Cortical Network Topology in Prodromal and Mild Dementia Due to Alzheimer\u2019s Disease: Graph Theory Applied to Resting State EEG

Graph theory analysis on resting state electroencephalographic rhythms disclosed topological properties of cerebral network. In Alzheimer\u2019s disease (AD) patients, this approach showed mixed results. Granger causality matrices were used as input to the graph theory allowing to estimate the strength and the direction of information transfer between electrode pairs. The number of edges (degree), the number of inward edges (in-degree), of outgoing edges (out-degree) were statistically compared among healthy controls, patients with mild cognitive impairment due to AD (AD-MCI) and AD patients with mild dementia (ADD) to evaluate if degree abnormality could involve low and/or high degree vertices, the so called hubs, in both prodromal and over dementia stage. Clustering coefficient and local efficiency were evaluated as measures of network segregation, path length and global efficiency as measures of integration, the assortativity coefficient as a measure of resilience. Degree, in-degree and out-degree values were lower in AD-MCI and ADD than the control group for non-hubs and hubs vertices. The number of edges was preserved for frontal electrodes, where patients\u2019 groups showed an additional hub in F3. Clustering coefficient was lower in ADD compared with AD-MCI in the right occipital electrode, and it was positively correlated with mini mental state examination. Local and global efficiency values were lower in patients\u2019 than control groups. Our results show that the topology of the network is altered in AD patients also in its prodromal stage, begins with the reduction of the number of edges and the loss of the local and global efficiency

Epilepsy in Neurodegenerative Dementias: A Clinical, Epidemiological, and EEG Study

BACKGROUND: Seizures are common in patients with dementia but precise epidemiologic data of epilepsy in neurodegenerative dementia is lacking. OBJECTIVE: The first aim of the study was to investigate prevalence and clinical characteristics of epilepsy in a large cohort of patients with neurodegenerative dementias. Subsequently, we explored clinical, neuropsychological, and quantitative electroencephalogram (qEEG) data of Alzheimer's disease (AD) patients with epilepsy (AD-EPI) as compared to AD patients without epilepsy (AD-CTR). METHODS: We retrospectively evaluated consecutive patients with a diagnosis of a neurodegenerative dementia and a clinically diagnosed epilepsy that required antiepileptic drugs (AED). All patients underwent baseline comprehensive neuropsychological assessment. A follow-up of at least one year was requested to confirm the dementia diagnosis. In AD patients, qEEG power band analysis was performed. AD-CTR and AD-EPI patients were matched for age, Mini-Mental State Examination score, and gender. RESULTS: Thirty-eight out of 2,054 neurodegenerative dementia patients had epilepsy requiring AED. The prevalence of epilepsy was 1.82% for AD, 1.28% for the behavioral variant of frontotemporal dementia (bvFTD), 2.47% for dementia with Lewy bodies (DLB), and 12% for primary progressive aphasia. Epilepsy were more drug-responsive in AD than in non-AD dementias. Finally, no significant differences were found in neuropsychological and qEEG data between AD-EPI and AD-CTR patients. CONCLUSION: In our cohort, AD, FTD, and DLB dementias have similar prevalence of epilepsy, even if AD patients were more responsive to AED. Moreover, AD-EPI patients did not have significant clinical, neuropsychological qEEG differences compared with AD-CTR patients

Effects of antiangiogenetic drugs on microcirculation and macrocirculation in patients with advanced-stage renal cancer

Adverse cardiovascular effects, including hypertension, were described in patients with different cancers treated with tyrosine kinase inhibitors (TKI). The mechanism of TKI-related hypertension is still debated. The aim of this work was to study the effects of TKI on blood pressure (BP), searching for a relationship with possible causative factors in patients with metastatic renal cell carcinoma. We included 29 patients in a prospective, observational study; 22 were treated with a first-line drug (sunitinib), while seven participated in the second-line treatment (axitinib or cabozantinib). Patients were investigated at the beginning of antiangiogenic therapy (T0) and at one (T1), three (T2), and six months (T3) after treatment. Patients were evaluated by office blood pressure (BP) and ultrasonography to measure flow-mediated dilatation (FMD), and carotid artery distensibility (cDC) by echocardiography and nailfold capillaroscopy. Plasma endothelin-1 (p-ET-1), urine nitrates, and proteins were also measured. At T1, systolic BP, along with U proteins and p-ET-1, increased significantly. In patients with a clinically significant increase in BP (defined as either the need for an antihypertensive drug or systolic blood pressure (SBP) T1\u207bT0 6510 and/or SBP 65140 mmHg and/or diastolic blood pressure (DBP) T1\u207bT0 655 and/or DBP 6590 mmHg), the urine nitrate concentration was lower at T0, whereas there were no differences in the p-ET-1 and U proteins. Seventeen participants showed changes in the capillaroscopic pattern at T1 with no association with BP increases. There were no differences in the FMD, cDC, and echocardiographic parameters. Our findings are consistent with those of previous studies about BP increases by TKI, and suggest a role of nitric oxide in BP maintenance in this population

The role of the serotonergic system in REM sleep behavior disorder

STUDY OBJECTIVES: REM sleep behavior disorder (RBD) can be induced by antidepressants, especially serotonin reuptake inhibitors (SSRI), thus a role of the serotonergic system in the pathogenesis of RBD has been proposed. However, the serotonergic system integrity in idiopathic RBD (iRBD) is still unknown. We aimed to study brain stem serotonergic system integrity, by means of (123)I-FP-CIT-SPECT, in a group of iRBD patients as compared to normal subjects. DESIGN: Single-center, prospective observational study. SETTING: University hospital. PATIENTS OR PARTICIPANTS: Twenty iRBD outpatients and 23 age-matched normal controls. MEASUREMENTS AND RESULTS: The diagnosis of RBD was determined clinically and confirmed by means of overnight, laboratory-based video-polysomnography. Both iRBD patients and normal subjects underwent (123)I-FP-CIT-SPECT as a marker of dopamine transporter (DAT) at basal ganglia level and of serotonin transporter (SERT) at brainstem and thalamus levels. (123)I-FP-CIT-SPECT images were analyzed and compared between iRBD patients and controls by means of both region of interest analysis at basal ganglia, midbrain, pons and thalamus levels, and voxel-based analysis, taking into account age and the use of SSRI as confounding factors. No difference in (123)I-FP-CIT-SPECT specific to nondisplaceable binding ratios (SBR) values was found between iRBD and normal subjects at brainstem and thalamus levels while iRBD patients showed lower SBR values in all basal ganglia nuclei (P < 0.0001) compared to controls. CONCLUSIONS: These results suggest that the serotonergic system is not directly involved in RBD pathogenesis while confirming nigro-striatal dopaminergic deafferentation in iRBD. CITATION: Arnaldi D, Famà F, De Carli F, Morbelli S, Ferrara M, Picco A, Accardo J, Primavera A, Sambuceti G, Nobili F. The role of the serotonergic system in REM sleep behavior disorder. SLEEP 2015;38(9):1505–1509

Polysomnographic correlates of sleep disturbances in de novo, drug na\uefve Parkinson's Disease

Background: Sleep disturbances are common non-motor symptoms of Parkinson's Disease (PD). Methods: The aim of this study was to investigate the polysomnographic correlates of sleep changes, as investigated by the Parkinson's Disease Sleep Scale-2 (PDSS-2), in a cohort of sixty-two consecutive de novo, drug na\uefve PD patients (71.40 \ub1 7.84 y/o). Results: PDSS-2 total score showed a direct correlation with stage shifts (p = 0.008). Fragmented sleep showed an inverse correlation with sleep efficiency (p = 0.012). Insomnia symptoms showed an inverse correlation with wake after sleep onset (p = 0.005) and direct correlation with periodic leg movements (p = 0.006) and stage shift indices (p = 0.003). Motor Symptoms showed a direct correlation with Apnoea-Hypopnoea (AHI; p = 0.02) and awakenings indices (p = 0.003). Dream distressing showed a direct correlation with REM without atonia (RWA, p = 0.042) and an inverse correlation with AHI (p = 0.012). Sleep quality showed an inverse correlation with RWA (p = 0.008). Conclusion: PDSS-2 features are significantly correlated with polysomnography objective findings, thus further supporting its reliability to investigate sleep disturbances in PD patients. Keywords: Parkinson\u2019s Disease; Sleep disturbances; Polysomnography; Sleep disorders

Metabolic correlates of rey auditory verbal learning test in elderly subjects with memory complaints

We evaluated the brain metabolic correlates of main indexes of a widely used word list learning test, the Rey Auditory Verbal Memory Test (RAVLT), in a group of elderly subjects with memory complaints. Fifty-four subjects (age: 72.02 \ub1 7.45; Mini-Mental State Examination (MMSE) score: 28.9 \ub1 1.24) presenting at a memory clinic complaining of memory deficit, but not demented, and thirty controls (age: 71.87 \ub1 7.08; MMSE score: 29.1 \ub1 1.1) were included. Subjects with memory complaints included both patients with (amnestic mild cognitive impairment, aMCI) and without (subjective memory complaints, SMC) impairment on memory tests. All subjects underwent 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), analyzed with statistical parametric. Patients with aMCI but not those with SMC showed the expected posterior cingulate-precuneus and parietal hypometabolism as compared to controls. Correlation was determined for between four indexes of the RAVLT and brain metabolism. The results show a significant correlation between the delayed recall score and metabolism in posterior cingulate gyrus of both hemispheres and in left precuneus, as well as between a score of long-term percent retention and metabolism in left posterior cingulate gyrus, precuneus, and orbitofrontal areas. These correlations survived correction for age, education, and MMSE score. No correlation was found between immediate or total recall scores and glucose metabolism. These data show the relevant role of posterior cingulate-precuneus and orbitofrontal cortices in retention and retrieval of de-contextualized verbal memory material in a group of elderly subjects with memory complaints and shed light on the topography of synaptic dysfunction in these subjects, overlapping that found in the earliest stages of Alzheimer-type neurodegeneration. \ua9 2014-IOS Press and the authors

REMeDio: a proof-of-concept neuroprotection study for prodromal synucleinopathies

OBJECTIVE: To explore the feasibility of a neuroprotection trial in prodromal synucleinopathy, using idiopathic REM sleep behavior disorder (iRBD) as the target population and 123 I-FP-CIT-SPECT as a biomarker of disease progression.METHODS: Consecutive iRBD patients were randomly assigned to a treatment arm, receiving selegiline and symptomatic RBD treatment, or to a control arm, receiving symptomatic treatment only. Selegiline was chosen because of a demonstrated neuroprotection effect in animal models. Patients underwent123 I-FP-CIT-SPECT at baseline and after 30 months in average. The clinical outcome was the emergence of parkinsonism and/or dementia. A repeated-measures general linear model (GLM) was applied, using group (control and treatment) as 'between' factor, and both time (baseline and follow-up) and regions (123 I-FP-CIT-SPECT putamen and caudate uptake) as 'within' factors, adjusting for age.RESULTS: Thirty iRBD patients completed the study (68.2\ub16.9 years; 29 males; 21% drop-out rate), 13 in the treatment arm and 17 in the control arm. At follow-up (29.8\ub19.0 months), three patients in the control arm developed dementia and one parkinsonism while two patients in the treatment arm developed parkinsonism. Both putamen and caudate uptake decreased over time in the control arm. In the treatment arm, only the putamen uptake decreased over time while caudate uptake remained stable. GLM analysis demonstrated an effect of treatment on the 123 I-FP-CIT-SPECT uptake change, with a significant interaction between the effect of group, time and regions (p=0.004).CONCLUSION: A 30-months neuroprotection study for prodromal synucleinopathy is feasible, using iRBD as the target population, and 123 I-FP-CIT-SPECT as a biomarker of disease progression

The fate of patients with REM sleep behavior disorder and Mild Cognitive Impairment

Abstract Objective: To investigate clinical and dopaminergic pre-synaptic brain imaging characteristics of subjects with idiopathic rapid eye movement (REM) behavior disorder (iRBD) and mild cognitive impairment (MCI), and to evaluate the combined predictive value of risk factors for short-term conversion to synucleinopathy. Method: In sum, 44 polysomnography (PSG)-confirmed iRBD patients (68.5\ub17.2 years; 38 males) underwent 123I-FP-CIT-SPECT, comprehensive neuropsychological evaluation, clinical examination and clinical follow-up every six months (30.6\ub121.5 months). Step-wise logistic regression was applied to identify those features discriminating iRBD patients with (iRBD-MCI; n=14) and without MCI (normal cognition, iRBD-NC; n=30). The risk of neurodegeneration was estimated with Kaplan-Meier analysis. Predictors of phenoconversion were assessed with Cox proportional-hazards analysis, adjusting for age, gender and education. A generalized linear model (GLM) was applied to define the best combination of risk factors predicting conversion at followup. Results: At baseline, patients with iRBD-MCI showed reduced striatal dopamine transporter (DAT) specific to non-displaceable binding ratio (SBR) and more constipation compared with iRBD-NC patients (p&lt;0.0001). During the follow-up, 10 patients (22.7%) develop an overt synucleinopathy. GLM analysis showed that patients with orthostatic hypotension, non-motor experiences of daily living, reduced putaminal DAT-SPECT SBR, and cognitive impairment in verbal memory/visuoconstruction abilities were at higher risk of phenoconversion (Hazard Ratio 26.05; Sensitivity 90%; Specificity 100%; Accuracy 97.73%; Positive Predictive Value 100%; Negative Predictive Value 97.14%). Conclusions. iRBD-MCI patients showed a more severe dopaminergic neuroimaging and clinical phenotype. Combining clinical and neuroimaging markers allowed to achieve excellent ability in identifying iRBD patients at high risk of developing a synucleinopathy within about three years from diagnosis

Resting State Alpha Electroencephalographic Rhythms Are Differently Related to Aging in Cognitively Unimpaired Seniors and Patients with Alzheimer's Disease and Amnesic Mild Cognitive Impairment

Background: In relaxed adults, staying in quiet wakefulness at eyes closed is related to the so-called resting state electroencephalographic (rsEEG) rhythms, showing the highest amplitude in posterior areas at alpha frequencies (8-13 Hz). Objective: Here we tested the hypothesis that age may affect rsEEG alpha (8-12 Hz) rhythms recorded in normal elderly (Nold) seniors and patients with mild cognitive impairment due to Alzheimer's disease (ADMCI). Methods: Clinical and rsEEG datasets in 63 ADMCI and 60 Nold individuals (matched for demography, education, and gender) were taken from an international archive. The rsEEG rhythms were investigated at individual delta, theta, and alpha frequency bands, as well as fixed beta (14-30 Hz) and gamma (30-40 Hz) bands. Each group was stratified into three subgroups based on age ranges (i.e., tertiles). Results: As compared to the younger Nold subgroups, the older one showed greater reductions in the rsEEG alpha rhythms with major topographical effects in posterior regions. On the contrary, in relation to the younger ADMCI subgroups, the older one displayed a lesser reduction in those rhythms. Notably, the ADMCI subgroups pointed to similar cerebrospinal fluid AD diagnostic biomarkers, gray and white matter brain lesions revealed by neuroimaging, and clinical and neuropsychological scores. Conclusion: The present results suggest that age may represent a deranging factor for dominant rsEEG alpha rhythms in Nold seniors, while rsEEG alpha rhythms in ADMCI patients may be more affected by the disease variants related to earlier versus later onset of the AD. Keywords: Aging; exact Low-resolution brain electromagnetic source tomography; mild cognitive impairment due to Alzheimer\u2019s disease; resting state electroencephalographic rhythms