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.

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.

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.

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.

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.

Misidentification Delusions: Prevalence in Different Types of Dementia and Validation of a Structured Questionnaire.

Misidentification delusions (MDs) are considered relatively rare psychopathologic phenomena that may occur within the context of psychiatric or neurological conditions. The purpose of this study was to assess the prevalence of MD in different types of dementia, correlate the presence of MD with demographic and clinical variables, and validate a specific questionnaire. We examined 146 subjects with Alzheimer disease, 21 with Lewy body dementia, 6 with frontotemporal dementia, and 13 with vascular dementia (subcortical type), who were consecutively enrolled in the study from 2 Memory Clinics. Patients had a mean age of 78.7±6.4 years and an Mini-Mental State Examination average score of 16.9±6.1. The Neuropsychiatric Inventory delusion subscale and a new Misidentification Delusion Questionnaire aimed at specific assessment of 11 delusional misidentification syndromes were administrated to the caregivers. On the basis of the Neuropsychiatric Inventory, MDs were present in 33.3% of the subjects, whereas according to the Misidentification Delusion Questionnaire they were present in 36.0% of the subjects. Specifically, 34.2% of Alzheimer disease, 52.4% of Lewy body dementia, and 46.1% of vascular dementia patients experienced at least 1 MD. None of the patients with frontotemporal dementia developed MD. The most frequent MD was house misidentification, followed by splitting of people and reduplicative paramnesia. Our self-administered questionnaire proved to be an accurate and specific tool for the detection of MD.

An exome study of Parkinson's disease in Sardinia, a Mediterranean genetic isolate.

Parkinson's disease (PD) is a common neurodegenerative disorder of complex aetiology. Rare, highly penetrant PD-causing mutations and common risk factors of small effect size have been identified in several genes/loci. However, these mutations and risk factors only explain a fraction of the disease burden, suggesting that additional, substantial genetic determinants remain to be found. Genetically isolated populations offer advantages for dissecting the genetic architecture of complex disorders, such as PD. We performed exome sequencing in 100 unrelated PD patients from Sardinia, a genetic isolate. SNPs absent from dbSNP129 and 1000 Genomes, shared by at least five patients, and of functional effects were genotyped in an independent Sardinian case-control sample (n = 500). Variants associated with PD with nominal p value <0.05 and those with odds ratio (OR) ≥3 were validated by Sanger sequencing and typed in a replication sample of 2965 patients and 2678 controls from Italy, Spain, and Portugal. We identified novel moderately rare variants in several genes, including SCAPER, HYDIN, UBE2H, EZR, MMRN2 and OGFOD1 that were specifically present in PD patients or enriched among them, nominating these as novel candidate risk genes for PD, although no variants achieved genome-wide significance after Bonferroni correction. Our results suggest that the genetic bases of PD are highly heterogeneous, with implications for the design of future large-scale exome or whole-genome analyses of this disease.

Parkinson's disease beyond 20†years.

BACKGROUND: A very limited number of studies report data on the clinical features of Parkinson's disease (PD) 20 years after onset and beyond. OBJECTIVE: To characterise PD 20 years after onset, investigating the impact of age at onset and disease duration on the clinical picture and the predictors of outcomes in patients reaching the 20-year time point. METHODS: We conducted a retrospective, cross-sectional study and a longitudinal study. All case visits of patients with a disease duration ≥20 years (N=401) were stratified by disease duration (20-22, 23-25, ≥26 years) and by age at onset (cut-off, 50 years). Patients with a disease duration of 20-22 years (N=320) were prospectively followed up for a median of 45 months (IQR 23-89) for the new occurrence of fracture, percutaneous endoscopic gastrostomy, institutionalisation, confinement to a wheelchair or bed and death. RESULTS: Older age at onset and longer disease duration were independently associated with a higher prevalence of major motor and non-motor milestones of disease disability (no interaction observed). In the longitudinal study, the most frequent outcomes were death (N=92), confinement to a wheelchair or bed (N=67) and fracture (N=52). Mortality was associated with the gender: male, older age, dysphagia, orthostatic hypotension, postural instability, fractures and institutionalisation. Fracture was associated with postural instability. Predictors of permanent confinement to a wheelchair or bed were older age, postural instability and institutionalisation. Comorbid dementia at the 20-year examination did not predict any of the outcomes. CONCLUSIONS: Age at onset and disease duration are independent determinants of the clinical features of PD beyond 20 years. Non-motor symptoms depend more on age at onset rather than the disease duration itself. Non-levodopa-responsive axial symptoms are the main predictors of all relevant outcomes.

Long-term cognitive follow-up of Parkinson's disease patients with impulse control disorders.

This study investigated cognitive functions in Parkinson's disease (PD) patients with impulse control disorders (ICDs) and aimed to identify possible predictors of behavioral outcome. In this longitudinal cohort study, 40 PD outpatients with ICDs and 40 without, were matched for sex, age at PD onset, age and disease duration at cognitive assessment. All patients had two neuropsychological assessments at least 2 years apart (mean, 3.5 years). Multivariate logistic regression analysis was performed to identify predictors of ICDs remission at follow-up. The PD patients with and without ICDs had overall comparable cognitive performance at baseline. When evaluating changes between baseline and follow-up, we found significant group × time interactions in several frontal lobe-related tests, with the ICDs group showing a less pronounced worsening over time. ICDs remission was associated with better performance at baseline in working memory-related tasks, such as digit span (odds ratio [OR] = 2.69 [95% confidence interval (CI), 1.09-6.66]) and attentive matrices (OR=1.19 [95%CI, 1.03-1.37]). ICDs remitters and non-remitters had no remarkable differences in baseline PD-related features and therapy management strategies (including the extent of dopamine agonist dose reduction). In conclusion, ICDs in PD patients are not related to greater cognitive impairment or executive dysfunction, but rather show relatively lower cognitive decline over time. The impaired top-down inhibitory control characterizing ICDs is likely attributable to a drug-induced overstimulation of relatively preserved prefrontal cognitive functions. Full behavioral remission in the long term was predicted by better working memory abilities. © 2015 International Parkinson and Movement Disorder Society.

Neuroanatomical, Clinical and Cognitive Correlates of Post-Stroke Dysphagia.

BACKGROUND AND PURPOSE: About half of the dysphagic stroke patients have persistent swallowing dysfunction after 7 days from symptom onset. The aim of the study was to evaluate incidence, prognosis, clinical and neuroradiological correlates of post-stroke dysphagia. METHODS: We prospectively examined consecutive patients with acute ischemic or hemorrhagic stroke. Patients' clinical and neuroradiological data were collected. Swallowing function was assessed by the water swallow test upon admission and after 14 days; patients were then classified as persistent dysphagic, non-persistent dysphagic or non-dysphagic. RESULTS: We recruited 275 patients, 121 of whom were dysphagic upon admission and 254 patients attended follow-up at 14 days; 141 never presented dysphagia, 21 had a non-persistent pattern of dysphagia and 92 had a persistent one. Stroke type, leukoaraiosis degree, previous cognitive impairment and stroke severity upon admission independently predicted the occurrence of dysphagia after stroke and its persistence as well. At receiver operating characteristic (ROC) analysis, the National Institutes of Health Stroke Scale (NIHSS) score of 11.5 was the best predictive value of persistent dysphagia, with a specificity of 90.1% and a sensitivity of 72.4%. CONCLUSION: Stroke severity is an important predictor of a persistent pattern of dysphagia, with a suggested NIHSS cutoff value of ≥12. An independent correlation was observed with leukoaraiosis and with previous cognitive impairment.

Dopamine dysregulation syndrome in Parkinson's disease: from clinical and neuropsychological characterisation to management and long-term outcome.

OBJECTIVE: Dopamine dysregulation syndrome (DDS) refers to a compulsive pattern of dopaminergic drug misuse complicating Parkinson's disease (PD). To date, few data are available on DDS risk factors, cognitive profile and long-term outcome. METHODS: In this retrospective case-control study, consecutive PD outpatients fulfilling criteria for DDS were assessed over a 6-year period (2005-2011). They were compared with 70 PD cases matched for age at onset, gender and disease duration, and with 1281 subjects with motor fluctuations and dyskinesias. DDS patients and matched controls underwent extensive neuropsychological assessment. Strategies for DDS patients management and the outcome at the last follow-up visit were recorded. RESULTS: Thirty-five patients with DDS were identified, reporting history of depression, family history of PD and drug abuse, greater difference between 'Off' versus 'On' motor symptoms compared to age-matched controls. They had younger age at onset (but not any gender difference) compared to general PD population. Cognitive profile of DDS did not show major abnormalities, including executive functions. DDS patients have been followed up for 3.2±2.1 years and remission was recorded in 40% of cases. Negative DDS outcome was significantly associated with poor caregiver supervision. Sustained remission occurred more commonly on clozapine and on duodenal levodopa infusion and subthalamic nucleus deep brain stimulation (STN-DBS) than on apomorphine pump treatment. CONCLUSIONS: Clinicians should be aware of risk factors predisposing to DDS. Duodenal levodopa infusion and, less consistently, STN-DBS were more commonly associated with DDS remission. Effective caregiving plays a key role in long-term behavioural outcome.

The SIRT2 polymorphism rs10410544 and risk of Alzheimer's disease in two Caucasian case-control cohorts.

BACKGROUND: Human sirtuins are a current hotspot for research in neurodegenerative disorders, including Alzheimer's disease (AD). This study investigated whether genetic variants in two members of the sirtuin family, SIRT2 and SIRT3, affected AD susceptibility. METHODS: A genetic case-control study was performed, comprising 534 probable AD cases and 638 nondemented control subjects from the north of Italy and Canton Ticino, Switzerland (discovery population). The study was focused on SIRT2 rs10410544, SIRT3 rs4980329, and SIRT3 rs536715 single nucleotide polymorphisms (SNPs). These SNPs were genotyped by real-time polymerase chain reaction allelic discrimination assay or restriction fragment length polymorphism. The SNPs rs7412 and rs429358, mapping within the apolipoprotein E (APOE) gene, were genotyped by real-time polymerase chain reaction allelic discrimination assay too. In a replication population comprising 756 AD cases and 847 nondemented control subjects, SIRT2 rs10410544, APOE rs7412, and APOE rs429358 were genotyped as mentioned previously. RESULTS: In the discovery population, we observed an association between SIRT2 rs10410544 T allele and AD (adjusted odds ratio [OR] = 1.23, 95% confidence interval [CI]: 1.02-1.50, P = .02, after correction for sex, age, and APOE ε4 genotype). The association between AD and SIRT2 rs10410544 T allele was only present in APOE ε4 noncarriers (adjusted OR = 1.29, 95% CI: 1.03-1.61, P = .03). The replication study did not confirm this evidence. However, the combined analysis on the two cohorts detected the association (adjusted OR = 1.17, 95% CI: 1.02-1.35, P = .02), and only APOE ε4 noncarriers were at risk (adjusted OR = 1.2, 95% CI: 1.02-1.43, P = .03). CONCLUSIONS: The SIRT2 rs10410544 T allele deserves further investigation as a novel minor genetic risk factor for AD in the APOE ε4-negative Caucasian population.

Angiogenin variants in Parkinson disease and amyotrophic lateral sclerosis.

OBJECTIVE: Several studies have suggested an increased frequency of variants in the gene encoding angiogenin (ANG) in patients with amyotrophic lateral sclerosis (ALS). Interestingly, a few ALS patients carrying ANG variants also showed signs of Parkinson disease (PD). Furthermore, relatives of ALS patients have an increased risk to develop PD, and the prevalence of concomitant motor neuron disease in PD is higher than expected based on chance occurrence. We therefore investigated whether ANG variants could predispose to both ALS and PD. METHODS: We reviewed all previous studies on ANG in ALS and performed sequence experiments on additional samples, which allowed us to analyze data from 6,471 ALS patients and 7,668 controls from 15 centers (13 from Europe and 2 from the USA). We sequenced DNA samples from 3,146 PD patients from 6 centers (5 from Europe and 1 from the USA). Statistical analysis was performed using the variable threshold test, and the Mantel-Haenszel procedure was used to estimate odds ratios. RESULTS: Analysis of sequence data from 17,258 individuals demonstrated a significantly higher frequency of ANG variants in both ALS and PD patients compared to control subjects (p = 9.3 × 10(-6) for ALS and p = 4.3 × 10(-5) for PD). The odds ratio for any ANG variant in patients versus controls was 9.2 for ALS and 6.7 for PD. INTERPRETATION: The data from this multicenter study demonstrate that there is a strong association between PD, ALS, and ANG variants. ANG is a genetic link between ALS and PD.

Does vascular burden contribute to the progression of mild cognitive impairment to dementia?

AIMS: To investigate the contribution of vascular risk factors (VRFs), vascular diseases (VDs) and white matter lesions (WMLs) to the progression of mild cognitive impairment (MCI) to dementia and Alzheimer's disease (AD). METHODS: Two hundred forty-five consecutive subjects with MCI (age 74.09 ± 6.92 years) were followed for an average of 2.4 years. The Hachinski Ischemic Score and the Framingham Stroke Risk Profile were used to summarize VRFs and VDs. WMLs were graded using the Age-Related White Matter Changes Scale. RESULTS: One hundred twenty-nine (52.6%) out of 245 subjects at risk converted to dementia, including 87 cases of AD. When hypertension occurred in MCI with deep WMLs, a 1.8-fold increased risk of dementia was observed (95% CI = 1.0-3.4). When deep WMLs occurred in MCI with high scores (≥4) on the Hachinski scale, a 3.5-fold (95% CI = 1.6-7.4) and 3.8-fold (95% CI = 1.2-11.5) risk of progression to dementia and AD was observed, respectively. Analogously, the joint effect of WMLs and high scores (≥14) on the Framingham scale nearly doubled the risk of dementia (hazard ratio = 1.9, 95% CI = 1.1-3.3). CONCLUSIONS: Accelerated progression of MCI to dementia and AD is to be expected when VRFs and VDs occur together with WMLs.

Closing-in behavior in mild cognitive impairment: an executive deficit.

This study explored Closing-in behavior (CIB), the tendency in figure copying to draw very close to or on top of the model, in mild cognitive impairment (MCI). The files of 154 people diagnosed with MCI were reviewed and CIB was identified in 21% of cases. Two approaches were used to explore CIB. First, we capitalized on the diverse cognitive profiles within MCI, subdividing the overall sample into people with and without memory deficits. The frequency of CIB was significantly higher in multidomain non-amnestic MCI than in multidomain amnestic MCI, suggesting that CIB is not associated with specific memory impairment. Second, we assessed the cognitive correlates of CIB, by selecting patients with MCI who completed a battery of executive, visuo-constructional and memory tasks. Sub-groups of patients with and without CIB showed a similar overall severity of cognitive decline and comparable performance in visuo-constructional and memory tasks, but those with CIB were slightly but significantly more impaired on executive function tasks. The study provides evidence against memory-based accounts of CIB, and supports recent suggestions that executive impairments are the dominant cognitive correlate of this clinical sign.

Memantine effects on behaviour in moderately severe to severe Alzheimer's disease: a post-marketing surveillance study.

The aim of this study is to evaluate memantine effectiveness on behavioural and psychological symptoms of dementia (BPSD) in clinical practice and to identify variables that may predict the therapy effects. The effects of memantine on behaviour were analysed in the database of a post-marketing surveillance study promoted by the Lombardy Region Health Office and involving 43 Alzheimer's disease (AD) Units. From July to December 2005, 399 moderately severe-to-severe AD patients free of cholinergic medications were enrolled, treated with memantine and followed-up for 6 months. BPSD were assessed in a subgroup of 297 patients [mean age 77 ± 8 years; 73% females; mean neuropsychiatric inventory (NPI) score 28 ± 24] for whom the 12-item NPI subscores at baseline, and at 3 and 6 months were available. The 12 BPSD were clustered as follows: affect, physical behaviour, psychosis and hypomania. The main outcome measure was the proportion of individual cluster responders at 6 months of therapy. The proportion of individual cluster responders was 30% affect, 24% physical behaviour, 29% psychosis, 27% hypomania. Patients taking 20 mg memantine daily during the study period had a statistically significant higher probability to experience behavioural improvement than those who discontinued treatment or did not complete memantine titration (affect OR 9.0; 95% CI 3.8-21.6; physical behaviour OR 17.8; 95% CI 5.9-53.6; psychosis OR 23.6; 95% CI 5.1-110.8). The logistic regression analysis was not applicable to the hypomania subsyndrome because of the low cluster prevalence. The standard 20 mg daily memantine treatment regimen was found to be associated with a modest 6-month behavioural improvement in the affect, physical behaviour and psychosis domains in 24-30% of patients.