Relationship between default mode network and resting-state electroencephalographic alpha rhythms in cognitively unimpaired seniors and patients with dementia due to Alzheimer's disease.

Here we tested the hypothesis of a relationship between the cortical default mode network (DMN) structural integrity and the resting-state electroencephalographic (rsEEG) rhythms in patients with Alzheimer's disease with dementia (ADD). Clinical and instrumental datasets in 45 ADD patients and 40 normal elderly (Nold) persons originated from the PDWAVES Consortium (www.pdwaves.eu). Individual rsEEG delta, theta, alpha, and fixed beta and gamma bands were considered. Freeware platforms served to derive (1) the (gray matter) volume of the DMN, dorsal attention (DAN), and sensorimotor (SMN) cortical networks and (2) the rsEEG cortical eLORETA source activities. We found a significant positive association between the DMN gray matter volume, the rsEEG alpha source activity estimated in the posterior DMN nodes (parietal and posterior cingulate cortex), and the global cognitive status in the Nold and ADD participants. Compared with the Nold, the ADD group showed lower DMN gray matter, lower rsEEG alpha source activity in those nodes, and lower global cognitive status. This effect was not observed in the DAN and SMN. These results suggest that the DMN structural integrity and the rsEEG alpha source activities in the DMN posterior hubs may be related and predict the global cognitive status in ADD and Nold persons.

Decisional capacity to consent to treatment and research in patients affected by Mild Cognitive Impairment. A systematic review and meta-analysis.

OBJECTIVES: To perform a meta-analysis of clinical studies on the differences in treatment or research decision-making capacity among patients with Mild Cognitive Impairment (MCI), Alzheimer's disease (AD), and healthy comparisons (HCs). DESIGN: A systematic search was conducted on Medline/Pubmed, CINAHL, PsycINFO, Web of Science, and Scopus. Standardized mean differences and random-effects model were used in all cases. SETTING: The United States, France, Japan, and China. PARTICIPANTS: Four hundred and ten patients with MCI, 149 with AD, and 368 HCs were included. MEASUREMENTS: The studies we included in the analysis assessed decisional capacity to consent by the MacArthur Competence Assessment Tool for Treatment (MAcCAT-T), MacArthur Competence Assessment Tool for Clinical Research (MacCAT-CR), Capacity to Consent to Treatment Instrument (CCTI), and University of California Brief Assessment of Capacity to Consent (UBACC). RESULTS: We identified 109 potentially eligible studies from 1672 records, and 7 papers were included in the meta-analysis. The meta-analysis showed that there was significant impairment in a decision-making capacity in MCI patients compared to the HCs group in terms of Understanding (SMD = -1.04, 95% CI: -1.31 to -0.77, P < 0.001; I2 = 52%, P = 0.07), Appreciation (SMD = -0.51, 95% CI: -0.66 to -0.36, P < 0.001; I2 = 0%, P = 0.97), and Reasoning (SMD = -0.62, 95% CI: -0.77, -0.47, P < 0.001; I2=0%, P =0.46). MCI patients scored significantly higher in Understanding (SMD = 1.50, 95% CI: 0.91, 2.09, P = 0.01, I2 = 78%, P = 0.00001) compared to patients affected by AD. CONCLUSIONS: Patients affected by MCI are at higher risk of impaired capacity to consent to treatment and research compared to HCs, despite being at lower risk compared to patients affected by AD. Clinicians and researchers need to carefully evaluate decisional capacity in MCI patients providing informed consent.

Psychosis of Alzheimer's disease: Neuropsychological and neuroimaging longitudinal study.

OBJECTIVES: Psychosis of Alzheimer's disease (AD) may represent a distinct disease phenotype; however, neuropsychological profile and neural basis linked to this phenotype have not yet been clarified. In this study, we aimed at detecting whether impairment in specific cognitive domains predicts the onset of psychosis in AD patients and what grey matter alterations, their location, and the rate of atrophy are associated with psychosis of AD. METHODS: Longitudinal neuropsychological data from AD patients with and without psychosis were analysed to determine whether the neuropsychological profile can predict the onset of psychosis. A voxel-based morphometry (VBM) on longitudinal T1-weighted images was used to explore differences in grey matter volume and in the rate of atrophy between groups. RESULTS: Noncognitive domain predicted the psychosis onset. However, AD patients with psychosis exhibited greater atrophy in the right anterior-inferior temporal lobe, including the fusiform gyrus (cluster-p-family-wise error [pfwe] < 0.05; peak-p uncorrected [pUNC] < 0.001) as well as greater rate of atrophy in the right insula than nonpsychotic patients (cluster-pFWE = 0.075; peak-pUNC < 0.001). The anterior-inferior temporal lobe is part of the ventral visual stream, and the insula plays a key role in the salience network. CONCLUSIONS: This finding suggests that damage in these areas underpins an impairment in the visual processing of the objects and an impairment in the attribution of salience to the misperceived stimuli, which in turn leads to the onset of psychosis. These findings tie in well with the neuropsychological model of psychosis, according to which the simultaneous presence of two factors, namely misperception and misattribution, underlies psychosis in dementia.

Inappropriate Sexual Behaviors Among Community-Dwelling Patients with Dementia.

OBJECTIVE: Inappropriate sexual behaviors (ISBs) represent challenging and stressful manifestations of dementia and are highly burdening for patients, families, and healthcare providers. Nevertheless, ISBs have so far attracted limited clinical and scientific interest compared with other neuropsychiatric symptoms occurring in dementing illnesses. The authors aimed to systematically investigate the prevalence and characteristics of ISBs in a population of patients with dementia attending a memory clinic. METHODS: In this cross-sectional study, individuals with dementia attending our memory clinic were consecutively enrolled between January 2015 and February 2016. Participating subjects underwent a detailed medical history collection and a comprehensive cognitive, functional, and neuropsychiatric assessment. The presence of ISBs (in the previous 30 days) was investigated by the adoption of an ad hoc questionnaire, administered to informants. A logistic regression model was carried out to identify sociodemographic and clinical variables associated with ISBs. RESULTS: In the 195 patients (48.7% women) with dementia recruited for the study, ISBs were detected in 35 patients (17.9% of the total sample). The logistic regression model showed that male sex (OR: 5.14; 95% CI: 1.44-18.41) and anxiety (OR: 4.92; 95% CI: 1.44-16.84) were statistically significantly associated with the presence of ISBs. CONCLUSION: ISBs represent common manifestations of dementing illnesses. Given the significant burden of ISBs on patients and families and the impact on care management, their occurrence should always be investigated in the clinical care of individuals with dementia. For this purpose, specific screening/assessment tools should be properly designed and validated.

Attenuation of Choroidal Thickness in Patients With Alzheimer Disease: Evidence From an Italian Prospective Study.

INTRODUCTION: To compare the 12-month choroidal thickness (CT) change between Alzheimer disease (AD) patients and normal subjects. METHODS: In this prospective, observational study, 39 patients with a diagnosis of mild to moderate AD and 39 age-matched control subjects were included. All the subjects underwent neuropsychological (Mini Mental State Examination, Alzheimer disease Assessment Scale-Cognitive Subscale, and the Clinical Dementia Rating Scale) and ophthalmological evaluation, including spectral domain optical coherence tomography, at baseline and after 12 months. CT was measured manually using the caliper tool of the optical coherence tomography device. RESULTS: After 12 months, AD patients had a greater reduction of CT than controls (P≤0.05, adjusted for baseline CT, age, sex, axial length, and smoking). DISCUSSION: CT in patients with AD showed a rate of thinning greater than what could be expected during the natural course of aging.

Poor reactivity of posterior electroencephalographic alpha rhythms during the eyes open condition in patients with dementia due to Parkinson's disease.

Here, we hypothesized that the reactivity of posterior resting-state electroencephalographic (rsEEG) alpha rhythms during the transition from eyes-closed to -open condition might be lower in patients with Parkinson's disease dementia (PDD) than in patients with Alzheimer's disease dementia (ADD). A Eurasian database provided clinical-demographic-rsEEG datasets in 73 PDD patients, 35 ADD patients, and 25 matched cognitively unimpaired (Healthy) persons. The eLORETA freeware was used to estimate cortical rsEEG sources. Results showed substantial (greater than -10%) reduction (reactivity) in the posterior alpha source activities from the eyes-closed to the eyes-open condition in 88% of the Healthy seniors, 57% of the ADD patients, and only 35% of the PDD patients. In these alpha-reactive participants, there was lower reactivity in the parietal alpha source activities in the PDD group than in the healthy control seniors and the ADD patients. These results suggest that PDD patients show poor reactivity of mechanisms desynchronizing posterior rsEEG alpha rhythms in response to visual inputs. That neurophysiological biomarker may provide an endpoint for (non) pharmacological interventions for improving vigilance regulation in those patients.

Memantine for Refractory Obsessive-Compulsive Disorder: Protocol for a Pragmatic, Double-blind, Randomized, Parallel-Group, Placebo-Controlled, Monocenter Trial.

BACKGROUND: Obsessive-compulsive disorder (OCD) is a psychiatric syndrome characterized by unwanted and repetitive thoughts and repeated ritualistic compulsions for decreasing distress. Symptoms can cause severe distress and functional impairment. OCD affects 2% to 3% of the population and is ranked within the 10 leading neuropsychiatric causes of disability. Cortico-striatal-thalamo-cortical circuitry dysfunction has been implicated in OCD, including altered brain activation and connectivity. Complex glutamatergic signaling dysregulation within cortico-striatal circuitry has been proposed in OCD. Data obtained by several studies indicate reduced glutamatergic concentrations in the anterior cingulate cortex, combined with overactive glutamatergic signaling in the striatum and orbitofrontal cortex. A growing number of randomized controlled trials have assessed the utility of different glutamate-modulating drugs as augmentation medications or monotherapies for OCD, including refractory OCD. However, there are relevant variations among studies in terms of patients' treatment resistance, comorbidity, age, and gender. At present, 4 randomized controlled trials are available on the efficacy of memantine as an augmentation medication for refractory OCD. OBJECTIVE: Our study's main purpose is to conduct a double-blind, randomized, parallel-group, placebo-controlled, monocenter trial to assess the efficacy and safety of memantine as an augmentative agent to a selective serotonin reuptake inhibitor in the treatment of moderate to severe OCD. The study's second aim is to evaluate the effect of memantine on cognitive functions in patients with OCD. The third aim is to investigate if responses to memantine are modulated by variables such as gender, symptom subtypes, and the duration of untreated illness. METHODS: Investigators intend to conduct a double-blind, randomized, parallel-group, placebo-controlled, monocenter trial to assess the efficacy and safety of memantine as an augmentative agent to a selective serotonin reuptake inhibitor in the treatment of patients affected by severe refractory OCD. Participants will be rated via the Yale-Brown Obsessive Compulsive Scale at baseline and at 2, 4, 6, 8, 10, and 12 months. During the screening period and T4 and T6 follow-up visits, all participants will undergo an extensive neuropsychological evaluation. The 52-week study duration will consist of 4 distinct periods, including memantine titration and follow-up periods. RESULTS: Recruitment has not yet started. The study will be conducted from June 2023 to December 2024. Results are expected to be available in January 2025. Throughout the slow-titration period, we will observe the minimum effective dose of memantine, and the follow-up procedure will detail its residual efficacy after drug withdrawal. CONCLUSIONS: The innovation of this research proposal is not limited to the evaluation of the efficacy and safety of memantine as an augmentation medication for OCD. We will also test if memantine acts as a pure antiobsessive medication or if memantine's ability to improve concentration and attention mimics an antiobsessive effect. TRIAL REGISTRATION: ClinicalTrials.gov NCT05015595; https://clinicaltrials.gov/ct2/show/NCT05015595. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/39223.

Multidimensional assessment of time perception along the continuum of Alzheimer's Disease and evidence of alterations in subjective cognitive decline.

Timing alterations occur in Alzheimer's disease (AD), even in early stages (mild cognitive impairment, MCI). Moreover, a stage named subjective cognitive decline (SCD), in which individuals perceive a change in cognitive performance not revealed by neuropsychological tests, has been identified as a preclinical phase of AD. However, no study to date has investigated different dimensions of time processing along the continuum from physiological to pathological aging, and whether timing alterations occur in SCD. Here a sample of participants with SCD, MCI, AD and healthy controls (HC) performed tasks assessing prospective duration estimation, production, reproduction, implicit temporal learning in conditions dependent from external cues (externally-cued learning, ECL) or independent from external cues (internally-based learning, IBL), retrospective duration estimation, the subjective experience of time and the temporal collocation of events. AD patients performed worse than HC and SCD in prospective timing, and in collocating events in time. The subjective experience of time did not differ between groups. Concerning temporal learning, AD performed worse in ECL than in IBL, whereas SCD performed worse in IBL than in ECL. SCD, MCI and AD patients all showed errors greater than HC in retrospective duration estimation. Results point to implicit temporal learning in externally-cued conditions and retrospective time estimation as possible early markers of cognitive decline.

Cortical complexity alterations in the medial temporal lobe are associated with Alzheimer's disease psychosis.

Psychosis is frequent in Alzheimer's disease (AD) and it is associated with a worse disease course. AD psychosis may represent a distinct AD phenotype, though its specific neurobiological underpinnings have yet to be identified. This study investigated neural underpinnings of AD psychosis using surface-based-morphometry.Data from 32 AD patients, 17 with psychosis (AD-P) and 15 without were analyzed. Average cortical complexity (fractal dimension, FD) was estimated for each theoretically motivated ROI and patient. First, we compared regional FD in AD-P and AD patients. Then we calculated the correlation coefficients between FD and the severity of misidentification and paranoid psychotic symptoms. AD-P showed decreased FD in ventral-visual-stream compared to AD, suggesting that perceptual processes might be pivotal in psychosis. A negative correlation was found between misidentification severity and FD in the entorhinal cortex suggesting that misidentification may be specifically associated with alterations in regions involved in high-level perceptual and contextualization processes.

DiaNe: A New First-Level Computerized Tool Assessing Memory, Attention, and Visuospatial Processing to Detect Early Pathological Cognitive Decline.

BACKGROUND: Detecting the beginning of cognitive decay is crucial to guarantee good management and the possible prevention of dementia progression. The present study arises from observations collected during an educational event to promote mental and physical health in which incidental neuropsychological data gathered on 290 citizens showed the importance of routine neuropsychological examination in detecting early signs of cognitive decay, since many individuals were unaware of the decrease in their cognitive efficiency. Accordingly, the availability of a screening tool that is computerized, portable, self-administrable, and sensitive to the main neurocognitive changes testifying the progression towards pathological aging is critical. OBJECTIVE: To this aim, we developed a computerized battery for the early, preclinical Diagnosis of Neurocognitive disease (DiaNe), that can be self-administered and performed autonomously by using a tablet. METHODS: DiaNe includes tests expected to evaluate the main cognitive domains involved in neurodegenerative diseases (memory, attention, executive functions) with a detailed assessment of visuospatial memory in particular. RESULTS: DiaNe is not just the translation of standard tests into telematics, rather it is a new tool that provides both accuracy and response time measurements, aimed to screen cognitive profile and monitor it over time, being able to detect changes in still normal performances that may be suggestive of an ongoing onset of neurocognitive disorders. CONCLUSION: Here we present an investigation of DiaNe concurrent validity showing that its results are comparable to those obtained by existing paper-and-pencil neuropsychological tests, and propose that DiaNe could be a useful, quick, and economical instrument for the monitoring of cognitive aging.

Visual hallucinations in Lewy body disease: pathophysiological insights from phenomenology.

Visual hallucinations (VH) in Lewy body disease (LBD) have a heterogenous phenomenology classified into minor phenomena (MVH) and complex hallucinations (CVH). Mechanisms underpinning VH and their temporal aspects are largely unknown. According to the hodotopic model, we investigated whether changes in distinct cognitive domains and neural networks in the hallucination trait underpin temporal aspects of MVH and CVH in the hallucination state. 35 LBD patients with VH underwent a complete neuropsychological evaluation and resting-state fMRI. North-East-Visual-Hallucinations-Interview was used to assess their typical VH content, duration, and frequency. We found that MVH was not associated with cognitive impairment, while CVH was associated with impairments in visuoperceptual processes, attention and visual abstract reasoning. In seed-to-seed functional connectivity (FC) analysis we identified functional couplings associated with MVH and CVH temporal severity (duration x frequency), duration and frequency. MVH severity was negatively associated with FC between early visual areas (EVA) and ventral-visual-stream regions, and negatively associated with FC between brainstem and EVA, which may be linked to LBD brainstem neuropathology. CVH duration was positively associated with FC between ventral-visual stream and salience network (SN). CVH frequency was negatively associated with FC between DMN and SN. Functional alterations in distinct visual and attentional networks and their dynamic interaction in trait LBD hallucinators are linked to both the phenomenology of state content and its temporal characteristics. Within a network, VH frequency and duration may be linked to different types of functional alterations: increased connectivity leading to sustained activity prolonging VH (duration) and decreased connectivity increasing dysregulated, spontaneous activity (frequency). These findings support the hodotopic hypothesis of VH and may reflect a link between VH phenomenology, LBD neuropathological progression and the involvement of specific neurotransmitter systems.

Reactivity of posterior cortical electroencephalographic alpha rhythms during eyes opening in cognitively intact older adults and patients with dementia due to Alzheimer's and Lewy body diseases.

Please modify the Abstract as follows:Here we tested if the reactivity of posterior resting-state electroencephalographic (rsEEG) alpha rhythms from the eye-closed to the eyes-open condition may differ in patients with dementia due to Lewy Bodies (DLB) and Alzheimer's disease (ADD) as a functional probe of the dominant neural synchronization mechanisms regulating the vigilance in posterior visual systems.We used clinical, demographical, and rsEEG datasets in 28 older adults (Healthy), 42 DLB, and 48 ADD participants. The eLORETA freeware was used to estimate cortical rsEEG sources.Results showed a substantial (> -10%) reduction in the posterior alpha activities during the eyes-open condition in 24 Healthy, 26 ADD, and 22 DLB subjects. There were lower reductions in the posterior alpha activities in the ADD and DLB groups than in the Healthy group. That reduction in the occipital region was lower in the DLB than in the ADD group.These results suggest that DLB patients may suffer from a greater alteration in the neural synchronization mechanisms regulating vigilance in occipital cortical systems compared to ADD patients.

Classification of Patients with Alzheimer's Disease and Dementia with Lewy Bodies using Resting EEG Selected Features at Sensor and Source Levels: A Proof-of-Concept Study.

BACKGROUND: Early differentiation between Alzheimer's disease (AD) and Dementia with Lewy Bodies (DLB) is important for accurate prognosis, as DLB patients typically show faster disease progression. Cortical neural networks, necessary for human cognitive function, may be disrupted differently in DLB and AD patients, allowing diagnostic differentiation between AD and DLB. OBJECTIVE: This proof-of-concept study assessed whether the application of machine learning techniques to data derived from resting-state electroencephalographic (rsEEG) rhythms (discriminant sensor power, 19 electrodes) and source connectivity (between five cortical regions of interest) allowed differentiation between DLB and AD. METHODS: Clinical, demographic, and rsEEG datasets from DLB patients (N=30), AD patients (N=30), and control seniors (NOld, N=30), matched for age, sex, and education, were taken from our international database. Individual (delta, theta, alpha) and fixed (beta) rsEEG frequency bands were included. The rsEEG features for the classification task were computed at both sensor and source levels. The source level was based on eLORETA freeware toolboxes for estimating cortical source activity and linear lagged connectivity. Fluctuations of rsEEG recordings (band-pass waveform envelopes of each EEG rhythm) were also computed at both sensor and source levels. After blind feature reduction, rsEEG features served as input to support vector machine (SVM) classifiers. Discrimination of individuals from the three groups was measured with standard performance metrics (accuracy, sensitivity, and specificity). RESULTS: The trained SVM two-class classifiers showed classification accuracies of 97.6% for NOld vs. AD, 99.7% for NOld vs. DLB, and 97.8% for AD vs. DLB. Three-class classifiers (AD vs. DLB vs. NOld) showed classification accuracy of 94.79%. CONCLUSION: These promising preliminary results should encourage future prospective and longitudinal cross-validation studies using higher resolution EEG techniques and harmonized clinical procedures to enable the clinical application of these machine learning techniques.

Altered speech-related cortical network in frontotemporal dementia.

BACKGROUND: In healthy subjects (HS), transcranial magnetic stimulation (TMS) demonstrated an increase in motor-evoked potential (MEP) amplitudes during specific linguistic tasks. This finding indicates functional connections between speech-related cortical areas and the dominant primary motor cortex (M1). OBJECTIVE: To investigate M1 function with TMS and the speech-related cortical network with neuroimaging measures in frontotemporal dementia (FTD), including the non-fluent variant of primary progressive aphasia (nfv-PPA) and the behavioral variant of FTD (bv-FTD). METHODS: M1 excitability changes during specific linguistc tasks were examined using TMS in 24 patients (15 with nfv-PPA and 9 with bv-FTD) and in 18 age-matched HS. In the same patients neuroimaging was used to assess changes in specific white matter (WM) bundles and grey matter (GM) regions involved in language processing, with diffusion tensor imaging (DTI) and voxel-based morphometry (VBM). RESULTS: During the linguistic task, M1 excitability increased in HS, whereas in FTD patients it did not. M1 excitability changes were comparable in nfv-PPA and bv-FTD. DTI revealed decreased fractional anisotropy in the superior and inferior longitudinal and uncinate fasciculi. Moreover, VBM disclosed GM volume loss in the left frontal operculum though not in the parietal operculum or precentral gyrus. Furthermore, WM and GM changes were comparable in nfv-PPA and bv-FTD. There was no correlation between neurophysiological and neuroimaging changes in FTD. Atrophy in the left frontal operculum correlated with linguistic dysfunction, assessed by semantic and phonemic fluency tests. CONCLUSION: We provide converging neurophysiological and neuroimaging evidence of abnormal speech-related cortical network activation in FTD.

Revisiting Criteria for Psychosis in Alzheimer's Disease and Related Dementias: Toward Better Phenotypic Classification and Biomarker Research.

BACKGROUND: Psychotic symptoms are common in Alzheimer's disease (AD) and related neurodegenerative disorders and are associated with more rapid disease progression and increased mortality. It is unclear to what degree existing criteria are utilized in clinical research and practice. OBJECTIVE: To establish research criteria for the diagnosis of psychosis in AD. METHODS: The International Society to Advance Alzheimer's Research and Treatment (ISTAART) Neuropsychiatric Symptoms (NPS) Professional Interest Area (PIA) psychosis subgroup reviewed existing criteria for psychosis in AD and related dementias. Through a series of in person and on-line meetings, a priority checklist was devised to capture features necessary for current research and clinical needs. PubMed, Medline and other relevant databases were searched for relevant criteria. RESULTS: Consensus identified three sets of criteria suitable for review including those of Jeste and Finkel, Lyketsos, and the Diagnostic and Statistical Manual for Mental Disorders, 5th edition. It was concluded that existing criteria could be augmented by including a more specific differentiation between delusions and hallucinations, address overlap with related conditions (agitation in particular), adding the possibility of symptoms emerging in the preclinical and prodromal phases, and building on developing research in disease biomarkers. CONCLUSION: We propose criteria, developed to improve phenotypic classification of psychosis in AD, and advance the research agenda in the field to improve epidemiological, biomarker, and genetics research in the field. These criteria serve as a complement to the International Psychogeriatric Association criteria for psychosis in neurocognitive disorders.

Abnormalities of resting-state EEG in patients with prodromal and overt dementia with Lewy bodies: Relation to clinical symptoms.

OBJECTIVE: Here we tested if cortical sources of resting state electroencephalographic (rsEEG) rhythms may differ in sub-groups of patients with prodromal and overt dementia with Lewy bodies (DLB) as a function of relevant clinical symptoms. METHODS: We extracted clinical, demographic and rsEEG datasets in matched DLB patients (N = 60) and control Alzheimer's disease (AD, N = 60) and healthy elderly (Nold, N = 60) seniors from our international database. The eLORETA freeware was used to estimate cortical rsEEG sources. RESULTS: As compared to the Nold group, the DLB and AD groups generally exhibited greater spatially distributed delta source activities (DLB > AD) and lower alpha source activities posteriorly (AD > DLB). As compared to the DLB "controls", the DLB patients with (1) rapid eye movement (REM) sleep behavior disorders showed lower central alpha source activities (p < 0.005); (2) greater cognitive deficits exhibited higher parietal and central theta source activities as well as higher central, parietal, and occipital alpha source activities (p < 0.01); (3) visual hallucinations pointed to greater parietal delta source activities (p < 0.005). CONCLUSIONS: Relevant clinical features were associated with abnormalities in spatial and frequency features of rsEEG source activities in DLB patients. SIGNIFICANCE: Those features may be used as neurophysiological surrogate endpoints of clinical symptoms in DLB patients in future cross-validation prospective studies.

Abnormal cortical neural synchronization mechanisms in quiet wakefulness are related to motor deficits, cognitive symptoms, and visual hallucinations in Parkinson's disease patients: an electroencephalographic study.

Compared with Alzheimer's disease (AD), Parkinson's disease (PD) shows peculiar clinical manifestations related to vigilance (i.e., executive cognitive deficits and visual hallucinations) that may be reflected in resting-state electroencephalographic rhythms. To test this hypothesis, clinical and resting-state electroencephalographic rhythms in age-, sex-, and education-matched PD patients (N = 136) and Alzheimer's disease patients (AD, N = 85), and healthy older participants (Nold, N = 65), were available from an international archive. Electroencephalographic sources were estimated by eLORETA software. The results are as follows: (1) compared to the Nold participants, the AD and PD patients showed higher widespread delta source activities (PD > AD) and lower posterior alpha source activities (AD > PD); (2) the PD patients with the most pronounced motor deficits exhibited very low alpha source activities in widespread cortical regions; (3) the PD patients with the strongest cognitive deficits showed higher alpha source activities in widespread cortical regions; and (4) compared to the PD patients without visual hallucinations, those with visual hallucinations were characterized by higher posterior alpha sources activities. These results suggest that in PD patients resting in quiet wakefulness, abnormalities in cortical neural synchronization at alpha frequencies are differently related to cognitive, motor, and visual hallucinations. Interestingly, parallel PD neuropathological processes may have opposite effects on cortical neural synchronization mechanisms generating cortical alpha rhythms in quiet wakefulness.

Modulation of the Cannabinoid System: A New Perspective for the Treatment of the Alzheimer's Disease.

The pathogenesis of Alzheimer's disease (AD) is somewhat complex and has yet to be fully understood. As the effectiveness of the therapy currently available for AD has proved to be limited, the need for new drugs has become increasingly urgent. The modulation of the endogenous cannabinoid system (ECBS) is one of the potential therapeutic approaches that is attracting a growing amount of interest. The ECBS consists of endogenous compounds and receptors. The receptors CB1 and CB2 have already been well characterized: CB1 receptors, which are abundant in the brain, particularly in the hippocampus, basal ganglia and cerebellum, regulate memory function and cognition. It has been suggested that the activation of CB1 receptors reduces intracellular Ca concentrations, inhibits glutamate release and enhances neurotrophin expression and neurogenesis. CB2 receptors are expressed, though to a lesser extent, in the central nervous system, particularly in the microglia and immune system cells involved in the release of cytokines. CB2 receptors have been shown to be upregulated in neuritic plaque-associated microglia in the hippocampus and entorhinal cortex of patients, which suggests that these receptors play a role in the inflammatory pathology of AD. The role of the ECBS in AD is supported by cellular and animal models. By contrast, few clinical studies designed to investigate therapies aimed at reducing behaviour disturbances, especially night-time agitation, eating behaviour and aggressiveness, have yielded positive results. In this review, we will describe how the manipulation of the ECBS offers a potential approach to the treatment of AD.

Neural substrates of internally-based and externally-cued timing: An activation likelihood estimation (ALE) meta-analysis of fMRI studies.

A dynamic interplay exists between Internally-Based (IBT) and Externally-Cued (ECT) time processing. While IBT processes support the self-generation of context-independent temporal representations, ECT mechanisms allow constructing temporal representations primarily derived from the structure of the sensory environment. We performed an activation likelihood estimation (ALE) meta-analysis on 177 fMRI experiments, from 79 articles, to identify brain areas involved in timing; two individual ALEs tested the hypothesis of a neural segregation between IBT and ECT. The general ALE highlighted a network involving supplementary motor area (SMA), intraparietal sulcus, inferior frontal gyrus (IFG), insula (INS) and basal ganglia. We found evidence of a partial dissociation between IBT and ECT. IBT relies on a subset of areas also involved in ECT, however ECT tasks activate SMA, right IFG, left precentral gyrus and INS in a significantly stronger way. Present results suggest that ECT involves the detection of environmental temporal regularities and their integration with the output of the IBT processing, to generate a representation of time which reflects the temporal metric of the environment.