Association Between CSF Beta-Amyloid and Apathy in Early-Stage Alzheimer Disease.

AIM: The apathetic syndrome is a common clinical feature in patients with Alzheimer diseases (AD), from preclinical phases to late stages of dementia, and it is strongly related to major disease outcomes. Unfortunately, no specific pharmacological treatments for apathy have been accomplished so far. Translational evidences have previously shown that a link between apathy and hallmarks of AD-related pathophysiology, that is, ß-amyloid (Aß) plaques and neurofibrillary tangles, exists. However, only few studies investigated the association between core biomarkers of AD and apathy scores, finding conflicting results. METHODS: Thirty-seven patients were identified as having AD dementia according to National Institute on Aging-Alzheimer Association 2011 criteria. All participants underwent an extensive diagnostic workup including cerebrospinal fluid (CSF) assessment to measure the concentrations of Aß42, t-tau, and pTau181. To follow, they were stratified as: apathy absence, apathy mild, and apathy severe according to the Neuro Psychiatric Inventory-apathy item scores. We investigated for potential associations between apathy scores and CSF biomarkers concentrations as well as for differences in terms of clinical and CSF biomarkers data across the 3 apathy groups. RESULTS: The CSF Aß42 concentrations were negatively correlated with apathy scores. In addition, patients with severe apathy had significantly lower Aß42 levels compared to nonapathetic ones. CONCLUSION: Based on our results, we encourage further studies to untangle the potential association between the complex pathophysiological dynamics of AD and apathy which may represent an innovative reliable clinical outcome measure to use in clinical trials, investigating treatments with either a symptomatic or a disease-modifying effect.

Oxidative Stress in Cerebral Small Vessel Disease Dizziness Patients, Basally and After Polyphenol Compound Supplementation.

BACKGROUND: Leukoaraiosis (LA) is a common radiological finding in elderly, frequently associated with several clinical disorders, including unexplained dizziness. The pathogenesis of LA is multifactorial, with a dysfunction of cerebral microcirculation resulting in chronic hypoperfusion and tissue loss, with oxidative stress involved in this cascade. OBJECTIVE: The aim of this study was to analyse some oxidative stress biomarkers in a cohort of LA patients. METHOD: Fifty-five consecutive patients (33 males, median age 75 years) with LA were recruited. In a subgroup of 33 patients with LA and unexplained dizziness, we have then performed an open study to evaluate if 60-day supplementation with a polyphenol compound may modify these biomarkers and influence quality of life, analysed with the Dizziness Handicap Inventory (DHI) scale. RESULTS: At baseline, blood oxidative stress parameters values were outside normal ranges and compared to matched healthy controls. After the two months supplementation, we observed a significant decrement of advanced oxidation protein products values and a significant improvement of DHI. CONCLUSION: Oxidative stress biomarkers may be useful to detect redox imbalance in LA and to provide non-invasive tools to monitor disease status and response to therapy.

Brain-Derived Neurotrophic Factor (BDNF) and Serotonin Transporter (SERT) in Platelets of Patients with Mild Huntington's Disease: Relationships with Social Cognition Symptoms.

Deficits in social-cognition processing have been identified during early stages of Huntington Disease (HD), attracting interest on their relevance as possible predictors of  neurodegenerative progression. Since the neurotrophin Brain-Derived Neurotrophic Factor (BDNF) and the serotonin (5-HT) transporter (SERT) are known to modulate human adaptive behavior, we appraised these two proteins in mild-HD using blood platelets, with the aim at finding relationships with cognitive/psychosocial skills. Thirteen gene positive and symptomatic patients (9M/4W, HD-stage II, age> 40y) together 11 gender/age matched controls without a concurrent diagnosis of psychiatric disorders, underwent a blood test to determine BDNF storage and membrane-bound SERT in platelets by an ELISA immune-enzyme dosage and [3H]-paroxetine ([3H]-PAR) binding, respectively. Enrolled subjects were concurrently evaluated through a battery of socio-cognitive tests and emotion recognition questionnaires.Results showed greater intra-platelet BDNF (~ +20-22%) in patients versus controls, whereas equilibrium [3H]-PAR binding parameters, maximum density (Bmax) and dissociation constant (KD), did not appreciably vary in the two comparison groups. Cognitive/emotion abilities were found significantly reduced in patients. Additionally, platelet BDNF was unrelated to psycho-cognitive scores, but positively correlated with the illness duration. As well, SERT Bmax was unconnected to HD signs or socio-cognitive scores, whilst KDs negatively correlated with scores for angry voice recognition in both controls and patients. This pilot study suggests that platelet BDNF and SERT do not specifically underlie psychosocial deficits in stage II-HD, while higher BDNF storage in delayed mild symptoms, would derive from compensatory mechanisms. Supplementary investigations are warranted, by also comparing patients in other illness's phases.

Endothelium and Oxidative Stress: The Pandora's Box of Cerebral (and Non-Only) Small Vessel Disease?

Common cerebral small vessel disease (cSVD) abnormalities are a common neuroradiological finding, especially in the elderly. They are associated with a wide clinical spectrum that leads to an increasing disability, impaired global function outcome and a reduced quality of life. A strong association is demonstrated with age and hypertension and other common vascular risk factors, including diabetes mellitus, dyslipoproteinemia, smoking, low vitamin B12 level, and hyperomocysteinemia. Although these epidemiological associations suggest a systemic involvement, etiopathogenetic mechanisms remain unclear. This review focuses on the potential role of endothelial dysfunction and oxidative stress in the pathogenic cascade leading to cSVD. We stressed on the central role of those pathways, and suggest the importance of quantifying the cerebral (and non-only) "endotheliopathic and oxidative load" and its clinical presentation that could lead to a better determination of vascular risk degree. In addition, understanding underlying pathogenic mechanisms could allow us to slow down the progression of vascular damage and, therefore, prevent the disability due to reiterated microvascular damage.

Epidemiology and cerebrovascular events related to cervical and intracranial arteries dissection: the experience of the city of Pisa.

Spontaneous dissection of cervical arteries (sCAD) is a major cause of ischemic stroke in young patients, with an incidence varying from 1.7 to 3/100,000/year for extracranial internal carotid artery (ICAD) and 1 to 1.9/100,000/year for extracranial vertebral artery (VAD). Reliable epidemiological data on stroke incidence related to sCAD are scarce in Italy. This study aims to evaluate the incidence, clinical features, and outcome of cerebrovascular events related to sCAD and spontaneous intracranial arteries dissections (sIAD) in the city of Pisa (Italy). We retrospectively analyzed consecutive patients admitted between December 1997 and June 2015 with a diagnosis of stroke, TIA, or Bernard-Horner syndrome due to acute cervical or intracranial artery dissection. Considering that our hospital collects presumptively all patients hospitalized with sCAD coming from the referral geographical area, data may provide a good approximation to real incidence of sCAD in our population. Clinical and radiological features, acute treatment and outcome were collected. Seventy-seven cases were included (mean age 48.1±10.4 years, range 23-77,72.7% males), 66 residents in the district of Pisa. Crude incidence rate of cerebrovascular events due to intra or extracranial dissection was 1.88/100,000/year. The incidence of ICAD was 0.80/100,000/year and 0.43/100,000/year for VAD. Stroke occurred in 76.6% of patients. VAD was more prone to cause ischemic stroke and present with cervical pain or focal signs (p < 0.01) than ICAD group, which had older age at onset. sIAD were more frequent in the posterior circle (p = 0.01) and more associated with ischemic lesions. A good outcome (mRS 0-2) was observed in 79% of patients. This is the first epidemiological attempt to investigate impact of sCAD and sIAD in Italy.

Influence of physical exercise on ß-amyloid, α-synuclein and tau accumulation: an in vitro model of oxidative stress in human red blood cells.

A common pathological feature of neurodegenerative disorders (NDs), such as Alzheimer's (AD) and Parkinson's (PD) diseases, is the abnormal accumulation and misfolding of specific proteins, primarily α-synuclein (α-syn), ß-amyloid1-42 (Aß) and tau, in brain and in peripheral tissues too. Oxidative stress has been proved to be involved in NDs at various levels and, in particular, in such protein alterations, on the contrary physical activity is emerging as a counteracting factor in NDs. In the present work, the content of Aß, α-syn and tau in red blood cells (RBCs) derived from ten endurance athletes (ATHL) and ten sedentary volunteers (SED) were compared before and after in vitrooxidative stress treatment. Total Aß, α-syn and tau were quantified in RBCs (isolated from the subjects) by immunoenzymatic assays. Oxidative stress was induced by in vitro H2O2 administration to RBCs. H2O2 treatment was confirmed to significantly enhance ROS accumulation in RBCs. Total Aß content in RBCs was lower in the ATHL subgroup with respect to the SED one. In the SED subgroup, but not in the ATHL one, total Aß levels were increased by oxidative stress. Total α-syn content was lower in the ATHL subgroup with respect to the SED one and α-syn levels were increased by oxidative stress in both subgroups, with the percentage of increase higher in SED. Total tau content was comparable in both ATHL and SED and it was not affected by oxidative stress. Our data confirm previous findings evidencing that both oxidative stress and sedentary style contribute to aberrant folding and accumulation of NDs-related proteins, pointing to the importance of both anti-oxidant therapies and exercising in the prevention and treating of such diseases.

Gait dynamics in Pisa syndrome and Camptocormia: The role of stride length and hip kinematics.

This is an observational cross-sectional study evaluating gait dynamics in patients with Parkinson's Disease (PD) and severe postural deformities, PD without axial deviations and healthy subjects. Ten PS individuals with Pisa syndrome (PS) and nine subjects with Camptocormia (CC) performed 3-D Gait Analysis and were evaluated with walking and balance scales. Correlations with clinical and functional scales were investigated. Spatio-temporal and kinematic data were compared to ten PD subjects without postural deformities (PP) and ten healthy matched individuals (CG). Data obtained showed decreased walking velocity, stride and step length in PP, PS and CC groups compared to controls. The correlation analysis showed that stride and step length were associated with reduced functional abilities and disease severity in PS and CC groups. Kinematic data revealed marked reduction in range of movements (ROMs) at all lower-extremity joints in PS group. While, in CC group the main differences were pronounced in hip and knee joints. PS and CC groups presented a more pronounced reduction in hip articular excursion compared to PP subjects, revealing an increased hip flexion pattern during gait cycle. Moreover, the increased hip and knee flexion pattern adversely affected functional performance during walking tests. Results obtained provide evidence that step length, along with stride length, can be proposed as simple and clear indicators of disease severity and reduced functional abilities. The reduction of ROMs at hip joint represented an important mechanism contributing to decreased walking velocity, balance impairment and reduced gait performance in PD patients with postural deformities.

Antipsychotic drugs in Huntington's disease.

INTRODUCTION: The aim of this review is to overview the pharmacological features of neuroleptics experienced in the treatment of Huntington's disease (HD) symptoms. Despite a large number of case reports, randomized controlled trials (RCT) and drug comparison studies are lacking. Areas covered: After evaluating current guidelines and clinical unmet needs we searched PubMed for the term 'Huntington's disease' cross referenced with the terms 'Antipsychotic drugs' 'Neuroleptic drugs' and single drug specific names. Expert commentary: In clinical practice antipsychotics represent the first choice in the management of chorea in the presence of psychiatric symptoms, when poor compliance is suspected or when there is an increased risk of adverse events due to tetrabenazine. Antipsychotics are considered valid strategies, with the second generation preferred to reduce extrapyramidal adverse events, however they may cause more metabolic side effects. In the future 'dopamine stabilizers', such as pridopidine, could replace antipsychotics modulating dopamine transmission.

Mitochondrial DNA haplogroups may influence Fabry disease phenotype.

While the genetic origin of Fabry disease (FD) is well known, it is still unclear why the disease presents a wide heterogeneity of clinical presentation and progression, even within the same family. Emerging observations reveal that mitochondrial impairment and oxidative stress may be implicated in the pathogenesis of FD. To investigate if specific genetic polymorphisms within the mitochondrial genome (mtDNA) could act as susceptibility factors and contribute to the clinical expression of FD, we have genotyped European mtDNA haplogroups in 77 Italian FD patients and 151 healthy controls. Haplogroups H and I, and haplogroup cluster HV were significantly more frequent in patients than controls. However, no correlation with gender, age of onset, organ involvement was observed. Our study seems to provide some evidence of a contribution of mitochondrial variation in FD pathogenesis, at least in Italy.

Current treatment and future prospects of dopa-induced dyskinesias.

Levodopa-induced dyskinesias (LID) are one of the main issues in the management of Parkinson's disease (PD); once these dyskinesias are established treatment becomes difficult, so preventive strategies should be first evaluated. Although levodopa (LD) treatment has recently been related as risk factor for LID, the main strategy to delay LID is to start PD treatment with dopamine agonists, adding LD at low doses. After LID onset, approaches include reducing single LD doses, reducing or discontinuing monoamine oxidase type B/catechol O-methyltransferase (MAO-B/COMT) inhibitors and extended-release (ER) LD. Amantadine represents the best antidyskinetic tool, and ER amantadine is the most promising upcoming antidyskinetic drug. New LD formulations such as IPX-066 (able to provide continuous dopaminergic stimulation) also represent promising new approaches. The involvement of a nondopaminergic system in the pathogenesis of LID suggests that the modulation of glutamate, serotonin and adenosine could have potential as new upcoming drug targets, but the role of such drugs will still need to be confirmed in randomized controlled trials.

A randomized clinical trial to evaluate the effects of rasagiline on depressive symptoms in non-demented Parkinson's disease patients.

BACKGROUND AND PURPOSE: Depressed mood is a common psychiatric problem associated with Parkinson's disease (PD), and studies have suggested a benefit of rasagiline treatment. METHODS: ACCORDO (see the ) was a 12-week, double-blind, placebo-controlled trial to evaluate the effects of rasagiline 1 mg/day on depressive symptoms and cognition in non-demented PD patients with depressive symptoms. The primary efficacy variable was the change from baseline to week 12 in depressive symptoms measured by the Beck Depression Inventory (BDI-IA) total score. Secondary outcomes included change from baseline to week 12 in cognitive function as assessed by a comprehensive neuropsychological battery; Parkinson's disease quality of life questionnaire (PDQ-39) scores; Apathy Scale scores; and Unified Parkinson's Disease Rating Scale (UPDRS) subscores. RESULTS: One hundred and twenty-three patients were randomized. At week 12 there was no significant difference between groups for the reduction in total BDI-IA score (primary efficacy variable). However, analysis at week 4 did show a significant difference in favour of rasagiline (marginal means difference ± SE: rasagiline -5.46 ± 0.73 vs. placebo -3.22 ± 0.67; P = 0.026). There were no significant differences between groups on any cognitive test. Rasagiline significantly improved UPDRS Parts I (P = 0.03) and II (P = 0.003) scores versus placebo at week 12. Post hoc analyses showed the statistical superiority of rasagiline versus placebo in the UPDRS Part I depression item (P = 0.04) and PDQ-39 mobility (P = 0.007) and cognition domains (P = 0.026). CONCLUSIONS: Treatment with rasagiline did not have significant effects versus placebo on depressive symptoms or cognition in PD patients with moderate depressive symptoms. Although limited by lack of correction for multiple comparisons, post hoc analyses signalled some improvement in patient-rated cognitive and depression outcomes.

Alzheimer's pathogenesis and its link to the mitochondrion.

Alzheimer's disease (AD) is the most common form of dementia in the elderly. This neurodegenerative disorder is clinically characterized by impairment of cognitive functions and changes in behaviour and personality. The pathogenesis of AD is still unclear. Recent evidence supports some role of mitochondria dysfunction and oxidative stress in the development of the neurodegenerative process. In this review, we discuss the role of mitochondrial dysfunction in AD, focusing on the mechanisms that lead to mitochondrial impairment, oxidative stress, and neurodegeneration, a "vicious circle" that ends in dementia.

Mesolimbic dopaminergic dysfunction in Parkinson's disease depression: evidence from a 123I-FP-CIT SPECT investigation.

We investigated the striatal and extrastriatal DAT availability (SPM8) by [(123)I]FP-CIT-SPECT in 15 PD patients with depression and 35 PD patients without depression. A cluster with significant (p < 0.05) lower tracer binding in PD with depression was found in left cingulate cortex, persistent after correction for age, disease severity and duration, and inversely correlated with depression scores (r -0.336, p < 0.05). Our data indicate a significant association between PD depression and cingulate dopaminergic denervation supporting the dopaminergic hypothesis of PD depression.

Serotonergic antidepressant drugs and L-dopa-induced dyskinesias in Parkinson's disease.

BACKGROUND: Serotonergic system is believed to play a role in levodopa-induced-dyskinesias pathogenesis, and serotonin transporter has been evaluated as potential target. AIM OF THE STUDY: To retrospectively investigate the potential effect of selective serotonin reuptake inhibitors (SSRIs) during dopaminergic treatment, in the development of dyskinesias in patients with Parkinson's disease (PD). METHODS: One hundred and thirty-five consecutive patients with PD, with 10-year follow-up since diagnosis. Age at PD onset, duration of levodopa treatment, maximum daily dose, and SSRIs exposure were collected. Risk, latency, and severity of dyskinesias were evaluated comparing patients with and without SSRIs exposure. RESULTS: Forty-nine patients received SSRIs for a variable period, 86 were never treated; no significant difference between the groups was observed (P = 0.897) in the prevalence of dyskinesias. Considering latency between PD diagnosis and dyskinesias onset, patients exposed to SSRIs developed dyskinesias later (6.48 ± 1.99 vs 5.70 ± 1.89 years, P = 0.020). The median dyskinesia severity score was 0 in the exposed group vs 1 in non-exposed patients (P = 0.025). Multivariate analysis demonstrated SSRIs exposure as the only independent predictor, protecting from severe dyskinesia. CONCLUSIONS: Use of SSRIs in patients with PD did not protect from dyskinesias; however, exposure may delay the onset and reduce the severity, confirming modulation of the serotonergic system as possible antidyskinetic strategy.

Comparison of 3T and 7T susceptibility-weighted angiography of the substantia nigra in diagnosing Parkinson disease.

BACKGROUND AND PURPOSE: Standard neuroimaging fails in defining the anatomy of the substantia nigra and has a marginal role in the diagnosis of Parkinson disease. Recently 7T MR target imaging of the substantia nigra has been useful in diagnosing Parkinson disease. We performed a comparative study to evaluate whether susceptibility-weighted angiography can diagnose Parkinson disease with a 3T scanner. MATERIALS AND METHODS: Fourteen patients with Parkinson disease and 13 healthy subjects underwent MR imaging examination at 3T and 7T by using susceptibility-weighted angiography. Two expert blinded observers and 1 neuroradiology fellow evaluated the 3T and 7T images of the sample to identify substantia nigra abnormalities indicative of Parkinson disease. Diagnostic accuracy and intra- and interobserver agreement were calculated separately for 3T and 7T acquisitions. RESULTS: Susceptibility-weighted angiography 7T MR imaging can diagnose Parkinson disease with a mean sensitivity of 93%, specificity of 100%, and diagnostic accuracy of 96%. 3T MR imaging diagnosed Parkinson disease with a mean sensitivity of 79%, specificity of 94%, and diagnostic accuracy of 86%. Intraobserver and interobserver agreement was excellent at 7T. At 3T, intraobserver agreement was excellent for experts, and interobserver agreement ranged between good and excellent. The less expert reader obtained a diagnostic accuracy of 89% at 3T. CONCLUSIONS: Susceptibility-weighted angiography images obtained at 3T and 7T differentiate controls from patients with Parkinson disease with a higher diagnostic accuracy at 7T. The capability of 3T in diagnosing Parkinson disease might encourage its use in clinical practice. The use of the more accurate 7T should be supported by a dedicated cost-effectiveness study.

Common Genetic Conditions of Ischemic Stroke to Keep in Mind.

Stroke is a complex disease resulting from the interplay of genetics and environment. In some instances (mainly in young adults) stroke is the direct result of a monogenic disease. Among the monogenic causes of stroke, the diseases which are most frequently encountered in the adult general neurological practice are CADASIL, Fabry and mitochondrial diseases. Brain MRI and clinical features may frequently lead to a correct molecular diagnosis. Here we review the single-gene causes of ischemic stroke, with special regard to the associated features which may help in the diagnostic approach.