Automated Assessment of the Substantia Nigra Pars Compacta in Parkinson's Disease: A Diffusion Tensor Imaging Study.

The substantia nigra (SN) pars compacta (SNpc) and pars reticulata (SNpr) are differentially affected in Parkinson's disease (PD). Separating the SNpc and SNpr is challenging with standard magnetic resonance imaging (MRI). Diffusion tensor imaging (DTI) allows for the characterization of SN microstructure in a non-invasive manner. In this study, 29 PD patients and 28 healthy controls (HCs) were imaged with 1.5T MRI for DTI. Images were nonlinearly registered to standard space and SNpc and SNpr DTI parameters were measured. ANCOVA and receiver operator characteristic (ROC) analyses were performed. Clinical associations were assessed with Spearman correlations. Multiple corrections were controlled for false discovery rate. PD patients presented with significantly increased SNpc axial diffusivity (AD) (1.207 ± 0.068 versus 1.156 ± 0.045, p = 0.024), with ROC analysis yielding an under the curve of 0.736. Trends with Unified Parkinson's Disease Rating Scale (UPDRS) III scores were identified for SNpc MD (rs = 0.449), AD (rs = 0.388), and radial diffusivity (rs = 0.391) (all p < 0.1). A trend between baseline SNpr MD and H&Y change (rs = 0.563, p = 0.081) over 2.9 years of follow-up was identified (n = 14). In conclusion, SN microstructure shows robust, clinically meaningful associations in PD.

Functional and Cognitive Improvement After an Intensive Inpatient Multidisciplinary Rehabilitation Program in Mild to Severe Parkinson's Disease: A Retrospective and Observational Study.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor (resting tremor, rigidity, bradykinesia, postural instability, and gait disturbances) and nonmotor symptoms (cognitive, neuropsychiatric, and autonomic problems). In recent years, several studies demonstrated that neurorehabilitation therapy is an effective treatment in addition to pharmacological personalized interventions in persons with PD (PwPD). The main aim of this study was to explore the short-term changes in functional, cognitive, and geriatric domains after a multidimensional rehabilitation program in PwPD (as primary condition) in mild-moderate (M-Ms) to severe (Ss) stages. Our second aim was to compare the effects of multidimensional rehabilitation in M-Ms versus Ss of PD. Twenty-four PwPD in M-Ms to Ss [age (mean ± SD) = 76.25 ± 9.42 years; male/female = 10/14; Hoehn and Yahr (median; IQR) = 4.00; 1.75] were included in a retrospective, observational study. Motor, cognitive, functional, and neuropsychiatric aspects were collected in admission (T0) and in discharge (T1). PwPD were involved in a person-tailored (to individual's needs), inpatient, intensive (5-7 days per week), multidisciplinary (combining cognitive, physical, occupational, and speech therapies), comprehensive, and rehabilitative program. According to Movement Disorders Society Unified Parkinson's Disease Rating Scale III cutoff, PwPD were classified in M-Ms or Ss (M-Ms ≤59; Ss >59); 87.50% of our sample reported significant reduction of functional disability at Barthel Index (p < 0.001). A significant improvement in Token test (p = 0.021), semantic fluency (p = 0.036), Rey's Figure-Copy (p < 0.001), and Raven's Colored Progressive Matrices (p = 0.004) was observed. The pain intensity perception (p < 0.001) and the risk of developing pressure ulcers (p < 0.001) as assessed, respectively, by the Numeric Rating Scale and by the Norton Scale were improved. With regard to the second aim, in M-Ms group, we found a positive correlation between the number of neuromotor sessions and the change in functional disability and language comprehension; in the Ss group, on the other hand, despite a higher number of hospitalization days, the total number of completed sessions was positively associated with the change in visuoconstructional abilities. Our findings suggest that an intensive, inpatient, and multidisciplinary rehabilitation program may improve functional abilities, some strategic cognitive functions, and geriatric aspects in PwPD with mild-moderate motor impairment.

The role of the dorsal striatum in the recognition of emotions expressed by voice in Parkinson's disease.

BACKGROUND AND PURPOSE: Non-motor impairment such as emotion recognition deficit in both facial and vocal expressions has been previously reported in Parkinson's disease (PD). We investigated whether the decoding of emotional prosody is impaired in PD and whether this deficit is related to striatal damage. METHODS: Fifteen PD patients and 15 healthy controls (HCs) were requested to listen to six audio tracks and to recognize the emotions expressed by a professional actor while reading a meaning-neutral sentence. All subjects also received a structural MRI examination. Volumetric measurements were extracted for the striatum, a key region involved in emotional processing and typically impaired in PD. RESULTS: Decoding sadness conveyed by voice was impaired in PD compared with HC and was related to the volume of the dorsal striatum bilaterally. CONCLUSIONS: The dorsal striatum is involved in the decoding of vocal negative emotions in PD.

Comparison of Transfer Learning and Conventional Machine Learning Applied to Structural Brain MRI for the Early Diagnosis and Prognosis of Alzheimer's Disease.

Alzheimer's Disease (AD) is the most common neurodegenerative disease, with 10% prevalence in the elder population. Conventional Machine Learning (ML) was proven effective in supporting the diagnosis of AD, while very few studies investigated the performance of deep learning and transfer learning in this complex task. In this paper, we evaluated the potential of ensemble transfer-learning techniques, pretrained on generic images and then transferred to structural brain MRI, for the early diagnosis and prognosis of AD, with respect to a fusion of conventional-ML approaches based on Support Vector Machine directly applied to structural brain MRI. Specifically, more than 600 subjects were obtained from the ADNI repository, including AD, Mild Cognitive Impaired converting to AD (MCIc), Mild Cognitive Impaired not converting to AD (MCInc), and cognitively-normal (CN) subjects. We used T1-weighted cerebral-MRI studies to train: (1) an ensemble of five transfer-learning architectures pretrained on generic images; (2) a 3D Convolutional Neutral Network (CNN) trained from scratch on MRI volumes; and (3) a fusion of two conventional-ML classifiers derived from different feature extraction/selection techniques coupled to SVM. The AD-vs-CN, MCIc-vs-CN, MCIc-vs-MCInc comparisons were investigated. The ensemble transfer-learning approach was able to effectively discriminate AD from CN with 90.2% AUC, MCIc from CN with 83.2% AUC, and MCIc from MCInc with 70.6% AUC, showing comparable or slightly lower results with the fusion of conventional-ML systems (AD from CN with 93.1% AUC, MCIc from CN with 89.6% AUC, and MCIc from MCInc with AUC in the range of 69.1-73.3%). The deep-learning network trained from scratch obtained lower performance than either the fusion of conventional-ML systems and the ensemble transfer-learning, due to the limited sample of images used for training. These results open new prospective on the use of transfer learning combined with neuroimages for the automatic early diagnosis and prognosis of AD, even if pretrained on generic images.

Multimodal Evaluation of Neurovascular Functionality in Early Parkinson's Disease.

Parkinson's disease (PD) is a multisystem neurological condition affecting different neurotransmitter pathways characterized by aberrant functional connectivity (FC) and perfusion alteration. Since the FC, measuring neuronal activity, and cerebral blood flow (CBF) are closely related through the neurovascular coupling (NVC) mechanism, we aim to assess whether FC changes found in PD mirror perfusion ones. A multimodal MRI study was implemented by acquiring resting state functional MRI (rsfMRI) and arterial spin labeling (ASL) datasets on a group of 26 early PD (66.8 ± 8 years, 22 males, median [interquartile range] Hoehn and Yahr = 1.5 [1]) and 18 age- and sex-matched healthy controls (HCs). In addition, a T1-weighted MPRAGE was also acquired in the same scan session. After a standard preprocessing, resting state networks (RSNs) and CBF maps were extracted from rsfMRI and ASL dataset, respectively. Then, by means of a dual regression algorithm performed on RSNs, a cluster of FC differences between groups was obtained and used to mask CBF maps in the subsequent voxel-wise group comparison. Furthermore, a gray matter (GM) volumetric assessment was performed within the FC cluster in order to exclude tissue atrophy as a source of functional changes. Reduced FC for a PD patient with respect to HC group was found within a sensory-motor network (SMN, pFWE = 0.01) and visual networks (VNs, primary pFWE = 0.022 and lateral pFWE = 0.01). The latter was accompanied by a decreased CBF (primary pFWE = 0.037, lateral pFWE = 0.014 VNs), while no GM atrophy was detected instead. The FC alteration found in the SMN of PD might be likely due to a dopaminergic denervation of the striatal pathways causing a functional disconnection. On the other hand, the changes in connectivity depicted in VNs might be related to an altered non-dopaminergic system, since perfusion was also reduced, revealing a compromised NVC. Finally, the absence of GM volume loss might imply that functional changes may potentially anticipate neurodegeneration. In this framework, FC and CBF might be proposed as early functional biomarkers providing meaningful insights in evaluating both disease progression and therapeutic/rehabilitation treatment outcome.

"Art, Colors, and Emotions" Treatment (ACE-t): A Pilot Study on the Efficacy of an Art-Based Intervention for People With Alzheimer's Disease.

Increasing evidence suggests that non-pharmacological therapies impact on neuropsychiatric symptoms and quality of life in people with Alzheimer's disease. Among these, art-based interventions seem particularly suitable for elders' rehabilitation as they act both on cognitive functions and quality of life. However, their benefits are not yet appropriately explored. The main aim of this quasi-experimental study was to test the feasibility and the likely efficacy of a novel multi-dimensional visual art intervention for people with Alzheimer's disease (PWAD), named Art, Colors, and Emotions treatment (ACE-t). A group of PWAD (N = 10) was recruited from the Memory Clinic of Don Gnocchi Foundation to take part in the ACE-t. A historical control group that followed a usual care program (N = 10) was used for comparison. We considered both feasibility output (adherence and acceptability) and efficacy outcome measures (neuropsychological and neurobehavioral scales). We observed a good adherence to and acceptability of the ACE-t. The following significant intervention-related changes were also observed in ACE-t with respect to usual care: improvement in general cognition, as assessed with the Alzheimer's Disease Assessment Scale-Cognitive, amelioration in language, and in executive functions, and reduction in Neuropsychiatric Inventory Scale score. In conclusion, ACE-t could be considered as a suitable intervention for the rehabilitation of PWAD, with positive effects on the cognitive and the behavioral status. ACE is a promising new art-based intervention that merits further research, including confirmatory trials of our preliminary results.

Parietal Perfusion Alterations in Parkinson's Disease Patients Without Dementia.

Fronto-parietal regions are involved in cognitive processes that are commonly affected in Parkinson's disease (PD). The aims of this study were to investigate cerebral blood flow (CBF) and gray matter (GM) volume within the regions belonging to the fronto-parietal circuit in people with PD (pwPD) without dementia, and to assess their association with cognitive performance. Twenty-seven pwPD without dementia (mean [SD] age = 67.4 [8.1] years, 20 males, mean [SD] Montreal Cognitive Assessment, MoCA score = 24.2 [2.9], median [IQR] Hoehn and Yahr scale = 1.5 [1-2]) and twenty-six age- and sex-matched healthy controls (HC) were scanned with arterial spin labeling (ASL) and T1-weighted magnetic resonance imaging (MRI) sequences to investigate CBF and GM volume, respectively. The cognitive performance of the enrolled pwPD was assessed with MoCA, Trail Making Test (TMT, part A, B, B-A), phonemic fluency and semantic fluency tests. The scores were adjusted for age and education. After standard preprocessing, CBF differences between pwPD and HC were tested with a voxel-wise approach. Voxel-based morphometry was used to compare pwPD and HC in terms of GM volume. Both voxel-wise comparisons between pwPD and HC were restricted to regions of the fronto-parietal circuit. The following additional voxel-wise analyses were performed within regions showing either perfusion or GM volume alterations: (1) correlation with neuropsychological test scores; (2) subgroup comparison after median split on each neuropsychological test score. Family-wise error-corrected (FWE) p-values lower than 0.05 were considered significant. Significant hypoperfusion was identified in the left inferior parietal lobule (IPL, ppeak = 0.037) and in the bilateral superior parietal lobule (SPL, left hemisphere: ppeak = 0.037; right hemisphere: ppeak = 0.049) of pwPD when compared to HC. No significant GM atrophy was observed. Local hypoperfusion did not correlate with any neuropsychological test scores. However, significantly lower CBF was observed in the left SPL and IPL of the pwPD subgroup who performed poorer on TMT part A in comparison with the pwPD subgroup that performed better. Perfusion alterations may occur in parietal regions of pwPD without dementia, and may be associated with lower visuomotor skills. Parietal CBF may be considered as a suitable early biomarker for longitudinal studies investigating cognitive decline in PD.

Uncinate fasciculus and word selection processing in Parkinson's disease.

We explored with Diffusion Tensor Imaging (DTI) technique whether the ability to select words among competitive alternatives during word production is related to the integrity of the left uncinate fasciculus (UF) in Parkinson's disease (PD). Nineteen PD patients (10 right-sided and 9 left-sided) and 17 matched healthy controls (HC) took part in the study. Participants were asked to derive nouns from verbs (reading from to read) or to generate verbs from nouns (to build from building). Noun and verb production, in this task, differ in the number of lexical entries among which the response is selected, as the noun must be selected from a larger number of alternatives compared to the verb, and thus is more demanding of processing resources. DTI evaluation was obtained for each subject. Fractional anisotropy (FA) and mean diffusivity (MD) maps were derived from DTI and median FA and MD values were computed within the left and right UF. Then, FA and MD of the left and right UF were correlated with noun and verb production. Both the left and right UF-FA correlated with the global (noun + verb) production and noun production in the whole PD group. In right-sided PD, correlations were found with the contralateral UF-FA; in left-sided PD the correlations emerged with both the left and right UF-FA. The most difficult task, noun production, significantly correlated with the right UF-FA in left-sided PD. The left UF is involved in word selection processes, and the right UF intervenes when the selection is particularly demanding of attentional resources.

Social Cognition in Rehabilitation Context: Different Evolution of Affective and Cognitive Theory of Mind in Mild Cognitive Impairment.

Maintaining social skills such as Theory of Mind (ToM) competences is important to counteract the conversion into dementia in Mild Cognitive Impairment (MCI). Multidimensional nonpharmacological interventions demonstrated their potential in improving cognitive and behavioral abilities; however, little is known about the long-term effect of such interventions on social skills in people with MCI. The aim of this longitudinal study was to monitor ToM competences considering both cognitive and affective domains in an amnestic MCI (aMCI) sample involved in a home-based multistimulation treatment (MST@H). 30 aMCI subjects (M : F = 15 : 15; mean age ± SD = 77.00 ± 4.60) were enrolled, and three steps of evaluation with neuropsychological tests and ToM tasks have been implemented. 21 healthy controls (HC) were also included (M : F = 9 : 12; mean age ± SD = 74.95 ± 3.88) to characterize the aMCI sample regarding differences in ToM performance compared to HC at the baseline evaluation. Our results show that the aMCI group statistically significantly underperformed the HC group only in the advanced ToM tasks, confirming an initial decline of high-level ToM competences in this population. The longitudinal evaluation revealed time changes not only in some subcognitive domains of MoCA (memory and executive functions) but also in cognitive and affective ToM dimensions in aMCI subjects. Our findings suggest that cognitive and affective ToM can be considered useful outcome measures to test the long-term effect of treatment over time.

Cerebrovascular reactivity and its correlation with age in patients with multiple sclerosis.

We assessed cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) within gray matter (GM), normal appearing white matter (NAWM) and white matter (WM) lesions in a group of multiple sclerosis (MS) patients. Furthermore, correlations between CBF, CVR and age were investigated. 31 MS patients and 25 healthy controls (HC) were examined on a 1.5 T MRI scanner, using pseudo-continuous arterial spin labeling MRI. MS vs HC CBF and CVR differences were assessed in GM regions of interest (i.e. resting state networks and vascular territories), and within WM. Correlations between CBF/CVR and age were then computed for MS and HC groups. Whereas no significant CBF and CVR differences were observed between MS and HC in any of the considered brain areas, significantly lower CBF was found in WM lesions with respect to NAWM (p < 0.001) in MS patients. Furthermore, CVR was significantly correlated with age in HC, but not in MS patients. The relatively low-grade of inflammation of our MS cohort may be associated with the observed lack of significant CVR differences between MS patients and HC. The loss of correlation between CVR and age in the MS group suggests that CVR may be influenced by MS-related factors.

Brain networks construction using Bayes FDR and average power function.

Brain functional connectivity is a widely investigated topic in neuroscience. In recent years, the study of brain connectivity has been largely aided by graph theory. The link between time series recorded at multiple locations in the brain and the construction of a graph is usually an adjacency matrix. The latter converts a measure of the connectivity between two time series, typically a correlation coefficient, into a binary choice on whether the two brain locations are functionally connected or not. As a result, the choice of a threshold τ over the correlation coefficient is key. In the present work, we propose a multiple testing approach to the choice of τ that uses the Bayes false discovery rate and a new estimator of the statistical power called average power function to balance the two types of statistical error. We show that the proposed average power function estimator behaves well both in case of independence and weak dependence of the tests and it is reliable under several simulated dependence conditions. Moreover, we propose a robust method for the choice of τ using the 5% and 95% percentiles of the average power function and False Discovery Rate bootstrap distributions, respectively, to improve stability. We applied our approach to functional magnetic resonance imaging and high density electroencephalogram data.

White matter alterations in early Parkinson's disease: role of motor symptom lateralization.

INTRODUCTION: Parkinson's disease (PD) is a motor disorder that initially presents with unilateral symptoms. Widespread white matter (WM) alterations have been reported since the early stages of the disease. The aim of this study was to investigate WM alterations in right-dominant and left-dominant symptom PD patients (RPD and LPD, respectively) with respect to healthy controls (HC) by diffusion-weighted magnetic resonance imaging (MRI). METHODS: Thirty-eight subjects participated in this study: 12 RPD (median H&Y [IQR] = 1.5 [1.1-2], median UPDRS III [IQR] = 23 [7.8-25]), 9 LPD (median H&Y [IQR] = 1.5 [1-2.5], median UPDRS III [IQR] = 17 [12-22]), and 17 HC. All the participants were scanned on a 1.5-T MRI scanner. Maps of fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were computed for all the subjects. Tract-based spatial statistics (TBSS) was performed for each diffusion parameter, to test WM differences between RPD, LPD, and HC (ANCOVA design). Family-wise error (FWE) correction was performed and p values lower than 0.05 were considered significant. RESULTS: No significant FA and RD differences were observed between RPD, LPD, and HC. Significantly increased MD and AD were observed in RPD with respect to HC within widespread WM regions, bilaterally. Conversely, no significant WM alterations were detected in LPD. CONCLUSION: WM integrity was found to be significantly altered in RPD but not in LPD, suggesting that LPD profile may be associated to more favorable prognosis. Since clinical laterality onset may affect the extent of WM integrity changes, it should be taken into account in neuroimaging studies investigating PD.

Herpes simplex virus-1 (HSV-1) infection induces a potent but ineffective IFN-λ production in immune cells of AD and PD patients.

BACKGROUND: The sequential activation of immediate early (IE), early (E) and late (L) genes is required to allow productive herpes simplex virus type 1 (HSV-1) infection. Several evidences suggest that, together with inflammation, an immunological response incapable to counteract HSV-1 reactivation plays a role in the pathogenesis of Alzheimer's (AD) and Parkinson's (PD) diseases. IFN-lambda (IFN-λ), a cytokine endowed with a robust antiviral activity, contains HSV-1 reactivation. HSV-1-induced IFN-λ, IL-10 and IL-1ß as well as the expression of viral IE, E and L genes were analyzed in vitro in peripheral blood mononuclear cells (PBMC) of AD and PD patients as well as of healthy controls (HC). METHODS: PBMC of AD, PD and HC were in vitro infected with one multiplicity of infection (1 MOI) HSV-1. IE, E, and L viral genes transcription as well as IFN-λ, IL-10 and IL-1ß production were analyzed. RESULTS: In HSV-1-infected cells of AD and PD patients compared to HC: (1) transcription of IE (ICP0, ICP27) genes was reduced whereas that of E (UL41, UL29) and L (UL48, LAT) genes was increased; (2) IFN-λ mRNA expression was increased. IL-1ß was augmented and IL-10 was reduced in unstimulated cells of AD and PD compared to HC; HSV-1 infection significantly increased IL-10 production in HC alone. CONCLUSIONS: Data herein show that a proinflammatory condition is present in AD and PD, in whom attempts to obstacle viral replication via an initial, possibly more potent IFN-λ-mediated control of IE viral genes is unsuccessful.

The PILRA G78R Variant Correlates with Higher HSV-1-Specific IgG Titers in Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by a progressive decline in cognitive performance; Mild Cognitive Impairment (MCI) is instead an objective decline in cognitive performance that does not reach pathology. Paired immunoglobulin-like type 2 receptor alpha (PILRA) is a cell surface inhibitory receptor that was recently suggested to be involved in AD pathogenesis. In particular, the arginine-to-glycine substitution in position 78 (R78, rs1859788) was shown to be protective against AD. Herpes simplex virus type 1 (HSV-1) infection is suspected as well to be involved in AD. Interestingly, HSV-1 uses PILRA to infect cells, and HSV-1 infects more efficiently PIRLA G78 compared to R78 macrophages. We analyzed PILRA rs1859788 polymorphism and HSV-1 humoral immune responses in AD (n = 61) and MCI patients (n = 48), and in sex and age matched healthy controls (HC; n = 57). The rs1859788 PILRA genotype distribution was similar among AD, MCI and HC; HSV-1 antibody (Ab) titers were increased in AD and MCI compared to HC (p < 0.05 for both comparisons). Notably, HSV-1-specific IgG1 were significantly increased in AD patients carrying PILRA R78 rs1859788 AA than in those carrying G78 AG or GG (p = 0.01 for both comparisons), and the lowest titers of HSV-1-specific IgG1 were observed in rs1859788 GG AD. HSV-1 IgG are increased in AD patients with the protective R78 PILRA genotype. Because in AD patients brain atrophy is inversely correlated with HSV-1-specific IgG titers, results herein suggest a possible link between two important genetic and infective factors suspected to be involved in AD pathogenesis.

Combined Assessment of Diffusion Parameters and Cerebral Blood Flow Within Basal Ganglia in Early Parkinson's Disease.

Diffusion tensor imaging (DTI) is a sensitive tool for detecting brain tissue microstructural alterations in Parkinson's disease (PD). Abnormal cerebral perfusion patterns have also been reported in PD patients using arterial spin labeling (ASL) MRI. In this study we aimed to perform a combined DTI and ASL assessment in PD patients within the basal ganglia, in order to test the relationship between microstructural and perfusion alterations. Fifty-two subjects participated in this study. Specifically, 26 PD patients [mean age (SD) = 66.7 (8.9) years, 21 males, median (IQR) Modified Hoehn and Yahr = 1.5 (1-1.6)] and twenty-six healthy controls [HC, mean age (SD) = 65.2 (7.5), 15 males] were scanned with 1.5T MRI. Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD) maps were derived from diffusion-weighted images, while cerebral blood flow (CBF) maps were computed from ASL data. After registration to Montreal Neurological Institute standard space, FA, MD, AD, RD and CBF median values were extracted within specific regions of interest: substantia nigra, caudate, putamen, globus pallidus, thalamus, red nucleus and subthalamic nucleus. DTI measures and CBF were compared between the two groups. The relationship between diffusion parameters and CBF was tested with Spearman's correlations. False discovery rate (FDR)-corrected p-values lower than 0.05 were considered significant, while uncorrected p-values <0.05 were considered a trend. No significant FA, MD and RD differences were observed. AD was significantly increased in PD patients compared with HC in the putamen (p = 0.005, pFDR = 0.035). No significant CBF differences were found between PD patients and HC. Diffusion parameters were not significantly correlated with CBF in the HC group, while a significant correlation emerged for PD patients in the caudate nucleus, for all DTI measures (with FA: r = 0.543, pFDR = 0.028; with MD: r = -0.661, pFDR = 0.002; with AD: r = -0.628, pFDR = 0.007; with RD: r = -0.635, pFDR = 0.003). This study showed that DTI is a more sensitive technique than ASL to detect alterations in the basal ganglia in the early phase of PD. Our results suggest that, although DTI and ASL convey different information, a relationship between microstructural integrity and perfusion changes in the caudate may be present.

An ecological measure to screen executive functioning in MS: the Picture Interpretation Test (PIT) 360°.

Executive functions are crucial for performance of everyday activities. In Multiple Sclerosis (MS), executive dysfunctions can be apparent from the early onset of the disease. Technology-based time-efficient and resource-saving tools for early evaluation of executive functions using an ecological approach are needed to assess functional performance in real-life. The aim was to compare the efficiency of the Picture Interpretation Test 360° (PIT 360°) with traditional measures on executive dysfunction in Persons with Multiple Sclerosis (PwMS) and Healthy Controls (HC). Participants were 31 patients with Relapsing-Remitting MS (mean age = 44.323 ± 13.149; mean Expanded Disability Status Scale = 2) and 39 HC (mean age = 39.538 ± 15.728). All were tested with standard neuropsychological tests of executive functions, PIT 360°, and measures of user experience. While standard neuropsychological tests failed to differentiate between PwMS and HC group, the PIT 360° was successful in detecting executive dysfunction in PwMS. All participants reported the PIT 360° to be an engaging tool and endorsed positive reactions to their experience. Overall, the PIT 360° is a quick, sensitive, and ecological tool that captures real-world executive dysfunction in PwMS. This engaging measure is sensitive for the detection of executive deficits since the early phases of the disease.

SNARE Complex Polymorphisms Associate with Alterations of Visual Selective Attention in Alzheimer's Disease.

The SNARE complex plays a crucial role in the synaptic exocytosis of neurotransmitters, a process involved in the Alzheimer's disease (AD), the most common form of dementia. SNAP-25, STX1a, and VAMP2 are the core proteins of the SNARE complex, and changes in protein level are suggested to contribute to cognitive impairment and neuropsychiatric disorders. Single nucleotide polymorphisms (SNPs) in SNARE complex genes were shown to be associated with different diseases and different cognitive impairments. Chi-square analysis was used to compare case-control difference of ApoE4, SNAP-25 rs363039, rs363043, rs363950, STX1a rs4717806, rs2293489, and VAMP2 26bp Ins/Del genotype distribution in 192 AD, 187 mild cognitive impairment (MCI), and 200 healthy controls (HC). Results of genotype and allelic distribution of SNAP-25 rs363050 showed that AA genotype (AD versus HC: p = 1.5×10-4; MCI versus HC: p = 8.7×10-3) as well as A allele (AD versus HC: p = 6.0×10-4; MCI versus HC: p = 5.7×10-3) are significantly more frequent in AD and MCI compared to HC. Genotype distribution of STX1a rs4717806 and rs2293489 resulted significantly different in AD compared to HC (p = 0.032 and p = 0.047, respectively). Moreover, distribution of the STX1a rs4717806 allele in SNAP-25 rs363050 AA carriers was significantly different between MCI and HC (p = 0.018). Notably, in MCI, visual selective attention impairment was associated with the STX1a rs4717806 AA (pc = 0.027) genotype as well as the SNAP-25/STX1a rs363050/rs4717806 AA/A (pc = 0.022) combination. These data suggest that SNPs in SNARE complex genes may interfere and/or modulate the activity of the SNARE complex resulting in impairments of neurotransmission that involve attention brain areas.

Cerebral blood flow and cerebrovascular reactivity correlate with severity of motor symptoms in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative disorder that is mainly characterized by movement dysfunction. Neurovascular unit (NVU) disruption has been proposed to be involved in the disease, but its role in PD neurodegenerative mechanisms is still unclear. The aim of this study was to investigate cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) within the regions belonging to the motor network, in patients with mild to moderate stages of PD. METHODS: Twenty-eight PD patients (66.6 ± 8.6 years, 22 males, median [interquartile range, IQR] Hoehn & Yahr = 1.5 [1-1.9]) and 32 age- and sex-matched healthy controls (HCs) were scanned with arterial spin labeling (ASL) magnetic resonance imaging (MRI) for CBF assessment. ASL MRI was also acquired in hypercapnic conditions to induce vasodilation and subsequently allow for CVR measurement in a subgroup of 13 PD patients and 13 HCs. Median CBF and CVR were extracted from cortical and subcortical regions belonging to the motor network and compared between PD patients and HCs. In addition, the correlation between these parameters and the severity of PD motor symptoms [quantified with Unified Parkinson's Disease Rating Scale part III (UPDRS III)] was assessed. The false discovery rate (FDR) method was used to correct for multiple comparisons. RESULTS: No significant differences in terms of CBF and CVR were found between PD patients and HCs. Positive significant correlations were observed between CBF and UPDRS III within the precentral gyrus, postcentral gyrus, supplementary motor area, striatum, pallidum, thalamus, red nucleus, and substantia nigra (pFDR < 0.05). Conversely, significant negative correlation between CVR and UPDRS III was found in the corpus striatum (pFDR < 0.05). CONCLUSION: CBF and CVR assessment provides information about NVU integrity in an indirect and noninvasive way. Our findings support the hypothesis of NVU involvement at the mild to moderate stages of PD, suggesting that CBF and CVR within the motor network might be used as either diagnostic or prognostic markers for PD.

SNAP-25 in Serum Is Carried by Exosomes of Neuronal Origin and Is a Potential Biomarker of Alzheimer's Disease.

A loss of synaptic density and connectivity is observed in multiple brain regions of Alzheimer's disease (AD) patients, resulting in a reduced expression of synaptic proteins such as SNAP-25 (synaptosomal-associated-protein-25). SNAP-25 alterations thus could be an index of the degree of synaptic degeneration in the central nervous system (CNS). We isolated from serum of both AD patients and healthy controls (HC) a population of neuron-derived exosomes (NDEs) and measured the concentrations of SNAP-25 contained in such NDEs. The levels of SNAP-25 carried by NDEs were reduced in AD patients (mean 459.05 ng/ml, SD 146.35 ng/ml) compared to HC (mean 686.42 ng/ml, SD 204.08 ng/ml) (p < 0.001). As a further confirmation of these results, ROC (receiver operating characteristic) analyses indicated that the level of SNAP-25 carried by NDEs has the power to discriminate between AD and HC (AUC = 0.826, sensitivity = 87.5%, specificity = 70.6%, p < 0.0001, cut-off value 587.07 ng/ml). Notably, a correlation between the levels of SNAP-25 carried by NDEs and levels and cognitive status measured by MMSE score (r = 0.465, 95% CI 0.11 to 0.714, p = 0.01) was detected. This is the first report of SNAP-25 measurement in serum. These data suggest that NDE-carried SNAP-25 could be an effective and accessible biomarker that reflects synapses integrity in the brain.

SNAP25 Gene Polymorphisms Protect Against Parkinson's Disease and Modulate Disease Severity in Patients.

Parkinson's disease (PD) is a α-synucleinopathy in which intracellular aggregates of α-synuclein (α-syn) result in neurodegeneration and in the impairment of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex-mediated release of neurotransmitters. SNAP25 is a SNARE complex component: its concentration is increased in the cerebrospinal fluid of PD patients and this is related to the severity of cognitive and motor symptoms. Five SNAP25 single-nucleotide polymorphisms (SNPs) that modulate gene expression and were described to play a role in neurologic conditions (rs363050, rs363039, rs363043, rs3746544, and rs1051312) were analyzed in a cohort of 412 sporadic Italian PD patients and 1103 healthy controls (HC) in order to identify possible correlation with the disease. The SNAP25 rs1051312 C allele and CC genotype confer protection against PD onset, in particular in males (p = 0.003, OR(95%CI) = 0.67(0.51-0.88)) (pc = 0.008, OR(95%CI) = 0.28(0.10-0.70)). Co-segregation analyses revealed that the rs1051312 effect was reinforced when present within the rs363043 C-rs3746544 T-rs1051312 C haplotype (p = 3.3 × 10-4, OR = 0.47, 95%CI = 0.31-0.72), once again in males. Finally, rs363039 influenced age at onset (p = 0.02) and MMSE (Mini-Mental State Examination) scores (p = 0.01). The SNAP25 SNPs analyzed herein modulate gene expression at different levels as they are involved in binding miRNA and transcription factors; this suggests a possible synergistic effect of SNAP25 SNPs in the pathogenesis of PD. A replication in a larger and independent sample will help to further explore this hypothesis.