Publications by authors named "Carlo de Lena"

37 Publications

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

Int Psychogeriatr 2021 Feb 15:1-14. Epub 2021 Feb 15.

Department of Human Neurosciences, "Sapienza" University of Rome, Rome, Italy.

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.
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http://dx.doi.org/10.1017/S1041610220004056DOI Listing
February 2021

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

Clin Neurophysiol 2020 11 23;131(11):2716-2731. Epub 2020 Sep 23.

Department of Neurology, School of Medicine, Istanbul Medipol University, Istanbul, Turkey.

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.
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http://dx.doi.org/10.1016/j.clinph.2020.09.004DOI Listing
November 2020

Altered speech-related cortical network in frontotemporal dementia.

Brain Stimul 2020 May - Jun;13(3):765-773. Epub 2020 Feb 26.

Department of Human Neurosciences, Sapienza University of Rome, Viale Dell'Università 30, 00185, Rome, Italy; IRCCS Neuromed, Via Atinense 18, 86077, Pozzilli, IS, Italy. Electronic address:

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.
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http://dx.doi.org/10.1016/j.brs.2020.02.029DOI Listing
November 2020

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.

Neurobiol Aging 2020 07 12;91:88-111. Epub 2020 Mar 12.

Department of Biophysics, International School of Medicine, Istanbul Medipol University, Istanbul, Turkey.

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.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.02.029DOI Listing
July 2020

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

J Alzheimers Dis 2020 ;73(3):1143-1156

Medical School, College of Medicine and Health, University of Exeter, Exeter, UK.

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.
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http://dx.doi.org/10.3233/JAD-190828DOI Listing
May 2021

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

Int J Geriatr Psychiatry 2019 11 14;34(11):1689-1697. Epub 2019 Aug 14.

Cognitive and Motor Rehabilitation and Neuroimaging Unit, IRCCS Fondazione Santa Lucia, Rome, Italy.

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.
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http://dx.doi.org/10.1002/gps.5183DOI Listing
November 2019

Somatosensory Temporal Discrimination Threshold in Patients with Cognitive Disorders.

J Alzheimers Dis 2019 ;70(2):425-432

Department of Human Neuroscience, Sapienza University of Rome, Rome Italy.

Background: The temporal processing of sensory information can be evaluated by testing the somatosensory temporal discrimination threshold (STDT), which is defined as the shortest interstimulus interval needed to recognize two sequential sensory stimuli as separate in time. The STDT requires the functional integrity of the basal ganglia and of the somatosensory cortex (S1). Although there is evidence that time processing is impaired in patients with Alzheimer's disease (AD), no study has yet investigated STDT in patients with various degree of cognitive impairment.

Objective: The aim of our study was to understand how cognition and attention deficits affect STDT values in patients with cognitive abnormalities.

Methods: We enrolled 63 patients: 28 had mild-moderate AD, 16 had mild cognitive impairment (MCI), and the remaining 19 had subjective cognitive deficit (SCD). A group of 45 age-matched healthy subjects acted as controls. Paired tactile stimuli for STDT testing consisted of square-wave electrical pulses delivered with a constant current stimulator through surface electrodes over the distal phalanx of the index finger.

Results: STDT values were higher in AD and MCI patients than in SCD subjects or healthy controls. Changes in the STDT in AD and MCI were similar in both conditions and did not correlate with disease severity.

Conclusions: STDT alterations in AD and MCI may reflect a dysfunction of the dopaminergic system, which signals salient events and includes the striatum and the mesocortical and mesolimbic circuits.
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http://dx.doi.org/10.3233/JAD-190385DOI Listing
October 2020

Is Losing One's Way a Sign of Cognitive Decay? Topographical Memory Deficit as an Early Marker of Pathological Aging.

J Alzheimers Dis 2019 ;68(2):679-693

Cognitive and Motor Rehabilitation Unit, IRCCS Fondazione Santa Lucia, Rome, Italy.

Spatial navigation tasks reveal small differences between normal and pathological aging and may thus disclose potential neuropsychological predictors of neurodegenerative diseases. The aim of our study was to investigate which navigational skills are compromised in the early phase of pathological aging as well as the extent to which they are compromised. We performed an extensive neuropsychological evaluation based on working memory and learning tasks (i.e., Corsi Block-Tapping Test and Walking Corsi Test) involving both reaching and navigational vista spaces. We also assessed spatial navigation skills in the real world by asking participants to perform route-learning and landmark-recognition tasks. We conducted a cross-sectional study on nineteen patients with a diagnosis of mild cognitive impairment (MCI) who displayed either an isolated memory deficit (single-domain amnestic MCI, MCIsd; N = 3) or a memory deficit associated with deficits in other cognitive functions (multi-domain MCI, MCImd; N = 16) as well as on nineteen healthy control participants. The groups' performances were compared by means of mixed factorial ANOVA and two-sample t-tests. We found that patients with MCI performed worse than controls, especially when they were required to learn spatial positions within the navigational vista space. Route-learning within the real environment was also impaired whereas landmark-recognition was spared. The same pattern of results emerged in the MCImd subgroup. Moreover, single case analyses on MCIsd patients revealed a dissociation between learning of spatial positions within navigational vista space and within reaching space. These results suggest that topographical learning is compromised in the early phase of MCIsd and MCImd and that spatial navigation tasks may be used to better characterize topographical disorientation in MCI patients as well as for the early diagnosis of pathological aging.
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http://dx.doi.org/10.3233/JAD-180890DOI Listing
July 2020

Abnormalities of functional cortical source connectivity of resting-state electroencephalographic alpha rhythms are similar in patients with mild cognitive impairment due to Alzheimer's and Lewy body diseases.

Neurobiol Aging 2019 05 24;77:112-127. Epub 2019 Jan 24.

Department of Biophysics, International School of Medicine, Istanbul Medipol University, Istanbul, Turkey.

Previous evidence has shown different resting-state eyes-closed electroencephalographic delta (<4 Hz) and alpha (8-10.5 Hz) source connectivity in subjects with dementia due to Alzheimer's (ADD) and Lewy body (DLB) diseases. The present study tested if the same differences may be observed in the prodromal stages of mild cognitive impairment (MCI). Here, clinical and resting-state eyes-closed electroencephalographic data in age-, gender-, and education-matched 30 ADMCI, 23 DLBMCI, and 30 healthy elderly (Nold) subjects were available in our international archive. Mini-Mental State Evaluation (MMSE) score was matched in the ADMCI and DLBMCI groups. The eLORETA freeware estimated delta and alpha source connectivity by the tool called lagged linear connectivity (LLC). Area under receiver operating characteristic curve (AUROCC) indexed the classification accuracy among individuals. Results showed that widespread interhemispheric and intrahemispheric LLC solutions in alpha sources were abnormally lower in both MCI groups compared with the Nold group, but with no differences were found between the 2 MCI groups. AUROCCs of LLC solutions in alpha sources exhibited significant accuracies (0.72-0.75) in the discrimination of Nold versus ADMCI-DLBMCI individuals, but not between the 2 MCI groups. These findings disclose similar abnormalities in ADMCI and DLBMCI patients as revealed by alpha source connectivity. It can be speculated that source connectivity mostly reflects common cholinergic impairment in prodromal state of both AD and DLB, before a substantial dopaminergic derangement in the dementia stage of DLB.
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http://dx.doi.org/10.1016/j.neurobiolaging.2019.01.013DOI Listing
May 2019

Misidentification Subtype of Alzheimer's Disease Psychosis Predicts a Faster Cognitive Decline.

CPT Pharmacometrics Syst Pharmacol 2019 05 15;8(5):308-315. Epub 2019 Mar 15.

UMR 1137 Infection, Antimicrobials, Modelling, Evolution (IAME) French Institute for Medical Research (INSERM), University Paris, Paris, France.

The presence of psychosis is associated with a more rapid decline in Alzheimer's disease (AD), but the impact of paranoid (persecutory delusions) and misidentification (misperceptions and/or hallucinations) subtypes of psychosis on the speed of decline in AD is still unclear. We analyzed data on Alzheimer's Disease Neuroimaging Initiative 2 participants with late mild cognitive impairment or AD, and we described individual trajectories of Alzheimer's Disease Assessment Scale-Cognitive Subscale scores using a semimechanistic logistic model with a mixed effects-based approach, which accounted for dropout and adjusted for baseline Mini Mental State Examination scores. The covariate model included psychosis subtypes, age, gender, education, medications, and Apolipoprotein E epsilon 4 (Apo-e ε4 genotype). We found that the Alzheimer's Disease Assessment Scale-Cognitive Subscale rate of increase was doubled in misidentification (β  = 0.63, P = 0.031) and mixed (both subtypes; β  = 0.70, P = 0.003) when compared with nonpsychotic (or paranoid) patients, suggesting that the misidentification subtype may represent a distinct AD sub-phenotype associated with an accelerated pathological process.
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http://dx.doi.org/10.1002/psp4.12389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6533361PMC
May 2019

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

Neurosci Biobehav Rev 2019 01 11;96:197-209. Epub 2018 Oct 11.

Department of Psychology, "Sapienza" University of Rome, Italy; IRCCS Fondazione Santa Lucia, Rome, Italy.

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.
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http://dx.doi.org/10.1016/j.neubiorev.2018.10.003DOI Listing
January 2019

Levodopa may affect cortical excitability in Parkinson's disease patients with cognitive deficits as revealed by reduced activity of cortical sources of resting state electroencephalographic rhythms.

Neurobiol Aging 2019 01 30;73:9-20. Epub 2018 Aug 30.

Department of Neurology, University of Istanbul-Medipol, Istanbul, Turkey.

We hypothesized that dopamine neuromodulation might affect cortical excitability in Parkinson's disease (PD) patients set in quiet wakefulness, as revealed by resting state eyes-closed electroencephalographic (rsEEG) rhythms at alpha frequencies (8-12 Hz). Clinical and rsEEG rhythms in PD with dementia (N = 35), PD with mild cognitive impairment (N = 50), PD with normal cognition (N = 35), and normal (N = 50) older adults were available from an international archive. Cortical rsEEG sources were estimated by exact low-resolution brain electromagnetic tomography. Compared with the normal older group, the PD groups showed reduced occipital alpha sources and increased widespread delta (<4 Hz) sources. Widespread frontal and temporal alpha sources exhibited an increase in PD with dementia compared with PD with mild cognitive impairment and PD with normal cognition groups, as function of dopamine depletion severity, typically greater in the former than the latter groups. A daily dose of levodopa induced a widespread reduction in cortical delta and alpha sources in a subgroup of 13 PD patients under standard chronic dopaminergic regimen. In PD patients in quiet wakefulness, alpha cortical source activations may reflect an excitatory effect of dopamine neuromodulation.
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http://dx.doi.org/10.1016/j.neurobiolaging.2018.08.010DOI Listing
January 2019

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

Curr Neuropharmacol 2019 ;17(2):176-183

Department of Human Neuroscience, Sapienza, University of Rome, Rome, Italy.

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.
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http://dx.doi.org/10.2174/1570159X16666180702144644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6343203PMC
May 2019

Parkinsonism is associated with altered primary motor cortex plasticity in frontotemporal dementia-primary progressive aphasia variant.

Neurobiol Aging 2018 09 29;69:230-238. Epub 2018 May 29.

IRCCS Neuromed Institute, Pozzilli, Province of Isernia, Italy; Department of Human Neuroscience, Sapienza University of Rome, Rome, Italy. Electronic address:

In frontotemporal dementia (FTD), the behavioral variant (bv-FTD) and nonfluent variant of primary progressive aphasia (nfv-PPA) reflect a prominent neurodegenerative involvement of the frontal lobe networks, which may include the premotor and motor areas and thus cause heterogeneous clinical symptoms including parkinsonism. With the technique of transcranial magnetic stimulation, we investigated long-term potentiation- and long-term depression-like plasticity in the primary motor cortex of bv-FTD and nfv-PPA patients, with and without parkinsonism, by using the theta-burst stimulation (TBS) protocol. We applied the intermittent TBS and continuous TBS in 20 FTD patients and 18 age-matched healthy subjects. Results were also compared with those achieved in a cohort of age-matched patients with Parkinson's disease. The responses to TBS were abnormal in FTD patients with parkinsonism. By contrast, the TBS induced normal responses in patients with both nfv-PPA and bv-FTD without parkinsonism. Finally, responses to TBS were comparable in patients with FTD with parkinsonism and patients with Parkinson's disease. We provide evidence of abnormal primary motor cortex long-term potentiation-/long-term depression-like plasticity in patients with FTD and parkinsonism suggesting neurodegenerative processes in the corticobasal ganglia-thalamo-cortical motor networks in these patients.
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http://dx.doi.org/10.1016/j.neurobiolaging.2018.05.026DOI Listing
September 2018

Functional cortical source connectivity of resting state electroencephalographic alpha rhythms shows similar abnormalities in patients with mild cognitive impairment due to Alzheimer's and Parkinson's diseases.

Clin Neurophysiol 2018 04 31;129(4):766-782. Epub 2018 Jan 31.

Department of Neurosciences, Dokuz Eylül University, Izmir, Turkey; Department of Neurology, Dokuz Eylül University Medical School, Izmir, Turkey.

Objective: This study tested the hypothesis that markers of functional cortical source connectivity of resting state eyes-closed electroencephalographic (rsEEG) rhythms may be abnormal in subjects with mild cognitive impairment due to Alzheimer's (ADMCI) and Parkinson's (PDMCI) diseases compared to healthy elderly subjects (Nold).

Methods: rsEEG data had been collected in ADMCI, PDMCI, and Nold subjects (N = 75 for any group). eLORETA freeware estimated functional lagged linear connectivity (LLC) from rsEEG cortical sources. Area under receiver operating characteristic (AUROC) curve indexed the accuracy in the classification of Nold and MCI individuals.

Results: Posterior interhemispheric and widespread intrahemispheric alpha LLC solutions were abnormally lower in both MCI groups compared to the Nold group. At the individual level, AUROC curves of LLC solutions in posterior alpha sources exhibited moderate accuracies (0.70-0.72) in the discrimination of Nold vs. ADMCI-PDMCI individuals. No differences in the LLC solutions were found between the two MCI groups.

Conclusions: These findings unveil similar abnormalities in functional cortical connectivity estimated in widespread alpha sources in ADMCI and PDMCI. This was true at both group and individual levels.

Significance: The similar abnormality of alpha source connectivity in ADMCI and PDMCI subjects might reflect common cholinergic impairment.
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http://dx.doi.org/10.1016/j.clinph.2018.01.009DOI Listing
April 2018

Abnormalities of Resting State Cortical EEG Rhythms in Subjects with Mild Cognitive Impairment Due to Alzheimer's and Lewy Body Diseases.

J Alzheimers Dis 2018 ;62(1):247-268

Department of Biophysics, Istanbul Medipol University, Istanbul, Turkey.

The present study tested the hypothesis that cortical sources of resting state eyes-closed electroencephalographic (rsEEG) rhythms reveal different abnormalities in cortical neural synchronization in groups of patients with mild cognitive impairment due to Alzheimer's disease (ADMCI) and dementia with Lewy bodies (DLBMCI) as compared to cognitively normal elderly (Nold) subjects. Clinical and rsEEG data in 30 ADMCI, 23 DLBMCI, and 30 Nold subjects were available in an international archive. Age, gender, and education were carefully matched in the three groups. The Mini-Mental State Evaluation (MMSE) score was matched between the ADMCI and DLBMCI groups. Individual alpha frequency peak (IAF) was used to determine the delta, theta, alpha1, alpha2, and alpha3 frequency band ranges. Fixed beta1, beta2, and gamma bands were also considered. eLORETA estimated the rsEEG cortical sources. Receiver operating characteristic curve (ROCC) classified these sources across individuals. Compared to Nold, IAF showed marked slowing in DLBMCI and moderate in ADMCI. Furthermore, the posterior alpha 2 and alpha 3 source activities were more abnormal in the ADMCI than the DLBMCI group, while widespread delta source activities were more abnormal in the DLBMCI than the ADMCI group. The posterior delta and alpha sources correlated with the MMSE score and correctly classified the Nold and MCI individuals (area under the ROCC >0.85). In conclusion, the ADMCI and DLBMCI patients showed different features of cortical neural synchronization at delta and alpha frequencies underpinning brain arousal and vigilance in the quiet wakefulness. Future prospective cross-validation studies will have to test the clinical validity of these rsEEG markers.
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http://dx.doi.org/10.3233/JAD-170703DOI Listing
March 2019

Abnormalities of resting-state functional cortical connectivity in patients with dementia due to Alzheimer's and Lewy body diseases: an EEG study.

Neurobiol Aging 2018 05 30;65:18-40. Epub 2017 Dec 30.

IBG, Departments of Neurology and Neurosciences, Dokuz Eylül University, Izmir, Turkey.

Previous evidence showed abnormal posterior sources of resting-state delta (<4 Hz) and alpha (8-12 Hz) rhythms in patients with Alzheimer's disease with dementia (ADD), Parkinson's disease with dementia (PDD), and Lewy body dementia (DLB), as cortical neural synchronization markers in quiet wakefulness. Here, we tested the hypothesis of additional abnormalities in functional cortical connectivity computed in those sources, in ADD, considered as a "disconnection cortical syndrome", in comparison with PDD and DLB. Resting-state eyes-closed electroencephalographic (rsEEG) rhythms had been collected in 42 ADD, 42 PDD, 34 DLB, and 40 normal healthy older (Nold) participants. Exact low-resolution brain electromagnetic tomography (eLORETA) freeware estimated the functional lagged linear connectivity (LLC) from rsEEG cortical sources in delta, theta, alpha, beta, and gamma bands. The area under receiver operating characteristic (AUROC) curve indexed the classification accuracy between Nold and diseased individuals (only values >0.7 were considered). Interhemispheric and intrahemispheric LLCs in widespread delta sources were abnormally higher in the ADD group and, unexpectedly, normal in DLB and PDD groups. Intrahemispheric LLC was reduced in widespread alpha sources dramatically in ADD, markedly in DLB, and moderately in PDD group. Furthermore, the interhemispheric LLC in widespread alpha sources showed lower values in ADD and DLB than PDD groups. At the individual level, AUROC curves of LLC in alpha sources exhibited better classification accuracies for the discrimination of ADD versus Nold individuals (0.84) than for DLB versus Nold participants (0.78) and PDD versus Nold participants (0.75). Functional cortical connectivity markers in delta and alpha sources suggest a more compromised neurophysiological reserve in ADD than DLB, at both group and individual levels.
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http://dx.doi.org/10.1016/j.neurobiolaging.2017.12.023DOI Listing
May 2018

External Validity of Randomized Controlled Trials on Alzheimer's Disease: The Biases of Frailty and Biological Aging.

Front Neurol 2017 27;8:628. Epub 2017 Nov 27.

Department of Neurology and Psychiatry, Sapienza University of Rome, Rome, Italy.

To date, the external validity of randomized controlled trials (RCTs) on Alzheimer's disease (AD) has been assessed only considering monodimensional variables. Nevertheless, looking at isolated and single characteristics cannot guarantee a sufficient level of appreciation of the AD patients' complexity. The only way to understand whether the two worlds (i.e., research and clinics) deal with the same type of patients is to adopt multidimensional approaches more holistically reflecting the biological age of the individual. In the present study, we compared measures of frailty/biological aging [assessed by a Frailty Index (FI)] of a sample of patients with AD resulted eligible and subsequently included in phase III RCTs compared to patients referring to the same clinical service, but not considered for inclusion. The "RCT sample" and the "real world sample" were found to be statistically similar for all the considered sociodemographic and clinical variables. Nevertheless, the "real world sample" was found to be significantly frailer compared to the "RCT sample," as indicated by higher FI scores [0.28 (SD 0.1) vs. 0.17 (SD 0.1);  < 0.001, respectively]. Moreover, when assessing the relationship between FI and age, we found that the correlation was almost null in the "RCT sample" (Spearman's  = 0.01;  = 0.98), while it was statistically significant in the "real world sample" ( = 0.49;  = 0.02). The application of too rigid designs may result in the poor representativeness of RCT samples. It may even imply the study of a condition biologically different from that observed in the "real world." The adoption of multidimensional measures capable to capture the individual's biological age may facilitate evaluating the external validity of clinical studies, implicitly improving the interpretation of the results and their translation in the clinical arena.
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http://dx.doi.org/10.3389/fneur.2017.00628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5712065PMC
November 2017

Cognitive Training in Patients with Alzheimer's Disease: Findings of a 12-month Randomized Controlled Trial.

Curr Alzheimer Res 2018 03;15(5):452-461

Department of Neurology and Psychiatry, "Sapienza" University of Rome, Rome, Italy.

Background: Cognitive training (CT) is a non-pharmacological intervention based on a set of tasks that reflect specific cognitive functions. CT is aimed at improving cognition in patients with cognitive impairment, though no definitive conclusions have yet been drawn on its efficacy in Alzheimer's disease (AD).

Objective: To assess the effectiveness of a CT program designed to improve cognition in AD patients.

Method: This is a randomized, controlled, single-blind, longitudinal trial with a no-treatment control condition in mild-to-moderate AD. Treated patients received in-group CT twice a week for six months, whereas controls did not. CT consisted of tasks ranging from paper-and-pencil to verbal-learning exercises. Participants' cognitive levels were assessed at baseline, post-intervention and 6 months later by means of a complete neuropsychological test battery. Repeated measures ANOVA was used to analyze the effect of time on the outcome measures, as well as to compare treated and untreated patients over time, with demographic data considered as covariates.

Results: Of the 140 patients enrolled, 45 in the treated group and 85 controls concluded the study. The CT significantly improved treated subjects' cognitive functions immediately after the CT. Six months later, some test scores remained stable when compared with those obtained at baseline. The control group performed significantly worse than the treated group at each time-point, displaying a progressive cognitive decline over time.

Conclusion: Our results suggest that CT may improve cognitive functions in patients with AD and may help to temporarily slow their cognitive decline.
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http://dx.doi.org/10.2174/1567205014666171113105044DOI Listing
March 2018

The Impact of Frailty on the Risk of Conversion from Mild Cognitive Impairment to Alzheimer's Disease: Evidences from a 5-Year Observational Study.

Front Med (Lausanne) 2017 23;4:178. Epub 2017 Oct 23.

Department of Neurology and Psychiatry, Sapienza University of Rome, Rome, Italy.

The frailty construct has increasingly been adopted in the field of cognitive disorders. The aim of the present study was to measure frailty in a cohort of individuals with mild cognitive impairment (MCI) and to explore whether frailty measures may consent to predict the risk of conversion to dementia. We retrospectively reviewed the clinical charts of outpatients with amnesic MCI (aMCI) consecutively recruited at our Department, and followed-up for 5 years. Individual frailty status was measured by means of a frailty index (FI) consisting of 39 deficits (including signs, symptoms, diagnoses, and disabilities). Univariate analyses were used to compare the socio-demographic and clinical characteristics between subjects converting or not converting to probable Alzheimer's disease (AD) dementia over the follow-up. Risk for conversion to AD dementia was assessed using Cox regression models. Ninety-one subjects with aMCI (mean age 72.7, SD 7.1 years; women 49.5%) were consecutively recruited over a period of 12 months. Low levels of frailty were documented in the sample (mean FI score 10.0, SD 5.3). A statistically significant correlation between age and FI was observed. Overall, 58 participants converted to AD dementia over time. The Cox regression analysis showed that age (HR: 1.04, 95% CI: 1.00-1.08), male sex (HR: 0.52, 95% CI: 0.30-0.91), Mini-Mental State Examination score (HR: 0.85, 95% CI: 0.77-0.94), and FI (HR: 1.11, 95% CI: 1.05-1.18) were all significantly associated with the probability of MCI conversion. Individual's frailty status may increase the risk of conversion from a condition of MCI to overt AD dementia. The adoption of constructs comprehensively reflecting the biological decline of the aging subject may add useful estimates and information in the clinical approach to cognitive disorders.
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http://dx.doi.org/10.3389/fmed.2017.00178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5660054PMC
October 2017

Abnormalities of Cortical Neural Synchronization Mechanisms in Subjects with Mild Cognitive Impairment due to Alzheimer's and Parkinson's Diseases: An EEG Study.

J Alzheimers Dis 2017 ;59(1):339-358

Department of Neurology, University of Istanbul-Medipol, Istanbul, Turkey.

The aim of this retrospective and exploratory study was that the cortical sources of resting state eyes-closed electroencephalographic (rsEEG) rhythms might reveal different abnormalities in cortical neural synchronization in groups of patients with mild cognitive impairment due to Alzheimer's disease (ADMCI) and Parkinson's disease (PDMCI) as compared to healthy subjects. Clinical and rsEEG data of 75 ADMCI, 75 PDMCI, and 75 cognitively normal elderly (Nold) subjects were available in an international archive. Age, gender, and education were carefully matched in the three groups. The Mini-Mental State Evaluation (MMSE) was matched between the ADMCI and PDMCI groups. Individual alpha frequency peak (IAF) was used to determine the delta, theta, alpha1, alpha2, and alpha3 frequency band ranges. Fixed beta1, beta2, and gamma bands were also considered. eLORETA estimated the rsEEG cortical sources. Receiver operating characteristic curve (ROC) classified these sources across individuals. Results showed that compared to the Nold group, the posterior alpha2 and alpha3 source activities were more abnormal in the ADMCI than the PDMCI group, while the parietal delta source activities were more abnormal in the PDMCI than the ADMCI group. The parietal delta and alpha sources correlated with MMSE score and correctly classified the Nold and diseased individuals (area under the ROC = 0.77-0.79). In conclusion, the PDMCI and ADMCI patients showed different features of cortical neural synchronization at delta and alpha frequencies underpinning brain arousal and vigilance in the quiet wakefulness. Future prospective cross-validation studies will have to test these rsEEG markers for clinical applications and drug discovery.
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http://dx.doi.org/10.3233/JAD-160883DOI Listing
April 2018

Abnormalities of cortical neural synchronization mechanisms in patients with dementia due to Alzheimer's and Lewy body diseases: an EEG study.

Neurobiol Aging 2017 07 5;55:143-158. Epub 2017 Apr 5.

Department of Neurology, University of Istanbul-Medipol, Istanbul, Turkey.

The aim of this retrospective exploratory study was that resting state eyes-closed electroencephalographic (rsEEG) rhythms might reflect brain arousal in patients with dementia due to Alzheimer's disease dementia (ADD), Parkinson's disease dementia (PDD), and dementia with Lewy body (DLB). Clinical and rsEEG data of 42 ADD, 42 PDD, 34 DLB, and 40 healthy elderly (Nold) subjects were available in an international archive. Demography, education, and Mini-Mental State Evaluation score were not different between the patient groups. Individual alpha frequency peak (IAF) determined the delta, theta, alpha 1, alpha 2, and alpha 3 frequency bands. Fixed beta 1, beta 2, and gamma bands were also considered. rsEEG cortical sources were estimated by means of the exact low-resolution brain electromagnetic source tomography and were then classified across individuals, on the basis of the receiver operating characteristic curves. Compared to Nold, IAF showed marked slowing in PDD and DLB and moderate slowing in ADD. Furthermore, all patient groups showed lower posterior alpha 2 source activities. This effect was dramatic in ADD, marked in DLB, and moderate in PDD. These groups also showed higher occipital delta source activities, but this effect was dramatic in PDD, marked in DLB, and moderate in ADD. The posterior delta and alpha sources allowed good classification accuracy (approximately 0.85-0.90) between the Nold subjects and patients, and between ADD and PDD patients. In quiet wakefulness, delta and alpha sources unveiled different spatial and frequency features of the cortical neural synchronization underpinning brain arousal in ADD, PDD, and DLB patients. Future prospective cross-validation studies should test these rsEEG markers for clinical applications and drug discovery.
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http://dx.doi.org/10.1016/j.neurobiolaging.2017.03.030DOI Listing
July 2017

Sundowning in Dementia: Clinical Relevance, Pathophysiological Determinants, and Therapeutic Approaches.

Front Med (Lausanne) 2016 27;3:73. Epub 2016 Dec 27.

Department of Neurology and Psychiatry, "Sapienza" University of Rome , Rome , Italy.

Sundowning means the emergence or worsening of neuropsychiatric symptoms (NPS) in the late afternoon or early evening. This syndrome has been recognized since a long time in the field of dementing illnesses and is well known among most of health-care providers involved in the assistance of people with dementia. Indeed, it represents a common manifestation among persons with dementia and is associated with several adverse outcomes (such as institutionalization, faster cognitive worsening, and greater caregiver burden). Its occurrence and phenotypic characteristics may be influenced by diverse neurobiological, psychosocial, and environmental determinants. Moreover, it may pose diagnostic challenges in relation to other common causes of behavioral disruptions. Beside these considerations, this phenomenon has so far drawn limited clinical and scientific interest compared to other specific NPS occurring in dementias, as indicated by the lack of commonly agreed definitions, specific screening/assessment tools, and robust estimates on its prevalence. Accordingly, no randomized controlled trial specifically investigating the effectiveness of pharmacological and non-pharmacological strategies in managing this condition among demented patients has been yet conducted. In the present narrative review, we present and discuss available evidence concerning sundowning occurring in people with dementia. A special focus is given to its definitions, pathophysiological determinants, and clinical relevance, as well as to the clinical and therapeutic approaches required for its management in the daily practice.
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http://dx.doi.org/10.3389/fmed.2016.00073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5187352PMC
December 2016

Inappropriate Sexual Behaviors Among Community-Dwelling Patients with Dementia.

Am J Geriatr Psychiatry 2017 Apr 2;25(4):365-371. Epub 2016 Dec 2.

Department of Neurology and Psychiatry, "Sapienza" University of Rome, Rome, Italy.

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.
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http://dx.doi.org/10.1016/j.jagp.2016.11.020DOI Listing
April 2017

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

Alzheimer Dis Assoc Disord 2017 Apr-Jun;31(2):128-134

Departments of *Neurology and Psychiatry †Ophthalmology, Sapienza University, Umberto I Hospital, Rome, Italy.

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.
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http://dx.doi.org/10.1097/WAD.0000000000000176DOI Listing
December 2017

Primary Progressive Orofacial Apraxia: A Ten-Year Long Follow-Up Case Report.

J Alzheimers Dis 2016 10;54(3):1039-1045

Department of Neurology and Psychiatry, Sapienza, University of Rome, Italy.

Orofacial apraxia (OA) as the main symptom in neurodegenerative disorders has not been yet reported. We present the case of a woman with a 22-month long history of isolated OA, studied with cerebrospinal fluid biomarkers and repeated clinical, neuropsychological, and morpho-functional evaluations. Baseline morpho-functional neuroimages revealed a left frontal operculum hypoperfusion with a widespread fronto-temporal involvement at follow-up. Cerebrospinal fluid concentrations of tau and amyloid-β were normal. The ten-year long clinical observation disclosed progressive OA worsening and the late onset of frontal functions impairment and extrapyramidal signs. The early and late stages of a neurodegenerative syndrome with OA as the main clinical feature were characterized.
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http://dx.doi.org/10.3233/JAD-160525DOI Listing
October 2016

Are we really tackling the "evidence-based medicine issue" in Alzheimer's disease?

Eur J Intern Med 2016 Nov 25;35:e29-e30. Epub 2016 Jul 25.

INSERM UMR 1027, Université Paul Sabatier - Toulouse III, France; Gérontopôle, Centre Hospitalier Universitaire de Toulouse, France.

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http://dx.doi.org/10.1016/j.ejim.2016.07.009DOI Listing
November 2016

Musical cognition in Alzheimer's disease: application of the Montreal Battery of Evaluation of Amusia.

Ann N Y Acad Sci 2016 07;1375(1):28-37

Department of Neurology and Psychiatry, "Sapienza" University of Rome, Rome, Italy.

The aim of this study was to assess certain musical abilities in 30 patients with Alzheimer's disease (AD) and 30 healthy controls by using the complete version of the Montreal Battery of Evaluation of Amusia (MBEA). This battery evaluates melodic (scale, contour, and interval) and temporal (rhythm and meter) perception of music and musical memory. We found that altered musical processing is a common feature in AD. Despite that, AD subjects show partially spared abilities for temporal organization of music, though not for melodic perception and musical memory. This peculiar dysfunctional pattern could depend on the neurodegenerative involvement of some specific areas for music perception and memory in the brains of AD patients. Further studies are needed to investigate the usefulness of additional musical tests like the MBEA on larger samples to confirm our preliminary data.
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http://dx.doi.org/10.1111/nyas.13155DOI Listing
July 2016