Association of retinal neurodegeneration with the progression of cognitive decline in Parkinson's disease.

Retinal thickness may serve as a biomarker in Parkinson's disease (PD). In this prospective longitudinal study, we aimed to determine if PD patients present accelerated thinning rate in the parafoveal ganglion cell-inner plexiform layer (pfGCIPL) and peripapillary retinal nerve fiber layer (pRNFL) compared to controls. Additionally, we evaluated the relationship between retinal neurodegeneration and clinical progression in PD. A cohort of 156 PD patients and 72 controls underwent retinal optical coherence tomography, visual, and cognitive assessments between February 2015 and December 2021 in two Spanish tertiary hospitals. The pfGCIPL thinning rate was twice as high in PD (ß [SE] = -0.58 [0.06]) than in controls (ß [SE] = -0.29 [0.06], p < 0.001). In PD, the progression pattern of pfGCIPL atrophy depended on baseline thickness, with slower thinning rates observed in PD patients with pfGCIPL below 89.8 µm. This result was validated with an external dataset from Moorfields Eye Hospital NHS Foundation Trust (AlzEye study). Slow pfGCIPL progressors, characterized by older at baseline, longer disease duration, and worse cognitive and disease stage scores, showed a threefold increase in the rate of cognitive decline (ß [SE] = -0.45 [0.19] points/year, p = 0.021) compared to faster progressors. Furthermore, temporal sector pRNFL thinning was accelerated in PD (ßtime x group [SE] = -0.67 [0.26] µm/year, p = 0.009), demonstrating a close association with cognitive score changes (ß [SE] = 0.11 [0.05], p = 0.052). This study suggests that a slower pattern of pfGCIPL tissue loss in PD is linked to more rapid cognitive decline, whereas changes in temporal pRNFL could track cognitive deterioration.

Prognostic factors for falls in Parkinson's disease: a systematic review.

BACKGROUND: Falls represent a critical concern in Parkinson's disease (PD), contributing to increased morbidity and reduced quality of life. PURPOSE: We conducted a systematic review to assess the prognostic factors associated with falls in PD, aiming to provide a comprehensive overview of relevant demographic and clinical parameters, and aid neurologists in identifying subsets of PD patients most susceptible to falls and associated injuries. METHODS: PubMed and Web of Science databases were searched for prospective studies assessing factors associated with falls in ambulatory PD patients across different settings, from inception to August 2023. Data extraction was conducted using CHARMS-PF checklist and risk of bias was assessed with QUIPS tool. PRISMA guidelines were followed. RESULTS: The initial search yielded 155 references. Thirty-four studies, involving a total of 3454 PD patients, were included in the final analysis. The mean pooled age was 67.6 years, and 45.1% were women. PD patients presented mild motor impairment (UPDRS III score 27.8) with mean pooled disease duration of 5.7 years. Gait and balance disorders and history of prior falls emerged as the most consistent predictors of falls across studies. Disease duration, disease severity, dysautonomic symptoms, freezing of gait, frontal cognitive functions, and PD medication dosages yielded inconsistent findings. Conversely, dyskinesias, age, sex, and depression were unrelated to future falls in PD. Logistic regression models were most commonly employed to identify factors significantly associated with falls in PD. Substantial heterogeneity prevailed in the inclusion of confounding factors. CONCLUSION: The evidence suggests that previous history of falls, gait disorders, and poor balance are robust prognostic markers for falls in PD.

Retinal thickness as a biomarker of cognitive impairment in manifest Huntington's disease.

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.

Brain Degeneration in Synucleinopathies Based on Analysis of Cognition and Other Nonmotor Features: A Multimodal Imaging Study.

BACKGROUND: We aimed to characterize subtypes of synucleinopathies using a clustering approach based on cognitive and other nonmotor data and to explore structural and functional magnetic resonance imaging (MRI) brain differences between identified clusters. METHODS: Sixty-two patients (n = 6 E46K-SNCA, n = 8 dementia with Lewy bodies (DLB) and n = 48 idiopathic Parkinson's disease (PD)) and 37 normal controls underwent nonmotor evaluation with extensive cognitive assessment. Hierarchical cluster analysis (HCA) was performed on patients' samples based on nonmotor variables. T1, diffusion-weighted, and resting-state functional MRI data were acquired. Whole-brain comparisons were performed. RESULTS: HCA revealed two subtypes, the mild subtype (n = 29) and the severe subtype (n = 33). The mild subtype patients were slightly impaired in some nonmotor domains (fatigue, depression, olfaction, and orthostatic hypotension) with no detectable cognitive impairment; the severe subtype patients (PD patients, all DLB, and the symptomatic E46K-SNCA carriers) were severely impaired in motor and nonmotor domains with marked cognitive, visual and bradykinesia alterations. Multimodal MRI analyses suggested that the severe subtype exhibits widespread brain alterations in both structure and function, whereas the mild subtype shows relatively mild disruptions in occipital brain structure and function. CONCLUSIONS: These findings support the potential value of incorporating an extensive nonmotor evaluation to characterize specific clinical patterns and brain degeneration patterns of synucleinopathies.

Multimodal visual system analysis as a biomarker of visual hallucinations in Parkinson's disease.

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.

Influence of ocular biometric factors on the defocus curve in an enlarged depth-of-focus intraocular lens.

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.

Spatial characterization of the effect of age and sex on macular layer thicknesses and foveal pit morphology.

Characterizing the effect of age and sex on macular retinal layer thicknesses and foveal pit morphology is crucial to differentiating between natural and disease-related changes. We applied advanced image analysis techniques to optical coherence tomography (OCT) to: 1) enhance the spatial description of age and sex effects, and 2) create a detailed open database of normative retinal layer thickness maps and foveal pit shapes. The maculae of 444 healthy subjects (age range 21-88) were imaged with OCT. Using computational spatial data analysis, thickness maps were obtained for retinal layers and averaged into 400 (20 x 20) sectors. Additionally, the geometry of the foveal pit was radially analyzed by computing the central foveal thickness, rim height, rim radius, and mean slope. The effect of age and sex on these parameters was analyzed with multiple regression mixed-effects models. We observed that the overall age-related decrease of the total retinal thickness (TRT) (-1.1% per 10 years) was mainly driven by the ganglion cell-inner plexiform layer (GCIPL) (-2.4% per 10 years). Both TRT and GCIPL thinning patterns were homogeneous across the macula when using percentual measurements. Although the male retina was 4.1 µm thicker on average, the greatest differences were mainly present for the inner retinal layers in the inner macular ring (up to 4% higher TRT than in the central macula). There was an age-related decrease in the rim height (1.0% per 10 years) and males had a higher rim height, shorter rim radius, and steeper mean slope. Importantly, the radial analysis revealed that these changes are present and relatively uniform across angular directions. These findings demonstrate the capacity of advanced analysis of OCT images to enhance the description of the macula. This, together with the created dataset, could aid the development of more accurate diagnosis models for macular pathologies.

Plasma and serum alpha-synuclein as a biomarker in Parkinson's disease: A meta-analysis.

BACKGROUND: 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. METHODS: 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. RESULTS: 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%). CONCLUSIONS: 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.

Heart-brain synchronization breakdown in Parkinson's disease.

Heart rate variability (HRV) abnormalities are potential early biomarkers in Parkinson's disease (PD) but their relationship with central autonomic network (CAN) activity is not fully understood. We analyzed the synchronization between HRV and brain activity in 31 PD patients and 21 age-matched healthy controls using blood-oxygen-level-dependent (BOLD) signals from resting-state functional brain MRI and HRV metrics from finger plethysmography recorded for 7.40 min. We additionally quantified autonomic symptoms (SCOPA-AUT) and objective autonomic cardiovascular parameters (blood pressure and heart rate) during deep breathing, Valsalva, and head-up tilt, which were used to classify the clinical severity of dysautonomia. We evaluated HRV and BOLD signals synchronization (HRV-BOLD-sync) with Pearson lagged cross-correlations and Fisher's statistics for combining window-length-dependent HRV-BOLD-Sync Maps and assessed their association with clinical dysautonomia. HRV-BOLD-sync was lower significantly in PD than in controls in various brain regions within CAN or in networks involved in autonomic modulation. Moreover, heart-brain synchronization index (HBSI), which quantifies heart-brain synchronization at a single-subject level, showed an inverse exposure-response relationship with dysautonomia severity, finding the lowest HBSI in patients with severe dysautonomia, followed by moderate, mild, and, lastly, controls. Importantly, HBSI was associated in PD, but not in controls, with Valsalva pressure recovery time (sympathetic), deep breathing E/I ratio (cardiovagal), and SCOPA-AUT. Our findings support the existence of heart-brain de-synchronization in PD with an impact on clinically relevant autonomic outcomes.

Impact of Visual Impairment on Vision-Related Quality of Life in Parkinson's Disease.

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.

Characterization of molecular biomarkers in cerebrospinal fluid and serum of E46K-SNCA mutation carriers.

INTRODUCTION: Blood and cerebrospinal fluid represent emerging candidate fluids for biomarker identification in Parkinson's disease (PD). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Multimodal brain and retinal imaging of dopaminergic degeneration in Parkinson disease.

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.

Potential Tear Biomarkers for the Diagnosis of Parkinson's Disease-A Pilot Study.

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.

Clinical long-term nocturnal sleeping disturbances and excessive daytime sleepiness in Parkinson's disease.

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.

Visual dysfunction is associated with cognitive impairment in Parkinson's disease.

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.

Foveal Pit Morphology Characterization: A Quantitative Analysis of the Key Methodological Steps.

Disentangling the cellular anatomy that gives rise to human visual perception is one of the main challenges of ophthalmology. Of particular interest is the foveal pit, a concave depression located at the center of the retina that captures light from the gaze center. In recent years, there has been a growing interest in studying the morphology of the foveal pit by extracting geometrical features from optical coherence tomography (OCT) images. Despite this, research has devoted little attention to comparing existing approaches for two key methodological steps: the location of the foveal center and the mathematical modelling of the foveal pit. Building upon a dataset of 185 healthy subjects imaged twice, in the present paper the image alignment accuracy of four different foveal center location methods is studied in the first place. Secondly, state-of-the-art foveal pit mathematical models are compared in terms of fitting error, repeatability, and bias. The results indicate the importance of using a robust foveal center location method to align images. Moreover, we show that foveal pit models can improve the agreement between different acquisition protocols. Nevertheless, they can also introduce important biases in the parameter estimates that should be considered.

Foveal Remodeling of Retinal Microvasculature in Parkinson's Disease.

BACKGROUND: Retinal microvascular alterations have been previously described in Parkinson's disease (PD) patients using optical coherence tomography angiography (OCT-A). However, an extensive description of retinal vascular morphological features, their association with PD-related clinical variables and their potential use as diagnostic biomarkers has not been explored. METHODS: We performed a cross-sectional study including 49 PD patients (87 eyes) and 40 controls (73 eyes). Retinal microvasculature was evaluated with Spectralis OCT-A and cognitive status with Montreal Cognitive Assessment. Unified PD Rating Scale and disease duration were recorded in patients. We extracted microvascular parameters from superficial and deep vascular plexuses of the macula, including the area and circularity of foveal avascular zone (FAZ), skeleton density, perfusion density, vessel perimeter index, vessel mean diameter, fractal dimension (FD) and lacunarity using Python and MATLAB. We compared the microvascular parameters between groups and explored their association with thickness of macular layers and clinical outcomes. Data were analyzed with General Estimating Equations (GEE) and adjusted for age, sex, and hypertension. Logistic regression GEE models were fitted to predict diagnosis of PD versus controls from microvascular, demographic, and clinical data. The discrimination ability of models was tested with receiver operating characteristic curves. RESULTS: FAZ area was significantly smaller in patients compared to controls in superficial and deep plexuses, whereas perfusion density, skeleton density, FD and lacunarity of capillaries were increased in the foveal zone of PD. In the parafovea, microvascular parameters of superficial plexus were associated with ganglion cell-inner plexiform layer thickness, but this was mainly driven by PD with mild cognitive impairment. No such associations were observed in controls. FAZ area was negatively associated with cognition in PD (non-adjusted models). Foveal lacunarity, combined with demographic and clinical confounding factors, yielded an outstanding diagnostic accuracy for discriminating PD patients from controls. CONCLUSION: Parkinson's disease patients displayed foveal microvascular alterations causing an enlargement of the vascular bed surrounding FAZ. Parafoveal microvascular alterations were less pronounced but were related to inner retinal layer thinning. Retinal microvascular abnormalities helped discriminating PD from controls. All this supports OCT-A as a potential non-invasive biomarker to reveal vascular pathophysiology and improve diagnostic accuracy in PD.

Differential exposure to N-ethyl N-nitrosourea during pregnancy is relevant to the induction of glioma and PNSTs in the brain.

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.

Quantitative analysis of dysautonomia in patients with autonomic dysreflexia.

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.