotransmission" networks.Procedures: One hundred forty-three subjects [84 with Parkinson's disease (PD) and 59 control individuals (CG)] underwent DATSCAN® imaging. The [123I]FP-CIT binding was evaluated by multivariate SBM approach, as well as by a whole-brain voxel-wise univariate (statistical parametric mapping, SPM) approach.Results: As compared to the univariate whole-brain approach (SPM) (only demonstrating striatal [123I]FP-CIT binding reduction in PD group), SBM identified six sources of non-artefactual origin, including basal ganglia and cortical regions as well as brainstem. Among them, three sources (basal ganglia and cortical regions) presented loading scores (as index of [123I]FP-CIT binding) significantly different between PD and CG. Notably, even if not significantly different between PD and CG, the remaining three non-artefactual sources were characterized by a predominant frontal, brainstem, and occipito-temporal involvement.Conclusion: The concept of source blind separation by the application of ICA (as implemented in SBM) represents a feasible approach to be considered in [123I]FP-CIT (DaTSCAN®) SPECT imaging. Taking advantage of this multivariate analysis, specific patterns of variance can be identified (involving either striatal than extrastriatal regions) that could be useful in differentiating neurodegenerative parkinsonisms. [ABSTRACT FROM AUTHOR]

Background: The Boston Cognitive Assessment (BOCA) is a self-administered online test developed for cognitive screening and longitudinal monitoring of brain health in an aging population. The study aimed to validate BOCA in an Italian population and to investigate the convergent validity with the Montreal Cognitive Assessment (MOCA) in healthy ageing population and patients within the Alzheimer Disease spectrum., Methods: BOCA was administered to 150 participants, including cognitively healthy controls (HC, n = 50), patients with mild cognitive impairment (MCI, n = 50), and dementia (DEM, n = 50). The BOCA reliability was assessed using (i) Spearman's correlation analysis between subscales; (ii) Cronbach's alpha calculation, and (iii) Principal Component Analysis. Repeated-measures ANOVA was employed to assess the impact of the sequence of test administrations between the groups. BOCA performance between HS, MCI and DEM and within different severity subgroups were compared using Kruskall Wallis test. Furthermore, a comparison was conducted between MCI patients who tested positive for amyloid and those who tested negative, utilizing Mann Whitney's U-test., Results: Test scores were significantly different between patients and controls (p < 0.001) suggesting good discriminative ability. The Cronbach's alpha was 0.82 indicating a good internal consistency of the BOCA subscales and strong-to-moderate Spearman's correlation coefficients between them. BOCA total and subscores differ across different MoCA severity subgroups and demonstrated strong correlation with MoCA scores (rho = 0.790, p < 0.001)., Conclusions: The Italian version of the BOCA test exhibited validity, feasibility, and accurate discrimination closely performing as MoCA., Competing Interests: Declarations. Competing Interest: All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript., (© 2024. The Author(s).)

Background and Objectives: Dementia presents not only differing neuropsychiatric symptoms (NPS) across Alzheimer disease (AD), frontotemporal dementia (FTD), dementia with Lewy bodies (DLB) but also subjective cognitive decline (SCD). This study examined sex-based variations in NPS severity and progression across these conditions., Methods: We performed a longitudinal cohort study including 1,068 participants. Hierarchical generalized linear mixed models were used to model NPS as a function of disease severity and biological sex at birth., Results: Female participants with AD exhibited NPS more frequently than male participants. In FTD, female participants had more frequent delusions, hallucinations, and depression/dysphoria, while male participants had higher instances of agitation/aggression, apathy, disinhibition, and irritability/lability. In DLB, male participants showed higher instances of depression, and female participants more frequently experienced anxiety. In SCD, female participants showed higher nighttime behaviors. The trajectory of NPS significantly differed between sexes., Discussion: These findings highlight sex-specific NPS impact in different neurodegenerative conditions., (© 2024 American Academy of Neurology.)

Introduction: Neurodegenerative diseases are a growing concern in an aging global population. Frailty, often conceptualized as a state of diminished physiological reserve and increased susceptibility to stressors, emerges as a pivotal factor in this context. While frailty may be modified, it is essential to recognize its frequently irreversible nature, necessitating a careful approach when considering its role and influence in the progression from mild cognitive impairment (MCI) to dementia and within dementia progression., Methods: A retrospective study including 1,284 participants, attending a Cognitive Disturbances and Dementia unit from January 2021 to May 2023, was conducted. Frailty was assessed using the clinical frailty scale (CFS) score. Multilevel univariate and multivariate logistic regression models were developed to determine the contributions of patient characteristics, including frailty, to disease progression., Results: Frailty significantly increased with higher global clinical dementia rating (CDR) subgroups, suggesting escalating frailty burden with disease progression. Age, CFS, and mini-mental state examination (MMSE) scores were significant predictors of progression from MCI to dementia and to more severe dementia stages, even when considering the independence from variables contributing to frailty. Patients transitioning to a higher CDR group exhibited higher CFS scores. Age, education, anticholinergic burden, cumulative illness rating scale - geriatric, MMSE, and neuropsychiatric inventory scores significantly contributed to frailty., Conclusions: Frailty plays a critical role in the transition from MCI to dementia and within dementia progression. Age, cognitive impairment, and frailty were identified as significant predictors of disease progression. The CFS is a clinically applicable tool for frailty assessment. Regular frailty assessments may be valuable in early detection and management of dementia., (© 2024 S. Karger AG, Basel.)

Introduction: Brain hypometabolism patterns have been previously associated with cognitive decline in Parkinson's disease (PD). Our aim is to evaluate the impact of single-subject fluorodeoxyglucose (FDG)-PET brain hypometabolism on long-term cognitive and motor outcomes in PD., Methods: Forty-nine non-demented PD patients with baseline brain FDG-PET data underwent an extensive clinical follow-up for 8 years. The ability of FDG-PET to predict long-term cognitive and motor progression was evaluated using Cox regression and mixed ANCOVA models., Results: Participants were classified according to FDG-PET pattern in PD with typical (n = 26) and atypical cortical metabolism (n = 23). Patients with atypical brain hypometabolic patterns showed higher incidence of dementia (60% vs 3%; HR = 18.3), hallucinations (56% vs 7%, HR = 7.3) and faster motor decline compared to typical pattern group., Conclusion: This study argues for specific patterns of FDG-PET cortical hypometabolism in PD as a prognostic marker for long term cognitive and motor outcomes at single-subject level., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Alterations in time awareness have been reported in dementia, particularly in Alzheimer's disease (AD) and frontotemporal dementia (FTD). However, the neurophysiological correlates underlying these alterations remain largely unexplored. This study aimed to investigate the neurophysiological correlates of altered time awareness in AD and FTD patients., Methods: A total of 150 participants (50 AD patients, 50 FTD patients, and 50 healthy controls [HC]) underwent a standardized neuropsychological assessment, an altered time awareness survey, and transcranial magnetic stimulation (TMS) to assess cholinergic (short latency afferent inhibition-SAI), GABAergic (short interval intracortical inhibition-SICI), and glutamatergic (intracortical facilitation-ICF) circuits., Results: In AD patients, the most frequent symptom was difficulty in ordering past events (52.0%), while FTD patients primarily struggled with estimating temporal intervals between events (40.0%). Significant differences were observed between HC and both patient groups, as well as between AD and FTD patients in their tendency to re-live past events. Binomial logistic regression analysis revealed that impairments in glutamatergic and cholinergic circuits significantly predicted the likelihood of participants manifesting altered time awareness symptoms., Conclusions: This study provides novel insights into the neurophysiological correlates of altered time awareness in AD and FTD patients, highlighting the involvement of specific neurotransmitter circuits, particularly glutamatergic and cholinergic circuits. Further research is needed to explore the potential clinical implications and therapeutic targets arising from these findings., (© 2023. Fondazione Società Italiana di Neurologia.)

Although Parkinson's disease (PD) key neuropathological hallmarks are well known, the underlying pathogenic mechanisms of the disease still need to be elucidated to identify innovative disease-modifying drugs and specific biomarkers. NF-κB transcription factors are involved in regulating several processes associated with neurodegeneration, such as neuroinflammation and cell death, that could be related to PD pathology. NF-κB/c-Rel deficient (c-rel -/- ) mice develop a progressive PD-like phenotype. The c-rel -/- mice present both prodromal and motor symptoms as well as key neuropathological features, including nigrostriatal dopaminergic neurons degeneration, accumulation of pro-apoptotic NF-κB/RelA acetylated at the lysine 310 residue (Ac-RelA(lys310)) and progressive caudo-rostral brain deposition of alpha-synuclein. c-Rel inhibition can exacerbate MPTP-induced neurotoxicity in mice. These findings support the claim that misregulation of c-Rel protein may be implicated in PD pathophysiology. In this study, we aimed at evaluating c-Rel levels and DNA-binding activity in human brains and peripheral blood mononuclear cells (PBMCs) of sporadic PD patients. We analyzed c-Rel protein content and activity in frozen substantia nigra (SN) samples from post-mortem brains of 10 PD patients and 9 age-matched controls as well as in PBMCs from 72 PD patients and 40 age-matched controls. c-Rel DNA-binding was significantly lower and inversely correlated with Ac-RelA(lys310) content in post-mortem SN of sporadic PD cases, when compared to healthy controls. c-Rel DNA-binding activity was also reduced in PBMCs of followed-up PD subjects. The decrease of c-Rel activity in PBMCs from PD patients appeared to be independent from dopaminergic medication or disease progression, as it was evident even in early stage, drug-naïve patients. Remarkably, the levels of c-Rel protein were comparable in PD and control subjects, pointing out a putative role for post-translational modifications of the protein in c-Rel dysfunctions. These findings support that PD is characterized by the loss of NF-κB/c-Rel activity that potentially has a role in PD pathophysiology. Future studies will be aimed at addressing whether the reduction of c-Rel DNA-binding could constitute a novel biomarker for PD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Objective: This study compared the performance of 18 F-Florbetapir PET/CT early acquisitions to 18 F-FDG PET/CT., Methods: We included 12 patients who underwent 18 F-FDG PET/CT and a dual-time 18 F-Florbetapir PET/CT (1-6 min early-scan and 50 min late-scan). PET/CT were analyzed visually by three nuclear medicine physicians with different experience using a four-point scale (0 = no reduction, 1 = slight, 2 = moderate, 3 = severe reduction) for 18 F-Florbetapir early-phase and 18 F-FDG images in 10 cortical regions (bilateral frontal, temporal, parietal, occipital, posterior cingulate/precuneus), and 18 F-Florbetapir late-phase in the same cortical regions using a three-point scale (0 = normal, 1 = abnormal with minor plaques, 2 = abnormal with major plaques). We used SPM12 for semiquantitative analysis applying a ROI-based correlation analysis (considering precuneus as target region and normalized for the mean global binding), a covariance-analysis taking precuneus as target and a comparison of global DMN (default mode network)., Results: Inter-reader agreement was high (Cohen's kappa 0.762 for 18 F-FDG, 0.775 for 18 F-Florbetapir early-phase and 0.794 for late-phase). Regional visual scores of early-phase and 18 F-FDG were significantly correlated (ρ = 0.867). Also ROI-based analysis, global brain visual analysis and DMN comparison revealed concordant results, especially at parietal and precuneus (p < 0.001)., Conclusions: 18 F-Florbetapir early-phase scans significantly correlate on quantitative and visual images with 18 F-FDG-PET/CT scans, suggesting that amyloid tracer could be instead of 18 F-FDG., (Copyright © 2021 Sociedad Española de Medicina Nuclear e Imagen Molecular. Published by Elsevier España, S.L.U. All rights reserved.)

New diagnostic methods have been developed for the early diagnosis of Alzheimer’s disease (AD) with the primary purpose of intercepting the transition-phase (mild cognitive impairment, MCI) between normal aging and dementia. We aimed to explore whether the five-word test (FWT) and the mini-mental state examination (MMSE) are predictive for the early diagnosis of MCI due to AD (AD-MCI). We computed ROC analyses to evaluate the sensitivity and specificity of MMSE and FWT in predicting abnormal CSF (t-Tau, p-Tau181, Aβ1−42) and amyloid-PET biomarkers. AD-MCI patients showed lower MMSE and FWT scores (all p < 0.001) than non-AD-MCI. The best predictor of amyloid plaques’ presence at amyloid-PET imaging was the encoding sub-score of the FWT (AUC = 0.84). Both FWT and MMSE had low/moderate accuracy for the detection of pathological CSF Aβ42, t-Tau and p-Tau181 values, with higher accuracy for the t-Tau/Aβ1−42 ratio. In conclusion, the FWT, as a single-domain cognitive screening test, seems to be prompt and moderately accurate tool for the identification of an underlying AD neuropathological process in patients with MCI, supporting the importance of associating biomarkers evaluation in the work-up of patients with dementing neurodegenerative disorders.

Plasma phosphorylated tau species have been recently proposed as peripheral markers of Alzheimer's disease (AD) pathology. In this cross-sectional study including 91 subjects, plasma and cerebrospinal fluid (CSF) p-tau181 and p-tau231 levels were elevated in the early symptomatic stages of AD. Plasma p-tau231 and p-tau181 were strongly related to CSF phosphorylated tau, total tau and amyloid and exhibited a high accuracy-close to CSF p-tau231 and p-tau181-to identify AD already in the early stage of the disease. The findings might support the use as diagnostic and prognostic peripheral AD biomarkers in both research and clinical settings.

Introduction: neurofilament light chain (NfL) levels have been proposed as reliable biomarkers of neurodegeneration in Parkinson's disease (PD) but the relationship between plasma NfL, clinical subtypes of PD and motor progression is still debated., Methods: plasma NfL concentration was measured in 45 healthy controls and consecutive 92 PD patients who underwent an extensive motor and non-motor assessment at baseline and after 2 years of follow-up. PD malignant phenotype was defined as the combination of at least two out of cognitive impairment, orthostatic hypotension and REM sleep behavior disorder. PD patients were divided according to the age-adjusted cut-offs of plasma NfL levels into high and normal NfL (H-NfL and N-NfL, respectively). A multivariable linear regression model was used to assess the value of plasma NfL as predictor of 2-years progression in PD., Results: NfL was higher in PD patients than in controls (p = 0.037). H-NfL (n = 16) group exhibited more severe motor and non-motor symptoms, higher prevalence of malignant phenotype and worse motor progression (MDS-UPDRS-III 11.3 vs 0.7 points, p = 0.003) compared to N-NfL group (n = 76). In linear regression analyses plasma NfL emerged as the best predictor of 2-year motor progression compared to age, sex, disease duration, baseline motor/non-motor variables., Conclusion: increased plasma NfL concentration is associated with malignant PD phenotype and faster motor progression. These findings support the role of NfL assessment as a useful measure for stratifying patients with different baseline slopes of decline in future clinical trials of putative disease-modifying treatments., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: Previous studies reported increased plasma levels of cystatin C (Cys-C) in Parkinson's disease (PD) and claimed for a possible association with disease severity and progression. The aim of this study was to evaluate plasma Cys-C in PD and healthy controls (HC) and test its association with markers of peripheral inflammation, neurodegeneration, and clinical progression in a longitudinal study., Methods: Plasma Cys-C, high-sensitive C-reactive protein, interleukin 6, and neurofilament light chain (NfL) were assessed at the baseline in 71 consecutive non-demented PD and 69 HC. PD patients underwent an extensive motor and cognitive assessment at baseline and after 2 years of follow-up. The association of Cys-C with disease severity was evaluated in a multilinear model adjusted for the effect of age, sex, disease duration, and peripheral inflammation., Results: Cys-C levels appeared to be higher in PD compared to controls and correlated with the plasma neuronal marker NfL (r = 0.204, p = 0.046). In longitudinal analyses, PD patients with higher Cys-C levels exhibited faster motor progression at 2 years of follow-up independently from the peripheral inflammatory profile., Conclusions: Cys-C was associated with higher NfL levels and a remarkably faster motor progression in PD independently from peripheral inflammation. Further studies are needed in order to understand the mechanisms underpinning the association of Cys-C with higher neuronal damage markers in neurodegenerative diseases., (© 2022 S. Karger AG, Basel.)

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 < 0.005). 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 < 0.005), while at the stepwise multiple regression analysis, SICI was the best predictor of disease progression, accounting for 72.5% of the variation in FTLD-CDR scores at 12 months (adjusted R 2  = 0.72, p < 0.001)., 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., Competing Interests: Declaration of competing interest Authors report no disclosures relevant to the manuscript., (Copyright © 2019. Published by Elsevier Inc.)

Background: The development of diagnostic tools capable of accurately identifying the pathophysiology of mild cognitive impairment (MCI) has become a crucial target considering the claim that disease-modifying treatments should be administered as early as possible in the disease course. Transcranial magnetic stimulation (TMS) protocols have demonstrated analytical validity in discriminating different forms of dementia; however, its value in daily clinical practice in MCI subjects is still unknown., Objective: To evaluate the clinical value of TMS compared to amyloid markers on diagnostic confidence and accuracy in MCI subjects, considering clinicians' expertise., Methods: One hundred seven MCI subjects were included and classified as MCI-Alzheimer disease (MCI-AD), MCI-frontotemporal dementia (MCI-FTD), MCI-dementia with Lewy bodies (MCI-DLB), or MCI-other in a three-step process based on (i) demographic, clinical, and neuropsychological evaluation (clinical work-up); (ii) clinical work-up PLUS amyloidosis markers or clinical work-up PLUS TMS measures; and (iii) clinical work-up PLUS both markers. Two blinded neurologists with different clinical expertise were asked to express a diagnostic confidence for each MCI subgroup, and ROC curve analyses were performed at each step., Results: The addition of TMS markers to clinical work-up significantly increased the diagnostic confidence for MCI-AD (p = 0.003), MCI-FTD (p = 0.044), and MCI-DLB (p = 0.033) compared to clinical work-up alone, but not for MCI-other (p > 0.05). No significant differences between the add-on effect of TMS and the add-on effect of amyloid markers to clinical work-up were observed (p > 0.732), while the diagnostic confidence further increased when both markers were available. The greater the clinical expertise, the greater the flexibility in considering alternative diagnosis, and the greater the ability to modify diagnostic confidence with TMS and amyloid markers., Conclusions: TMS in addition to routine clinical assessment in MCI subjects has a significant effect on diagnostic accuracy and confidence, comparable to well-established biomarkers of amyloidosis.

Objective: To determine whether motor cortex inhibition by stimulation over the cerebellum with a figure-of eight coil (MISC8) may be reduced in patients with Progressive Supranuclear Palsy (PSP)., Methods: Paired pulse TMS was used to evaluate MISC8, in patients with different forms of parkinsonism and dementia. The primary outcome measures were sensitivity and specificity of motor cortex inhibition, derived from receiver operator curve analysis, in discriminating PSP from other neurodegenerative disorders., Results: A total of 150 participants met inclusion criteria. According to clinical criteria, the study population included 19 PSP, 26 Parkinson's disease, 25 dementia with Lewy bodies, 15 corticobasal syndrome, 25 frontotemporal dementia and 15 Alzheimer's disease patients, and 25 healthy controls. PSP patients were characterized by a specific impairment of MISC8 (0.99 ± 0.08) compared to the healthy control group and to other neurodegenerative disorders (mean range = 0.63-0.80, all p-values<0.001). Using the best cut-off index, MISC8 differentiated PSP from other diagnoses with an overall sensitivity of 100%, a specificity of 94%, and an accuracy of 97%., Conclusions: TMS is a non-invasive procedure which reliably distinguishes PSP from other neurodegenerative disorders. MISC8 could represent a useful additional diagnostic tool to be used in clinical practice., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: The aim of the study was to evaluate extrastriatal dopaminergic and serotonergic pathways in patients with Parkinson's disease (PD) and dementia with Lewy bodies (DLB) using 123 I-FP-CIT SPECT imaging., Methods: The study groups comprised 56 PD patients without dementia, 41 DLB patients and 54 controls. Each patient underwent a standardized neurological examination and 123 I-FP-CIT SPECT. Binding in nigrostriatal and extrastriatal regions of interest was calculated in each patient from spatially normalized images. The occipital-adjusted specific to nondisplaceable binding ratio (SBR) in the different regions was compared among the PD patients, DLB patients and controls adjusting for the effects of age, sex, disease duration and serotonergic/dopaminergic treatment. Covariance analysis was used to determine the correlates of local and long-distance regions with extrastriatal 123 I-FP-CIT deficits., Results: Both PD and DLB patients showed lower 123 I-FP-CIT SPECT SBR in several regions beyond the nigrostriatal system, especially the insula, cingulate and thalamus. DLB patients showed significantly lower 123 I-FP-CIT SBR in the thalamus than controls and PD patients. Thalamic and cingulate 123 I-FP-CIT SBR deficits were correlated, respectively, with limbic serotonergic and widespread cortical monoaminergic projections only in DLB patients but exhibited only local correlations in PD patients and controls., Conclusion: PD and DLB patients both showed insular dopamine deficits, whereas impairment of thalamic serotonergic pathways was specifically associated with DLB. Longitudinal studies are necessary to determine the clinical value of the assessment of extrastriatal 123 I-FP-CIT SPECT.

Objective: The goal of the present work, based on a collaborative research registry in Italy (the Salento-Brescia Registry), was to assess the incidence of frontotemporal lobar degeneration (FTLD) and to define the frequencies of different FTLD phenotypes in the general population., Methods: The study was conducted from January 1, 2017, to December 31, 2017, in 2 Italian provinces: Lecce (in Puglia) in the south (area 2,799.07 km 2 , inhabitants 802,082) and Brescia (in Lombardy) in the north (area 4,785.62 km 2 , inhabitants 1,262,678). During the study period, all new cases of FTLD (incident FTLD) were counted, and all patients' records were reviewed. The incidence was standardized to the Italian general population in 2017., Results: In the 2 provinces, 63 patients with FTLD were diagnosed. The incidence rate for FTLD was 3.05 (95% confidence interval [CI] 2.34-3.90) per 100,000 person-years (py), while the age-sex standardized incidence rate was 3.09 (95% CI 2.95-3.23) per 100,000 py. In the Italian population, the lifetime risk was 1:400. There was a progressive increase in FTLD incidence across age groups, reaching its peak in the 75- to 79-year-old group, with an incidence rate of 15.97 (95% CI 8.94-26.33) per 100,000 py. The behavioral variant of frontotemporal dementia was the most common phenotype (37%). No difference in crude incidence rate between the 2 provinces was observed., Conclusion: FTLD is a more common form of dementia than previously recognized, with a risk spanning in a wide age range and with maximum incidence in the mid-70s. Improved knowledge of FTLD epidemiology will help to provide appropriate public health service policies., (© 2019 American Academy of Neurology.)

Background: Cholinergic dysfunction is a key abnormality in Alzheimer disease (AD) that can be detected in vivo with transcranial magnetic stimulation (TMS) protocols. Although TMS has clearly demonstrated analytical validity, its clinical utility is still debated. In the present study, we evaluated the incremental diagnostic value, expressed in terms of diagnostic confidence of Alzheimer disease (DCAD; range 0-100), of TMS measures in addition to the routine clinical diagnostic assessment in patients evaluated for cognitive impairment as compared with validated biomarkers of amyloidosis., Methods: One hundred twenty patients with dementia were included and scored in terms of DCAD in a three-step assessment based on (1) demographic, clinical, and neuropsychological evaluations (clinical work-up); (2) clinical work-up plus amyloid markers (cerebrospinal fluid or amyloid positron emission tomographic imaging); and (3) clinical work-up plus TMS intracortical connectivity measures. Two blinded neurologists were asked to review the diagnosis and diagnostic confidence at each step., Results: TMS measures increased the discrimination of DCAD in two clusters (AD-like vs FTD-like) when added to the clinical and neuropsychological evaluations with levels comparable to established biomarkers of brain amyloidosis (cluster distance of 55.1 for clinical work-up alone, 76.0 for clinical work-up plus amyloid markers, 80.0 for clinical work-up plus TMS). Classification accuracy for the "gold standard" diagnosis (dichotomous - AD vs FTD - variable) evaluated in the three-step assessment, expressed as AUC, increased from 0.82 (clinical work-up alone) to 0.98 (clinical work-up plus TMS) and to 0.99 (clinical work-up plus amyloidosis markers)., Conclusions: TMS in addition to routine assessment in patients with dementia has a significant effect on diagnosis and diagnostic confidence that is comparable to well-established amyloidosis biomarkers.

Objective: To 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)., Methods: Fifty-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., Results: The 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., Conclusions: This study suggests that FDG-PET SPM at the single-subject level might help in identifying patients with PD at risk of developing dementia., (© 2018 American Academy of Neurology.)

Objective: Frontotemporal dementia (FTD) is a common cause of young onset dementia. Very few reports on disease duration are currently available and predictors of survival are still undefined. The aim of the present study was to assess the natural history of FTD and to define predictors of survival., Methods: Four hundred amd eleven FTD patients, including 294 with behavioural variant FTD, 77 with agrammatic variant primary progressive aphasia (PPA) and 40 with semantic variant PPA, were consecutively enrolled and demographic and clinical variables carefully recorded. Each patient underwent genetic screening for monogenic disease., Results: The mean survival time from onset of the symptoms was 7.8 ± 4.0 years. The presence of a pathogenic mutation (GRN, C9orf72 or MAPT) (Hazard ratio [HR] = 1.85, 95% CI 1.04-3.31, p = 0.037) and older age at disease onset (HR = 1.04, 95% CI 1.02-1.07, p = 0.002) were associated with shorter life expectancy. However, a significant negative interaction between age at onset and genetic mutation was found, suggesting that the effect of age is different in patients with and without a genetic mutation (p = 0.028). Gender, clinical phenotype or education and occupation were not associated with survival risk., Conclusions: Our findings suggest that monogenic disease and age at onset are independent predictors of survival and should be considered in future clinical intervention trials and in patients' and caregivers' counselling.

Background: Considering the increasing evidence that disease-modifying treatments for Alzheimer's disease (AD) must be administered early in the disease course, the development of diagnostic tools capable of accurately identifying AD at early disease stages has become a crucial target. In this view, transcranial magnetic stimulation (TMS) has become an effective tool to discriminate between different forms of neurodegenerative dementia., Objective: To determine whether a TMS multi-paradigm approach can be used to correctly identify mild cognitive impairment (MCI) due to AD (AD MCI)., Methods: A sample of 69 subjects with MCI were included and classified as AD MCI or MCI unlikely due to AD (non-AD MCI) based on 1) extensive neurological and neuropsychological evaluation, 2) MRI imaging, and 3) cerebrospinal fluid analysis or/and amyloid PET imaging. A paired-pulse TMS multi-paradigm approach assessing short interval intracortical inhibition-facilitation (SICI-ICF), dependent on GABAergic and glutamatergic intracortical circuits, respectively, and short latency afferent inhibition (SAI), dependent on cholinergic circuits, was performed., Results: We observed a significant impairment of SAI and unimpaired SICI and ICF in AD MCI as compared to non-AD MCI. According to ROC curve analysis, the SICI-ICF / SAI index differentiated AD MCI from non-AD MCI with a specificity of 87.9% and a sensitivity of 94.4%., Conclusions: The assessment of intracortical connectivity with TMS could aid in the characterization of MCI subtypes, correctly identifying AD pathophysiology. TMS can be proposed as an adjunctive, non-invasive, inexpensive, and time-saving screening tool in MCI differential diagnosis.

Background: Progressive supranuclear palsy is a neurodegenerative disorder characterized by high functional disability and rapidly progressive dependency. The predictors of survival are still unclear., Methods: The predictors of survival were evaluated in a group of clinically diagnosed PSP patients, focusing primarily on extensive cognitive assessment., Results: The mean survival time from symptom onset was 8.25±3.0years. Sex, age at onset, education, occupation and severity of extrapyramidal symptoms did not correlate with survival. The only factor associated with a shorter life expectancy in our cohort was the presence of dementia at diagnosis. Impairment of executive functions was the best predictor of an unfavorable outcome., Conclusions: Our findings suggest that dementia and executive functions need to be evaluated in order to define survival probability in PSP patients., (Copyright © 2017 Elsevier B.V. All rights reserved.)

To explore the effects of PD pathology on brain connectivity, we characterized with an emergent computational approach the brain metabolic connectome using [18F]FDG-PET in early idiopathic PD patients. We applied whole-brain and pathology-based connectivity analyses, using sparse-inverse covariance estimation in thirty-four cognitively normal PD cases and thirty-four age-matched healthy subjects for comparisons. Further, we assessed high-order resting state networks by interregional correlation analysis. Whole-brain analysis revealed altered metabolic connectivity in PD, with local decreases in frontolateral cortex and cerebellum and increases in the basal ganglia. Widespread long-distance decreases were present within the frontolateral cortex as opposed to connectivity increases in posterior cortical regions, all suggestive of a global-scale connectivity reconfiguration. The pathology-based analyses revealed significant connectivity impairment in the nigrostriatal dopaminergic pathway and in the regions early affected by α-synuclein pathology. Notably, significant connectivity changes were present in several resting state networks especially in frontal regions. These findings expand previous imaging evidence of altered connectivity in cognitively stable PD patients by showing pathology-based connectivity changes and disease-specific metabolic architecture reconfiguration at multiple scale levels, from the earliest PD phases. These alterations go well beyond the known striato-cortical connectivity derangement supporting in vivo an extended neural vulnerability in the PD synucleinopathy.

Background: Cognitive deficits are common in progressive supranuclear palsy (PSP), but their relevance and the progression to dementia are still poorly described. The recently revised criteria for PSP consider cognitive dysfunction in the diagnostic work-up., Methods: The study retrospectively evaluated a series of 99 PSP patients with Richardson syndrome (PSP-RS), subgrouped according to cognitive and behavioural performances into PSP with normal cognition (PSP-NC), PSP with mild cognitive impairment (PSP-MCI), and PSP with dementia (PSP-D). The progression to dementia at the 3-year follow-up was assessed., Results: At baseline, 15.2% of patients were classified as PSP-NC, 43.4% as PSP-MCI, and 41.4% as PSP-D. During the 3-year follow-up, 21 out of 29 patients, previously classified as PSP-NC or PSP-MCI, converted to dementia, with an incidence rate of 241 per 1,000 patients/year. Nineteen out of 21 PSP patients (90%) developed the behavioural variant frontotemporal dementia phenotype. The only factor associated with conversion to dementia was MCI diagnosis at baseline (p = 0.023)., Conclusion: Cognitive decline occurs in a great proportion of PSP-RS patients early during the disease course. In the absence of a specific phenotype, the diagnosis of MCI might identify PSP patients at greatest risk of developing dementia and should be considered further in the diagnostic assessment., (© 2017 S. Karger AG, Basel.)

Transcranial direct current stimulation (tDCS) is a non-invasive technique for inducing prolonged functional changes in the human cerebral cortex. This simple and safe neurostimulation technique for modulating motor functions in Parkinson's disease could extend treatment option for patients with movement disorders. We assessed whether tDCS applied daily over the cerebellum (cerebellar tDCS) and motor cortex (M1-tDCS) improves motor and cognitive symptoms and levodopa-induced dyskinesias in patients with Parkinson's disease (PD). Nine patients (aged 60-85 years; four women; Hoehn & Yahr scale score 2-3) diagnosed as having idiopathic PD were recruited. To evaluate how tDCS (cerebellar tDCS or M1-tDCS) affects motor and cognitive function in PD, we delivered bilateral anodal (2 mA, 20 min, five consecutive days) and sham tDCS, in random order, in three separate experimental sessions held at least 1 month apart. In each session, as outcome variables, patients underwent the Unified Parkinson's Disease Rating Scale (UPDRS III and IV) and cognitive testing before treatment (baseline), when treatment ended on day 5 (T1), 1 week later (T2), and then 4 weeks later (T3), at the same time each day. After patients received anodal cerebellar tDCS and M1-tDCS for five days, the UPDRS IV (dyskinesias section) improved (p < 0.001). Conversely, sham tDCS, cerebellar tDCS, and M1-tDCS left the other variables studied unchanged (p > 0.05). Despite the small sample size, our preliminary results show that anodal tDCS applied for five consecutive days over the motor cortical areas and cerebellum improves parkinsonian patients' levodopa-induced dyskinesias.

Vascular risk factors have been associated with cognitive deficits and incident dementia in the general population, but their role on cognitive dysfunction in Parkinson's disease (PD) is still unclear. The present study addresses the single and cumulative effect of vascular risk factors on cognition in PD patients, taking clinical confounders into account. Standardized neuropsychological assessment was performed in 238 consecutive PD patients. We evaluated the association of single and cumulative vascular risk factors (smoking, diabetes, hypercholesterolemia, hypertension, and heart disease), with the diagnosis of PD normal cognition (PDNC, n = 94), mild cognitive impairment (PD-MCI, n = 111), and dementia (PDD, n = 33). The association between single neuropsychological tests and vascular risk factors was evaluated with covariance analyses adjusted for age at onset, educational levels, gender, disease duration, and motor performance. Age, educational levels, disease duration, and motor function were significantly different between PDNC, PD-MCI, and PDD. Heart disease was the only vascular factor significantly more prevalent in PDD compared with PDNC in adjusted analyses. Performance of tests assessing executive and attention functions were significantly worse in patients with hypertension, heart disease, and/or diabetes (p <  0.05). Heart disease is associated with dementia in PD, suggesting a potential window of intervention. Vascular risk factors act especially on attention and executive functions in PD. Vascular risk stratification may be useful in order to identify PD patients with a greater risk of developing dementia. These findings need to be verified in longitudinal studies.

Introduction: Dementia with Lewy Bodies (DLB) and Parkinson's disease with Dementia (PDD) are neurodegenerative disorders with complex clinical picture (parkinsonism, cognitive decline and neuropsychiatric disturbances). The conundrum of whether DLB and PDD represent the same or different entities is still under debate. Advanced neuroimaging techniques may represent a point of view to assess brain correlates in DLB and PDD. The study aimed at evaluating whether DLB and PDD may be labelled under the same disease entity or be considered distinctive pathologies. We compared DLB and PDD patients by assessing structural and functional brain imaging and including PD patients., Methods: Patients with diagnosis of PD, PDD, DLB and a group of healthy controls for neuroimaging comparisons were recruited and changes in structural and resting-state functional MR (Regional Homogeneity, ReHo) were studied., Results: No significant atrophy in VBM analysis was evident in PD. Conversely, PDD showed a significant bilateral frontal atrophy, whereas DLB was characterized by a predominant parietal, occipital atrophy; a similar involvement of subcortical regions in PDD and DLB was observed. ReHo demonstrated reduced local coherence of frontal regions in PD and in PDD, whereas DLB patients presented a reduced local connectivity in posterior regions., Conclusion: Different brain areas are specifically involved in PDD and DLB. In the former group, greater atrophy of frontal regions with concomitant functional connectivity impairment was evident; conversely, structural and functional damage in the posterior regions characterized DLB. Despite an overlapping clinical spectrum, DLB and PDD have different networks involved and different underlying pathogenic pathways., (Copyright © 2015 Elsevier Ltd. All rights reserved.)