Publications by authors named "Elena Sinforiani"

72 Publications

Evaluation of the efficacy of physical therapy on cognitive decline at 6-month follow-up in Parkinson disease patients with mild cognitive impairment: a randomized controlled trial.

Aging Clin Exp Res 2021 May 12. Epub 2021 May 12.

IRCCS Mondino Foundation, Via Mondino 2, 20100, Pavia, Italy.

Background: In Parkinson's disease (PD), physical activity may represent a possible non-pharmacological intervention not only for improving motor symptoms but also for modulating cognitive impairment.

Aims: To evaluate the efficacy of an intensive physical program on cognitive functions in mid-stage PD patients with mild cognitive impairment (PD-MCI) over a 6-month follow-up.

Methods: This is a 6-month randomized controlled follow-up study. 40 PD-MCI patients were randomized to receive physical therapy (PT) or no specific intervention beside drug treatment (CT). Cognitive and motor assessments were performed at baseline (T0), 4 weeks after baseline (T1) and 6 months after T0. In a previous study, we reported a significant improvement in global cognitive functioning and attention/working-memory at T1. Here, we evaluated the residual effect of the training intervention at 6 months on both cognitive and motor performances.

Results: Intra-group analysis showed that at T2 most of cognitive and motor performances remained stable in the PT when compared to T0, while a significant worsening was observed in the CT. Between-group comparison at T2 showed significantly better results in PT than CT as regards MoCA and motor scales. The percentage change of cognitive and motor performances between T1 and T2 confirmed the benefit of physical therapy on global cognitive functioning scores (MMSE and MoCA).

Conclusions: In this follow-up extension of a longitudinal randomized controlled study, we demonstrated that physical therapy has a positive effect on cognitive functions, which extends beyond the duration of the treatment itself to, at least temporarily, reducing cognitive decline.

Trial Registration: Trial registration number (ClinicalTrials.gov): NCT04012086 (9th July 2019).
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http://dx.doi.org/10.1007/s40520-021-01865-4DOI Listing
May 2021

The Smart Aging Platform for Assessing Early Phases of Cognitive Impairment in Patients With Neurodegenerative Diseases.

Front Psychol 2021 15;12:635410. Epub 2021 Mar 15.

National Neurological Institute C. Mondino Foundation, Pavia, Italy.

Smart Aging is a serious game (SG) platform that generates a 3D virtual reality environment in which users perform a set of screening tasks designed to allow evaluation of global cognition. Each task replicates activities of daily living performed in a familiar environment. The main goal of the present study was to ascertain whether Smart Aging could differentiate between different types and levels of cognitive impairment in patients with neurodegenerative disease. Ninety-one subjects (mean age = 70.29 ± 7.70 years)-healthy older adults (HCs, = 23), patients with single-domain amnesic mild cognitive impairment (aMCI, = 23), patients with single-domain executive Parkinson's disease MCI (PD-MCI, = 20), and patients with mild Alzheimer's disease (mild AD, = 25)-were enrolled in the study. All participants underwent cognitive evaluations performed using both traditional neuropsychological assessment tools, including the Mini-Mental State Examination (MMSE), Montreal Overall Cognitive Assessment (MoCA), and the Smart Aging platform. We analyzed global scores on Smart Aging indices (i.e., accuracy, time, distance) as well as the Smart Aging total score, looking for differences between the four groups. The findings revealed significant between-group differences in all the Smart Aging indices: accuracy ( < 0.001), time ( < 0.001), distance ( < 0.001), and total Smart Aging score ( < 0.001). The HCs outperformed the mild AD, aMCI, and PD-MCI patients in terms of accuracy, time, distance, and Smart Aging total score. In addition, the mild AD group was outperformed both by the HCs and by the aMCI and PD-MCI patients on accuracy and distance. No significant differences were found between aMCI and PD-MCI patients. Finally, the Smart Aging scores significantly correlated with the results of the neuropsychological assessments used. These findings, although preliminary due to the small sample size, suggest the validity of Smart Aging as a screening tool for the detection of cognitive impairment in patients with neurodegenerative diseases.
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http://dx.doi.org/10.3389/fpsyg.2021.635410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005545PMC
March 2021

Cognitive Telerehabilitation for Older Adults With Neurodegenerative Diseases in the COVID-19 Era: A Perspective Study.

Front Neurol 2020 14;11:623933. Epub 2021 Jan 14.

Scientific Institute for Research, Hospitalization and Healthcare (IRCCS) Mondino Foundation, Pavia, Italy.

The COVID-19 pandemic is a global health problem that is radically transforming public and private healthcare organizations around the world, negatively affecting the rehabilitative treatments of non-COVID pathologies as well. In this situation, it becomes crucial to be able to guarantee the continuity of care also to all those patients with neurodegenerative diseases unable to reach healthcare services. Remote communication technologies are gaining momentum as potentially effective options to support health care interventions-including cognitive rehabilitation-while patients can stay safely at home. In this context, we are implementing HomeCoRe (i.e., Home Cognitive Rehabilitation software) in order to offer an innovative approach and a valid support for home-based cognitive rehabilitation in neurodegenerative diseases, such as mild cognitive impairment and early dementia. HomeCoRe has been developed within a research project between engineers and clinicians in order to obtain a usable and safe cognitive rehabilitation tool. This software has multiple advantages for patients and therapists over traditional approaches, as shown in its use in hospital settings. HomeCoRe could then represent an opportunity for accessing cognitive rehabilitation in all those situations where patients and therapists are not in the same location due to particular restrictions, such as COVID-19 pandemic.
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http://dx.doi.org/10.3389/fneur.2020.623933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840692PMC
January 2021

Frontal and Cerebellar Atrophy Supports FTSD-ALS Clinical Continuum.

Front Aging Neurosci 2020 26;12:593526. Epub 2020 Nov 26.

Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.

Background: Frontotemporal Spectrum Disorder (FTSD) and Amyotrophic Lateral Sclerosis (ALS) are neurodegenerative diseases often considered as a continuum from clinical, epidemiologic, and genetic perspectives. We used localized brain volume alterations to evaluate common and specific features of FTSD, FTSD-ALS, and ALS patients to further understand this clinical continuum.

Methods: We used voxel-based morphometry on structural magnetic resonance images to localize volume alterations in group comparisons: patients (20 FTSD, seven FTSD-ALS, and 18 ALS) versus healthy controls (39 CTR), and patient groups between themselves. We used mean whole-brain cortical thickness ( ) to assess whether its correlations with local brain volume could propose mechanistic explanations of the heterogeneous clinical presentations. We also assessed whether volume reduction can explain cognitive impairment, measured with frontal assessment battery, verbal fluency, and semantic fluency.

Results: Common (mainly frontal) and specific areas with reduced volume were detected between FTSD, FTSD-ALS, and ALS patients, confirming suggestions of a clinical continuum, while at the same time defining morphological specificities for each clinical group (e.g., a difference of cerebral and cerebellar involvement between FTSD and ALS). values suggested extensive network disruption in the pathological process, with indications of a correlation between cerebral and cerebellar volumes and in ALS. The analysis of the neuropsychological scores indeed pointed toward an important role for the cerebellum, along with fronto-temporal areas, in explaining impairment of executive, and linguistic functions.

Conclusion: We identified common elements that explain the FTSD-ALS clinical continuum, while also identifying specificities of each group, partially explained by different cerebral and cerebellar involvement.
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http://dx.doi.org/10.3389/fnagi.2020.593526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726473PMC
November 2020

Multicenter Study on Sleep and Circadian Alterations as Objective Markers of Mild Cognitive Impairment and Alzheimer's Disease Reveals Sex Differences.

J Alzheimers Dis 2020 ;78(4):1707-1719

Neurology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

Background: Circadian and sleep disturbances are associated with increased risk of mild cognitive impairment (MCI) and Alzheimer's disease (AD). Wearable activity trackers could provide a new approach in diagnosis and prevention.

Objective: To evaluate sleep and circadian rhythm parameters, through wearable activity trackers, in MCI and AD patients as compared to controls, focusing on sex dissimilarities.

Methods: Based on minute level data from consumer wearable devices, we analyzed actigraphic sleep parameters by applying an electromedical type I registered algorithm, and the corresponding circadian variables in 158 subjects: 86 females and 72 males (42 AD, 28 MCI, and 88 controls). Moreover, we used a confusion-matrix chart method to assess accuracy, precision, sensitivity, and specificity of two decision-tree models based on actigraphic data in predicting disease or health status.

Results: Wake after sleep onset (WASO) was higher (p < 0.001) and sleep efficiency (SE) lower (p = 0.003) in MCI, and Sleep Regularity Index (SRI) was lower in AD patients compared to controls (p = 0.004). SE was lower in male AD compared to female AD (p = 0.038) and SRI lower in male AD compared to male controls (p = 0.008), male MCI (p = 0.047), but also female AD subjects (p = 0.046). Mesor was significantly lower in males in the overall population. Age reduced the dissimilarities for WASO and SE but demonstrated sex differences for amplitude (p = 0.009) in the overall population, controls (p = 0.005), and AD subjects (p = 0.034). The confusion-matrices showed good predictive power of actigraphic data.

Conclusion: Actigraphic data could help identify disease or health status. Sex (possibly gender) differences could impact on neurodegeneration and disease trajectory with potential clinical applications.
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http://dx.doi.org/10.3233/JAD-200632DOI Listing
January 2020

NREM sleep arousal-related disorders reflect cognitive impairment in Parkinson's disease.

Sleep Med 2020 11 5;75:491-496. Epub 2020 Sep 5.

Sleep and Epilepsy Unit, IRCCS Mondino Foundation, Pavia, Italy.

Background: Sleep disorders and cognitive impairment are frequently reported in Parkinson's disease (PD) as non-motor disabling symptoms. While it is known that REM sleep Behaviour Disorder (RBD) in PD is associated with motor and cognitive decline, little is known about the neurobiological significance of NREM sleep arousal-related disorders.

Objectives: to evaluate the cognitive and clinical correlates of arousal-related disorders in PD.

Methods: Clinical data and video-polysomnography were analysed from one hundred-seventy consecutive subjects with PD. Based on the neuropsychological assessment, the subjects were divided into three groups: no cognitive impairment (PD; n = 58), mild cognitive impairment (PD-MCI; n = 58) and overt dementia (PDD; n = 54).

Results: Arousal-related disorders by history were reported in 32.9% of the subjects: 10.3% PD, 31.6% PD-MCI and 59.3% PDD (p = 0.001). Video-PSG captured arousal-related disorders in 1.7% PD, 21.2% MCI-PD and 35.6% PDD (p = 0.001). Arousal-related disorders and RBD were recorded in the same night in 7.7% PD, 9.8% MCI-PD and 15.6% PDD (p = 0.04). Patients with arousal-related disorders captured at V-PSG have a longer disease duration (p = 0.003), higher UPDRS score (p = 0.039), longer duration of treatment with levodopa (p = 0.017) and dopamine agonists (p = 0.018), worse H&Y staging (p = 0.001), lower MMSE score (p = 0.019) and more frequently hallucinations (p = 0.004). In multivariate analysis, cognitive impairment significantly increases the risk of arousal-related disorders (OR 3.387-95% CI 1.395-8.220, p = 0.007).

Conclusion: Arousal-related disorders appear to be a marker of cognitive decline in PD. Recognizing arousal-related disorders should make clinicians aware of a possible cognitive decline in PD and eventually modify the therapeutic approach.
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http://dx.doi.org/10.1016/j.sleep.2020.08.029DOI Listing
November 2020

A double-blind randomized controlled trial of the efficacy of cognitive training delivered using two different methods in mild cognitive impairment in Parkinson's disease: preliminary report of benefits associated with the use of a computerized tool.

Aging Clin Exp Res 2021 Jun 8;33(6):1567-1575. Epub 2020 Sep 8.

IRCCS Mondino Foundation, Pavia, Italy.

Background: The effectiveness of computer-based cognitive training (CCT) remains controversial, especially in older adults with neurodegenerative diseases.

Aims: To evaluate the efficacy of CCT in patients with Parkinson's disease and mild cognitive impairment (PD-MCI).

Methods: In this randomized controlled trial, 53 patients were randomized to receive CCT delivered by means of CoRe software, traditional paper-and-pencil cognitive training (PCT), or an unstructured activity intervention (CG). In each group, the intervention lasted 3 consecutive weeks (4 individual face-to-face sessions/week). Neuropsychological assessment was administered at baseline (T0) and post-intervention (T1). Outcome measures at T0 and T1 were compared within and between groups. The Montreal Overall Cognitive Assessment (MoCA) was taken as the primary outcome measure.

Results: Unlike the PCT group and the CG, the patients receiving CCT showed significant medium/large effect size improvements in MoCA performance, global cognition, executive functions, and attention/processing speed. No baseline individual/demographic variables were associated with greater gains from the intervention, although a negative correlation with baseline MoCA performance was found.

Conclusion: CCT proved effective in PD-MCI patients when compared with traditional PCT. Further follow-up assessments are being conducted to verify the retention of the gains and the potential ability of the tool to delay conversion to PD-dementia. Trial registration number (ClinicalTrials.gov): NCT04111640 (30th September 2019).
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http://dx.doi.org/10.1007/s40520-020-01665-2DOI Listing
June 2021

A Machine Learning Approach for the Differential Diagnosis of Alzheimer and Vascular Dementia Fed by MRI Selected Features.

Front Neuroinform 2020 11;14:25. Epub 2020 Jun 11.

NMR Research Unit, Department of Neuroinflammation, Faculty of Brain Sciences, Queen Square MS Centre, UCL Queen Square Institute of Neurology, London, United Kingdom.

Among dementia-like diseases, Alzheimer disease (AD) and vascular dementia (VD) are two of the most frequent. AD and VD may share multiple neurological symptoms that may lead to controversial diagnoses when using conventional clinical and MRI criteria. Therefore, other approaches are needed to overcome this issue. Machine learning (ML) combined with magnetic resonance imaging (MRI) has been shown to improve the diagnostic accuracy of several neurodegenerative diseases, including dementia. To this end, in this study, we investigated, first, whether different kinds of ML algorithms, combined with advanced MRI features, could be supportive in classifying VD from AD and, second, whether the developed approach might help in predicting the prevalent disease in subjects with an unclear profile of AD or VD. Three ML categories of algorithms were tested: artificial neural network (ANN), support vector machine (SVM), and adaptive neuro-fuzzy inference system (ANFIS). Multiple regional metrics from resting-state fMRI (rs-fMRI) and diffusion tensor imaging (DTI) of 60 subjects (33 AD, 27 VD) were used as input features to train the algorithms and find the best feature pattern to classify VD from AD. We then used the identified VD-AD discriminant feature pattern as input for the most performant ML algorithm to predict the disease prevalence in 15 dementia patients with a "mixed VD-AD dementia" (MXD) clinical profile using their baseline MRI data. ML predictions were compared with the diagnosis evidence from a 3-year clinical follow-up. ANFIS emerged as the most efficient algorithm in discriminating AD from VD, reaching a classification accuracy greater than 84% using a small feature pattern. Moreover, ANFIS showed improved classification accuracy when trained with a multimodal input feature data set (e.g., DTI + rs-fMRI metrics) rather than a unimodal feature data set. When applying the best discriminant pattern to the MXD group, ANFIS achieved a correct prediction rate of 77.33%. Overall, results showed that our approach has a high discriminant power to classify AD and VD profiles. Moreover, the same approach also showed potential in predicting earlier the prevalent underlying disease in dementia patients whose clinical profile is uncertain between AD and VD, therefore suggesting its usefulness in supporting physicians' diagnostic evaluations.
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http://dx.doi.org/10.3389/fninf.2020.00025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7300291PMC
June 2020

Unsuspected Involvement of Spinal Cord in Alzheimer Disease.

Front Cell Neurosci 2020 30;14. Epub 2020 Jan 30.

Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.

: Brain atrophy is an established biomarker for dementia, yet spinal cord involvement has not been investigated to date. As the spinal cord is relaying sensorimotor control signals from the cortex to the peripheral nervous system and vice-versa, it is indeed a very interesting question to assess whether it is affected by atrophy due to a disease that is known for its involvement of cognitive domains first and foremost, with motor symptoms being clinically assessed too. We, therefore, hypothesize that in Alzheimer's disease (AD), severe atrophy can affect the spinal cord too and that spinal cord atrophy is indeed an important imaging biomarker contributing to understanding neurodegeneration associated with dementia. : 3DT1 images of 31 AD and 35 healthy control (HC) subjects were processed to calculate volume of brain structures and cross-sectional area (CSA) and volume (CSV) of the cervical cord [per vertebra as well as the C2-C3 pair (CSA23 and CSV23)]. Correlated features ( > 0.7) were removed, and the best subset identified for patients' classification with the Random Forest algorithm. General linear model regression was used to find significant differences between groups ( ≤ 0.05). Linear regression was implemented to assess the explained variance of the Mini-Mental State Examination (MMSE) score as a dependent variable with the best features as predictors. : Spinal cord features were significantly reduced in AD, independently of brain volumes. Patients classification reached 76% accuracy when including CSA23 together with volumes of hippocampi, left amygdala, white and gray matter, with 74% sensitivity and 78% specificity. CSA23 alone explained 13% of MMSE variance. : Our findings reveal that C2-C3 spinal cord atrophy contributes to discriminate AD from HC, together with more established features. The results show that CSA23, calculated from the same 3DT1 scan as all other brain volumes (including right and left hippocampi), has a considerable weight in classification tasks warranting further investigations. Together with recent studies revealing that AD atrophy is spread beyond the temporal lobes, our result adds the spinal cord to a number of unsuspected regions involved in the disease. Interestingly, spinal cord atrophy explains also cognitive scores, which could significantly impact how we model sensorimotor control in degenerative diseases with a primary cognitive domain involvement. Prospective studies should be purposely designed to understand the mechanisms of atrophy and the role of the spinal cord in AD.
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http://dx.doi.org/10.3389/fncel.2020.00006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002560PMC
January 2020

Early phases of cognitive disorders in the elderly patients: report of an Italian center for dementia.

Aging Clin Exp Res 2020 05 13;32(5):967-968. Epub 2019 Nov 13.

Neuropsychology/Alzheimer's Disease Assessment Unit, IRCCS C. Mondino Foundation, Via Mondino 2, 27100, Pavia, Italy.

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http://dx.doi.org/10.1007/s40520-019-01408-yDOI Listing
May 2020

Evening melatonin timing secretion in real life conditions in patients with Alzheimer disease of mild to moderate severity.

Sleep Med 2019 11 31;63:122-126. Epub 2019 May 31.

Unit of Sleep Medicine and Epilepsy, IRCCS Mondino Foundation, Via Mondino 2, 27100, Pavia, Italy; Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy.

Background: Circadian dysfunction is thought to take part in the pathogenesis of sleep disorders in Alzheimer's disease (AD) and in AD pathophysiology itself.

Objective: Our study aims to calculate dim light melatonin onset (DLMO) secretion in order to define the circadian phase in patients with AD at an early stage of the disease.

Methods: Twenty-one patients (M/F: 11/10; mean age 74.1 ± 5.4 years; mean disease duration 3.4 ± 1.6 years) with a diagnosis of AD and 17 healthy controls (HC; M/F: 10/7; mean age 67.47 ± 3.8 years) were investigated for subjective nocturnal sleep quality and chronotype, for DLMO and quantitative aspects of the evening melatonin secretion by means of a 5-point in-home evening melatonin saliva test.

Results: Subjective sleep quality score on the Pittsburgh Sleep Quality Index questionnaire (PSQI) above 5 (p = 0.24), insomnia frequency as measured by Sleep Condition Indicator Questionnaire (p = 0.823) and the subjective chronotype according to Morning Evening Questionnaire (MEQ) scores distribution (p = 0.464) did not differ between AD and HC. However, DLMO occurred significantly later (55 min; p = 0.028), and melatonin secretion following DLMO was significantly decreased in AD patients compared to HC.

Conclusion: Initial evening secretion of melatonin proves to be delayed and mildly impaired in patients with a mild/moderate form of Alzheimer disease while patients' subjective sleep parameters and chronotype are reported to be similar to those of HC. These results indicate that subclinical altered patterns of melatonin secretion occur in subjects with AD at an early stage of the disease.
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http://dx.doi.org/10.1016/j.sleep.2019.04.018DOI Listing
November 2019

HomeCoRe: Bringing Cognitive Rehabilitation at Home.

Stud Health Technol Inform 2019 Aug;264:1755-1756

IRCCS C. Mondino, Pavia, Italy.

CoRe is a system for cognitive rehabilitation that has been successfully used for several years in hospital settings. Leveraging on the positive survey results from the potential final users (patients and their home caregivers), we developed HomeCoRe. This new version of the system will allow discharged patients to continue the rehabilitation treatment at home.
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http://dx.doi.org/10.3233/SHTI190632DOI Listing
August 2019

A computer-based cognitive training in Mild Cognitive Impairment in Parkinson's Disease.

NeuroRehabilitation 2019 ;44(4):555-567

Neuropsychology/Alzheimer's Disease Assessment Unit, IRCCS Mondino Foundation, Pavia, Italy.

Background: There is no successful pharmacological treatment for cognitive impairment in Parkinson's Disease, therefore treatments capable of slowing down the progression of cognitive dysfunction are needed.

Objective: To evaluate the effectiveness of a cognitive training, supported by the CoRe computerized tool, in patients with Parkinson's Disease Mild Cognitive Impairment.

Methods: This is a prospective, open-unblinded, randomized, controlled study. After baseline cognitive assessment (T0), enrolled patients were randomized to receive motor rehabilitation plus cognitive intervention (G1) or motor rehabilitation only (G2). Follow-up assessments were scheduled 4 weeks (T1) and 6 months after (T2). Global cognitive functioning scores (MOCA and MMSE) were considered as primary outcome. Outcome measures at T0, T1 and T2 were compared within- and between-groups. A percentage change score between T0 and next assessments was calculated to identify patients who improved, remain stable or worsened.

Results: Differently from G2, G1 showed a medium/large effect size improvement in primary (MoCA) and secondary outcome, both between T0 and T1 and T0 and T2. Moreover, within G1, most patients improved their cognitive state compared to the baseline.

Conclusions: Patients trained with CoRe showed a better evolution of cognitive decline, while untreated patients tended to get worse over time.
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http://dx.doi.org/10.3233/NRE-192714DOI Listing
October 2019

Cognitive impairment in depression: recent advances and novel treatments.

Neuropsychiatr Dis Treat 2019 10;15:1249-1258. Epub 2019 May 10.

Center of Cognitive and Behavioral Disorders, IRCCS Fondazione Mondino, National Institute of Neurology, Pavia, Italy.

In the past, little or no attention was paid to cognitive disorders associated with depression (a condition sometimes termed pseudodementia). However, recent years have seen a growing interest in these changes, not only because of their high frequency in acute-stage depression, but also because they have been found to persist, as residual symptoms (in addition to affective and psychomotor ones), in many patients who respond well to antidepressant treatment. These cognitive symptoms seem to impact significantly not only on patients' functioning and quality of life, but also on the risk of recurrence of depression. Therefore, over the past decade, pharmacological research in this field has focused on the development of new agents able to counteract not only depressive symptoms, but also cognitive and functional ones. In this context, novel antidepressants with multimodal activity have emerged. This review considers the different issues, in terms of disease evolution, raised by the presence of cognitive disorders associated with depression and considers, particularly from the neurologist's perspective, the ways in which the clinical approach to cognitive symptoms, and their interpretation to diagnostic and therapeutic ends, have changed in recent years. Finally, after outlining the pharmacodynamics and pharmacokinetics of the first multimodal antidepressant, vortioxetine, it reports the main results obtained with the drug in depressed patients, also in consideration of the ever-increasing evidence on its different mechanisms of action in animal models.
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http://dx.doi.org/10.2147/NDT.S199746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520478PMC
May 2019

Assessment of cognitive profile as a prodromal marker of the evolution of rapid eye movement sleep behavior disorder.

Sleep 2019 08;42(8)

Unit of Sleep Medicine and Epilepsy, IRCCS Mondino Foundation, Pavia, Italy.

Study Objectives: To search for a specific neuropsychological profile in idiopathic REM sleep behavior disorder (iRBD), able to predict the onset of neurodegenerative disorders.

Methods: In a longitudinal follow-up study of 63 consecutive iRBD patients (follow-up duration 6.7 ± 3.8 years), the baseline cognitive profile of converters to neurodegenerative disease was compared with that of the nonconverters. Five cognitive domains were assessed: memory, attention-working memory, executive functions, visuospatial abilities, language. Mild cognitive impairment (MCI) was diagnosed according to the Movement Disorder Society's diagnostic criteria for Parkinson's disease.

Results: 30 subjects (47.6%) developed a neurodegenerative disease (latency to conversion 60.33 ± 44.81 months). MCI was found in 50% of the converters and 12% of the nonconverters (p = .001), and its presence conferred a neurodegenerative disease risk of 10% at 3 years, 36% at 5 years, and 73% at 10 years (p = .002). Pathological equivalent scores on at least one neuropsychological test were detected in 46.7% of the converters versus 21.2% of the nonconverters in the memory domain (p = .032), in 40.0% versus 6.1% in that of executive functions (p = .002), and in 20.0% versus 3% in the visuospatial abilities domain (p = .047). On multivariate analysis, impaired executive functions significantly correlated with phenoconversion (p = .018). Lower Mini Mental State Examination (MMSE) scores (p = .004) and memory deficits (p = .031) were found in patients who developed dementia first.

Conclusions: Cognitive profile is useful for stratifying risk of phenoconversion in patients with iRBD. The presence of MCI and impaired executive functions, memory, and visuospatial abilities discriminated the converters. Lower MMSE scores and memory deficits may characterize those subjects who first develop dementia.
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http://dx.doi.org/10.1093/sleep/zsz103DOI Listing
August 2019

Role of Cerebrospinal Fluid Biomarkers and (18)F-florbetapir PET Imaging in the Diagnosis of Primary Progressive Aphasia: A Retrospective Analysis.

Alzheimer Dis Assoc Disord 2019 Jul-Sep;33(3):282-284

Center of Cognitive and Behavioral Disorders.

The use of biomarkers has recently supported the association between Alzheimer disease (AD) pathology and the logopenic variant of primary progressive aphasia (PPA). We aim to investigate possible differences in cerebrospinal fluid (CSF) biomarker concentrations in the three PPA variants, and to assess any agreement between CSF biomarkers and (18)F-florbetapir PET. A group of 10 PPA were retrospectively enrolled. Patients with logopenic variant (lvPPA) showed different levels of Aβ1-42 and p-tau compared to nonfluent/agrammatic and semantic variants (nfv/svPPA). All nfv/svPPA patients had negative amyloid PET. Among the lvPPA group, a negative amyloid PET was found only in one patient, who was also the only one to display a normal CSF. Thus, this small cohort appeared to display an excellent agreement between CSF and (18)F-florbetapir PET and suggest that these examinations may have the same validity in detecting in vivo evidence of AD pathology in PPA clinical variants.
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http://dx.doi.org/10.1097/WAD.0000000000000289DOI Listing
July 2020

The Multidisciplinary Approach to Alzheimer's Disease and Dementia. A Narrative Review of Non-Pharmacological Treatment.

Front Neurol 2018 13;9:1058. Epub 2018 Dec 13.

Neurorehabilitation Unit, Department of Rehabilitation, HABILITA, Bergamo, Italy.

Alzheimer's disease (AD) and dementia are chronic diseases with progressive deterioration of cognition, function, and behavior leading to severe disability and death. The prevalence of AD and dementia is constantly increasing because of the progressive aging of the population. These conditions represent a considerable challenge to patients, their family and caregivers, and the health system, because of the considerable need for resources allocation. There is no disease modifying intervention for AD and dementia, and the symptomatic pharmacological treatments has limited efficacy and considerable side effects. Non-pharmacological treatment (NPT), which includes a wide range of approaches and techniques, may play a role in the treatment of AD and dementia. To review, with a narrative approach, current evidence on main NPTs for AD and dementia. PubMed and the Cochrane database of systematic reviews were searched for studies written in English and published from 2000 to 2018. The bibliography of the main articles was checked to detect other relevant papers. The role of NPT has been largely explored in AD and dementia. The main NPT types, which were reviewed here, include exercise and motor rehabilitation, cognitive rehabilitation, NPT for behavioral and psychological symptoms of dementia, occupational therapy, psychological therapy, complementary and alternative medicine, and new technologies, including information and communication technologies, assistive technology and domotics, virtual reality, gaming, and telemedicine. We also summarized the role of NPT to address caregivers' burden. Although NPT is often applied in the multidisciplinary approach to AD and dementia, supporting evidence for their use is still preliminary. Some studies showed statistically significant effect of NPT on some outcomes, but their clinical significance is uncertain. Well-designed randomized controlled trials with innovative designs are needed to explore the efficacy of NPT in AD and dementia. Further studies are required to offer robust neurobiological grounds for the effect of NPT, and to examine its cost-efficacy profile in patients with dementia.
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http://dx.doi.org/10.3389/fneur.2018.01058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6300511PMC
December 2018

Curcumin and Novel Synthetic Analogs in Cell-Based Studies of Alzheimer's Disease.

Front Pharmacol 2018 3;9:1404. Epub 2018 Dec 3.

Genomic and Post-Genomic Center, IRCCS Mondino Foundation, Pavia, Italy.

Alzheimer's disease (AD) is a chronic neurodegenerative disorder that is associated with the most common type of dementia and is characterized by the presence of deposits of the protein fragment amyloid beta (Aβ) in the brain. The natural product mixture of curcuminoids that improves certain defects in innate immune cells of AD patients may selectively enhance Aβ phagocytosis by alteration of gene transcription. In this work, we evaluated the protective effects of curcuminoids in cells from AD patients by investigating the effect on NF-κB and BACE1 signaling pathways. These results were compared to the gene expression profile of the clearance of Aβ. The minor curcumin constituent, bisdemethoxycurcumin (BDC) showed the most potent protective action to decrease levels of and , decrease the inflammatory cascade and diminish Aβ aggregates in cells from AD patients. Moreover, mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase () and vitamin D receptor () gene mRNAs were up-regulated in peripheral blood mononuclear cells from AD patients treated with BDC. BDC treatment impacts both gene expression including Mannosyl (Beta-1,4-)-Glycoprotein Beta-1,4-N-Acetylglucosaminyltransferase, Vitamin D and Toll like receptor mRNA and Aβ phagocytosis. The observation of down-regulation of and following administration of BDC to cells from AD patients as a model system may have utility in the treatment of asymptomatic AD patients.
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http://dx.doi.org/10.3389/fphar.2018.01404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287206PMC
December 2018

Disease progression in relation to age at onset in a population with Alzheimer's Dementia.

Aging Clin Exp Res 2019 May 28;31(5):723-725. Epub 2018 Aug 28.

Neuropsychology/Alzheimer's Disease Assessment Unit, IRCCS C. Mondino Foundation, Via Mondino 2, 27100, Pavia, Italy.

One thousand and 679 Alzheimer's Disease patients (early onset EO: 152 and late onset LO: 1527) were evaluated after 12, 36 and 60 months. At baseline EO patients have higher Mini Mental State examination (MMSE) and fewer comorbidities in respect to LO group. The MMSE score did not significantly differ after 12, 36 and 60 months; a more marked worsening in instrumental daily activities was observed after 36 months in the EO compared with the LO group. These data allow to conclude that EO patients may have a slight faster progression in the disease within the first 3 years after the diagnosis, but in a longer follow-up no differences exist in respect to LO group. The literature failed to identify specific factors capable to influence the disease progression in AD. Our data are in substantial agreement with the literature and seem to confirm the great heterogeneity of AD patients.
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http://dx.doi.org/10.1007/s40520-018-1027-5DOI Listing
May 2019

Specific Patterns of White Matter Alterations Help Distinguishing Alzheimer's and Vascular Dementia.

Front Neurosci 2018 25;12:274. Epub 2018 Apr 25.

Department of Emergency Neurology, IRCCS Mondino Foundation, Pavia, Italy.

Alzheimer disease (AD) and vascular dementia (VaD) together represent the majority of dementia cases. Since their neuropsychological profiles often overlap and white matter lesions are observed in elderly subjects including AD, differentiating between VaD and AD can be difficult. Characterization of these different forms of dementia would benefit by identification of quantitative imaging biomarkers specifically sensitive to AD or VaD. Parameters of microstructural abnormalities derived from diffusion tensor imaging (DTI) have been reported to be helpful in differentiating between dementias, but only few studies have used them to compare AD and VaD with a voxelwise approach. Therefore, in this study a whole brain statistical analysis was performed on DTI data of 93 subjects (31 AD, 27 VaD, and 35 healthy controls-HC) to identify specific white matter patterns of alteration in patients affected by VaD and AD with respect to HC. Parahippocampal tracts were found to be mainly affected in AD, while VaD showed more spread white matter damages associated with thalamic radiations involvement. The genu of the corpus callosum was predominantly affected in VaD, while the splenium was predominantly affected in AD revealing the existence of specific patterns of alteration useful in distinguishing between VaD and AD. Therefore, DTI parameters of these regions could be informative to understand the pathogenesis and support the etiological diagnosis of dementia. Further studies on larger cohorts of subjects, characterized for brain amyloidosis, will allow to confirm and to integrate the present findings and, furthermore, to elucidate the mechanisms of mixed dementia. These steps will be essential to translate these advances to clinical practice.
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http://dx.doi.org/10.3389/fnins.2018.00274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5996902PMC
April 2018

Evaluation of an ontology-based system for computerized cognitive rehabilitation.

Int J Med Inform 2018 07 21;115:64-72. Epub 2018 Apr 21.

IRCCS Neurological National Institute C. Mondino Foundation, Pavia, Italy.

Objectives: This paper describes the results of a randomized clinical trial about the effectiveness of a computerized rehabilitation treatment on a sample of 31 patients affected by Parkinson disease.

Methods: Computerized exercises were administered by the therapists to the intervention group (n = 17) through the CoRe tool, which automatically generates a big variety of exercises leveraging on a stimuli set (words, sounds and images) organized into a dedicated ontology. A battery of standard neuropsychological tests was performed for patients' assessment at baseline, after the treatment (that lasted 1 month), and after 6 months from the treatment stop. The control group underwent a sham intervention.

Results: Results show a statistically significant clinical benefit from computerized rehabilitation with respect to sham treatment. For the intervention group, response time and response accuracy were integrated into a weighted score that accounts also for the specific cognitive burden of each exercise. Differently from the control group, the majority of patients in the intervention group showed an improvement in that score, more marked in the first week of treatment, and which lasts for the entire treatment period, which could account both for a quick learning effect and for an improvement of cognitive conditions. Good usability of CoRe, already observed in previous studies, was confirmed by the present trial, where the percentage of protocol completion in the intervention group is very high (all but one patient are above 90%).

Conclusions: The CoRe system showed to be effective to improve some cognitive abilities in patients with Parkinson disease. However, after the end of the training, the benefit is hardly maintained over time. These findings support the implementation of CoRe in the clinical routine and the continuation of the treatment after discharge through the use of a homecare version of the system.
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http://dx.doi.org/10.1016/j.ijmedinf.2018.04.005DOI Listing
July 2018

Smart Aging Platform for Evaluating Cognitive Functions in Aging: A Comparison with the MoCA in a Normal Population.

Front Aging Neurosci 2017 21;9:379. Epub 2017 Nov 21.

Headache Science Centre, C. Mondino National Neurological Institute, Pavia, Italy.

Smart Aging is a Serious games (SGs) platform in a 3D virtual environment in which users perform a set of screening tests that address various cognitive skills. The tests are structured as 5 tasks of activities of daily life in a familiar environment. The main goal of the present study is to compare a cognitive evaluation made with Smart Aging with those of a classic standardized screening test, the Montreal Cognitive Assessment (MoCA). One thousand one-hundred thirty-one healthy adults aged between 50 and 80 ( = 64.3 ± 8.3) were enrolled in the study. They received a cognitive evaluation with the MoCA and the Smart Aging platform. Participants were grouped according to their MoCA global and specific cognitive domain (i.e., memory, executive functions, working memory, visual spatial elaboration, language, and orientation) scores and we explored differences among these groups in the Smart Aging indices. One thousand eighty-six older adults ( = 64.0 ± 8.0) successfully completed the study and were stratified according to their MoCA score: Group 1 with MoCA < 27 ( = 360); Group 2 with 27 ≥ MoCA < 29 ( = 453); and Group 3 with MoCA ≥ 29 ( = 273). MoCA groups significantly differed in most of the Smart Aging indices considered, in particular as concerns accuracy (s < 0.001) and time (s < 0.001) for completing most of the platform tasks. Group 1 was outperformed by the other two Groups and was slower than them in these tasks, which were those supposed to assess memory and executive functions. In addition, significant differences across groups also emerged when considering the single cognitive domains of the MoCA and the corresponding performances in each Smart Aging task. In particular, this platform seems to be a good proxy for assessing memory, executive functions, working memory, and visual spatial processes. These findings demonstrate the validity of Smart Aging for assessing cognitive functions in normal aging. Future studies will validate this platform also in the clinical aging populations.
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http://dx.doi.org/10.3389/fnagi.2017.00379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5702318PMC
November 2017

Correlations among age, cognitive impairment, and comorbidities in Alzheimer's disease: report from a center for cognitive disorders.

Aging Clin Exp Res 2017 Dec 21;29(6):1299-1300. Epub 2017 Aug 21.

Neuropsychology/Alzheimer's Disease Assessment Unit, C. Mondino National Neurological Institute, IRCCS C. Mondino, Via Mondino 2, 27100, Pavia, Italy.

We report an update of our previous observations in Alzheimer's disease (AD) patients in the routine clinical practice considering in particular the interactions between age, concomitant pathologies, and treatment adherence. 2379 AD patients (M/F: 1058/1321, mean age: 74.1 ± 8.8) referred for a first visit to our center from September 2000 to April 2017. An increase of percentage of patients aged over 80 years along the years was confirmed (27% between September 2000 and December 2010, and 39% between January 2011 to April 2017). The patients over 80 years presented a Cumulative Illness Rating Scale (CIRS) significantly higher than patients under 80 years (p < 0.00001). Higher CIRS scores were associated with a lower treatment adherence (p < 0.0002) and greater cognitive impairment (p < 0.01). As people in advanced age with cognitive disorders will increase, our approach to dementing conditions has to change and fit to social and epidemiological modifications.
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http://dx.doi.org/10.1007/s40520-017-0807-7DOI Listing
December 2017

Modeling Alzheimer Disease Through Functional Independence and Participation.

Alzheimer Dis Assoc Disord 2017 Jul-Sep;31(3):218-224

*Neuro-Oncology Unit, IRCCS Regina Elena Cancer Institute, Rome †Department of Rehabilitation, Neurorehabilitation Unit, HABILITA Care & Research Rehabilitation Hospitals, Zingonia di Ciserano, Bergamo ‡Alzheimer Assessment Unit/Laboratory of Neuropsychology, IRCCS Neurological National Institute C. Mondino Foundation, Pavia, Italy.

Introduction: The relationship between cognitive and functional impairment in Alzheimer Disease (AD) at the earliest stages of the disease is not well characterized. This study aimed at investigating such relationships along AD evolution by means of the Disability Assessment for Dementia (DAD).

Methods: Consecutive pairs of AD outpatients and their primary informal caregivers were enrolled. Patients were evaluated by means of the Mini Mental State Examination and neuropsychological tests. A clinician completed the Clinical Dementia Rating Scale to stage dementia severity and interviewed the caregivers to complete the Neuropsychiatric Inventory to assess behavioral disturbances and the DAD to evaluate patients' functional competence.

Results: A total of 158 dyads were enrolled; the Mini Mental State Examination score was used to stratify patients into 4 groups (>24; 20 to 23.9; 10 to 19.9; <10) that were compared. The statistical analysis revealed that all the cognitive domains were positively related to functional independence, but only logical and executive functions seemed to predict autonomy. An intergroup comparison did not show significant differences in the DAD subscales measuring initiation, planning and organization, and performance. The role of education emerged, confirming the relevance of cognitive reserve.

Discussion: As the field moves toward earlier intervention in preclinical AD, the detection of early functional changes may drive the definition of trials on prevention or intervention for dementia.
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http://dx.doi.org/10.1097/WAD.0000000000000167DOI Listing
May 2018

Exploring Patterns of Alteration in Alzheimer's Disease Brain Networks: A Combined Structural and Functional Connectomics Analysis.

Front Neurosci 2016 7;10:380. Epub 2016 Sep 7.

Brain Connectivity Center, C. Mondino National Neurological InstitutePavia, Italy; Department of Brain and Behavioural Sciences, University of PaviaPavia, Italy.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a severe derangement of cognitive functions, primarily memory, in elderly subjects. As far as the functional impairment is concerned, growing evidence supports the "disconnection syndrome" hypothesis. Recent investigations using fMRI have revealed a generalized alteration of resting state networks (RSNs) in patients affected by AD and mild cognitive impairment (MCI). However, it was unclear whether the changes in functional connectivity were accompanied by corresponding structural network changes. In this work, we have developed a novel structural/functional connectomic approach: resting state fMRI was used to identify the functional cortical network nodes and diffusion MRI to reconstruct the fiber tracts to give a weight to internodal subcortical connections. Then, local and global efficiency were determined for different networks, exploring specific alterations of integration and segregation patterns in AD and MCI patients compared to healthy controls (HC). In the default mode network (DMN), that was the most affected, axonal loss, and reduced axonal integrity appeared to compromise both local and global efficiency along posterior-anterior connections. In the basal ganglia network (BGN), disruption of white matter integrity implied that main alterations occurred in local microstructure. In the anterior insular network (AIN), neuronal loss probably subtended a compromised communication with the insular cortex. Cognitive performance, evaluated by neuropsychological examinations, revealed a dependency on integration and segregation of brain networks. These findings are indicative of the fact that cognitive deficits in AD could be associated not only with cortical alterations (revealed by fMRI) but also with subcortical alterations (revealed by diffusion MRI) that extend beyond the areas primarily damaged by neurodegeneration, toward the support of an emerging concept of AD as a "disconnection syndrome." Since only AD but not MCI patients were characterized by a significant decrease in structural connectivity, integrated structural/functional connectomics could provide a useful tool for assessing disease progression from MCI to AD.
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http://dx.doi.org/10.3389/fnins.2016.00380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5013043PMC
September 2016

A review of cognitive impairment and differential diagnosis in idiopathic normal pressure hydrocephalus.

Funct Neurol 2015 Oct-Dec;30(4):217-28

Idiopathic normal pressure hydrocephalus (iNPH) is a complex and still underestimated pathology. In the early stages, the cognitive profile is characterized mainly by impairments of attention, psychomotor speed and memory, suggesting frontal involvement; patients with more advanced iNPH show overall cognitive deterioration. The memory impairment, however, seems to be milder than that seen in Alzheimer's disease (AD). Clinical and neuroimaging data are crucial for the diagnosis of iNPH, but the presence of different variables, such as comorbidities, and the possible overlapping with other neurodegenerative diseases, AD in particular, make the differential diagnosis difficult. To date studies seeking to identify possible biological markers have provided inconclusive results; moreover reliable indices predictive of a good response to surgery are still lacking. There is a need for further studies with longer follow-ups and for closer interaction among the different professionals involved.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4758774PMC
http://dx.doi.org/10.11138/fneur/2015.30.4.217DOI Listing
September 2016

Computer-based cognitive rehabilitation: the CoRe system.

Disabil Rehabil 2017 02 27;39(4):407-417. Epub 2015 Oct 27.

c IRCCS S. Maugeri Foundation , Pavia , Italy , and.

Purpose: This work aims at providing a tool for supporting cognitive rehabilitation. This is a wide field, that includes a variety of diseases and related clinical pictures; for this reason the need arises to have a tool available that overcomes the difficulties entailed by what currently is the most common approach, that is, the so-called pen and paper rehabilitation.

Methods: We first organized a big number of stimuli in an ontology that represents concepts, attributes and a set of relationships among concepts. Stimuli may be words, sounds, 2D and 3D images. Then, we developed an engine that automatically generates exercises by exploiting that ontology. The design of exercises has been carried on in synergy with neuropsychologists and speech therapists. Solutions have been devised aimed at personalizing the exercises according to both patients' preferences and performance.

Results: Exercises addressed to rehabilitation of executive functions and aphasia-related diseases have been implemented. The system has been tested on both healthy volunteers (n = 38) and patients (n = 9), obtaining a favourable rating and suggestions for improvements.

Conclusions: We created a tool able to automate the execution of cognitive rehabilitation tasks. We hope the variety and personalization of exercises will allow to increase compliance, particularly from elderly people, usually neither familiar with technology nor particularly willing to rely on it. The next step involves the creation of a telerehabilitation tool, to allow therapy sessions to be undergone from home, thus guaranteeing continuity of care and advantages in terms of time and costs for the patients and the National Healthcare System (NHS). Implications for rehabilitation Cognitive impairments can greatly impact an individual's existence, appreciably reducing his abilities and autonomy, as well as sensibly lowering his quality of life. Cognitive rehabilitation can be used to restore lost brain function or slow down degenerative diseases. Computerization of rehabilitation entails many advantages, but patients - especially elderly people - might be less prone to the use of technology and consequently reluctant towards this innovative therapeutic approach. Our software system, CoRe, supports a therapist during the administration of rehabilitation sessions: exercises can be generated dynamically, thus reducing repetitivity, and patients' performance trends automatically analysed to facilitate the assessment of their progress. Tests performed on both healthy subjects and patients provided useful information that allowed us to define an implementation strategy able to reduce patients' resistance to computerized rehabilitation as much as possible.
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http://dx.doi.org/10.3109/09638288.2015.1096969DOI Listing
February 2017

The Possible Involvement of HLA Class III Haplotype (RAGE, HSP70 and TNF Genes) in Alzheimer's Disease.

Curr Alzheimer Res 2015 ;12(10):997-1005

IRCCS National Neurological Institute "C. Mondino", University of Pavia, Via Mondino 2, 27100 Pavia, Italy.

In the central nervous system Hsp70s seems to have a protective role in repair and removal of cellular proteins damaged by stress conditions. A protective role of Hsp70 was also shown in Alzheimer Disease. The HSP70-1 +190 G/C polymorphism is located in the gene 5'UTR region and it is implicated in alteration of the transcription binding factor; HSP70-2 +1267 A/G causes a silent mutation in the coding region and it seems to influence the mechanism of mRNA translation; HSP70-hom +2437 A/G causes a substitution Met → The (M493T) in the coding region and it seems to influence the bond with the substrate and therefore on the chaperone activity of hsp70. The aim of our study will be to investigate Alzheimer susceptibility to Hsp70 polymorphisms, taking into account our previous findings on HLA class III region, and to hypothesize a role of HLA class III haplotype configuration based on the variants of three genes: RAGE, HSP70 and TNF. We studied these polymorphisms with PCR-RFLP and PCR-TSP. We investigated 173 AD patients and 211 control subjects. Our results have shown a statistically significant decrease of the C allele frequency of the HSP70-1 +190 G/C polymorphism in AD patients vs controls (P value = 0,018), as well as the G allele of HSP70-2 +1267 G/A (p value = 0,02). We focalized our attention on haplotype reconstruction. We have observed a significant statistically decrease of GGT haplotype frequency (empirical p-value=0.0133 ); GAT haplotype was statistically significant increase in AD patients compared with control (empirical p-value=0.007). The total HLA class III haplotype are reconstructed. The causative haplotypes are the following ones: TTGATGGG ( p value =0,005; empirical p =0,0042); TTGATAGG (p value =0,45; empirical p =0,034). Patients with these haplotypes may show an earlier onset of the disease than patients with TTGGTGGG (p value=0,0138; empirical p =0,0102); TTCGTGGG (p value=0,021; empirical p =0,017); TTCGTGGA (p value =0,058; empirical p =0,043) haplotypes. The overall variation of the haplotypes formed by the RAGE and TNF and HSP70 variants influenced the presence of the AD phenotype (omnibus association LR test p-value 0.00185), HSP701 and HSP702 showed independent effect on AD risk after adjusting for the effect of the entire haplotype (conditional LR test p-value=0.0114 and p-value=0.0044 respectively). These data confirm the involvement of HLA class III in AD.
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http://dx.doi.org/10.2174/1567205012666151027130635DOI Listing
August 2016

Clinical characteristics of population referred to an Italian center for dementia: an update.

Aging Clin Exp Res 2015 Oct 28;27(5):755-6. Epub 2015 Jul 28.

Alzheimer's Disease Assessment Unit, Laboratory of Neuropsychology, IRCCS C. Mondino National Neurological Institute, Via Mondino 2, 27100, Pavia, Italy.

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http://dx.doi.org/10.1007/s40520-015-0429-xDOI Listing
October 2015