Impairment In Early Stages Research Articles

Association of Basal Forebrain Atrophy With Cognitive Decline in Early Alzheimer Disease.

In early Alzheimer disease (AD), β-amyloid (Aβ) deposition is associated with volume loss in the basal forebrain (BF) and cognitive decline. However, the extent to which Aβ-related BF atrophy manifests as cognitive decline is not understood. This study sought to characterize the relationship between BF atrophy and the decline in memory and attention in patients with early AD. Participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study who completed Aβ-PET imaging and repeated MRI and cognitive assessments were included. At baseline, participants were classified based on their clinical dementia stage and Aβ status, yielding groups that were cognitively unimpaired (CU) Aβ-, CU Aβ+, and mild cognitive impairment (MCI) Aβ+. Linear mixed-effects models were used to assess changes in volumetric measures of BF subregions and the hippocampus and changes in AIBL memory and attention composite scores for each group compared with CU Aβ- participants. Associations between Aβ burden, brain atrophy, and cognitive decline were evaluated and explored further using mediation analyses. The cohort included 476 participants (72.6 ± 5.9 years, 55.0% female) with longitudinal data from a median follow-up period of 6.1 years. Compared with the CU Aβ- group (n = 308), both CU Aβ+ (n = 107) and MCI Aβ+ (n = 61) adults showed faster decline in BF and hippocampal volumes and in memory and attention (Cohen d = 0.73-1.74). Rates of atrophy in BF subregions and the hippocampus correlated with cognitive decline, and each individually mediated the impact of Aβ burden on memory and attention decline. When all mediators were considered simultaneously, hippocampal atrophy primarily influenced the effect of Aβ burden on memory decline (β [SE] = -0.139 [0.032], proportion mediated [PM] = 28.0%) while the atrophy of the posterior nucleus basalis of Meynert in the BF (β [SE] = -0.068 [0.029], PM = 13.1%) and hippocampus (β [SE] = -0.121 [0.033], PM = 23.4%) distinctively influenced Aβ-related attention decline. These findings highlight the significant role of BF atrophy in the complex pathway linking Aβ to cognitive impairment in early stages of AD. Volumetric assessment of BF subregions could be essential in elucidating the relationships between the brain structure and behavior in AD.

Sex-Specific Differences in Serum Kallikrein-8 (KLK8): An Exploratory Study.

There are indications for sex-specific differences regarding the association between kallikrein-8 (KLK8) and cognitive impairment in early stages of Alzheimer's disease for which KLK8 may be an early blood-based biomarker. These may be due to different levels of sex hormones. To correctly interpret KLK8 blood concentrations, sex-specific analyses are needed. The aim of our exploratory study was to investigate sex-specific differences in blood-based KLK8 in participants of the population-based Heinz Nixdorf Recall study with different cognitive status and the association between KLK8 and sex hormones. In 290 participants (45% women, 69.7±7.4 years (mean±SD)) we investigated sex-specific serum KLK8 differences between cognitively unimpaired (CU, 43%) and cognitively impaired (CI) participants and the association between KLK8 and dehydroepiandrosteronsulfate (DHEAS), estradiol and testosterone, using adjusted multiple linear regression. The mean±SD KLK8 was similar for CU men (808.1±729.6 pg/ml) and women (795.9±577.7 pg/ml); adjusted mean-difference [95%-CI]: -95.3 [-324.1;133.5] pg/ml. KLK8 was lower in CI women (783.5±498.7 pg/ml) than men (1048.4±829 pg/ml); -261 [-493.1; -29] pg/ml. In men but not women, there was a weak indication for a positive slope between estradiol (11.9 [-0.4;24.3] pg/ml) and DHEAS (1.4 [-0.5;3.3] pg/ml) with KLK8, while testosterone had no impact. The results suggested a different role for KLK8 in the development of cognitive impairment in men and women, potentially influenced by sex hormones. To use blood KLK8 as an early biomarker, further research on hormonal regulation of KLK8 expression is needed as a part of the investigation of the KLK8 involvement in cognitive impairment and Alzheimer's disease pathology.

The effective of a training program to improve self-concept among students with speech disorders in the primary school

This study aims to measure whether a training program for children with impairments in early stages is useful at enhancing their sense of self-concept. To accomplish research’s objective, two hypotheses were formulated; one alternative and the other one invalid. The empirical method was used in which the design was to select one group with pre and post-test. The procedure requires the presence of one group for which a pre-test is conducted and then exposed to the training program, after which a post-test and a follow up test are conducted one month after the end of the application. The research participants consisted of the students of the third, fourth, and fifth grades in the primary stage at the Emirati Dar Al-Ataa Center affiliated to the General Directorate of Education in the center of Erbil Governorate for the academic year (2021-2022). The study sample consisted of (5) students, with (4) males and one female, from the age groups (9-12) years. The researchers prepared the self-concept scale and the number of its items in its final form reached (34). The scale was applied to the main sample after calculating the validity and correlation coefficient for each dimension of the scale and its total score, extracting the discriminatory power, ensuring its stability by using Cronbach's alpha coefficient of (0.850), and calculating the half- segmentation of it which was (0.827). The data was analyzed based on a fundamental sample, the statistical package program (SPSS) to reach the results of the research. According to the study’s findings, the post-test significantly improved self-concept compared to the pre-test, while there was no statistically significant difference between the two tests in terms of enhancing self-concept (post and follow up). The researchers made several recommendations and other ideas in light of the research findings.

Montreal Cognitive Assessment (MoCA) as a screening tool for cognitive impairment in early stages of psychosis

BackgroundCognitive alterations have been reported in early stages of psychosis including people with First Episode Psychosis (FEP), Clinical High-Risk Mental State (CHR), and Psychotic-Like Experience (PLE). This study aimed to compare the cognitive function in early stages of psychosis using the Montreal Cognitive Assessment (MoCA), a low-cost and brief assessment tool of cognitive functions. MethodsA total of 154 individuals, including 35 with FEP, 38 CHR, 44 PLE, and 37 healthy controls (HC), were evaluated with the MoCA in Santiago, Chile. We calculated the mean total score of the MoCA and the standard deviation of the mean. Groups were assessed for a trend to lower scores in a pre-determined sequence (HC > PLE > CHR > FEP) using the Jonckheere-Terpstra test (TJT). ResultsThe mean total MoCA scores were 24.8 ± 3.3 in FEP, 26.4 ± 2.4 in CHR, 26.4 ± 2.3 in PLE, and 27.2 ± 1.8 in HC. The analyses revealed a significant trend (p < 0.05) toward lower MoCA individual domain scores and MoCA total scores in the following order: HC > PLE > CHR > FEP. The mean total scores of all groups were above the cut-off for cognitive impairment (22 points). ConclusionsThe MoCA describes lower scores in cognition across early stages of psychosis and may be a useful low-cost assessment instrument in early intervention centers of poorly resourced settings.

Early impairment of magnocellular visual pathways mediated by isolated-check visual evoked potentials in primary open-angle glaucoma: a cross-sectional study

ObjectiveTo explore different performances in the magnocellular (MC) and parvocellular (PC) visual pathways in patients with primary open-angle glaucoma (POAG) and to objectively assess impairment in early stage of POAG.Methods...

Dopamine and motion perception: Unveiling retinal connections in Parkinson's disease

Aims/Purpose: Parkinson's disease (PD) is characterized by degeneration of dopaminergic neurons, which occurs not only in the pars compacta of the sustantia nigra of the midbrain, but also in the retina, where dopaminergic amacrine cells (DAC) have been well characterized. Indeed, parkinsonian patients display visual impairments in early stages of the disease, including motion perception deterioration. Retinal cells responsible of motion perception are the directional selective ganglion cells (DSGC) which receive inhibitory synapses from starburst amacrine cells (SAC). Consequences of DAC degeneration in PD on the functionality of SAC and DSGC is unknown. In this work, we studied the functional connections between DAC and SAC in order to understand the pathophysiological mechanisms that determine the visual dysfunction in PD patients.Methods: Using immunohistochemistry and confocal imaging, we studied the retinal connections between DAC and SAC in wild‐type mice. To determine the type of Dopamine (DA) receptor expressed by SAC, we used transgenic mice whose cells expressing D1 or D2 receptors also express fluorescent markers. Intravitreal injections of 6‐OHDA were performed in a series of animals, followed by immunohistochemistry and optokinetic test.Results: We observed that DAC and SAC have direct synaptic contacts, and that the SAC located in the OFF sublamina of the inner plexiform layer express D2 receptors (D2R) but not D1 receptors. Moreover, depletion of DA in the 6‐OHDA injected mice induced a significant reduction of motion perception.Conclusions: This study shows for the first time in mice that the amacrine retinal cells responsible for perceiving directional selective moving stimuli express D2R. These findings provide new ways of detecting visual impairments in preclinical models of retinal DA degeneration.

Description of the ARMADA (assessing reliable measurement in Alzheimer’s disease) general population study cohorts

AbstractBackgroundGiven the growing population of aging adults, and subsequently individuals with dementia, there is a need for instruments that can detect cognitive impairment in early stages. The NIH Toolbox® for Assessment of Neurological and Behavioral Function (NIHTB) is a computerized battery of assessments measuring multiple domains cognition, emotion, sensation, and motor abilities. The goal of the ARMADA study is to validate the NIHTB in individuals with mild cognitive impairment (MCI) and dementia of the Alzheimer type (DAT). Here, we describe the demographic and clinical characteristics of participants ages 65 to 85 from the general population sample.MethodNormal control (NC), MCI, and DAT groups racially proportional to the US population were recruited from existing cohorts across nine Alzheimer’s Disease Research Centers and sites with cognitive aging studies. Diagnoses were based on the Uniform Data Set methodology, and included multiple clinical and cognitive assessments. Participants completed the NIH Toolbox at baseline, 12‐, and 24‐month visits.ResultGroups were matched with respect to multiple demographic characteristics. There were some differences in age and sex, such that the NC group had more female participants and was the youngest. Dementia severity levels differed as expected, with the DAT group demonstrating greater cognitive and functional impairment compared to the MCI group, and the NC group demonstrating minimal cognitive or functional symptoms. Additionally, the DAT group reported more neuropsychiatric symptoms compared to the NC and MCI groups. There was no difference in reported family history of cognitive impairment across groups. Many participants across groups had at least one Alzheimer biomarker collected.ConclusionThe study cohorts included in the ARMADA study accurately reflect their respective clinical syndromes for validating the NIHTB across the cognitive aging spectrum. The goals for the ARMADA study include comparing performance on all four modules of the NIHTB across groups, evaluating the relationship between Alzheimer biomarkers and NIHTB measures, and measuring changes in performance longitudinally. Special emphasis groups, including individuals over age 85, African American participants, and Spanish‐Speaking participants, were also recruited and are reported elsewhere.

Audiovestibular manifestations in patients with rheumatologic diseases: a review

Rheumatologic disorders are chronic and systemic disorders with an estimated global prevalence of 3,200 per 100,000 inhabitants. Several clinical manifestations are known and may lead to physical disability and altered quality of life. The most common audio vestibular manifestations commonly reported are hearing loss, tinnitus, vertigo, and fullness, however, there are some more still unregistered. The aim of this review is to describe the most common audio vestibular features in three of the most common rheumatologic conditions such as rheumatoid arthritis (RA), systemic erythematous lupus and systemic sclerosis (SSc). A literature search was performed with articles published between 2000 to 2021. In this literature review an increased prevalence of hearing loss for RA of 40% and 70% for systemic erythematous lupus was observed. In SSc, due to its early onset and progression, there is no estimated prevalence, however, a notorious hearing impairment in early stages of the disease was described. Vertigo was also described in these disorders, affecting more than 60% of patients. Further studies are in need to describe the affection on early stages of all disorders as well as its progression.

Reduced contrast sensitivity function correlated with superficial retinal capillary plexus impairment in early stage of dysthyroid optic neuropathy

BackgroundTo assess the accuracy of contrast sensitivity function (CSF) in detecting dysthyroid optic neuropathy (DON) at an early stage in thyroid-associated ophthalmopathy (TAO) patients and to examine potential factors that may be linked to early visual impairments in these individuals.MethodsA total of 81 TAO patients (50 non-DON and 31 DON), and 24 control subjects participated in the study. CSF was measured with the quick CSF (qCSF) method. Optical coherence tomography angiography (OCTA) images of the ganglion cell complex layer (GCCL), superficial and deep retinal capillary plexuses (SRCP and DRCP) in a 3 mm diameter area around the macula were evaluated.ResultsCompared with the controls, the area under the log contrast sensitivity function (AULCSF) and SRCP density were significantly reduced in non-DON and DON patients (all P < 0.05). The GCCL thickness of the DON patients was thinner than that of the controls and non-DON patients (all P < 0.05). The AULCSF was significantly correlated with spherical equivalent refractive error, muscle index, SRCP density and GCCL thickness in TAO patients, respectively (all P < 0.05). However, stepwise multi-regression analysis showed that the AULCSF was only significantly correlated with SRCP density (P < 0.001). Receiver operating characteristic curve analysis showed that the AULCSF produced the most accurate discrimination between non-DON and DON patients from the controls (AUC = 0.831, 0.987, respectively; all P < 0.001).ConclusionsCSF change in the early stage of DON is related to SRCP density. It can be an early indicator of visual impairments associated with DON in TAO patients.

How animacy processing is affected in early stages of AD

AbstractBackgroundPrevious studies have shown that cognitive impairment in early stages of Alzheimer’s disease (AD) is not limited to memory; other cognitive domains are also disrupted including impairment in visual processing (Boucart, Bubbico et al. 2014). Additionally, it is shown that in healthy human subjects, images are categorized by their animacy status (i.e. animate vs. inanimate) in the higher‐level visual areas (Kriegeskorte, Mur et al. 2008). Here we used fMRI to investigate the spatial patterns of animacy processing in the brain of patients with mild cognitive impairment (MCI)/AD in comparison to healthy controls(HC).MethodWe recruited 20 HCs, 15 MCIs and 10 mild‐ADs. Participants completed the Integrated Cognitive Assessment (ICA) test (Khaligh‐Razavi, Habibi et al. 2019) in the fMRI scanner. ICA is a rapid visual‐categorization task, in which participants indicate whether a presented image contains an animal or not, as fast and accurately as they can. In addition to the conventional univariate analysis –looking at the mean brain responses– we used multivariate‐pattern‐analysis (MVPA) to investigate differences in patterns of brain activity between the three groups. In MVPA, we trained a linear classifier for each brain area, to do animal/non‐animal categorization based on the patterns of brain responses to the images.ResultIn some of the key brain regions, such as R‐parahippocampus and R‐fusiform, overlapping with early tau‐pathology (Braak, Alafuzoff et al. 2006), both HC and MCI showed a significantly higher level of mean brain activity in response to all images compared to the AD group (p‐value&lt;0.0001). Additionally, looking at the patterns of brain activity in the L‐fusiform, HC and MCI could be discriminated based on their MVPA responses(p‐value&lt;0.0015), while there was no univariate difference between the two groups.ConclusionWe demonstrated HC and MCI/AD can be differentiated not only based on univariate analysis, but also by multivariate measures, i.e. patterns of brain responses to images. Moreover, we showed that the rapid visual categorization task used in this study could engage key brain areas affected by tau pathology in early stages of the disease. This highlights the potential application of such task for earlier detection of the disease, ideally before the onset of memory symptoms.

Olfactory Function and Diffusion Tensor Imaging as Markers of Mild Cognitive Impairment in Early Stages of Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative disorder that is typified by motor signs and symptoms but can also lead to significant cognitive impairment and dementia Parkinson's Disease Dementia (PDD). While dementia is considered a nonmotor feature of PD that typically occurs later, individuals with PD may experience mild cognitive impairment (PD-MCI) earlier in the disease course. Olfactory deficit (OD) is considered another nonmotor symptom of PD and often presents even before the motor signs and diagnosis of PD. We examined potential links among cognitive impairment, olfactory functioning, and white matter integrity of olfactory brain regions in persons with early-stage PD. Cognitive tests were used to establish groups with PD-MCI and with normal cognition (PD-NC). Olfactory functioning was examined using the University of Pennsylvania Smell Identification Test (UPSIT) while the white matter integrity of the anterior olfactory structures (AOS) was examined using magnetic resonance imaging (MRI) diffusion tensor imaging (DTI) analysis. Those with PD-MCI demonstrated poorer olfactory functioning and abnormalities based on all DTI parameters in the AOS, relative to PD-NC individuals. OD and microstructural changes in the AOS of individuals with PD may serve as additional biological markers of PD-MCI.

A Comparative Study of Serum Cystatin C, Serum Electrolytes, Urea and Creatinine in Early Detection of Kidney Injuries in Albino Rats Exposed to Formaldehyde

Aim: To ascertain early detection of possible kidney injuries in albino rats exposed to formaldehyde by assessing cystatin C, serum electrolytes, urea and creatinine. Materials/Methods: Thirty healthy adult male albino rats, weighing between 100 to 120 grams were randomly divided into three groups A, B and C. Group A served as control. Group B was exposed to low dose (100ppm of Formaldehyde), 3 hrs per day for four weeks, while group C was exposed to high Dose-200ppm of formaldehyde 3 hrs per day for four weeks. At the end of the exposure period, the rats were sacrificed by decapitation under chloroform anesthesia, and 4 ml of blood samples was collected from each rat into a plain bottle. The whole blood was allowed to clot, retracted and centrifuged at 3000 rpm for 10 minutes and serum separated. The serum was stored at -20˚C until analyses for serum electrolytes, creatinine and cystatin C. Serum electrolytes were determined using Ion selective electrode, urea and creatinine were determined using spectrophotometric methods while cystatin C was analyzed using Eliza. Data obtained was analyzed using SPSS. Results: The concentrations of the serum electrolytes, sodium. Potassium, bicarbonate and chloride were compared across the three group, they were not statistically significant (p&gt;0.05). Urea was significantly higher in group C when compared with low dose B and control group A (P&lt;0.05). Also, when the low dose group B was compared with the high dose group C, it was statistically significant. Creatinine concentrations were significantly higher in group C when compared with the control group A, while group B was not significant when compared with group A. Finally, the cystatin C concentrations were also significant when groups B, C were compared with the control group. Conclusion: Formaldehyde exposures may induce a gradual deterioration of renal functions in chronically exposed albino rats. Serum electrolytes, urea and creatinine may not be sufficient to indicate an early signs of kidney damage. From the study, serum cystatin C may be a better marker of renal impairment in early stages.

Accelerated long-term forgetting in healthy older adults predicts cognitive decline over 1\xa0year

BackgroundHere, we address a pivotal factor in Alzheimer’s prevention—identifying those at risk early, when dementia can still be avoided. Recent research highlights an accelerated forgetting phenotype as a risk factor for Alzheimer’s disease. We hypothesized that delayed recall over 4 weeks would predict cognitive decline over 1 year better than 30-min delayed recall, the current gold standard for detecting episodic memory problems which could be an early clinical manifestation of incipient Alzheimer’s disease. We also expected hippocampal subfield volumes to improve predictive accuracy.MethodsForty-six cognitively healthy older people (mean age 70.7 ± 7.97, 21/46 female), recruited from databases such as Join Dementia Research, or a local database of volunteers, performed 3 memory tasks on which delayed recall was tested after 30 min and 4 weeks, as well as Addenbrooke’s Cognitive Examination III (ACE-III) and CANTAB Paired Associates Learning. Medial temporal lobe subregion volumes were automatically measured using high-resolution 3T MRI. The ACE-III was repeated after 12 months to assess the change in cognitive ability. We used univariate linear regressions and ROC curves to assess the ability of tests of delayed recall to predict cognitive decline on ACE-III over the 12 months.ResultsFifteen of the 46 participants declined over the year (≥ 3 points lost on ACE-III). Four-week verbal memory predicted cognitive decline in healthy older people better than clinical gold standard memory tests and hippocampal MRI. The best single-test predictor of cognitive decline was the 4-week delayed recall on the world list (R2 = .123, p = .018, β = .418). Combined with hippocampal subfield volumetry, 4-week verbal recall identifies those at risk of cognitive decline with 93% sensitivity and 86% specificity (AUC = .918, p < .0001).ConclusionsWe show that a test of accelerated long-term forgetting over 4 weeks can predict cognitive decline in healthy older people where traditional tests of delayed recall cannot. Accelerated long-term forgetting is a sensitive, easy-to-test predictor of cognitive decline in healthy older people. Used alone or with hippocampal MRI, accelerated forgetting probes functionally relevant Alzheimer’s-related change. Accelerated forgetting will identify early-stage impairment, helping to target more invasive and expensive molecular biomarker testing.

Facial expressions recognition and discrimination in Parkinson's disease.

Emotion processing impairment is a common non-motor symptom in Parkinson's Disease (PD). Previous literature reported conflicting results concerning, in particular, the performance for different emotions, the relation with cognitive and neuropsychiatric symptoms and the affected stage of processing. This study aims at assessing emotion recognition and discrimination in PD. Recognition of six facial expressions was studied in order to clarify its relationship with motor, cognitive and neuropsychiatric symptoms. Sensitivity in discriminating happy and fearful faces was investigated to address controversial findings on impairment in early stages of emotion processing. To do so, seventy PD patients were tested with the Ekman 60 Faces test and compared with 46 neurologically unimpaired participants. Patients' performances were correlated with clinical scales and neuropsychological tests. A subsample of 25 PD patients and 25 control participants were also tested with a backward masking paradigm for sensitivity in happiness and fear discrimination. Results showed that PD patients were impaired in facial emotion recognition, especially for fearful expressions. The performance correlated with perceptual, executive and general cognitive abilities, but facial expression recognition deficits were present even in cognitively unimpaired patients. In contrast, patients' sensitivity in backward masking tasks was not reduced as compared to controls. Taken together our data demonstrate that facial emotion recognition, and fear expression in particular, is critically affected by neurodegeneration in PD and related to cognitive abilities; however, it appears before other cognitive impairments. Preserved performances in discriminating shortly presented facial expressions, suggest unimpaired early stages of emotion processing.

The Norwegian translation of the brief international cognitive assessment for multiple sclerosis (BICAMS)

BackgroundCognitive impairment is a common symptom in all stages of multiple sclerosis (MS), yet it is underreported and not routinely evaluated. The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) is a short and easily administered test battery for screening of cognitive impairment in MS that can be completed within 15 min and incorporated into routine clinical practice. The test battery consists of the oral version of the Symbols Digit Modalities Test (SDMT) and the initial learning trials of the California Verbal Learning Test 2nd edition (CVLT-II) and the Brief Visuospatial Memory Test Revised (BVMT-R). ObjectiveTo investigate if the Norwegian version of the BICAMS could identify cognitive impairment in early stages of MS and be used as part of routine follow-up procedures. MethodsA total of 65 relapsing-remitting MS (RRMS) patients and 68 healthy controls were examined with the BICAMS test battery. A randomly selected subset of 29 controls were retested 1–4 weeks after baseline. All participants were screened for anxiety and depression using the Hospital Anxiety and Depression Scale (HADS). ResultsThere were statistically significant differences between the patients with MS and the healthy controls on all three subtests, and the differences remained significant for the CVLT-II (p = 0.003) and BVMT-R (p = 0.011) after adjusting for education. There were no statistically significant correlations between BICAMS scores and anxiety and depression. SDMT and BVMT-R results in the control group at baseline and re-test were strongly correlated (r ≥ 0.70, p < 0.001), and CVLT-II achieved an adequate value of r = 0.60 (p = 0.001). On the SDMT, there was a statistically significant improvement between the two test-sessions. Cognitive impairment, defined as an abnormal test score on ≥1 subtest, was identified in 46.2% of the patient sample, whereas 15.4% were considered cognitively impaired on ≥2 subtests. ConclusionThis study supports that the Norwegian version of the BICAMS should be included as a screening procedure for cognitive impairment in Norwegian MS patients.

Tossing and Turning in Bed: A Wearable Sensor Documents Abnormal Nocturnal Movements in Parkinson's Disease

Background: Sleep interruptions and nocturnal hypokinesia are common in Parkinson's disease (PD). Pilot work using wearable technologies showed fewer nocturnal movements in patients with advanced PD compared to controls. However, the prevalence of these impairments in early stage of the disease and the influence of non-motor symptoms, and dopaminergic medication are unknown. Methods: This study evaluated wearable sensor data collected in 305 patients with PD at different Hohen and Yahr disease stages (HY HY H&Y3=77) and 205 healthy controls (HC). Subjects wore a tri-axial accelerometer continuously (24/7) on the lower back for at least 2 days. Percent upright-time and nighttime walking were defined based on the vertical axis of the acceleration signal and were classified as sleep interruptions. The number, velocity, time, side, and degree of rotations in bed during the night evaluated nocturnal movements. Findings: Nocturnal lying-time was similar between PD and controls (p=0.501), however, the number of turns and the turn velocity significantly decreased (p<0.001) with H&Y stage. Advanced patients (H&Y3) had more upright periods during the night while the number and velocity of their turns were reduced (p<=0.021). Recently diagnosed patients (<1 year from diagnosis) were similar to controls in number of nocturnal turns (p=0.148) but showed longer turning time (p=0.001) and reduced turn magnitude (p=0.002). Nocturnal movements were significantly correlated with non-motor symptoms, cognition, and dopaminergic medication. Interpretation: Reduced nocturnal movements are already detectable in recently diagnosed patients and are associated with increased PD motor severity and dysautonomia. Using wearable sensors for continuous monitoring at night may offer an unbiased, objective measure of disease severity that could enhance optimal nighttime dopaminergic treatment and utilization of turning strategies. Funding Statement: European Commission (FP7 project V-TIME-278169), The Michael J Fox Foundation for Parkinson's research, a grant from Biogen Inc and by the NIHR/Wellcome Trust Clinical Research Facility (CRF). Declaration of Interests: Anat Mirelman, Jeff Hausdorff and Nir Giladi report having submitted a patent for assessment of mobility using wearable sensors in Parkinson's disease. The intellectual property rights are held by the Tel Aviv Medical Center. Prof. Mirelman and Hausdorff also serve as consultants for the Michael J Fox Foundation, Biogen, Sanofi (JH) and Neuroderm (AM) in areas relating to the use of wearable sensors to assess mobility in PD. JMH and AM have received grant funding from the European Commission and MJFF. Lynn Rochester reports no conflict of interests pertaining to the manuscript. She receives grants from the Medical Research Council, European Commission, NIHR, Wellcome Trust, EPSRC, Parkinson's UK, and the Stroke Association. Alice Nieuwboer reports no conflict of interest pertaining to the manuscript. She has received grant funding from the European Commission. Bastiaan R Bloem currently serves on the editorial of Practical Neurology and Digital Biomarkers, has received honoraria from serving on the scientific advisory board for Abbvie, Biogen, UCB and Walk with Path, has received fees for speaking at conferences from AbbVie, Zambon, Roche, GE Healthcare and Bial, and has received research support from the Netherlands Organization for Scientific Research, the Michael J Fox Foundation, UCB, Abbvie, the Stichting Parkinson Fonds, the Hersenstichting Nederland, the Parkinson’s Foundation, Verily Life Sciences, Horizon 2020, the Topsector Life Sciences and Health, and the Parkinson Vereniging. Jesse Cederbaum and Mirek Brys are shareholders in Biogen, Inc. Nir Giladi reports reports counseling for: Neuroderm, Intec Pharma, Teva, Genzyme-Sanofi, Biogen, Lysosomal Therapeutics, Denali, Cellanis, GaitBetter, Vibrant and Sionara; that he holds shares or options in Lysosomal Therapeutics, Cellanis, GaitBetter and Vibrant; that he has received royalties from Lysosomal Therapeutics; that he received honorarium from UCB, Teva, Novartis, Abbvie, Genzyme-Sanofie, Neuroderm, Bial, Shire, MDS; that he has chaired the DSMBs for Teva and Pharma2B; that he is a PI on a Center Grant given by Biogen to TLVMC. Inbar Hillel, Silvia Sel Din, Laura Avanzino, Inbal Maidan, Talia Herman, Meir Kestenbaum, Avner Thaler, Tanya Gurevich and Avi Orr Urtreger report no disclosures pertaining to the manuscript. Ethics Approval Statement: The studies were approved by local ethical committees and were performed according to the principles of the Declaration of Helsinki. All participants gave their informed written consent prior to participation.

Cell cycle reentry triggers hyperploidization and synaptic dysfunction followed by delayed cell death in differentiated cortical neurons

Cell cycle reentry followed by neuronal hyperploidy and synaptic failure are two early hallmarks of Alzheimer’s disease (AD), however their functional connection remains unexplored. To address this question, we induced cell cycle reentry in cultured cortical neurons by expressing SV40 large T antigen. Cell cycle reentry was followed by hyperploidy in ~70% of cortical neurons, and led to progressive axon initial segment loss and reduced density of dendritic PSD-95 puncta, which correlated with diminished spike generation and reduced spontaneous synaptic activity. This manipulation also resulted in delayed cell death, as previously observed in AD-affected hyperploid neurons. Membrane depolarization by high extracellular potassium maintained PSD-95 puncta density and partially rescued both spontaneous synaptic activity and cell death, while spike generation remained blocked. This suggests that AD-associated hyperploid neurons can be sustained in vivo if integrated in active neuronal circuits whilst promoting synaptic dysfunction. Thus, cell cycle reentry might contribute to cognitive impairment in early stages of AD and neuronal death susceptibility at late stages.

Retinal Microvascular Impairment in the Early Stages of Parkinson's Disease

To detect the retinal microvascular impairment using optical coherence tomography angiography (OCT-A) in patients with Parkinson's disease (PD) and find a correlation between the microvascular impairment and the neuronal damage. This is a prospective, observational study including 49 eyes from 38 PD patients in their early stages and 34 eyes from 28 healthy controls with comparable age range. Macula microvasculature was evaluated with the spectral-domain optical coherence tomography (SD-OCT) angiography and intraretinal layer thickness evaluated with the SD-OCT. A custom algorithm was used for custom segmentation of retinal thickness and quantification of the superficial and deep microvascular density of the macula, respectively. PD patients showed reduced microvascular density in most of the areas of the whole retina. In the superficial retinal capillary plexus, statistical difference (P < 0.01) was seen in the total annular zone (TAZ), superior, temporal, inferior, and nasal zones. In PD patients, there was a strong correlation between the average ganglion cell layer and inner plexiform (GCIP) thickness and the TAZ of the superficial microvascular density (r = 0.062, P = 0.032). We demonstrated that retinal microvascular density decreased in PD patients. The correlation between microvascular impairment in the superficial retinal capillary layer and GCIP thinning also revealed that the retinal microvascular abnormality may contribute to the neurodegeneration in PD patients. OCT-A with quantitative analysis offers a new path of study and will likely be useful in the future as an objective biomarker for detecting vessel impairment in early stages of PD.

Cognitive impairment in early stages of multiple sclerosis is associated with high cerebrospinal fluid levels of chitinase 3-like 1 and neurofilament light chain.

Chitinase 3-like 1 (CHI3L1) and neurofilament light chain (NF-L) are promising biomarkers of disability in multiple sclerosis (MS). However, their role in cognitive dysfunction remains elusive. Here, we aimed to correlate cerebrospinal fluid (CSF) levels of CHI3L1 and NF-L with cognitive status in MS. Fifty one recently diagnosed patients were cognitively evaluated and CSF was collected. Levels of CHI3L1 and NF-L were determined by ELISA. Spearman's partial correlation coefficient was performed. After adjusting cognitive scores by age, anxiety and EDSS, association was detected between CHI3L1 levels and Trail Making Test A (rs = 0.348; p = 0.016) and between NF-L levels and Word List Generation (rs = -0.324; p = 0.025). High levels of CSF CHI3L1 and NF-L are associated with cognitive impairment in the early phases of MS.

Vascular Cognitive Impairment Linked to Brain Endothelium Inflammation in Early Stages of Heart Failure in Mice.

BackgroundAlthough advanced heart failure (HF) is a clinically documented risk factor for vascular cognitive impairment, the occurrence and pathomechanisms of vascular cognitive impairment in early stages of HF are equivocal. Here, we characterize vascular cognitive impairment in the early stages of HF development and assess whether cerebral hypoperfusion or prothrombotic conditions are involved.Methods and ResultsTgαq*44 mice with slowly developing isolated HF triggered by cardiomyocyte‐specific overexpression of G‐αq*44 protein were studied before the end‐stage HF, at the ages of 3, 6, and 10 months: before left ventricle dysfunction; at the stage of early left ventricle diastolic dysfunction (with preserved ejection fraction); and left ventricle diastolic/systolic dysfunction, respectively. In 6‐ to 10‐month‐old but not in 3‐month‐old Tgαq*44 mice, behavioral and cognitive impairment was identified with compromised blood‐brain barrier permeability, most significantly in brain cortex, that was associated with myelin sheet loss and changes in astrocytes and microglia. Brain endothelial cells displayed increased E‐selectin immunoreactivity, which was accompanied by increased amyloid‐β1‐42 accumulation in piriform cortex and increased cortical oxidative stress (8‐OHdG immunoreactivity). Resting cerebral blood flow measured by magnetic resonance imaging in vivo was preserved, but ex vivo NO‐dependent cortical arteriole flow regulation was impaired. Platelet hyperreactivity was present in 3‐ to 10‐month‐old Tgαq*44 mice, but it was not associated with increased platelet‐dependent thrombogenicity.ConclusionsWe report for the first time that vascular cognitive impairment is already present in the early stage of HF development, even before left ventricle systolic dysfunction. The underlying pathomechanism, independent of brain hypoperfusion, involves preceding platelet hyperreactivity and brain endothelium inflammatory activation.