Publications by authors named "Alessandro Trebbastoni"

26 Publications

  • Page 1 of 1

Motor dysfunction in mild cognitive impairment as tested by kinematic analysis and transcranial magnetic stimulation.

Clin Neurophysiol 2021 02 2;132(2):315-322. Epub 2020 Dec 2.

Department of Human Neurosciences, Sapienza University of Rome, Italy; IRCCS Neuromed, Pozzilli (IS), Italy.

Objective: Previous studies have demonstrated voluntary movement alterations as well as motor cortex excitability and plasticity changes in patients with mild cognitive impairment (MCI). To investigate the pathophysiology of movement abnormalities in MCI, we tested possible relationships between movement abnormalities and primary motor cortex alterations in patients.

Methods: Fourteen amnestic MCI (aMCI) patients and 16 healthy controls were studied. Cognitive assessment was performed using clinical scales. Finger tapping was recorded by a motion analysis system. Transcranial magnetic stimulation was used to test the input/output curve of motor evoked potentials, intracortical inhibition, and short-latency afferent inhibition. Primary motor cortex plasticity was probed by theta burst stimulation. We investigated correlations between movement abnormalities, clinical scores, and cortical neurophysiological parameters.

Results: MCI patients showed less rhythmic movement but no other movement abnormalities. Cortical excitability measures were normal in patients, whereas plasticity was reduced. Movement rhythm abnormalities correlated with frontal dysfunction scores.

Conclusion: Our study in MCI patients demonstrated abnormal voluntary movement and plasticity changes, with no correlation between the two. Altered rhythm correlated with frontal dysfunction.

Significance: Our results contribute to the understanding of pathophysiological mechanisms of motor impairment in MCI.
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http://dx.doi.org/10.1016/j.clinph.2020.10.028DOI Listing
February 2021

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

Bradykinesia in Alzheimer's disease and its neurophysiological substrates.

Clin Neurophysiol 2020 04 27;131(4):850-858. Epub 2020 Jan 27.

Department of Human Neurosciences, Sapienza University of Rome, Italy; IRCCS Neuromed, Pozzilli (IS), Italy. Electronic address:

Objective: Alzheimer's disease is primarily characterized by cognitive decline; recent studies, however, emphasize the occurrence of motor impairment in this condition. Here, we investigate whether motor impairment, objectively evaluated with kinematic techniques, correlates with neurophysiological measures of the primary motor cortex in Alzheimer's disease.

Methods: Twenty patients and 20 healthy subjects were enrolled. Repetitive finger tapping was assessed by means of a motion analysis system. Primary motor cortex excitability was assessed by recording the input/output curve of the motor-evoked potentials and using a conditioning-test paradigm for the assessment of short-interval intracortical inhibition and short-latency afferent inhibition. Plasticity-like mechanisms were indexed according to changes in motor-evoked potential amplitude induced by the intermittent theta-burst stimulation.

Results: Patients displayed slowness and altered rhythm during finger tapping. Movement slowness correlated with reduced short-latency afferent inhibition in patients, thus suggesting that degeneration of the cholinergic system may also be involved in motor impairment in Alzheimer's disease. Moreover, altered movement rhythm in patients correlated with worse scores in the Frontal Assessment Battery.

Conclusion: This study provides new information on the pathophysiology of altered voluntary movements in Alzheimer's disease.

Significance: The study results suggest that a cortical cholinergic deficit may underlie movement slowness in Alzheimer's disease.
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http://dx.doi.org/10.1016/j.clinph.2019.12.413DOI Listing
April 2020

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

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

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

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

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

Retinal nerve fibre layer thickness changes in Alzheimer's disease: Results from a 12-month prospective case series.

Neurosci Lett 2016 08 6;629:165-170. Epub 2016 Jul 6.

Department of Ophthalmology, Sapienza University of Rome, Italy.

Purpose: To compare the 12-month peripapillary retinal nerve fibre layer (pRNFL) thickness change between AD patients and normal subjects.

Methods: In this prospective case series, thirty-six patients with a diagnosis of mild to moderate AD and 36 age-matched control subjects were included. All the subjects underwent neuropsychological (MMSE, ADAS-Cog and CDR) and ophthalmological evaluation, including spectral domain optical coherence tomography (SD-OCT), at baseline and after 12 months.

Results: Compared with controls, AD patients had a significant reduction of the total pRNFL thickness, as well as the pRNFL thickness of the inferior and superior quadrants (p=0.04, p=0.001, and p=0.01, respectively, adjusted for baseline pRNFL measurement, age, gender, and axial length). Correlation analysis showed a significant relationship between inferior pRNFL thickness change and ADAS-Cog scores change (r=-0.35, p=0.02) as well as CDR scores at 12 months (r=-0.39, p=0.008).

Conclusions: Compared with controls, AD patients had a significant reduction in pRNFL thickness over a period of 12 months. The pRNFL reduction was more prominent in the inferior quadrant and paralleled patient's cognitive decline.
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http://dx.doi.org/10.1016/j.neulet.2016.07.006DOI Listing
August 2016

Progressive Language Impairment in an English-Italian Bilingual Woman With Alzheimer Disease: An 18-Month Follow-up.

Alzheimer Dis Assoc Disord 2016 Oct-Dec;30(4):354-356

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

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http://dx.doi.org/10.1097/WAD.0000000000000139DOI Listing
March 2018

Altered Cortical Synaptic Plasticity in Response to 5-Hz Repetitive Transcranial Magnetic Stimulation as a New Electrophysiological Finding in Amnestic Mild Cognitive Impairment Converting to Alzheimer's Disease: Results from a 4-year Prospective Cohort Study.

Front Aging Neurosci 2015 12;7:253. Epub 2016 Jan 12.

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

Introduction: To investigate cortical excitability and synaptic plasticity in amnestic mild cognitive impairment (aMCI) using 5 Hz repetitive transcranial magnetic stimulation (5 Hz-rTMS) and to assess whether specific TMS parameters predict conversion time to Alzheimer's disease (AD).

Materials And Methods: Forty aMCI patients (single- and multi-domain) and 20 healthy controls underwent, at baseline, a neuropsychological examination and 5 Hz-rTMS delivered in trains of 10 stimuli and 120% of resting motor threshold (rMT) intensity over the dominant motor area. The rMT and the ratio between amplitude of the 1st and the 10th motor-evoked potential elicited by the train (X/I-MEP ratio) were calculated as measures of cortical excitability and synaptic plasticity, respectively. Patients were followed up annually over a period of 48 months. Analysis of variance for repeated measures was used to compare TMS parameters in patients with those in controls. Spearman's correlation was performed by considering demographic variables, aMCI subtype, neuropsychological test scores, TMS parameters, and conversion time.

Results: Thirty-five aMCI subjects completed the study; 60% of these converted to AD. The baseline rMT and X/I-MEP ratio were significantly lower in patients than in controls (p = 0.04 and p = 0.01). Spearman's analysis showed that conversion time correlated with the rMT (0.40) and X/I-MEP ratio (0.51).

Discussion: aMCI patients displayed cortical hyperexcitability and altered synaptic plasticity to 5 Hz-rTMS when compared with healthy subjects. The extent of these changes correlated with conversion time. These alterations, which have previously been observed in AD, are thus present in the early stages of disease and may be considered as potential neurophysiological markers of conversion from aMCI to AD.
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http://dx.doi.org/10.3389/fnagi.2015.00253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4709411PMC
January 2016

Choroidal thinning as a new finding in Alzheimer's disease: evidence from enhanced depth imaging spectral domain optical coherence tomography.

J Alzheimers Dis 2014 ;40(4):907-17

Department of Neurology and Psychiatry, Sapienza University, Umberto I Hospital, Rome, Italy.

Background: The involvement of retina and its vasculature has been recently described in Alzheimer's disease (AD). However, none of the previous works have yet investigated the choroid in vivo.

Objective: Spectral domain optical coherence tomography (SD-OCT) and enhanced depth imaging (EDI) technique is non-invasively used to assess choroidal thickness in patients with AD and to determine whether the peripapillary retinal nerve fiber layer (RNFL) and central retinal thickness are reduced compared to normal subjects.

Methods: Forty-two eyes of 21 patients (mean age, 73.1 ± 6.9 years) with a diagnosis of mild to moderate AD and 42 eyes of 21 age-matched control subjects (mean age, 70.3 ± 7.3 years) were included in this prospective, cross-sectional study. All the subjects underwent neuropsychological (MMSE, ADAS-Cog, and CDR) and ophthalmological evaluation. The SD-OCT images of the choroid were obtained by EDI modality. Choroidal thickness was assessed by manual measurement. The following parameters, measured automatically by the OCT software, were also analyzed for each eye: 1-mm central subfield (CSF) retinal thickness, peripapillary RNFL thickness.

Results: Choroidal thickness was significantly thinner in AD than in control eyes (p < 0.05). No difference in CSF retinal thickness was found between groups (p > 0.05). Mean peripapillary RNFL thickness in all four quadrants was similar between groups (p > 0.05). OCT measurements were not correlated with any of the tested psychometric parameters (p > 0.05).

Conclusion: Compared with healthy subjects, patients with AD showed a significant reduction in choroidal thickness. Choroidal thinning may represent an adjunctive biomarker for the diagnosis and follow-up of this disease.
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http://dx.doi.org/10.3233/JAD-132039DOI Listing
January 2015

Attentional processing in bulbar- and spinal-onset amyotrophic lateral sclerosis: insights from event-related potentials.

Amyotroph Lateral Scler Frontotemporal Degener 2014 Mar 2;15(1-2):30-8. Epub 2013 May 2.

Department of Neurology and Psychiatry, Sapienza University of Rome.

Our objective was to evaluate attentional processing with respect to the clinical-onset subtype in amyotrophic lateral sclerosis (ALS) using event-related potentials (ERPs). Thirty-three non-demented ALS patients (22 spinal onset, 11 bulbar onset) and 32 age- and gender-matched controls underwent a psychophysiological evaluation. Mismatch Negativity (MMN), P300 components and Contingent Negative Variation (CNV) were obtained. Latencies and amplitudes of the MMN, P3a and P3b waves and CNV amplitude were then evaluated. Clinical parameters were correlated with ERP data. No differences emerged between ALS patients and controls with regard to the MMN and P3b components. N1-P3a inter-peak latency (Fz, p = 0.003; Cz, p = 0.001; Pz, p = 0.002) was longer in ALS-b than in ALS-s. Total CNV area (Cz, p = 0.01) and W1-CNV area were significantly reduced (Cz, p = 0.05; Pz, p = 0.03) in ALS-b with respect to the one of the controls, while no differences were found between ALS-s patients and controls. In conclusion, automatic pre-attentive processing of stimuli seems to be preserved in ALS. However, a significant delay in the time-course of selective attentive processing and a difficulty in initiating and sustaining attention may be present in ALS-b, which points to a possible dysfunction in the frontal neural network that responds to novelty and to abnormal integration of associative functions. This attentional impairment should be taken in account while developing alternative communicative strategies in ALS patients.
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http://dx.doi.org/10.3109/21678421.2013.787628DOI Listing
March 2014

Repetitive deep transcranial magnetic stimulation improves verbal fluency and written language in a patient with primary progressive aphasia-logopenic variant (LPPA).

Brain Stimul 2013 Jul 24;6(4):545-53. Epub 2012 Oct 24.

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

Background: To date, no therapies are available for the logopenic variant of primary progressive aphasia (LPPA). Even though deep repetitive transcranial magnetic stimulation (rTMS) may improve cognitive functions in some neurodegenerative disorders, no previous studies investigated its effects in patients with LPPA.

Objective: Our aim was to investigate the effects on cognitive function of high frequency rTMS (hf-rTMS) delivered over the left dorso-lateral prefrontal cortex (DLPFC) through a coil designed for deep rTMS, compared to a SHAM stimulation, in a right-handed patient with LPPA.

Methods: The patient presented a progressive language impairment (phonological errors in speech and naming, impaired single word retrieval and sentences repetition) and predominant left perisylvian atrophy and hypoperfusion. He received four stimulation cycles (two REAL and two SHAM) each of whom lasted 20 min for 5 consecutive days. Patient's performances in frontal, visuo-spatial and linguistic tasks were evaluated before and after each stimulation session. Test scores after REAL were compared with those obtained at baseline and after SHAM.

Results: We found a temporary and highly significant improvement in the linguistic skills (both oral and written tasks) but not in the other cognitive domains tested, after REAL, but not SHAM stimulations.

Discussion: Hf-rTMS delivered over the DLPFC could improve language in LPPA by enhancing long-term potentiation and synaptic plasticity within the stimulated and interconnected areas involved in language network. Our findings might prompt future researches into the feasibility and efficacy of deep hf-rTMS as a therapeutic tool in progressive aphasia syndromes and other neurodegenerative disorders.
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http://dx.doi.org/10.1016/j.brs.2012.09.014DOI Listing
July 2013

Seizures in Alzheimer's disease: a retrospective study of a cohort of outpatients.

Epileptic Disord 2010 Mar 22;12(1):16-21. Epub 2010 Feb 22.

Department of Neuroscience, Sapienza University of Rome, Italy.

Purpose: The aim of our study was to define the frequency of seizures in a population of outpatients attending a cognitive function clinic in Italy and to identify risk factors for seizures in patients with Alzheimer's disease.

Methods: In this retrospective study, we analyzed our clinical records to gather information on patients' demographic, metabolic, cardiovascular and cognitive features. We sought to determine the significance of abnormal neuroimaging findings and the use of potentially epileptogenic drugs on the onset of seizures. From the records of 583 patients referred to the clinic for cognitive disturbances, we identified 145 patients with Alzheimer's disease.

Results: Of these 145 patients, 14 (9.7%) had a history of complex partial or generalised seizures, or both. Of the risk factors identified, onset of seizures was associated with male gender and none of the patients with seizures had diabetes. The risk of seizure onset was higher in Alzheimer's disease patients with hyperlipaemia and severe dementia. No other risk factors were identified, although hypertensive patients seemed to be protected.

Conclusions: Seizures in Alzheimer's disease are frequent and often under-recognized. In elderly patients, especially those with Alzheimer's disease, correct diagnosis and treatment are important to prevent disease from worsening and disability from increasing. Patients with dementia should routinely undergo history-taking designed to elicit a history of seizures and define patients at high risk.
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http://dx.doi.org/10.1684/epd.2010.0290DOI Listing
March 2010

Asymmetric responses to repetitive transcranial magnetic stimulation (rTMS) over the left and right primary motor cortex in a patient with lateralized progressive limb-kinetic apraxia.

Neurosci Lett 2008 May 28;437(2):125-9. Epub 2008 Mar 28.

Neurology Neurophysiopathology Unit S. Pertini Hospital, Rome, Italy.

Repetitive transcranial magnetic stimulation (5 Hz-rTMS, 10 stimuli, 120% resting motor threshold intensity, RMT) produces in healthy subjects a progressive facilitation of motor-evoked potential (MEP) amplitude probably through a short-term enhancement of cortical excitatory interneurones. We had the opportunity to investigate the effect of 5 Hz-rTMS delivered over the right and left primary motor cortex (M1) in a patient with limb-kinetic apraxia of the left hand and fingers and reduced cerebral perfusion in the fronto-parietal cortex of the right hemisphere documented by single-photon emission computed tomography scans. Changes in the MEP size during the trains and the RMT were measured and compared between the hemispheres. 5 Hz-rTMS was also delivered in a group of healthy subjects over both hemispheres in order to compare changes in the MEP size from the right and left M1. In the patient, 5 Hz-rTMS delivered over the left hemisphere elicited normal MEPs that progressively increased in size during the trains whereas 5 Hz-rTMS delivered over the right affected hemisphere failed to facilitate the MEP size. RMT was similar in both hemispheres. In healthy subjects, 5 Hz-rTMS delivered over either hemisphere elicited a similar, significant MEP size facilitation. Despite the limitations of a single case, our findings suggest an altered response to 5 Hz-rTMS over the M1 of the affected hemisphere. This asymmetric response correlated with the altered perfusion in the right hemisphere and the patient's lateralized clinical manifestations of apraxia.
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http://dx.doi.org/10.1016/j.neulet.2008.03.072DOI Listing
May 2008