A systematic review on the risk of neurodegenerative diseases and neurocognitive disorders in professional and varsity athletes.

OBJECTIVE: The aim of this systematic review (SR) was to gather all available epidemiological evidence on former participation in any type of sport, at a professional and varsity level, as a potential risk factor for neurodegenerative diseases (NDs) and neurocognitive disorders (NCDs). DESIGN: Systematic searches were performed on PubMed, the Cochrane databases, and the ISI Web of Knowledge databases. Included studies were assessed using the NOS checklist. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: All epidemiological studies reporting data on the possible association between a clinical diagnosis of amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND), dementia or mild cognitive impairment (MCI), Parkinson's disease (PD), chronic traumatic encephalopathy (CTE) at any stage and with any clinical pattern and the former participation in any types of sport at a varsity and professional level were included. RESULTS: Data from the 17 included studies showed a higher frequency of NDs and NCDs in former soccer and American football players. Updating the previous SR confirmed a higher frequency of ALS/MND in former soccer players. Data reported a significantly higher risk of dementia/AD in former soccer players, and of MCI in former American football players. Results also showed a significantly higher risk of PD in former soccer and American football players, and a significantly higher risk of CTE in former boxers and American football players. This SR confirmed a higher risk of NDs and NCDs in former professional/varsity athletes. However, the pathological mechanisms underlying this association remain unclear, and further high-quality studies should be performed to clarify whether the association could be sport specific.

A systematic review on drugs for synaptic plasticity in the treatment of dementia.

The aim of the present systematic review (SR) was to provide an overview of all published and unpublished clinical trials investigating the safety and efficacy of disease-modifying drugs targeting synaptic plasticity in dementia. Searches on CT.gov and EuCT identified 27 trials (4 phase-1, 1 phase-1/2, 18 phase-2, 1 phase-2/3, 1 phase-3, 1 phase-4, and 1 not reported). Twenty of them completed, and seven are currently active or enrolling. The structured bibliographic searches yielded 3585 records. A total of 12 studies were selected on Levetiracetam, Masitinib, Saracatinib, BI 40930, Bryostatin 1, PF-04447943 and Edonerpic drugs. We used RoB tool for quality analysis of randomized studies. Efficacy was assessed as a primary outcome in all studies except one and the main scale used was ADAS-Cog (7 studies), MMSE and CDR (4 studies). Safety and tolerability were reported in eleven studies. The incidence of SAEs was similar between treatment and placebo. At the moment, only one molecule reached phase-3. This could suggest that research on these drugs is still preliminary. Of all, three studies reported promising results on Levetiracetam, Bryostatin 1 and Masitinib.

Overtreating Alzheimer's Disease.

The management of frailty in older persons is not easy, implying interventions beyond the simple prescription of medications. Biological complexity, multimorbidity, polypharmacy, and social issues often hamper the possibility to directly translate the evidence coming from research into clinical practice. Frailty indeed represents the most relevant cause of the "evidence-based medicine issue" influencing clinical decisions in geriatric care. Today, patients with Alzheimer's disease (AD) are much older and frailer than some decades ago. They also tend to have more drugs prescribed. In parallel, research on AD has evolved over the years, hypothesizing that anticipating the interventions to the earliest stages of the disease may provide beneficial effects (to date, still lacking). In this article, we argue that, by focusing exclusively on "the disease" and pushing to anticipate its detection (sometimes even before the appareance of its clinical manifestations) may overshadow the person's values and priorities. Research should be developed for better integrating the concept of aging and frailty in the design of clinical trials in order to provide results that can be implemented in real life. On the other hand, clinicians should be less prone to the easy (but unsupported by evidence) pharmacological prescription.

Ongoing Research Protocols for the Pharmacological Treatment of Neuropsychiatric Symptoms in Dementia.

The implementation of effective interventions for neuropsychiatric symptoms (NPS) is perceived as one of the most pressing research priorities in the field of dementia and one of the main unmet needs from the perspective of affected individuals and their caregivers and relatives. Nevertheless, to date, only a relatively marginal part of dementia research has focused on NPS. This study aimed to describe and discuss the state of the art concerning the identification and development of new pharmacological treatments for NPS in dementia. A review of 320 ongoing phase 1, 2, 3, and 4 protocols registered in the clinicaltrials.gov database was performed. All the trials enrolling patients with dementia were selected. Only studies adopting clinical measures of NPS frequency and/or severity as primary outcome were retained and analyzed. Overall, only a minority of ongoing phase 1, 2, 3 and 4 protocols on dementia (i.e., 9.0%) is primarily targeting NPS. Most of these studies are adopting a placebo-controlled parallel assignment design, testing oral compounds, and targeting specific NPS (mostly agitation and/or aggression). A total of 3,445 subjects with dementia will tentatively be recruited in these trials. The methodologies adopted in these studies, the characteristics of the tested interventions, the eligibility criteria, and the operational definitions of NPS are presented and discussed. The relevance of NPS is not yet matched by an adequate research effort. The current tendency at privileging disease-modifying approaches and other symptoms of dementia and the methodological complexity of studying NPS are still substantially contributing to the gap between research activities and clinical needs.

Evaluation of physiotherapy and speech therapy treatment in patients with apraxia: a systematic review and meta-analysis.

Apraxia affects 20% of the right brain-damaged patients and 50% of the left brain-damaged patients. This disorder of motor programming reduces patients' independence and there are few guidelines on the rehabilitative treatment in the physiotherapy and speech therapy field.The aim of this study was to assess which therapeutic interventions are the most effective in stroke patients with apraxia in considering the mentioned purviews. Four databases were systematically searched in order to detect all available studies investigating the physical and speech rehabilitation of patients. The literature research produced five studies including 168 patients for the physiotherapy and 50 for speech therapy fields; two were eligible for meta-analysis. Quality was rated with Jadad, PEDro scale and Cochrane Risk Of Bias Tool. Both for physiotherapy and speech therapy fields, the RCTs interventions obtained statistically significant results for outcomes of interest. Despite this, it is still not possible to determine the best approach due to the low number of patients involved, the lack of maintenance of the results at follow up and the timing of the revaluation period being very short to confirm the efficacy of treatments.

Estimating dementia cases amongst migrants living in Europe.

BACKGROUND AND PURPOSE: The phenomenon of dementia amongst migrants and ethnic minorities represents an emerging concern for European healthcare systems, posing additional challenges in terms of clinical approach, access to care and resource utilization. The aim of the present study was to estimate the cases of dementia amongst immigrant older subjects living in Europe and in each European country. METHODS: The estimated cases of dementia amongst older (i.e. 65+) migrants living in the European Union (EU-28) and European Free Trade Association member states were calculated by multiplying the number of migrants (obtained through the data provided by Eurostat) with the age- and sex-specific prevalence rates (derived by a recent meta-analysis). RESULTS: Overall, 6 507 360 older migrants lived in Europe in 2017. In addition, 1 204 671 migrants were registered in Germany in 2010. Nearly 475 000 dementia cases (329 028 women, 147 410 men) were estimated in this population by applying age- and sex-specific prevalence rates. When considering each European country, the number of estimated cases ranged from 108 (Iceland) to 119 161 (France). In parallel, the proportion of dementia cases occurring in migrants ranged from 0.9% (Czech Republic) to 51.2% (Liechtenstein). CONCLUSIONS: The issue of dementia in migrants and ethnic minorities is emerging but already relevant for European healthcare systems. The magnitude of this phenomenon and its complexities reinforce the need for coordinated initiatives both at a national and continental level. These epidemiological data should ideally be integrated with those coming from 'real world' services in order to better calibrate these actions.

Intercepting Parkinson disease non-motor subtypes: A proof-of-principle study in a clinical setting.

The construct of non-motor symptoms (NMS) subtyping in Parkinson Disease (PD) is emerging as a line of research in the light of its potential role in etiopathological interpretation of PD heterogeneity. Different approaches of NMS subtyping have been proposed: an anatomical model suggests that NMS aggregate according to the underpinning pathology; other researchers find aggregation of NMS according to the motor phenotype; the contribution of genetic background to NMS has also been assessed, primarily focusing on cognitive impairment. We have analyzed NMS burden assessed through an extensive clinical and neuropsychological battery in 137 consecutive non-demented PD patients genotyped for MAPT haplotypes (H1/H1 vs H2 carriers) in order to explore the applicability of the "anatomo-clinical", "motor" or "genetic" models for subtyping PD in a clinical setting; a subsequent independent analysis was conducted to verify a possible cluster distribution of NMS. No clear-cut NMS profiles according to the previously described models emerged: in our population, the autonomic dysfunctions and depressive symptoms represent the leading determinant of NMS clusters, which seems to better fit with the hypothesis of a "neurotransmitter-based" model. Selective preferential neurotransmitter network dysfunctions may account for heterogeneity of PD and could address translational research.

Socioeconomic disparities in clinical trials on Alzheimer's disease: a systematic review.

BACKGROUND AND PURPOSE: There is now a wide consensus at recognizing social and economic circumstances as main determinants of an individual's health status. Nevertheless, characteristics relating to socioeconomic status (SES) are poorly described in research reports. The aim of the present review was to verify whether the SES of participants is adequately reported in interventional studies targeting Alzheimer's disease (AD), and to explore the impact of SES proxy measures on the efficacy of the considered medications. METHODS: A systematic review of available randomized controlled trials (RCTs) on the currently marketed drugs for AD (i.e. cholinesterase inhibitors and memantine) was conducted by performing a structured search on PubMed and the Cochrane databases. The following indicators of SES were considered in the retained studies: (i) educational level, (ii) lifetime job category, (iii) income and (iv) wealth. The study quality was assessed using the Cochrane Risk of Bias Tool for Randomized Controlled Trials. RESULTS: A total of 48 articles were finally selected. Overall, only eight RCTs reported data concerning the four considered SES indicators. Indeed, only information pertaining to the educational level of participants was provided. Only one RCT (n = 60) performed ad hoc, secondary analyses accounting for the SES of participating subjects. CONCLUSIONS: The research and clinical relevance of SES has mistakenly been overlooked by the vast majority of RCTs on AD. A greater effort should be made to collect and report data on those SES indicators that may significantly affect the clinical manifestations and trajectories of patients with cognitive disturbances.

Establishment of an Italian chronic migraine database: a multicenter pilot study.

To optimize chronic migraine (CM) ascertainment and phenotype definition, provide adequate clinical management and health care procedures, and rationalize economic resources allocation, we performed an exploratory multicenter pilot study aimed at establishing a CM database, the first step for developing a future Italian CM registry. We enrolled 63 consecutive CM patients in four tertiary headache centers screened with face-to-face interviews using an ad hoc dedicated semi-structured questionnaire gathering detailed information on life-style, behavioral and socio-demographic factors, comorbidities, and migraine features before and after chronicization and healthcare resource use. Our pilot study provided useful insights revealing that CM patients (1) presented in most cases symptoms of peripheral trigeminal sensitization, a relatively unexpected feature which could be useful to unravel different CM endophenotypes and to predict trigeminal-targeted treatments' responsiveness; (2) had been frequently admitted to emergency departments; (3) had undergone, sometime repeatedly, unnecessary or inappropriate investigations; (4) got rarely illness benefit exemption or disability allowance only. We deem that the expansion of the database-shortly including many other Italian headache centers-will contribute to more precisely outline CM endophenotypes, hence improving management, treatment, and economic resource allocation, ultimately reducing CM burden on both patients and health system.

Adaptation and psychometric properties of the Italian version of the Non-Motor Symptoms Questionnaire for Parkinson's disease.

Although non-motor symptoms (NMS) of Parkinson's disease (PD) are very common also in early stages of the disease, they are still under-recognized. Screening tools for non-motor symptoms, such as non-motor symptoms questionnaire (NMSQuest), help clinicians to recognize NMS and to evaluate if patients could require further assessment or specific treatments. To validate an adapted Italian version of NMSQuest and study its psychometric properties, Italian PD patients self-completed Italian NMSQuest, and then underwent a standard clinical evaluation including motor assessment (by Hoehn and Yahr staging, unified Parkinson's disease rating scale part III) and non-motor assessment (by Montreal cognitive assessment, Beck depression inventory, neuropsychiatric inventory, Epworth sleepiness scale, scale for outcomes in Parkinson's disease-Autonomic and movement disorder society-sponsored revision of the unified Parkinson's disease rating scale part I). Somatic comorbidities were quantified using the modified cumulative illness rating scale (CIRS). Seventy-one subjects were assessed (mean age years 69.8 ± 9.6 SD; 31% women; mean duration of disease 6.3 ± 4.6 years; H&Y median 2). Italian NMSQuest showed adequate satisfactory clinimetrics in terms of data quality, precision, acceptability, internal consistency and reliability. A significant correlation was found between NMSQuest and most of non-motor assessment scales, while no significant correlation appeared with motor severity as well as with age of patients, disease duration, levodopa equivalent daily dose, L-DOPA/dopamine agonists assumption and CIRS total score. The Italian version of the NMSQuest resulted as a reliable instrument for screening NMS in Italian PD patients.

Validation of the Italian version of the Non Motor Symptoms Scale for Parkinson's disease.

OBJECTIVE: To validate the adapted Italian version of the Non-Motor Symptoms Scale (NMSS), a tool to assess non-motor symptoms (NMS) in Parkinson's disease (PD). METHODS: A cross cultural adaptation of the NMSS into Italian and a psychometric analysis of the translated version of the NMSS was carried out in patients with PD from two university centres-affiliated hospitals. The quality of data and the acceptability, reliability and construct validity of NMSS were analyzed. The following standard scales were also applied: Hoehn and Yahr staging, Unified Parkinson's Disease Rating Scale (UPDRS) part III, Montreal Cognitive Assessment, Beck Depression Inventory, Neuropsychiatric Inventory, Epworth Sleepiness Scale, Autonomic Scale for Outcomes in Parkinson's disease-Motor, Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale part I and Modified Cumulative Illness Rating Scale (CIRS). Levodopa equivalent daily dose (LEDD) was calculated. RESULTS: Seventy-one patients with PD were assessed (mean age years 69.8 ± 9.6 SD; 31% women; mean length of disease 6.3 ± 4.6 years; H&Y median: 2). Mean NMSS was 39.76 (SD 31.9; skewness 0.95). The total score of NMSS was free of floor or ceiling effects and showed a satisfactory reliability (Cronbach's alpha coefficient on total score was 0.72 [range for domains: 0.64-0.73], SEM value was 3.88 [½ SD = 31.90]). Significant positive correlations were found among total NMSS and other NMS standard tests, but no significant correlation appeared with UPDRS part III, CIRS and LEDD. CONCLUSIONS: The Italian NMSS is a comprehensive and helpful measure for NMS in native Italian patients with PD.

General cognition predicts post-stroke recovery defined through minimal clinically important difference (MCID): a cohort study in an Italian rehabilitation clinic.

BACKGROUND: In the field of rehabilitation it is crucial to define if changes in functional scores correspond to relevant clinical improvements. AIM: To assess whether cognition affects motor recovery in post-stroke patients using a clinical meaningful criterion: the minimal clinically important difference (MCID). DESIGN: Retrospective cohort study. SETTING: Inpatient rehabilitation clinic POPULATION: Two hundred nine first-ever stroke patients undergoing a post-acute inpatient rehabilitation. METHODS: Cognitive status was assessed with the cognitive FIM and the Mini-Mental State Examination (MMSE). The response to the rehabilitation was defined as the achievement of the MCID between admission and discharge in the motor FIM (responder) and both in the motor and in the cognitive FIM (best-responder). RESULTS: Subjects with a baseline higher MMSE>24.9 had a near four-fold higher probability of being responder (OR 3.91; 95% CI 1.72-8.89) and a two-fold higher probability of being best-responder (OR 2.69; 95% CI 1.24-5.84) on motor FIM as compared to those with a MMSE≤24.9. A duration of the rehabilitation of 55-61 days implies a three-fold higher probability (OR 3.17; 95% CI 1.15-8.72) to be responder as compared to shorter period of treatment; a treatment >61 days does not involve a greater probability of response. CONCLUSIONS: This is the first study that examined post-stroke motor recovery mainly in terms of clinical relevance (MCID). Subjects with a higher cognitive level are more likely to achieve a clinically meaningful recovery. CLINICAL REHABILITATION IMPACT: MCID can be applied extensively to post-stroke patients undergoing to an inpatient rehabilitation in order to have a clinically useful instrument that assess the recovery.

Mismatch Negativity in essential tremor: role of age at onset in pre-attentive auditory discrimination.

OBJECTIVE: To investigate whether pre-attentive auditory discrimination is impaired in patients with essential tremor (ET) and to evaluate the role of age at onset in this function. METHODS: Seventeen non-demented patients with ET and seventeen age- and sex-matched healthy controls underwent an EEG recording during a classical auditory MMN paradigm. RESULTS: MMN latency was significantly prolonged in patients with elderly-onset ET (>65 years) (p=0.046), while no differences emerged in either latency or amplitude between young-onset ET patients and controls. CONCLUSIONS: This study represents a tentative indication of a dysfunction of auditory automatic change detection in elderly-onset ET patients, pointing to a selective attentive deficit in this subgroup of ET patients. SIGNIFICANCE: The delay in pre-attentive auditory discrimination, which affects elderly-onset ET patients alone, further supports the hypothesis that ET represents a heterogeneous family of diseases united by tremor; these diseases are characterized by cognitive differences that may range from a disturbance in a selective cognitive function, such as the automatic part of the orienting response, to more widespread and complex cognitive dysfunctions.

Attention in essential tremor: evidence from event-related potentials.

Clinically subtle executive dysfunctions have recently been described in essential tremor (ET), though the presence of attentional deficits is still unclear. We investigated the psychophysiological aspects of attention in ET, using event-related potentials (ERPs). Twenty-one non-demented patients with ET and 21 age- and sex-matched healthy controls underwent a psychophysiological evaluation. P300 components and the Contingent Negative Variation (CNV) were recorded. The latencies and amplitudes of the P3a and P3b subcomponents and CNV areas were evaluated. Possible correlations between clinical parameters and ERP data were investigated. P3a latency was significantly longer in the ET group (p < 0.05), while no differences emerged between patients and controls in P3b latency. No differences were observed between the two groups in the CNV parameters. ET patients display a difficulty in the response to novelty and in the recruitment of prefrontal attentive circuits, while the memory context-updating process appears to be spared. This selective cognitive dysfunction does not appear to interfere with the attentional set linked to the expectancy evaluated during a complex choice-reaction time task, which is preserved in ET. This multitask psychophysiological approach reveals the presence of a peculiar attentional deficit in patients with ET, thus expanding the clinical features of this disease.

Restless legs syndrome in a group of patients with Alzheimer's disease.

BACKGROUND: Restless legs syndrome (RLS) is a neurological disorder characterized by the urge to move the legs associated with peculiar unpleasant sensations during periods of rest and inactivity that are relieved by movement. A few studies analyzed RLS in neurodegenerative diseases such as Alzheimer's Disease (AD). The aim of our study was to assess the prevalence and the clinical characteristics of RLS in a cohort of AD patients. METHODS: Three hundred and thirty-nine subjects with a diagnosis of AD were recruited. Cognitive, functional, and neuropsychiatric measures were collected at baseline and six-monthly for a 2-years follow-up RESULTS: Fourteen subjects met the RLS criteria. RLS subjects were more frequently male (p:0,006) and younger than AD subject without RLS (p:0,029). MMSE, ADL and IADL were not significantly different. NPI total scores did not differ significantly, however, AD patients with RLS were found to be more apathetic (p:0,001) than AD subjects without RLS. CONCLUSION: RLS prevalence in our AD cohort was estimated to be about 4%. RLS appeared to be associated with neuropsychiatric symptoms such as apathy. RLS and apathy might share a common pathophysiological basis represented by a dysfunction of the central dopaminergic system.

Free and Cued Selective Reminding Test: an Italian normative study.

The presence of episodic memory impairment is required for the diagnosis of Alzheimer's dementia by all current diagnostic criteria. The new research criteria proposed by Dubois et al. (Lancet Neurol 6:734-746, 2007) require that the impairment should not improve significantly with cueing, recognition testing nor after the control of effective encoding. This is considered to be the core deficit of "prodromal Alzheimer's disease". The Free and Cued Selective Reminding Test (FCSRT) is a memory test that allows in assessing these specific features of memory impairment. Here, we report normative data for an Italian version of the FCSRT. The test is based on the 12 pictorial stimuli, 6 belonging to the living domain, and 6 to the non-living domain. Six scores were derived from the performance of 227 healthy Italian adults, with age, sex and education homogenously distributed across subgroups: immediate free recall (IFR), immediate total recall (ITR), delayed-free recall (DFR), delayed total recall (DTR), Index of Sensitivity of Cueing (ISC), number of intrusions. In multiple regression analyses, age emerged as an influencing factor for both IFR and DFR, with older people obtaining lower scores. Education and gender appear to influence only IFR, with better performance by more educated subjects and females. Adjusted scores were used to determine inferential cutoff scores and to compute equivalent scores.

Altered oxidative stress profile in the cortex of mice fed an enriched branched-chain amino acids diet: possible link with amyotrophic lateral sclerosis?

Branched-chain amino acids (BCAAs), valine, isoleucine, and leucine, are widely used among athletes as dietary integrators. Although the occurrence of untoward effects of BCCA supplementation, with particular regard to neurological disturbances, cannot be excluded, no specific studies have been performed so far. The aim of this work was to evaluate the effects of a diet enriched in BCAAs on the expression of oxidative stress pathway genes in the brain of C57Bl/6J mice. Animals were fed a standard or a BCAA diet for 95 days starting from postnatal day 21 until sacrifice. BCAA treatment, at doses comparable to human usage, significantly down-regulated the expression of some antioxidant genes, while up-regulating the expression of some oxygen transporters. In conclusion, it appears that BCAAs administered by diet could alter some specific oxidative stress pathways in the brain. Caution should thus be exercised in the widespread use of BCAAs as dietary integrators in sports practice.

A simplified algorithm may lead to overestimate dementia in PD. A clinical and epidemiological study using criteria for PD-D proposed by the Movement Disorders Task Force.

Making an accurate diagnosis of dementia in Parkinson's disease (PD-D) patients is a challenge that neurologists will have to face in the coming years. In 2007, a Task force of the Movement Disorders Society proposed operational diagnostic criteria for the diagnosis of PD-D, consisting of step I and step II. We assessed the validity of step I with reference to the diagnosis made after a formal neuropsychological evaluation and by applying the current gold standard for the diagnosis of PD-D (DSM IV). Step I had a sensitivity of 78% and a specificity of 95.5%. Step I displayed a positive predictive value of 70%, a negative predictive value of 97%, and an accuracy of 93.4%. The clinimetric properties observed in our setting suggest that step I may be considered as a good screening tool (negative predictive value of 97%); however, using step I alone to make a diagnosis of PD-D may lead to an overestimation of dementia in PD, particularly in patients with considerable dysexecutive deficits (positive predictive value of 70%). In conclusion, formal neuropsychology and longitudinal follow-up are still required for the diagnosis and categorization of dementia in PD.