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Visual hallucinations (VH) are present in up to 75% of Parkinson's disease (PD) patients. However, their neural bases and participation of the visual system in VH are not well-understood in PD. Seventy-four participants, 12 PD with VH (PDVH), 35 PD without VH (PDnoVH) and 27 controls underwent a battery of primary visual function and visual cognition tests, retinal optical coherence tomography and structural and resting-state functional brain MRI. We quantified cortical thickness with Freesurfer and functional connectivity (FC) of Visual (VIS), Fronto-Parietal (FP), Ventral Attention (VAN) and Dorsal Attention (DAN) networks with CONN toolbox. Group comparisons were performed with MANCOVA. Area Under the Curve (AUC) was computed to assess the ability of visual variables to differentiate PDVH and PDnoVH. There were no significant PDVH vs PDnoVH differences in disease duration, motor manifestations, general cognition or dopamine agonist therapy (DA) use. Compared to PDnoVH and HC, and regardless of DA use, PDVH showed significantly reduced contrast sensitivity, visuoperceptive and visuospatial abilities, increased retina photoreceptor layer thickness, reduced cortical thickness mostly in right visual associative areas, decreased between-network VIS-VAN and VAN-DAN connectivity and increased within-network DAN connectivity. The combination of clinical and imaging variables that best discriminated PDVH and PDnoVH (highest AUC), where within-network DAN FC, photoreceptor layer thickness and cube analysis test from Visual Object and Space Perception Battery (accuracy of 81.8%). Compared to PDnoVH, PDVH have specific functional and structural abnormalities within the visual system, which can be quantified non-invasively and could potentially constitute biomarkers for VH in PD.

Background To assess the influence of biometric measurements on the defocus curve after the implantation of enlarged depth-of-focus (EDoF) intraocular lens (IOL). Methods Patients who underwent cataract surgery with bilateral implantation of Tecnis Symfony IOL were enrolled. Preoperatively, axial length (AL), corneal keratometry (K), pupil size and corneal aberrations were measured. 1 month after surgery, distance, intermediate, and near visual acuities (VA) were recorded. At 3 months, monocular and binocular corrected contrast sensitivities under photopic and mesopic lighting conditions were measured with CSV-1000E test. At 6-months, the defocus curve between −5.00 to + 3.00 diopters (D) was assessed in steps of 0.50 D, and NEI-RQL-42 questionnaire was administered. Results One hundred thirty one eyes of 66 patients were included. Binocular logMAR VA better than 0.1 for intermediate vision was obtained in 90% of patients, whereas only 17.7% obtained that result in near vision. The rate of satisfaction was high (96%) and most of them (85.5%) had no or little difficulties in near vision. The mean amplitude of the defocus curve was 2.35D ± 0.73D, and smaller AL, smaller pupils, younger age, and male sex were associated with wider range of clear vision. Conclusions Tecnis Symfony IOL enables functional vision at all distances, but demographic variables and preoperative biometric measurements like AL and pupil size influence the postoperative amplitude of the defocus curve. These parameters could be used to predict the performance of EDoF IOLs.

Background Cognitive decline has been reported in premanifest and manifest Huntington’s disease but reliable biomarkers are lacking. Inner retinal layer thickness seems to be a good biomarker of cognition in other neurodegenerative diseases. Objective To explore the relationship between optical coherence tomography-derived metrics and global cognition in Huntington’s Disease. Methods Thirty-six patients with Huntington’s disease (16 premanifest and 20 manifest) and 36 controls matched by age, sex, smoking status, and hypertension status underwent macular volumetric and peripapillary optical coherence tomography scans. Disease duration, motor status, global cognition and CAG repeats were recorded in patients. Group differences in imaging parameters and their association with clinical outcomes were analyzed using linear mixed-effect models. Results Premanifest and manifest Huntington’s disease patients presented thinner retinal external limiting membrane-Bruch’s membrane complex, and manifest patients had thinner temporal peripapillary retinal nerve fiber layer compared to controls. In manifest Huntington’s disease, macular thickness was significantly associated with MoCA scores, inner nuclear layer showing the largest regression coefficients. This relationship was consistent after adjusting for age, sex, and education and p-value correction with False Discovery Rate. None of the retinal variables were related to Unified Huntington’s Disease Rating Scale score, disease duration, or disease burden. Premanifest patients did not show a significant association between OCT-derived parameters and clinical outcomes in corrected models. Conclusions In line with other neurodegenerative diseases, OCT is a potential biomarker of cognitive status in manifest HD. Future prospective studies are needed to evaluate OCT as a potential surrogate marker of cognitive decline in HD.

Non-motor manifestations of Parkinson’s disease (PD) appear early and have a significant impact on the quality of life of patients, but few studies have evaluated their predictive potential with machine learning algorithms. We evaluated 9 algorithms for discriminating PD patients from controls using a wide collection of non-motor clinical PD features from two databases: Biocruces (96 subjects) and PPMI (687 subjects). In addition, we evaluated whether the combination of both databases could improve the individual results. For each database 2 versions with different granularity were created and a feature selection process was performed. We observed that most of the algorithms were able to detect PD patients with high accuracy (>80%). Support Vector Machine and Multi-Layer Perceptron obtained the best performance, with an accuracy of 86.3% and 84.7%, respectively. Likewise, feature selection led to a significant reduction in the number of variables and to better performance. Besides, the enrichment of Biocruces database with data from PPMI moderately benefited the performance of the classification algorithms, especially the recall and to a lesser extent the accuracy, while the precision worsened slightly. The use of interpretable rules obtained by the RIPPER algorithm showed that simply using two variables (autonomic manifestations and olfactory dysfunction), it was possible to achieve an accuracy of 84.4%. Our study demonstrates that the analysis of non-motor parameters of PD through machine learning techniques can detect PD patients with high accuracy and recall, and allows us to select the most discriminative non-motor variables to create potential tools for PD screening. Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. This work was partially funded by the Department of Education, Universities and Research of the Basque Government (ADIAN, IT-980-16); by the Spanish Ministry of Science, Innovation and Universities - National Research Agency and the European Regional Development Fund - ERDF (PhysComp, TIN2017-85409-P), and from the State Research Agency (AEI, Spain) under grant agreement No RED2018-102312-T (IA-Biomed); by Michael J. Fox Foundation [RRIA 2014 (Rapid Response Innovation Awards) Program (Grant ID: 10189)]; by the Instituto de Salud Carlos III through the project “PI14/00679” and “PI16/00005”, the Juan Rodes grant “JR15/00008” (IG) (Co-funded by European Regional Development Fund/European Social Fund - “Investing in your future”); and by the Department of Health of the Basque Government through the projects “2016111009” and “2019111100”.

Gero eta ebidentzia gehiagok adierazten du sexu biologikoa faktore garrantzitsua dela Parkinson gaixotasunaren garapenean eta adierazpen fenotipikoan. Jakina da Parkinson gaixotasunaren prebalentzia ia bi aldiz altuagoa dela gizonezkoetan emakumezkoetan baino. Hala ere, emakumezkoek gaixotasunaren progresio azkarragoa izaten dute. Gainera, azken urteotan egindako ikerketek agerian utzi dute Parkinson gaixotasunaren ondorioz agertzen diren sintoma motorrak eta ez-motorrak maiztasun edota larritasun desberdina dutela sexuaren arabera. Halaber, emakumeek eta gizonezkoek tratamendu farmakologikoen eta kirurgikoen aurrean duten erantzuna ere desberdina dela uste da. Sexu-desberdintasun hauen oinarriak zehatz-mehatz ezagutzen ez badira ere, mekanismo fisiopatologikoak desberdinak direla iradoki da. Berrikuspen honetan Parkinsona duten emakumezkoen eta gizonezkoen artean dauden desberdintasunak laburbiltzen dira, besteak beste, ezaugarri klinikoetan, arrisku-faktoreetan, gaixotasunaren fisiopatologian eta tratamenduen erantzunean. Patologiak sexu bakoitzari nola eragiten dion argitzeak pazienteen arreta hobetzea ahalbidetu dezake, gizonen eta emakumeen maneiu terapeutikoa neurrira diseinatuz eta behar ezberdinei erantzuteko programa berritzaileak garatuz.

Introduction Visual dysfunction and cognitive impairment are common in Parkinson's disease (PD) but the precise contribution of lower-level visual impairment to visual-input based cognitive performance has not been extensively characterized in PD. Methods We included 49 PD patients and 22 healthy controls (HC). Lower-level visual function tests [high and low contrast visual acuity (HCVA and LCVA) and contrast sensitivity (CS)] and a neuropsychological battery (involving visual cognition) were performed. Pairwise correlations between lower-level visual functions and visual cognition were computed and stepwise linear regressions were fitted introducing age, Geriatric Depression Scale, and lower-level visual functions in the model to calculate their predicted effect on visual cognition. Results Compared to controls, patients presented a significant impairment in all cognitive domains (visual attention, visual processing speed and visual perception, visuospatial abilities, visuoconstructive abilities, and visual memory), and lower-level visual functions. HCVA and LCVA were significantly associated with visual cognition in PD. HCVA explained up to 49.3% and 34.2% of the variability in visual perception and visuospatial abilities, respectively, whereas LCVA was mainly associated with short- and long-term visual memory and visuospatial abilities. Conclusion Lower-level visual dysfunction is highly associated with cognitive performance in PD, when cognitive tests are based on visual input. Our results support that lower-level visual functions should be considered when assessing cognitive status of PD patients and might be useful for predicting cognitive deterioration.

Parkinson disease (PD) is a common neurodegenerative disease, characterized pathologically by the presence of Lewy bodies and the progressive loss of dopaminergic neurons. Currently, the diagnosis of PD is based on clinical criteria; that is, it is diagnosed when motor symptoms appear such as limb tremor, slowness of movement or muscle stiffness. However, by the time motor symptoms appear, more than half of the dopaminergic neurons in the midbrain have been lost. Furthermore, as clinical diagnosis of PD is challenging, misdiagnosis is common. This highlights the need for disease-specific and early-stage biomarkers. Lewy bodies are rich in α-synuclein protein, who plays a fundamental role in the pathogenesis of PD. Therefore, α-synuclein may be useful as a PD biomarker. Therefore, the objective of this review is to summarize the efficacy of body fluid α-synuclein and its proteoforms measurements in the detection of PD. In fact, the identification of specific, sensitive, and non-invasive biomarkers is essential especially in regard to existing and future disease modifying treatments. Although the main candidate has been the measurement of α-synuclein in cerebrospinal fluid (CSF), CSF collection procedure is quite invasive and unsuitable in most clinical settings. Consequently, the presence of this protein and its proteoforms in biofluids such as blood plasma, saliva and tears has been investigated. Based on the results of these studies, phosphorylated and oligomeric α-synuclein are the best candidates for PD diagnosis. Until now, the measurement of α-synuclein has had multiple technical limitations, but the repeatability and reliability of immunoassays created in the last years has increased considerably. Therefore, it is expected that the potential of the main candidate biomarkers for PD diagnosis will be verified in the upcoming years.; Parkinson gaixotasuna ohiko gaixotasun neurodegeneratiboa da, patologikoki Lewy gorputzen presentziagatik eta neurona dopaminergikoen galera progresiboagatik bereizten dena. Gaur egun, Parkinson gaixotasunaren diagnostikoa irizpide klinikoetan oinarrituta dago; hau da, gorputz-adarren dardara, mugimenduen moteltasuna edo muskuluen gogortasuna bezalako sintoma motorrak agertzen direnean diagnostikatzen da. Hala ere, sintoma motorrak azaleratzen direnerako, mesentzefaloko neurona dopaminergikoen erdia baino gehiago galdu direla uste da. Gainera, Parkinsonaren diagnostiko klinikoa erronka bat denez, ohikoak dira diagnostiko okerrak. Horrek argi uzten du gaixotasunaren berariazko diagnostikorako biomarkatzaileak behar direla, batez ere fase goiztiarretan. Lewyren gorputzak aberatsak dira alfa-sinukleina (α-sinukleina) proteinatan, eta hauek funtsezko eginkizuna dute Parkinson gaixotasunaren patogenesian. Hori dela eta, α-sinukleina baliagarria izan daiteke Parkinsonaren biomarkatzaile gisa. Berrikuspen honen helburua, beraz, gorputzeko fluido desberdinetan α-sinukleinaren eta haren proteoformen neurketaren erabilgarritasun-diagnostikoari buruzko ebidentzia laburbiltzea da. Izan ere, espezifikoak, sentikorrak eta eskuragarriak diren biomarkatzaileak identifikatzea ezinbestekoa da Parkinson gaixotasuna aldatzeko dauden eta etorkizunean izango diren tratamenduei dagokienez. Nahiz eta hautagai nagusia α-sinukleina likido zefalorrakideoan (LZR) neurtzea izan den, LZR biltzeko prozedura nahiko inbaditzailea da, eta ez da egokia ingurune kliniko gehienetan. Ondorioz, odol-plasma, listua eta malkoa bezalako biofluidoetan ikertu da proteina honen eta haren proteoformen presentzia. Ikerketa hauen emaitzen arabera, α-sinukleina fosforilatua eta oligomerikoa izan daitezke hautagai egokienak Parkinson gaixotasunaren diagnostikorako. Orain arte α-sinukleinaren neurketak muga tekniko anitz izan dituen arren, azken urteetan sortutako tekniken bitartez entseguen errepikakortasuna eta fidagarritasuna nabarmen areagotu da. Beraz, hautagai nagusiek Parkinsonaren diagnostikorako biomarkatzailegisa izan dezaketen potentziala hurrengo urteetan egiaztatzea espero da.

Background: Visual impairment is frequent and highly disabling in Parkinson’s disease (PD); however, few studies have comprehensively evaluated its impact on vision-related quality of life. Objective: To evaluate the relationship between visual function tests and the visual impairment perceived by PD patients in daily living activities. Methods: We cross-sectionally evaluated 62 PD patients and 33 healthy controls (HC). Visual disability was measured with a comprehensive battery of primary visual function and visual cognition tests (visual outcomes), and vision-related quality of life was evaluated with the National Eye Institute 25-Item Visual Function Questionnaire (NEI VFQ-25). The relationship between visual outcomes and NEI VFQ-25 sub-scores was analyzed with Pearson’s correlations and stepwise linear regression. Results: In PD patients, and not in HC, most NEI VFQ-25 sub-scores were significantly correlated with Cube Analysis and Dot Counting from Visual Object and Space Perception (VOSP) battery (visual perception), Clock Drawing Test (visuoconstructive capacity) and Trail Making Test part-A (visual attention and processing speed) and to a lesser extent with high- and low-contrast visual acuity. Dot Counting (VOSP) was the test primarily associated with most NEI VFQ-25 sub-scores (5 out of 12). Roth-28 color test was the one that best explained the variance of Peripheral Vision (R2: 0.21) and Role Difficulties (R2: 0.36) sub-scores of NEI VFQ-25, while photopic contrast sensitivity explained 41% of Driving sub-score variance. Conclusion: Vision-related quality of life in PD is mainly influenced by alterations in visual perception, visuoconstructive capacity and visual attention and processing speed. Future studies are warranted to confirm and further extend our findings.

This study aimed to analyze the association of autonomic dysfunction with cognition, depression, apathy, and fatigue in Lewy body disease (LBD). We included 61 patients [49 with idiopathic Parkinson’s disease, 7 with dementia with Lewy bodies, and 5 E46K-SNCA mutation carriers] and 22 healthy controls. All participants underwent a comprehensive battery of neuropsychological and clinical measures, autonomic symptom assessment with the SCOPA-AUT, analysis of non-invasive hemodynamic parameters during deep breathing, the Valsalva maneuver, and a 20-min tilt test, and electrochemical skin conductance measurement at rest (Sudoscan). Student’s t tests were used to assess group differences, and bivariate correlations and stepwise linear regressions to explore associations between autonomic function, cognition, depression, apathy, and fatigue. Compared to controls, patients who had significant impairment (p

Reliable biomarkers for Parkinson's disease (PD) diagnosis are urgently needed. Alpha-synuclein (α-syn) and its proteoforms play a key role in PD pathology but in vivo measurements have raised conflicting results, and whether α-syn in blood could distinguish PD patients from healthy controls is still controversial.A systematic literature search yielded 35 eligible studies for meta-analysis reporting the concentration of total, oligomeric or phosphorylated α-syn in plasma and/or serum of PD patients and healthy controls. Standardized mean differences (SMD) were pooled using multivariate/multilevel linear mixed-effects models. Meta-regression analyses were conducted to investigate possible modifiers.A meta-analysis of 32 articles involving 2683 PD patients and 1838 controls showed a significant overall effect of PD on total α-syn levels (SMD = 0.85, p = 0.004). Meta-regression showed that increased SMD of total α-syn in PD was significantly associated with lower age, shorter disease duration, mild motor impairment, and Immunomagnetic Reduction assay for protein quantification. In contrast, no significant differences were observed for oligomeric or phosphorylated α-syn between PD and controls but increased oligomeric α-syn was significantly associated with shorter disease duration. The heterogeneity among studies was high (98%).These findings suggest that increased total plasma/serum α-syn levels in PD primarily occur in early phases of the disease. The evidence obtained from a small number of studies measuring plasma/serum concentrations of oligomeric and phosphorylated species of α-syn shows no difference. The clinical applicability of measuring plasma or serum α-syn species for differentiating PD from healthy control warrants further studies with better clinical profiling of PD patients.

Parkinson disease (PD) is a progressive disorder characterized by dopaminergic neurodegeneration in the brain. The development of parkinsonism is preceded by a long prodromal phase, and >50% of dopaminergic neurons can be lost from the substantia nigra by the time of the initial diagnosis. Therefore, validation of in vivo imaging biomarkers for early diagnosis and monitoring of disease progression is essential for future therapeutic developments. PET and single-photon emission CT targeting the presynaptic terminals of dopaminergic neurons can be used for early diagnosis by detecting axonal degeneration in the striatum. However, these techniques poorly differentiate atypical parkinsonian syndromes from PD, and their availability is limited in clinical settings. Advanced MRI in which pathological changes in the substantia nigra are visualized with diffusion, iron-sensitive susceptibility and neuromelanin-sensitive sequences potentially represents a more accessible imaging tool. Although these techniques can visualize the classic degenerative changes in PD, they might be insufficient for phenotyping or prognostication of heterogeneous aspects of PD resulting from extranigral pathologies. The retina is an emerging imaging target owing to its pathological involvement early in PD, which correlates with brain pathology. Retinal optical coherence tomography (OCT) is a non-invasive technique to visualize structural changes in the retina. Progressive parafoveal thinning and fovea avascular zone remodelling, as revealed by OCT, provide potential biomarkers for early diagnosis and prognostication in PD. As we discuss in this Review, multimodal imaging of the substantia nigra and retina is a promising tool to aid diagnosis and management of PD.

Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease. In this study, the tear proteome profile of patients with idiopathic PD (iPD, n = 24), carriers of the E46K-SNCA mutation (n = 3) and healthy control (CT, n = 27) subjects was analyzed to identify candidate biomarkers for the diagnosis of PD. An observational, prospective and case-control pilot study was carried out, analyzing the participants tear samples by nano-liquid chromatography–mass spectrometry (nLC–MS/MS) and assessing their neurological impairment. The proteomic data obtained are available at ProteomeXchange with identifier 10.6019/PXD028811. These analyses led to the identification of 560 tear proteins, some of which were deregulated in PD patients and that have been implicated in immune responses, inflammation, apoptosis, collagen degradation, protein synthesis, defense, lipid transport and altered lysosomal function. Of these proteins, six were related to neurodegenerative processes and showed a good capacity to classify patients and controls. These findings revealed that certain proteins were upregulated in the tears of PD patients, mainly proteins involved in lysosomal function. Thus, in this study, tear proteins were identified that are implicated in neurodegeneration and that may be related to an aggressive disease phenotype in PD patients.

Blood and cerebrospinal fluid represent emerging candidate fluids for biomarker identification in Parkinson's disease (PD).We studied 8 individuals carrying the E46K-SNCA mutation (3 PD dementia (PDD), 1 tremor-dominant PD, 2 young rigid-akinetic PD and 2 asymptomatic) and 8 age- and sex-matched healthy controls. We quantified the levels of total alpha-synuclein (a-syn), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), Tau and ubiquitin carboxy-terminal hydrolase L1 (UCHL1) with SiMoA (Quanterix) in cerebrospinal fluid (CSF) of mutation carriers and in serum of all participants. The correlation between the concentration of biofluid markers and clinical outcomes was evaluated.Although based on a small number of cases, CSF a-syn was decreased in symptomatic E46K-SNCA carriers compared to the asymptomatic ones. Asymptomatic carriers exhibited similar serum biomarker levels as compared to matched controls, except for serum a-syn, which was higher in asymptomatic individuals. Carriers with PDD diagnosis displayed increased levels of serum NfL and GFAP compared to matched controls. These findings highly correlated with cognitive and motor status of E46K-SNCA carriers, but not with disease duration.Patients with familial forms of neurodegenerative disease exhibit variable penetrance of the phenotype and are exceptionally valuable for delineating biomarkers. Serum and CSF molecular biomarkers in E46K-SNCA mutation carriers show that a-syn might be suitable to track the conversion from asymptomatic to PD, whereas NfL and GFAP might serve to foresee the progression to PD dementia. These findings should be interpreted with caution and need to be replicated in other genetic synucleinopathy cohorts.

Dysregulation of the inhibitory drive has been proposed to be a central mechanism to explain symptoms and pathophysiological hallmarks in schizophrenia. A number of recent neuroanatomical studies suggest that certain types of inhibitory cells are deficient in schizophrenia, including somatostatin-immunoreactive interneurons (SST+). The present study sought to use stereological methods to investigate whether the number of SST+ interneurons decreased after repeated injections of NMDA receptor antagonist MK-801 (0.5 mg/kg) and to determine the effect of limited exposure to an enriched environment (EE) in adult life on this sub-population of inhibitory cells. Considering that somatostatin expression is highly dependent on neurotrophic support, we explored the changes in the relative expression of proteins related to brain-derived neurotrophic factor-tyrosine kinase B (BDNF-TrkB) signaling between the experimental groups. We observed that early-life MK-801 treatment significantly decreased the number of SST+ interneurons in the medial prefrontal cortex (mPFC) and the hippocampus (HPC) of adult Long Evans rats. Contrarily, short-term exposure to EE increased the number of SST+ interneurons in MK-801-injected animals, except in the CA1 region of the hippocampus, whereas this increase was not observed in vehicle-injected rats. We also found upregulated BDNF-TrkB signaling after EE that triggered an increase in the pERK/ERK ratio in mPFC and HPC, and the pAkt/Akt ratio in HPC. Thus, the present results support the notion that SST+ interneurons are markedly affected after early-life NMDAR blockade and that EE promotes SST+ interneuron expression, which is partly mediated through the BDNF-TrkB signaling pathway. These results may have important implications for schizophrenia, as SST+ interneuron loss is also observed in the MK-801 pre-clinical model, and its expression can be rescued by non-pharmacological approaches.

Background Retinal optical coherence tomography findings in Lewy body diseases and their implications for visual outcomes remain controversial. We investigated whether region-specific thickness analysis of retinal layers could improve the detection of macular atrophy and unravel its association with visual disability in Parkinson's disease. Methods Patients with idiopathic Parkinson's disease (n = 63), dementia with Lewy bodies (n = 8), and E46K mutation carriers in the alpha-synuclein gene (E46K-SNCA) (n = 4) and 34 controls underwent Spectralis optical coherence tomography macular scans and a comprehensive battery of visual function and cognition tests. We computed mean retinal layer thicknesses of both eyes within 1-, 2-, 3-, and 6-mm diameter macular discs and in concentric parafoveal (1- to 2-mm, 2- to 3-mm, 1- to 3-mm) and perifoveal (3- to 6-mm) rings. Group differences in imaging parameters and their relationship with visual outcomes were analyzed. A multivariate logistic model was developed to predict visual impairment from optical coherence tomography measurements in Parkinson's disease, and cutoff values were determined with receiver operating characteristic analysis. Results When compared with controls, patients with dementia with Lewy bodies had significant thinning of the ganglion cell-inner plexiform layer complex within the central 3-mm disc mainly because of differences in 1- to 3-mm parafoveal thickness. This parameter was strongly correlated in patients, but not in controls, with low contrast visual acuity and visual cognition outcomes (P < .05, False Discovery Rate), achieving 88% of accuracy in predicting visual impairment in Parkinson's disease. Conclusion Our findings support that parafoveal thinning of ganglion cell-inner plexiform complex is a sensitive and clinically relevant imaging biomarker for Lewy body diseases, specifically for Parkinson's disease. (c) 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. This study was partially cofunded by the Michael J. Fox Foundation (2014 Rapid Response Innovation Awards; Grant 10189), by the Carlos III Health Institute through Projects PI14/00679 and PI16/00005, and Juan Rodes Grant JR15/00008 (I.G.) (cofunded by the European Regional Development Fund/European Social Fund "Investing in Your Future"), and by the Department of Health of the Basque Government through Project 2016111009

Schizophrenia is a mental disorder characterized by psychosis, negative symptoms and cognitive impairment. Cognitive deficits are enduring and represent the most disabling symptom but are currently poorly treated. N-methyl D-aspartate receptor (NMDAR) hypofunction hypothesis has been notably successful in explaining the pathophysiological findings and symptomatology of schizophrenia. Thereby, NMDAR blockade in rodents represents a useful tool to identify new therapeutic approaches. In this regard, enriched environment (EE) could play an essential role. Using a multilevel approach of behavior, electrophysiology and protein analysis, we showed that a short-term exposure to EE in adulthood ameliorated spatial learning and object-place associative memory impairment observed in postnatally MK-801-treated Long Evans rats. Moreover, EE in adult life restored long-term potentiation (LTP) in hippocampal-medial prefrontal pathway abolished by MK-801 treatment. EE in adulthood also induced a set of modifications in the expression of proteins related to glutamatergic neurotransmission. Taken together, these findings shed new light on the neurobiological effects of EE to reverse the actions of MK-801 and offer a preclinical testing of a therapeutic strategy that may be remarkably effective for managing cognitive symptoms of schizophrenia.

Exposure to N-nitroso compounds (NOCs) during pregnancy has been associated with an increase in brain tumors in the progeny. This study investigated the brain tumorigenic effect of N-ethyl N-nitrosourea (ENU) after differential exposure of rats during pregnancy. Sprague Dawley rats were exposed to a single dose of ENU (80 mg/kg) in three different circumstances: 1) at first, second or third week of gestation; 2) at the 15th embryonic day (E15) in consecutive litters and 3) at E15 in three successive generations. Location and characterization of the offspring's brain tumors were performed by magnetic resonance imaging and histopathological studies. Finally, tumor incidence and latency and the animals' survival were recorded. ENU-exposure in the last two weeks of pregnancy induced intracranial tumors in over 70% of the offspring rats, these being mainly gliomas with some peripheral nerve sheath tumors (PNSTs). Tumors appeared in young adults; glioma-like small multifocal neoplasias converged on large glioblastomas in senescence and PNSTs in the sheath of the trigeminal nerve, extending to cover the brain convexity. ENU-exposure at E15 in subsequent pregnancies lead to an increase in glioma and PNST incidence. However, consecutive generational ENU-exposure (E15) decreased the animals' survival due to an early onset of both types of tumors. Moreover, PNST presented an inheritable component because progeny, which were not themselves exposed to ENU but whose progenitors were, developed PNSTs. Our results suggest that repeated exposure to ENU later in pregnancy and in successive generations favours the development of intracranial gliomas and PNSTs in the offspring. This study has been financially supported by the University of the Basque Country (UPV/EHU) (GIU 092/19 and PPG 17/51) and the Basque Government (SAN20/25)

Background and objective Multiple system atrophy is a rare and fatal neurodegenerative disorder, characterized by autonomic dysfunction in association with either parkinsonism or cerebellar signs. The pathologic hallmark is the presence of alpha-synuclein aggregates in oligodendrocytes, forming glial cytoplasmic inclusions. Clinically, it may be difficult to distinguish form other parkinsonisms or ataxias, particularly in the early stages of the disease. In this case series we aim to describe in detail the features of MSA patients. Material and methods Unified MSA Rating Scale (UMSARS) score, structural and functional imaging and cardiovascular autonomic testing, are summarized since early stages of the disease. Results UMSARS proved to be useful to perform a follow-up being longitudinal examination essential to stratify risk of poor outcome. Neuropathological diagnosis showed an overlap between parkinsonian and cerebellar subtypes, with some peculiarities that could help to distinguish from other subtypes. Conclusion A better description of MSA features with standardized test confirmed by means of neuropathological studies could help to increase sensitivity.

Autonomic dysreflexia (AD) is a life-threatening condition for individuals with cervical or high-thoracic spinal cord injury (SCI). The profile of autonomic dysfunction in AD using validated clinical autonomic tests has not been described so far, although it could be useful to identify SCI patients at greater risk of developing AD non-invasively. With this objective, 37 SCI patients (27% female) were recruited, and hemodynamic and cardiac parameters were continuously monitored to determine the presence of AD, defined as an increase of systolic blood pressure of 20 mmHg or higher after bladder filling with saline. Then, standard autonomic function testing was performed, including Deep Breathing, Valsalva Manoeuvre and Tilt Table Test. Finally, baroreflex sensitivity (BRS), and spectral analysis of heart rate and blood pressure variability were measured at rest. Catecholamines and vasopressin levels were also measured at supine and upright positions. The severity of SCI was assessed through clinical and radiological examinations. AD was observed in 73.3% of SCI patients, being 63.6% of them asymptomatic during the dysreflexive episode. AD patients displayed a drop in sympathetic outflow, as determined by decreased noradrenalin plasma levels, reduced sympathovagal balance and increased BRS. In line with decreased sympathetic activity, the incidence of neurogenic orthostatic hypotension was higher in AD patients. Our results provide novel evidence regarding the autonomic dysfunction in SCI patients with AD compared to non-AD patients, posing non-invasively measured autonomic parameters as a powerful clinical tool to predict AD in SCI patients.

Objective This study was undertaken to analyze longitudinal changes of retinal thickness and their predictive value as biomarkers of disease progression in idiopathic Parkinson's disease (iPD). Methods Patients with Lewy body diseases were enrolled and prospectively evaluated at 3 years, including patients with iPD (n = 42), dementia with Lewy bodies (n = 4), E46K-SNCA mutation carriers (n = 4), and controls (n = 17). All participants underwent Spectralis retinal optical coherence tomography and Montreal Cognitive Assessment, and Unified Parkinson's Disease Rating Scale score was obtained in patients. Macular ganglion cell-inner plexiform layer complex (GCIPL) and peripapillary retinal nerve fiber layer (pRNFL) thickness reduction rates were estimated with linear mixed models. Risk ratios were calculated to evaluate the association between baseline GCIPL and pRNFL thicknesses and the risk of subsequent cognitive and motor worsening, using clinically meaningful cutoffs. Results GCIPL thickness in the parafoveal region (1- to 3-mm ring) presented the largest reduction rate. The annualized atrophy rate was 0.63 mu m in iPD patients and 0.23 mu m in controls (p < 0.0001). iPD patients with lower parafoveal GCIPL and pRNFL thickness at baseline presented an increased risk of cognitive decline at 3 years (relative risk [RR] = 3.49, 95% confidence interval [CI] = 1.10-11.1, p = 0.03 and RR = 3.28, 95% CI = 1.03-10.45, p = 0.045, respectively). We did not identify significant associations between retinal thickness and motor deterioration. Interpretation Our results provide evidence of the potential use of optical coherence tomography-measured parafoveal GCIPL thickness to monitor neurodegeneration and to predict the risk of cognitive worsening over time in iPD This study was cofunded by the Michael J. Fox Foundation (RRIA [Rapid Response Innovation Awards] 2014 Program, grant ID: 10189), the Carlos III Health Institute, and the European Union (ERDF/ESF, "A Way to Make Europe"/"Investing in Your Future") through the projects PI14/00679 and PI16/00005; the Juan Rodes grant JR15/00008 (I.G.); and the Department of Health of the Basque Government through the projects 2016111009 and 2020333033. We thank all the patients and participants involved in the study.

Objective To prospectively evaluate nocturnal sleep problems and excessive daytime sleepiness (EDS) in Parkinson’s disease (PD) patients, and analyze the influence of motor symptoms, treatment, and sex differences on sleep problems in PD. Methods Sleep disturbances of 103 PD patients were assessed with Parkinson’s Disease Sleep Scale (PDSS) and the Epworth Sleepiness Scale (ESS). Student’s t-test for related samples, one-way ANOVA with Tukey’s HSD post hoc test were used to assess group differences. Bivariate correlations and mixed-effects linear regression models were used to analyze the association between clinical aspects and sleep disturbances over time. Results At baseline, 48.5% of PD patients presented nocturnal problems and 40% of patients presented EDS. The PDSS and ESS total score slightly improve over time. Nocturnal problems were associated with age and motor impartment, explaining the 51% of the variance of the PDSS model. Males presented less nocturnal disturbances and more EDS than females. Higher motor impairment and combined treatment (L-dopa and agonist) were related to more EDS, while disease duration and L-dopa in monotherapy were related to lower scores, explaining the 59% of the model. Conclusions Sleep disturbances changed over time and age, diseases duration, motor impairment, treatment and sex were associated with nocturnal sleep problems and EDS. Agonist treatment alone or in combination with L-dopa might predict worse daytime sleepiness, while L-dopa in monotherapy is related to lower EDS, which significantly affects the quality of life of PD patients.

To identify myocardial sympathetic denervation patterns suggestive of Lewy body (LB) pathology in patients with genetic and idiopathic parkinsonisms by 123I-metaiodobenzylguanidine (MIBG) scintigraphy. We retrospectively analysed myocardial MIBG images acquired with a dual-head gamma camera and low-energy high-resolution collimator (LEHR) in 194 patients with suspected synucleinopathy or atypical parkinsonism, including 34 with genetic Parkinson’s disease (PD; 4 PARK1, 8 PARK2 and 22 PARK8), 85 with idiopathic PD (iPD), 6 with idiopathic REM sleep behaviour disorder (iRBD), 17 with dementia with LB (DLB), 40 with multiple system atrophy (MSA) and 12 with progressive supranuclear palsy (PSP), and in 45 healthy controls. We calculated heart-to-mediastinum MIBG uptake ratios (HMR) at 15 min and 4 h (HMR4H) for the LEHR and standardized medium-energy collimators, to obtain classification accuracies and optimal cut-off values for HMR using supervised classification and ROC analyses. While patients with LB disorders had markedly lower HMR4HLEHR than controls (controls 1.86 ± 0.26, iPD 1.38 ± 0.29, iRBD 1.23 ± 0.09, PARK1 1.20 ± 0.09, DLB 1.17 ± 0.11; p 0.05). The diagnostic accuracy of HMR4HLEHR was highest in patients with LB disorders (PARK1, iPD, DLB, iRBD; 89% to 97%) and lowest in those with PARK2, PARK8, PSP and MSA (65% to 76%), with an optimal HMR4HLEHR cut-off value of 1.72 for discriminating most patients with LB disorders including iPD and 1.40 for discriminating those with aggressive LB spectrum phenotypes (DLB, PARK1 and iRBD). Our study including patients with a wide spectrum of genetic and idiopathic parkinsonisms with different degrees of LB pathology further supports myocardial MIBG scintigraphy as an accurate tool for discriminating patients with LB spectrum disorders.

Exposure to an enriched environment (EE) has neuroprotective benefits and improves recovery from brain injury due to, among other, increased neurotrophic factor expression. Through these neurotrophins, important cortical and hippocampal changes occur. Vandetanib acts as a tyrosine kinase inhibitor of cell receptors, among others, the vascular endothelial growth factor receptor (VEGFR). Our aim was to investigate the effectiveness of EE counteracting cognitive and cellular effects after tyrosine kinase receptor blockade. Animals were reared under standard laboratory condition or EE; both groups received vandetanib or vehicle. Visuospatial learning was tested with Morris water maze. Neuronal, interneuronal, and vascular densities were measured by inmunohistochemistry and histochemistry techniques. Quantifications were performed in the hippocampus and in the visual cortex. Brain-derived neurotrophic factor (BDNF), tyrosine kinase B receptor (TrkB), Akt, and Erk were measured by Western blot technique. Vandetanib produces a significant decrease in vascular and neuronal densities and reduction in the expression of molecules involved in survival and proliferation processes such as phospho-Akt/Akt and phospho-Erk/Erk. These results correlated to a cognitive impairment in visuospatial test. On the other hand, animals reared in an EE are able to reverse the negative effects, activating PI3K-AKT and MAP kinase pathways mediated by BDNF-TrkB binding. Present results provide novel and consistent evidences about the usefulness of living in EE as a strategy to improve deleterious effects of blocking neurotrophic pathways by vandetanib and the notable role of the BDNF-TrkB pathway to balance the neurovascular unit and cognitive effects.

IntroductionThe use of non-motor Parkinson’s disease (PD) features and genetic PD variants for clustering analyses may refine the phenotypic classification of idiopathic Lewy body (LB) diseases.MethodsOne-hundred participants [n=7 E46K-SNCA (n=5 symptomatic and n=2 asymptomatic), n=4 PARK2, n=3 LRRK2, n=8 dementia with Lewy bodies (DLB), n=48 idiopathic PD (iPD), n=30 healthy controls (HC)] underwent a comprehensive evaluation of non-motor and motor PD features. Non-motor features were used to perform a hierarchical clustering analysis with patients and HC using a Scikit-learn toolkit.ResultsClustering analysis suggested three clusters of subjects including Cluster 1 or “Normal-to-mild”: young iPD (< 60 years) classified together with most HC and the variable LB burden genetic PD variants (PARK2 and LRRK2) characterized by having normal-to-mild cognitive disabilities and mild-to-moderate motor disability with few axial symptoms; Cluster 2 or “Mild-to-moderate”: old iPD patients (>60 years) classified together with the lowest symptomatic E46K-SNCA, PARK2 carriers and HCs, characterizing by having mild-to-moderate cognitive and motor disabilities with few axial symptoms; and Cluster 3 or “Severe”: old iPD (>60 years) classified together with all DLB and the most symptomatic E46K-SNCA carriers, characterized by having severe pattern-specific cognitive disabilities (visual attention, perception, processing speed, memory and executive functions) and severe motor PD manifestations with marked axial symptoms.ConclusionsOur study supports the potential value of incorporating genetic PD variants in data-driven iPD classification algorithms and the usefulness of non-motor PD features, especially visual cognition abnormalities, to facilitate the identification of aggressive LB diseases.

Background and objective In 2004 we described the E46K mutation in alpha-synuclein gene (E46K-SNCA), a rare point mutation causing an aggressive Lewy body disease with early prominent non-motor features and small fiber denervation of myocardium. Considering the potential interest of the skin as a target for the development of biomarkers in Parkinson's Disease (PD), in this work we aimed to evaluate structural and functional integrity of small autonomic nerve fibers and phosphorylated alpha-synuclein (p-synuclein) deposition in the skin of E46K-SNCA carriers as compared to those observed in parkin gene mutation (PARK2) carriers and healthy controls. Patients and methods We studied 7 E46K-SNCA carriers (3 dementia with Lewy bodies, 2 pure autonomic failure, 1 PD and 1 asymptomatic), 2 PARK2 carriers and 2 healthy controls to quantify intraepidermal nerve fiber density and p-synuclein deposition with cervical skin punch biopsies (immunohistochemistry against anti PGP9.5/UCHL-1, TH and p-synuclein) and sudomotor function with electrochemical skin conductance (ESC) (SudoScan). Results All E46K-SNCA carriers had moderate to severe p-synuclein deposits and small fiber neurodegeneration in different epidermal and dermal structures including nerve fascicles and glands, especially in carriers with Pure Autonomic Failure, while p-synuclein aggregates where absent in healthy controls and in one of two PARK2 carriers. The severity of the latter skin abnormalities in E46K-SNCA were correlated with sudomotor dysfunction (lower ESC) in hands (p = 0.035). Interpretation These results together with our previous findings support the relevance of E46K-SNCA mutation as a suitable model to study small fiber neuropathy in Lewy body diseases.

Currently, several laser ablation techniques are available for refractive error correction. Among these techniques, photorefractive keratectomy and Laser Assisted in Situ Keratomileusis are the most widely performed. With the advent of femtosecond laser for corneal flap creation, visual outcomes have improved and intraoperative complications have been reduced. Recently, Small-Incision Lenticule Extraction (SMILE) has emerged as a new promising technique for myopia and myopic astigmatism correction. This procedure is a flapless corneal refractive surgery in which an intrastromal refractive lenticule is created and extracted through a small peripheral incision. Several studies have analyzed the visual results and corneal changes after SMILE. Safety, efficacy and predictability seem to be comparable to Laser Assisted in Situ Keratomileusis, but SMILE is not exempt of complications. This article reviews studies on corneal morphological changes, optical quality and visual outcomes following SMILE as well as on complications associated to this technique.

Several findings indicate that schizophrenia is associated with multiple abnormalities in different subtypes of interneurons, which result in a loss of inhibitory control of pyramidal cell activity. Perturbed excitatory/inhibitory balance or maladaptive disinhibition leads to cognitive impairment, a core disturbance of schizophrenia. Interneurons are crucial for governing the complex interactions between principal cells to coordinate spatiotemporal firing patterns of excitatory action potentials, thereby regulating network operations, controlling plastic periods, and generating brain oscillations. Increasing body of evidence suggests that these inhibitory cells are essential for normal perceptual processing and cognitive behavior. Although the precise contribution of interneurons to learning and memory needs to be elucidated, evidence support the notion that interneurons might be engaged in different stages of acquisition and storage of information. In this chapter, we review the current state of knowledge regarding the role of interneurons at microcircuit and network levels to shed new light on their contribution to neuronal computations for perceptual processing and their influence on high-order cognitive functions. We discuss how the functional alteration of inhibitory neurons might be responsible for the cognitive impairment in schizophrenia, suggesting that interneurons could be interesting candidates for therapeutic interventions to improve core cognitive symptoms of schizophrenia.

EnglishThe brain has a remarkable capacity to record daily experiences and recall the stored information to guide behavior. Specific neuronal brain circuits have been linked to dedicated functions, and the role of prefrontal cortex and hippocampus is particularly important in learning and memory processes. Moreover, the N-methyl-D-as-partate (NMDA) receptor has been termed as the molecular substrate for learning and memory. The subunit composition and neurodevelopmental regulation of this receptor has important implications in synaptic plasticity. Likewise, neurotrophic factors play a central role in mediating plastic changes that might be crucial for enhancing cognitive functions. Here, we review the anatomy, function and the interplay of prefrontal cortex and hippocampus, as well as how these brain structures engage in learning and memory processes. We also discuss the effects of the modulation of molecular targets with a special focus on NMDA receptors and neurotrophic factors. euskaraAzpimarratzekoa da garunak egunerokotasunean bizi izandako esperientziak gordetzeko eta, portaera gidatzeko, informazio hori gogorarazteko duen gaitasuna. Garuneko neurona-zirkuitu espezifikoek funtzio jakinetan parte hartzen dute, eta bekoki aurreko kortexa eta hipokanpoa bereziki garrantzitsuak dira ikasketa eta oroimen prozesuetan. Are gehiago, N-metil-D-aspartato (NMDA) hartzailea prozesu hauen substratu molekular gisa identifikatu da. Izan ere, NMDA hartzaileen azpiunitateen konposizioa eta neurogarapeneko erregulazioa plastikotasun sinaptikoarekin zuzenki erlazionatuta daude. Halaber, faktore neurotrofikoak ezinbestekoak dira plastikotasun sinaptikoan aldaketak eragiteko eta, ondorioz, kognizioaren hobekuntza bat lortzeko. Artikulu honetan, bekoki aurreko kortexaren eta hipokanpoaren anatomia, funtzioa eta eremu bien arteko elkarrekintzaren berrikuspena egiteaz gain, ikasketa eta oroimen prozesuetan duten parte-hartzea deskribatzen da. Azkenik, itu molekularren modulazioak duen efektua ere aztertzen da, NMDA hartzaileei eta faktore neurotrofikoei arreta berezia jarriz.

The original version of this article unfortunately contained a mistake. The name of author was changed from "Pascual Gargiulo" to "Pascual Ángel Gargiulo.

Perinatal injections of N-methyl-D-aspartate (NMDA) receptor antagonist in rodents emulate some cognitive impairments and neurochemical alterations, such as decreased GABAergic (gamma aminobutyric acid) interneuron immunoreactivity, also found in schizophrenia. These features are pervasive, and developing neuroprotective or neurorestorative strategies is of special interest. In this work, we aimed to investigate if a short exposure to enriched environment (EE) in early adulthood (P55?P73) was an effective strategy to improve cognitive dysfunction and to restore interneuron expression in medial prefrontal cortex (mPFC) and hippocampus (HPC). For that purpose, we administered MK-801 intraperitoneally to Long Evans rats from postnatal days 10 to 20. Twenty-four hours after the last injection, MK-801 produced a transient decrease in spontaneous motor activity and exploration, but those abnormalities were absent at P24 and P55. The open field test on P73 manifested that EE reduced anxiety-like behavior. In addition, MK-801-treated rats showed cognitive impairment in novel object recognition test that was reversed by EE. We quantified different interneuron populations based on their calcium-binding protein expression (parvalbumin, calretinin, and calbindin), glutamic acid decarboxylase 67, and neuronal nuclei-positive cells by means of unbiased stereology and found that EE enhanced interneuron immunoreactivity up to normal values in MK-801-treated rats. Our results demonstrate that a timely intervention with EE is a powerful tool to reverse long-lasting changes in cognition and neurochemical markers of interneurons in an animal model of schizophrenia. Fil: Murueta Goyena, Ane. Universidad del País Vasco; España Fil: Ortuzar, Naiara. Universidad del País Vasco; España Fil: Gargiulo, Pascual Angel. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Departamento de Patología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza; Argentina Fil: Lafuente, José Vicente. Universidad Autónoma de Chile; Chile. BioCruces Health Research Institute; España. Universidad del País Vasco; España Fil: Bengoetxea, Harkaitz. Universidad del País Vasco; España