A semi-quantitative sport-specific assessment of recurrent traumatic brain injury: the TraQ questionnaire and its application in American football.

Chronic traumatic encephalopathy (CTE) is very frequent and studied among contact sport players, above all American Football. Now, the defined diagnosis is only post-mortem and, consequently, more detailed diagnostic in-vivo instruments are needed to facilitate diagnosis and to allow a follow up. This clinical questionnaire (Trauma Questionnaire-TraQ) has been designed to investigate in parallel the traumatic load and clinical and cognitive subjective symptoms. It evaluates 4 anamnestic fields (specific sport activity, all previous pathological events, clinical manifestations compatible with TBI (traumatic brain injury) or CTE and subjective perception of personal memory efficacy with PRMQ questionnaire). The aim of TraQ questionnaire is to allow a standardized follow-up of active players and to identify subclinical disturbances that may become warnings. A pilot comparative study with TraQ on 105 subjects (75 AF players and 30 comparable people without a history of contact-sports activity) revealed that AF players have an increased amount of severe head trauma, an amplified level of subjective aggressiveness, more olfactory deficits but also more speech subjective problems, previously never related with CTE. In view of the obtained results, the TraQ seems to be useful (1) to obtain a better quantification of the traumatic load; (2) to differentiate the risk of long-term neurological consequences, allowing better management of different athletes right from the pre-symptomatic phases; (3) to manage prevention strategies if regularly applied to periodic visits to sports fitness; and (4) to identify the predisposing factors for the development of CTE and other neurological consequences of TBI with follow-up studies.

Free and cued selective reminding test predicts progression to Alzheimer's disease in people with mild cognitive impairment.

INTRODUCTION: To assess the diagnostic accuracy of the free and cued selective reminding test (FCSRT) for the development of Alzheimer's disease (AD) in people with mild cognitive impairment (MCI). METHODS: We enrolled 187 consecutive MCI outpatients from a memory clinic that were evaluated at baseline and every 6 to 12 months through an extensive clinical and neuropsychological protocol. For each test, measures of diagnostic accuracy were obtained. To improve the overall specificity of the neuropsychological battery, we also used the diagnostic tests in parallel combination. The association between FCSRT indexes and AD was tested through proportional hazard regression models with other dementia subtypes as competing event. Laplace regression was used to model time-to-AD diagnosis as a function of FCSRT indexes. RESULTS: The area under the curve of the FCSRT indexes ranged from 0.69 (95% CI: 0.62-0.76) to 0.76 (95% CI: 0.70-0.82). The specificity peaked up to 100% when we combined the category fluency test with the delayed total recall index of the FCSRT. Participants who tested positive at the FCSRT, as compared with those with negative tests, presented a twofold to fivefold higher risk of developing AD (median follow-up time 2.5 years; p < 0.001) and were diagnosed with AD 2-3 years earlier (p < 0.001). DISCUSSION: The FCSRT assessment suite shows the best predictive performance in detecting AD in people with MCI. These findings might help to reliably and timely identify people at higher risk of AD that is crucial both for properly selecting participants to clinical trials and to fine tune an effective and patient-centered care.

Living Alone and Dementia Incidence: A Clinical-Based Study in People With Mild Cognitive Impairment.

INTRODUCTION: Social isolation and living alone have been associated with negative outcomes, especially in the older population. We aim to investigate the effect of living alone on the development of dementia in people with mild cognitive impairment (MCI). MATERIALS AND METHODS: In this longitudinal study, we enrolled 345 outpatients with MCI evaluated at baseline through a clinical and neuropsychological protocol. Data on living situation (living alone vs. living with someone) were also collected. The development of dementia at follow-up was the outcome of the study. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox regression analyses. Laplace regression was used to model the time-to-dementia diagnosis as a function of living situation. RESULTS: During the follow-up time (mean [SD]: 2.8 [2.2] years), 172 (50%) participants developed dementia. After controlling for age, sex, years of education, MCI subtype, presence of comorbidities, and antidepressant therapy, people with MCI living alone were more likely to develop dementia (HR: 1.5; 95% CI: 1.1-2.1), when compared to those living with someone. In addition, participants with MCI living alone were diagnosed with dementia 1 year earlier than those living with someone ( P = .012). CONCLUSION: Living alone increases by 50% the risk of developing dementia and anticipates by 1 year the diagnosis in people with MCI. These results, in line with findings of previous population-based studies, emphasize the pivotal role of the living situation in identifying a frailer share of the population at higher risk of dementia to which devote ad hoc assessment and care.

The LRRK2 Variant E193K Prevents Mitochondrial Fission Upon MPP+ Treatment by Altering LRRK2 Binding to DRP1.

Mutations in leucine-rich repeat kinase 2 gene (LRRK2) are associated with familial and sporadic Parkinson's disease (PD). LRRK2 is a complex protein that consists of multiple domains, including 13 putative armadillo-type repeats at the N-terminus. In this study, we analyzed the functional and molecular consequences of a novel variant, E193K, identified in an Italian family. E193K substitution does not influence LRRK2 kinase activity. Instead it affects LRRK2 biochemical properties, such as phosphorylation at Ser935 and affinity for 14-3-3ε. Primary fibroblasts obtained from an E193K carrier demonstrated increased cellular toxicity and abnormal mitochondrial fission upon 1-methyl-4-phenylpyridinium treatment. We found that E193K alters LRRK2 binding to DRP1, a crucial mediator of mitochondrial fission. Our data support a role for LRRK2 as a scaffolding protein influencing mitochondrial fission.

Self-Awareness for Memory Impairment in Amnestic Mild Cognitive Impairment: A Longitudinal Study.

AIM: To assess memory impairment insight as a predictor of dementia and Alzheimer's disease (AD) in amnestic mild cognitive impairment (MCI). METHODS: To verify whether the awareness of memory impairment assessed by Geriatric Depression Scale (GDS) was associated with the risk of progression to dementia and AD in a cohort of MCI, we used a Cox regression model adjusted for age, sex, education, subtypes of amnestic MCI, Mini-Mental State Examination, Cumulative Illness Rating Scale severity index, and apolipoprotein E genotype. RESULTS: During a follow-up of 27.7 (20.8) months, 205 (63.3%) of 324 patients with amnestic MCI progressed to dementia, including 141 to AD. No association was found in the unadjusted, partially adjusted (for sociodemographic variables), and fully adjusted multivariate Cox analysis between the awareness of memory impairment and the progression to dementia and AD. DISCUSSION: Awareness or anosognosia of memory deficits, identified by GDS, is not useful to predict progression to dementia of patients with amnestic MCI.

Efficacy of rasagiline and selegiline in Parkinson's disease: a head-to-head 3-year retrospective case-control study.

Monoamine oxidase type B (MAO-B) inhibitors, such as selegiline and rasagiline, can be used as monotherapy or adjuvant therapy to levodopa in Parkinson's disease (PD). Data on long-term efficacy of MAO-B inhibitors are limited with no head-to-head comparison available to date. The aim of this case-control retrospective study was to analyze data from patients with PD attending the Parkinson Institute (Milan, Italy) over a 6-year period (2009-2015) and compare the effects of selegiline and rasagiline on levodopa treatment outcomes. Patients with PD treated with either selegiline (n = 85) or rasagiline (n = 85) for 3 years as well as a control group of patients (N = 170) who have never received MAO-B inhibitors, were matched for gender, disease duration (±1 year) and age (±1 year) at baseline assessment (ratio 1:1:2). The Unified PD Rating Scale and the Hoehn-Yahr staging system were used for clinical comparisons. At baseline, mean PD duration was 6.5 years and clinical features were comparable across all three groups. After a mean follow-up of approximately 37 months, no differences in clinical progression of motor and non-motor symptoms were observed between the three groups. However, MAO-B inhibitor use was associated with ~2-fold lower change in daily dose of levodopa (p < 0.001) and lower dyskinesia scores (p = 0.028) than non-users. No intra-class differences were observed between selegiline and rasagiline. Long-term use of MAO-B inhibitors resulted in a significant reduction in levodopa requirements and a lower frequency of dyskinesias in patients with PD. Selegiline and rasagiline had equal efficacy in controlling motor symptoms in PD patients on optimized therapy.

Nutritional status and body composition by bioelectrical impedance vector analysis: A cross sectional study in mild cognitive impairment and Alzheimer's disease.

AIMS: Analysis of nutritional status and body composition in Alzheimer's disease (AD) and Mild Cognitive Impairment (MCI). METHODS: A cross-sectional study was performed in a University-Hospital setting, recruiting 59 patients with AD, 34 subjects with MCI and 58 elderly healthy controls (HC). Nutritional status was assessed by anthropometric parameters (body mass index; calf, upper arm and waist circumferences), Mini Nutritional Assessment (MNA) and body composition by bioelectrical impedance vector analysis (BIVA). Variables were analyzed by analysis of variance and subjects were grouped by cognitive status and gender. RESULTS: Sociodemographic variables did not differ among the three groups (AD, MCI and HC), except for females' age, which was therefore used as covariate in a general linear multivariate model. MNA score was significantly lower in AD patients than in HC; MCI subjects achieved intermediate scores. AD patients (both sexes) had significantly (p<0.05) higher height-normalized impedance values and lower phase angles (body cell mass) compared with HC; a higher ratio of impedance to height was found in men with MCI with respect to HC. With BIVA method, MCI subjects showed a significant displacement on the RXc graph on the right side indicating lower soft tissues (Hotelling's T2 test: men = 10.6; women = 7.9;p < 0,05) just like AD patients (Hotelling's T2 test: men = 18.2; women = 16.9; p<0,001). CONCLUSION: Bioelectrical parameters significantly differ from MCI and AD to HC; MCI showed an intermediate pattern between AD and HC. Longitudinal studies are required to investigate if BIVA could reflect early AD-changes in body composition in subjects with MCI.

Construct validity of the Free and Cued Selective Reminding Test in older adults with memory complaints.

INTRODUCTION: The Free and Cued Selective Reminding Test (FCSRT) is the memory test recommended by the International Working Group on Alzheimer's disease (AD) for the detection of amnestic syndrome of the medial temporal type in prodromal AD. Assessing the construct validity and internal consistency of the Italian version of the FCSRT is thus crucial. METHODS: The FCSRT was administered to 338 community-dwelling participants with memory complaints (57% females, age 74.5 ± 7.7 years), including 34 with AD, 203 with Mild Cognitive Impairment, and 101 with Subjective Memory Impairment. Internal Consistency was estimated using Cronbach's alpha coefficient. To assess convergent validity, five FCSRT scores (Immediate Free Recall, Immediate Total Recall, Delayed Free Recall, Delayed Total Recall, and Index of Sensitivity of Cueing) were correlated with three well-validated memory tests: Story Recall, Rey Auditory Verbal Learning test, and Rey Complex Figure (RCF) recall (partial correlation analysis). To assess divergent validity, a principal component analysis (an exploratory factor analysis) was performed including, in addition to the above-mentioned memory tasks, the following tests: Word Fluencies, RCF copy, Clock Drawing Test, Trail Making Test, Frontal Assessment Battery, Raven Coloured Progressive Matrices, and Stroop Colour-Word Test. RESULTS: Cronbach's alpha coefficients for immediate recalls (IFR and ITR) and delayed recalls (DFR and DTR) were, respectively, .84 and .81. All FCSRT scores were highly correlated with those of the three well-validated memory tests. The factor analysis showed that the FCSRT does not load on the factors saturated by non-memory tests. CONCLUSIONS: These findings indicate that the FCSRT has a good internal consistency and has an excellent construct validity as an episodic memory measure.

Sleep, headaches and cerebral energy control: a synoptic view.

INTRODUCTION: The amount of cerebral functions is particularly elevated. This intense activity requires a great expenditure of energy: the restoration of energy is the fundamental function of sleep whilst the slowdown in energy consumption may be considered the physiological effect of primary headaches. The continuous interaction of sleep and primary headaches is possible as they share many anatomical and functional cerebral systems. Areas covered: This review describes how sleep and headaches are reciprocally involved in preservation and restoration of brain energy. Data were obtained from the most relevant and recent works available in PubMed about this topic. Expert commentary: The energetic view of sleep, primary headaches and their relationship may have relevant clinical consequences: the investigation and the modification of the multiple aspects, primarily environmental, that may influence sleep and headache, become mandatory to facilitate the cerebral energy preservation by reducing its consumption and by ensuring its recovery.

Survival and dementia in GBA-associated Parkinson's disease: The mutation matters.

OBJECTIVE: The objective of this work was to investigate survival, dementia, and genotype-phenotype correlations in patients with Parkinson's disease (PD) with and without mutations on the glucocerebrosidase gene (GBA). METHODS: We included 2,764 unrelated consecutive PD patients: 123 GBA carriers (67 mild-p.N370S and 56 severe mainly p.L444P) and 2,641 noncarriers. Brain perfusion and dopamine transporter imaging was analyzed, including dementia with Lewy Bodies (DLB) as an additional control group. RESULTS: Multivariable analysis adjusted by sex, age at onset, and disease duration attributed to GBA carriers a greater risk for dementia (hazard ratio [HR] = 3.16; p < 0.001) and death (HR = 1.85; p = 0.002) than noncarriers. When dementia was introduced in the model as a time-dependent covariate, the mortality risk remained greater in carriers (HR = 1.65; p = 0.016), suggesting that other clinical features are likely to contribute to reduced survival. At last examination, GBA carriers had worse motor symptoms, particularly nondopaminergic features. Carriers of severe mutations had greater risk for dementia compared to mild mutations (p < 0.001), but similar mortality risk. Consistent with clinical data, GBA carriers showed reduced posterior parietal and occipital cortical synaptic activity and nigrostriatal function than PD noncarriers. Neuroimaging features of carriers of mild mutations overlapped with PD noncarriers, whereas carriers of severe mutations were closer to DLB. INTERPRETATION: Survival is reduced in GBA carriers compared to noncarriers; this seems to be partially independent from the increased risk for early dementia. The risk for dementia is strongly modulated by type of mutation. In the clinical continuum between PD and DLB, patients with GBA mutations seem to localize midway, with carriers of severe mutations closer to DLB than to idiopathic PD. Ann Neurol 2016;80:662-673.

Spontaneous Reversion of Mild Cognitive Impairment to Normal Cognition: A Systematic Review of Literature and Meta-Analysis.

OBJECTIVES: The issue of subjects with mild cognitive impairment (MCI) reverting to normal cognition (NC) has to date been taken in limited consideration, and no conclusive data are available on the rate of reversion. We aimed at systematically reviewing available longitudinal studies on MCI and meta-analyzing data with the purpose of estimating the proportion of subjects reverting to NC. DESIGN: We performed a systematic bibliographic search on PubMed, the Cochrane Library, and the ISI Web of Science databases. We included in the review all longitudinal studies on MCI published from 1999 up to November 2015. Only studies with a longitudinal design, a follow-up ≥2 years, enrolling subjects with MCI, and reporting the number or the percentage of subjects reverting to NC were included. Data extraction was performed independently by 2 authors. The methodological quality of studies was also assessed by 2 independent authors using the QUIPS tool. RESULTS: Twenty-five studies were included. The quality of evidence was found to be moderate. We observed an overall 18% (95% CI 14-22) reversion rate from MCI to NC. Results from the metaregression showed a significant association between effect size and study setting. In particular, estimates significantly varied according to study setting, with an 8% (95% CI 4-11) reversion rate in clinical-based studies and a 25% (95% CI 19-30) rate in population-based studies. The frequency of reversion from MCI to NC further increased to 26% when considering only studies of better quality. Only a few studies were designed to specifically investigate the reversion from MCI to NC, thus relevant information on this topic was frequently missing. CONCLUSION: Our data confirm that reversion to normality is a common outcome in subjects with MCI, thus leading to recommend a more balanced view when approaching the construct of MCI both in a clinical and in a research setting.

Brain plasticity and migraine transformation: fMRI evidences.

INTRODUCTION: Chronification transforms episodic migraine into the pathologic chronic form. Biological characteristics of the migrainous brain progressively change, in predisposed subjects, under the repetition of external and internal stimuli. Modifications involve neurons, synapses, neurotransmitters, receptors, connectivity and pain control. f-MRI is a promising way to explore the still unclear biology of this progression. Areas covered: Data included were obtained from the most relevant and updated works available on PubMed about this topic. We summarized the pathophysiology of migraine chronification and of brain plasticity, and we described the different fMRI techniques and their main evidences about migraine transformation. Expert commentary: Functional-MRI has revealed many aspects regarding the peculiarity of the migrainous brain and its tendency toward chronicity but a series of questions are still open: What are the hallmarks of the predisposition to chronification? Which elements are the cause and which the consequence of this process?

Body Mass Index Predicts Progression of Mild Cognitive Impairment to Dementia.

AIMS: To examine the relationship between body mass index (BMI) and progression to dementia and Alzheimer's disease (AD) in mild cognitive impairment (MCI). MATERIALS AND METHODS: Two hundred and twenty-eight MCI subjects (mean age 74.04 ± 6.94 years; 57% female) from a memory clinic were followed for 2.40 ± 1.58 years. Baseline height and weight were used to calculate the BMI. The main outcome was progression to dementia (DSM-IV criteria) and AD (NINCDS-ADRDA criteria). Cox proportional hazard models were used to assess the longitudinal association of BMI with dementia and AD, adjusting for a comprehensive set of covariates, including vascular risk factors/diseases and neuroimaging profiles. RESULTS: Out of 228 subjects with MCI, 117 (51.3%) progressed to dementia. Eighty-nine (76%) of the incident dementia cases had AD. In both unadjusted and multi-adjusted models, a higher BMI was associated with a reduced risk of dementia (multi-adjusted HR 0.9; 95% CI 0.8-0.9) and AD (multi-adjusted HR 0.9; 95% CI 0.8-0.9). Being underweight increased the risk of all types of dementia (multi-adjusted HR 2.5; 95% CI 1.2-5.1) but was not specifically associated with AD (multi-adjusted HR 2.2; 95% CI 0.9-5.3). CONCLUSIONS: BMI predicted progression of MCI to dementia and AD. In particular, a higher BMI was associated with a lower risk of dementia and AD, and underweight was associated with a higher risk of dementia. BMI assessment may improve the prognostic accuracy of MCI in clinical practice.