Motor learning and performance in schizophrenia and aging: two different patterns of decline.

Psychomotor slowing has consistently been observed in schizophrenia, however research on motor learning in schizophrenia is limited. Additionally, motor learning in schizophrenia has never been compared with the waning of motor learning abilities in the elderly. Therefore, in an extensive study, 30 individuals with schizophrenia, 30 healthy age-matched controls and 30 elderly participants were compared on sensorimotor learning tasks including sequence learning and adaptation (both explicit and implicit), as well as tracking and aiming. This paper presents new findings on an explicit motor sequence learning task, an explicit verbal learning task and a simple aiming task and summarizes all previously published findings of this large investigation. Individuals with schizophrenia and elderly had slower Movement Time (MT)s compared with controls in all tasks, however both groups improved over time. Elderly participants learned slower on tracking and explicit sequence learning while individuals with schizophrenia adapted slower and to a lesser extent to movement perturbations in adaptation tasks and performed less well on cognitive tests including the verbal learning task. Results suggest that motor slowing is present in schizophrenia and the elderly, however both groups show significant but different motor skill learning. Cognitive deficits seem to interfere with motor learning and performance in schizophrenia while task complexity and decreased movement precision interferes with motor learning in the elderly, reflecting different underlying patterns of decline in these conditions. In addition, evidence for motor slowing together with impaired implicit adaptation supports the influence of cerebellum and the cerebello-thalamo-cortical-cerebellar (CTCC) circuits in schizophrenia, important for further understanding the pathophysiology of the disorder.

Comparing the test-retest reliability of resting-state functional magnetic resonance imaging metrics across single band and multiband acquisitions in the context of healthy aging.

The identification of meaningful functional magnetic resonance imaging (fMRI) biomarkers requires measures that reliably capture brain performance across different subjects and over multiple scanning sessions. Recent developments in fMRI acquisition, such as the introduction of multiband (MB) protocols and in-plane acceleration, allow for increased scanning speed and improved temporal resolution. However, they may also lead to reduced temporal signal to noise ratio and increased signal leakage between simultaneously excited slices. These methods have been adopted in several scanning modalities including diffusion weighted imaging and fMRI. To our knowledge, no study has formally compared the reliability of the same resting-state fMRI (rs-fMRI) metrics (amplitude of low-frequency fluctuations; seed-to-voxel and region of interest [ROI]-to-ROI connectivity) across conventional single-band fMRI and different MB acquisitions, with and without in-plane acceleration, across three sessions. In this study, 24 healthy older adults were scanned over three visits, on weeks 0, 1, and 4, and, on each occasion, underwent a conventional single band rs-fMRI scan and three different rs-fMRI scans with MB factors 4 and 6, with and without in-plane acceleration. Across all three rs-fMRI metrics, the reliability scores were highest with MB factor 4 with no in-plane acceleration for cortical areas and with conventional single band for subcortical areas. Recommendations for future research studies are discussed.

Impaired Sensorimotor Adaption in Schizophrenia in Comparison to Age-Matched and Elderly Controls.

BACKGROUND: The "cognitive dysmetria hypothesis" of schizophrenia proposes a disrupted communication between the cerebellum and cerebral cortex, resulting in sensorimotor and cognitive symptoms. Sensorimotor adaptation relies strongly on the function of the cerebellum. OBJECTIVES: This study investigated whether sensorimotor adaptation is reduced in schizophrenia compared with age-matched and elderly healthy controls. METHODS: Twenty-nine stably treated patients with schizophrenia, 30 age-matched, and 30 elderly controls were tested in three motor adaptation tasks in which visual movement feedback was unexpectedly altered. In the "rotation adaptation task" the perturbation consisted of a rotation (30° clockwise), in the "gain adaptation task" the extent of the movement feedback was reduced (by a factor of 0.7) and in the "vertical reversal task," up- and downward pen movements were reversed by 180°. RESULTS: Patients with schizophrenia adapted to the perturbations, but their movement times and errors were substantially larger than controls. Unexpectedly, the magnitude of adaptation was significantly smaller in schizophrenia than elderly participants. The impairment already occurred during the first adaptation trials, pointing to a decline in explicit strategy use. Additionally, post-adaptation aftereffects provided strong evidence for impaired implicit adaptation learning. Both negative and positive schizophrenia symptom severities were correlated with indices of the amount of adaptation and its aftereffects. CONCLUSIONS: Both explicit and implicit components of sensorimotor adaptation learning were reduced in patients with schizophrenia, adding to the evidence for a role of the cerebellum in the pathophysiology of schizophrenia. Elderly individuals outperformed schizophrenia patients in the adaptation learning tasks.

Clinical evaluation of [18F] JNJ-64326067, a novel candidate PET tracer for the detection of tau pathology in Alzheimer's disease.

PURPOSE: The accumulation of misfolded tau is a common feature of several neurodegenerative disorders, with Alzheimer's disease (AD) being the most common. Earlier we identified JNJ-64326067, a novel isoquinoline derivative with high affinity and selectivity for tau aggregates from human AD brain. We report the dosimetry of [18F] JNJ-64326067 and results of a proof-of-concept study comparing subjects with probable Alzheimer's disease to age-matched healthy controls. METHODS: [18F] JNJ-64326067 PET scans were acquired for 90 min and then from 120 to 180 min in 5 participants with [18F]-florbetapir PET amyloid positive probable AD (73 ± 9 years) and 5 [18F]-florbetapir PET amyloid negative healthy controls (71 ± 7 years). Whole-body [18F] JNJ-64326067 PET CT scans were acquired in six healthy subjects for 5.5 h in 3 scanning sessions. Brain PET scans were visually reviewed. Regional quantification included kinetic analysis of distribution volume ration (DVR) estimated by Logan graphical analysis over the entire scan and static analysis of SUVr in late frames. Both methods used ventral cerebellar cortex as a reference region. RESULTS: One of the healthy controls had focal areas of PET signal in occipital and parietal cortex underlying the site of a gunshot injury as an adolescent; the other four healthy subjects had no tau brain signal. Four of the 5 AD participants had visually apparent retention of [18F] JNJ-64326067 in relevant cortical regions. One of the AD subjects was visually negative. Cortical signal in visually positive subjects approached steady state by 120 min. Temporal and frontal cortical SUVr/DVR values in visually positive AD subjects ranged from 1.21 to 3.09/1.2 to 2.18 and from 0.92 to 1.28/0.91 to 1.16 in healthy controls. Whole-body effective dose was estimated to be 0.0257 mSv/MBq for females and 0.0254 mSv/MBq for males. CONCLUSIONS: [18F] JNJ-64326067 could be useful for detection and quantitation of tau aggregates.

A mood state-specific interaction between kynurenine metabolism and inflammation is present in bipolar disorder.

OBJECTIVES: Cytokines are thought to contribute to the pathogenesis of psychiatric symptoms by kynurenine pathway activation. Kynurenine metabolites affect neurotransmission and can cause neurotoxicity. We measured inflammatory markers in patients with bipolar disorder (BD) and studied their relation to kynurenine metabolites and mood. METHODS: Patients with BD suffering from an acute mood episode were assigned to the depressive (n = 35) or (hypo)manic (n = 32) subgroup. Plasma levels of inflammatory markers [cytokines, C-reactive protein] and kynurenine metabolites [tryptophan (TRP), kynurenine (KYN), 3-hydroxykynurenine (3-HK), quinolinic acid (QA), kynurenic acid (KYNA)] were measured on 6 time points during 8 months follow-up. Biological marker levels in patients were compared to controls (n = 35) and correlated to scores on mood scales. Spearman correlations and linear mixed models were used for statistical analysis. RESULTS: Twenty patients of the manic subgroup, 29 of the depressive subgroup, and 30 controls completed the study. The manic subgroup had a rapid remission of mood symptoms, but in the depressive subgroup subsyndromal symptoms persisted. No differences in inflammation were found between groups. A strong correlation between tumor necrosis factor-α and KYN, KYN/TRP, 3-HK and QA (ρ > 0.60) was specific for the manic group, but only at baseline (during mania). The depressive subgroup had a lower neuroprotective ratio (KYNA/3-HK, P = .0004) and a strong association between interferon-y and kynurenine pathway activation (P < .0001). KYNA was low in both patient groups versus controls throughout the whole follow-up (P = .0008). CONCLUSIONS: Mania and chronic depressive symptoms in BD are accompanied by a strong interaction between inflammation and a potentially neurotoxic kynurenine metabolism.

State-associated changes in longitudinal [18F]-PBR111 TSPO PET imaging of psychosis patients: Evidence for the accelerated ageing hypothesis?

OBJECTIVE: To determine whether state-associated changes in microglial activity, measured with translocator-protein positron emission tomography (TSPO PET), can be identified in psychosis patients through longitudinal evaluation of their regional tracer uptake over the clinical course from acute psychosis to post-treatment follow-up, and comparison to healthy controls. We also evaluated the relation between tracer uptake, clinical symptoms and peripheral immunological markers. METHOD: Second-generation radioligand [18F]-PBR111 TSPO PET-CT was used for longitudinal dynamic imaging in 14 male psychosis patients and 17 male age-matched healthy control subjects. Patients were first scanned during an acute psychotic episode followed by a second scan after treatment. Prior genotyping of subjects for the rs6917 polymorphism distinguished high- and mixed-affinity binders. The main outcome was regional volume of distribution (VT), representing TSPO binding. Plasma concentrations of CRP, cytokines and kynurenines were measured at each timepoint. RESULTS: We found a significant three-way interaction between time of scan, age and cohort (cortical grey matter F6.50, p.020). Age-dependent differences in VT existed between cohorts during the psychotic state, but not at follow-up. Patients' relative change in VT over time correlated with age (cortical grey matter Pearson's r.574). PANSS positive subscale scores correlated with regional VT during psychosis (cortical grey matter r.767). Plasma CRP and quinolinic acid were independently associated with lower VT. CONCLUSIONS: We identified a differential age-dependent pattern of TSPO binding from psychosis to follow-up in our cohort of male psychosis patients. We recommend future TSPO PET studies in psychosis patients to differentiate between clinical states and consider potential age-related effects.

Implicit motor sequence learning in schizophrenia and in old age: reduced performance only in the third session.

Although there still is conflicting evidence whether schizophrenia is a neurodegenerative disease, cognitive changes in schizophrenia resemble those observed during normal aging. In contrast to extensively demonstrated deficits in explicit learning, it remains unclear whether implicit sequence learning is impaired in schizophrenia and normal aging. Implicit sequence learning was investigated using a computerized drawing task, the 'implicit pattern learning task (IPLT)' in 30 stable patients with schizophrenia, 30 age-matched controls and 30 elderly subjects on two consecutive days and after 1 week (sessions 1, 2 and 3). Fixed sequence trials were intermixed with random trials, and sequence learning was assessed by subtraction of the response time in fixed sequence trials from random trials. Separate analyses of response times and movement accuracy (i.e., directional errors) were performed. Explicit sequence knowledge was assessed using three different awareness tasks. All groups learned equally during sessions 1 and 2. In session 3, control subjects showed significantly larger learning scores than patients with schizophrenia (p = .012) and elderly subjects (p = .021). This group difference is mainly expressed in movement time and directional errors. Patients with schizophrenia demonstrated less subjective sequence awareness, and both patients with schizophrenia and elderly subjects had less explicit sequence recall. Explicit recall was positively correlated with task performance in all groups. After a short 24 h interval, all subjects showed similar improvements in implicit sequence learning. However, no benefit of prior task exposure 1 week later was observed in patients with schizophrenia and elderly subjects compared to controls. As patients with schizophrenia and elderly both display less explicit sequence recall, the control group superiority after 1 week could be explained by an explicit learning component. The few patients with schizophrenia and elderly subjects who had some sequence recall could possibly utilize this explicit knowledge to improve their task performance but did this by distinct mechanisms.

Bioavailability and bioequivalence of a darunavir 800-mg tablet formulation compared with the 400-mg tablet formulation.

UNLABELLED: Once-daily darunavir/ritonavir (800/100 mg), plus other antiretrovirals, is recommended for HIV-1-infected patients. Low therapy adherence is linked with poor outcomes. Pill burden can impact adherence. An 800-mg darunavir tablet would reduce pill burden. OBJECTIVES: To assess the relative oral bioavailability (NCT01052883) and bioequivalence (NCT01308658) of a darunavir 800-mg tablet vs. 2 × 400-mg tablets. METHODS: In two phase I, open-label, randomized, crossover, single-center studies, healthy volunteers received once-daily ritonavir (100 mg, days 1 - 5) and a single 800-mg darunavir dose: 2 × 400-mg tablets (reference) or 1 × 800- mg tablet (test) on day 3 and vice versa after a ≥ 7-day wash-out. Each study had fasted (n = 16 (bioavailability); n = 83 (bioequivalence)) and fed panels (n = 16; n = 45, respectively). Pharmacokinetic profiles and tolerability were assessed. RESULTS: No volunteers discontinued for treatment-related reasons. Least-square mean ratios (test vs. reference) for darunavir maximum plasma concentrations (C(max)), area under the concentration-time curve from zero to infinity (AUC(0-∞)) were: 1.06 and 1.15 (bioavailability), and 1.02 and 1.00 (bioequivalence), respectively (fasted); 0.89 and 0.88 (bioavailability), and 0.96 and 0.98 (bioequivalence), respectively (fed). 90% confidence intervals (CI) were within 80.00 - 125.00%, except bioavailability AUC(0-∞) (fed and fasted conditions). Median time to C(max) was comparable for both formulations. No clinically relevant differences in adverse events or laboratory abnormalities occurred between formulations. CONCLUSIONS: Bioequivalence was demonstrated for the 800-mg darunavir tablet (fasted and fed conditions). This formulation can reduce pill burden and potentially increase adherence for HIV-1-infected patients in whom once-daily darunavir/ritonavir 800/100 mg is appropriate.

Evaluation of progression markers in the premotor phase of Parkinson's disease: the progression markers in the premotor phase study.

BACKGROUND: The clinical diagnosis of Parkinson's disease (PD) is proposed to be too late for the application of beneficial neuroprotective treatment. Thus, it is important to identify and follow individuals at risk for PD in order to gain knowledge about the prodromal course of the disease. Substantia nigra hyperechogenicity (SN+) has been confirmed as a risk factor for PD and appears promising as a predictor of PD, particularly in combination with other putative PD markers. We present the design and initial data of a 2-year longitudinal investigation of subjects proposed to be at high risk of developing PD (HRPD), compared to early PD patients and control subjects. The aim of the presented study is to monitor progression of the neurodegenerative process to motor PD. METHODS: In total, 40 HRPD, 16 PD and 41 control individuals were recruited. The HRPD subjects had SN+ and additionally either 1 cardinal PD motor sign or 2 further risk (e.g. positive family history) or prodromal markers (e.g. hyposmia). In this cohort, motor function, olfaction, mood and blood markers will be evaluated every 6 months, complemented by a comprehensive clinical, imaging and electrophysiological assessment. RESULTS: PD, HRPD and control subjects did not differ significantly regarding age, but the HRPD group consisted mainly of males (72.5% of HRPD subjects vs. 43.9% of controls; p = 0.013). Mean disease duration in PD patients was 31 months (range 15-56). HRPD subjects were predominantly recruited according to the occurrence of slight motor signs (HRPD 77.5%, PD 100%, p = 0.05; controls 0%, HRPD vs. controls, p < 0.017). The Unified Parkinson's Disease Rating Scale motor score (mean, range) indicated that the HRPD group (4, 0-12) had values between those of controls (0, 0-2; p < 0.017) and PD subjects (26, 9-55; p < 0.017). Among nonmotor symptoms, hyposmia was more common in both HRPD (47.5%) and PD subjects (75%) than in controls (5.1%; p < 0.017 for both comparisons). CONCLUSIONS: Here, we describe the recruitment of a highly enriched-risk cohort and a promising study design to assess progression to motor PD. Whether the HRPD group indeed suffers from early, PD-specific neurodegeneration remains to be verified in the ongoing follow-up examinations.

CSF biomarker analysis of ABCA7 mutation carriers suggests altered APP processing and reduced inflammatory response.

BACKGROUND: The Alzheimer's disease (AD) risk gene ABCA7 has suggested functions in lipid metabolism and the immune system. Rare premature termination codon (PTC) mutations and an expansion of a variable number of tandem repeats (VNTR) polymorphism in the gene, both likely cause a lower ABCA7 expression and hereby increased risk for AD. However, the exact mechanism of action remains unclear. By studying CSF biomarkers reflecting different types of AD-related pathological processes, we aim to get a better insight in those processes and establish a biomarker profile of mutation carriers. METHODS: The study population consisted of 229 AD patients for whom CSF was available and ABCA7 sequencing and VNTR genotyping had been performed. This included 28 PTC mutation and 16 pathogenic expansion carriers. CSF levels of Aß1-42, Aß1-40, P-tau181, T-tau, sAPPα, sAPPß, YKL-40, and hFABP were determined using ELISA and Meso Scale Discovery assays. We compared differences in levels of these biomarkers and the Aß ratio between AD patients with or without an ABCA7 PTC mutation or expansion using linear regression on INT-transformed data with APOE-status, age and sex as covariates. RESULTS: Carriers of ABCA7 expansion mutations had significantly lower Aß1-42 levels (P = 0.022) compared with non-carrier patients. The effect of the presence of ABCA7 mutations on CSF levels was especially pronounced in APOE ε4-negative carriers. In addition, VNTR expansion carriers had reduced Aß1-40 (P = 0.023), sAPPα (P = 0.047), sAPPß (P = 0.016), and YKL-40 (P = 0.0036) levels. CONCLUSIONS: Our results are suggestive for an effect on APP processing by repeat expansions given the changes in the amyloid-related CSF biomarkers that were found in carriers. The decrease in YKL-40 levels in expansion carriers moreover suggests that these patients potentially have a reduced inflammatory response to AD damage. Moreover, our findings suggest the existence of a mechanism, independent of lowered expression, affecting neuropathology in expansion carriers.

Foreign bodies in a pediatric emergency department in South Africa.

OBJECTIVES: Foreign body-related pediatric trauma has a high incidence, but studies with large data sets are rare and typically stem from Western settings. The aim of this study was to identify characteristics of foreign body-related trauma in children treated at our trauma unit in South Africa. METHODS: In this retrospective study, we analyzed all foreign body-related trauma admissions from 1991 to 2009. We collected detailed data including age, sex, type of foreign body, injury severity, and anatomical location of the foreign body. RESULTS: We analysed 8149 cases. Marginally more boys (54.9%) than girls were involved. The overall median age was 3 years (interquartile range, 2-6 years); 78.8% were younger than 7 years. The predominant anatomical sites were the respiratory tract and the gastrointestinal tract (39.1%); ears (23.9%); nose (19.4%); and extremities (8.8%). The commonest objects were coins (20.8 %), (parts of) jewelry (9.5%), and food (8.7%). Three quarters (74.5%) of patients presented between 1 and 2 hours after the injury (median, 1 hour). A total of 164 cases (2.0%) were marked as possible child abuse; 17 cases were filed as confirmed child abuse. CONCLUSIONS: Preventive parent education programs targeting foreign body-related injury should mainly focus on both sexes younger than 7 years. Parents should be taught to keep small objects out of reach of young children, especially coins, because these most often result in a trauma unit visit.

Profiling classical neuropsychiatric biomarkers across biological fluids and following continuous lumbar puncture: A guide to sample type and time.

Identification of putative biomarkers for neuropsychiatric disorders has produced a diverse list of analytes involved in inflammation, hypothalamic-pituitary-adrenal axis (HPA) regulation, growth factor and metabolic pathways. However, translation of these findings to accurate and robust assays has been stalled, affecting objective diagnoses, tracking relapse/remission, and prediction/monitoring of drug affect. Two important factors to control are the sample matrix (e.g. serum, plasma, saliva, or cerebrospinal fluid) and time of sample collection. Additionally, sample collection procedures may affect analyte level. In this study, a panel of 14 core neuropsychiatric biomarkers was measured in serum, plasma, saliva, and cerebrospinal fluid (CSF), all collected from 8 healthy volunteers at the same time. In a second cohort of 7 healthy volunteers, 6 analytes were measured in serum and CSF collected at 13 timepoints over a 24-h period after catheter placement. We found that many of the analytes were quantifiable in all sample types examined, but often at quite different concentrations and without correlation between the sample types. After catheter placement, a diurnal pattern was observed for cortisol and interleukin-6 in serum, and transient spikes were observed in interleukin-1ß. In CSF, a chronic elevation of several cytokines was observed instead, perhaps due to the continuous sampling procedure. These findings enable more informed decision-making around sample type and collection time, which can be implemented in future biomarker studies. Clinicaltrialgov identifiers: NCT02933762, NCT02475148.

Test-retest reliability of time-varying patterns of brain activity across single band and multiband resting-state functional magnetic resonance imaging in healthy older adults.

Leading Eigenvector Dynamics Analysis (LEiDA) is an analytic approach that characterizes brain activity recorded with functional Magnetic Resonance Imaging (fMRI) as a succession of discrete phase-locking patterns, or states, that consistently recur over time across all participants. LEiDA allows for the extraction of three state-related measures which have previously been key to gaining a better understanding of brain dynamics in both healthy and clinical populations: the probability of occurrence of a given state, its lifetime and the probability of switching from one state to another. The degree to which test-retest reliability of the LEiDA measures may be affected by increasing MRI multiband (MB) factors in comparison with single band sequences is yet to be established. In this study, 24 healthy older adults were scanned over three sessions, on weeks 0, 1, and 4. On each visit, they underwent a conventional single band resting-state fMRI (rs-fMRI) scan and three different MB rs-fMRI scans, with MB factors of 4, with and without in-plane acceleration, and 6 without in-plane acceleration. We found test-retest reliability scores to be significantly higher with MB factor 4 with and without in-plane acceleration for most cortical networks. These findings will inform the choice of acquisition parameters for future studies and clinical trials.

Pharmacokinetic-pharmacodynamic relationships of central nervous system effects of scopolamine in healthy subjects.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: • The cholinergic system is important for different central nervous system functions, including memory, learning and attention. Scopolamine, a centrally active muscarinic antagonist, has been used to model dementia and to demonstrate the pharmacological effects of cholinergic drugs, but for most effects the concentration-effect relationships are unknown. WHAT THIS STUDY ADDS: • We determined the pharmacokinetic-pharmacodynamic relationships of scopolamine using a multidimensional central nervous system test battery in a large group of healthy volunteers. The results suggested there are various functional cholinergic systems with different pharmacological characteristics, which can be used to study the effects of drugs that directly or indirectly modify cholinergic systems. The design of such studies should take the different concentration-effect relationships into account. AIM(S) Although scopolamine is a frequently used memory impairment model, the relationships between exposure and corresponding central nervous system (CNS) effects are mostly unknown. The aim of our study was to characterize these using pharmacokinetic-pharmacodynamic (PK-PD) modelling. METHODS: In two double-blind, placebo-controlled, four-way crossover studies, 0.5-mg scopolamine was administered i.v. to 90 healthy male subjects. PK and PD/safety measures were monitored pre-dose and up to 8.5 h after administration. PK-PD relationships were modelled using non-linear mixed-effect modelling. RESULTS: Most PD responses following scopolamine administration in 85 subjects differed significantly from placebo. As PD measures lagged behind the plasma PK profile, PK-PD relationships were modelled using an effect compartment and arbitrarily categorized according to their equilibration half-lives (t(1/2) k(eo) ; hysteresis measure). t(1/2) k(eo) for heart rate was 17 min, saccadic eye movements and adaptive tracking 1-1.5 h, body sway, smooth pursuit, visual analogue scales alertness and psychedelic 2.5-3.5 h, pupil size, finger tapping and visual analogue scales feeling high more than 8 h. CONCLUSIONS: Scopolamine affected different CNS functions in a concentration-dependent manner, which based on their distinct PK-PD characteristics seemed to reflect multiple distinct functional pathways of the cholinergic system. All PD effects showed considerable albeit variable delays compared with plasma concentrations. The t(1/2) k(eo) of the central effects was longer than of the peripheral effects on heart rate, which at least partly reflects the long CNS retention of scopolamine, but possibly also the triggering of independent secondary mechanisms. PK-PD analysis can optimize scopolamine administration regimens for future research and give insight into the physiology and pharmacology of human cholinergic systems.

Association of Hippocampal Subfields, CSF Biomarkers, and Cognition in Patients With Parkinson Disease Without Dementia.

OBJECTIVE: To examine whether hippocampal volume loss is primarily associated with cognitive status or pathologic ß-amyloid 1-42 (Aß42) levels, this study compared hippocampal subfield volumes between patients with Parkinson disease (PD) with mild cognitive impairment (PD-MCI) and without cognitive impairment (PD-CN) and between patients with low and high Aß42 levels, in addition exploring the relationship among hippocampal subfield volumes, CSF biomarkers (Aß42, phosphorylated and total tau), neuropsychological tests, and activities of daily living. METHODS: Forty-five patients with PD without dementia underwent CSF analyses and MRI as well as comprehensive motor and neuropsychological examinations. Hippocampal segmentation was conducted using FreeSurfer image analysis suite 6.0. Regression models were used to compare hippocampal subfield volumes between groups, and partial correlations defined the association between variables while controlling for intracranial volume (ICV). RESULTS: Linear regressions revealed cognitive group as a statistically significant predictor of both the hippocampal-amygdaloid transition area (HATA; ß = -0.23, 95% CI -0.44 to -0.02) and the cornu ammonis 1 region (CA1; ß = -0.28, 95% confidence interval [CI] -0.56 to -0.02), independent of disease duration and ICV, with patients with PD-MCI showing significantly smaller volumes than PD-CN. In contrast, no subfields were predicted by Aß42 levels. Smaller hippocampal volumes were associated with worse performance on memory, language, spatial working memory, and executive functioning tests. The subiculum was negatively correlated with total tau levels (r = -0.37, 95% CI -0.60 to -0.09). CONCLUSION: Cognitive status, but not CSF Aß42, predicted hippocampal volumes, specifically the CA1 and HATA. Hippocampal subfields were associated with various cognitive domains, as well as with tau pathology.

Motor cortical excitability and paired-associative stimulation-induced plasticity in amnestic mild cognitive impairment and Alzheimer's disease.

OBJECTIVE: Synaptopathy including alterations of synaptic plasticity (long-term potentiation, LTP) may precede neurodegeneration in Alzheimer's disease (AD). We studied LTP-like corticospinal plasticity induced by paired-associative stimulation (PASLTP) in AD and its prodromal stage, amnestic mild cognitive impairment (aMCI). METHODS: 15 AD and 15 aMCI patients, and 23 demographically matched healthy controls (HC) were included. Resting motor threshold (RMT) and stimulus intensity needed to evoke motor evoked potentials (MEP) of 1 mV (SI1mV) were obtained as single-pulse transcranial magnetic stimulation (TMS) measures of corticospinal excitability in a hand muscle at baseline, followed by PASLTP using standard methodology. MEP amplitude change after PASLTP normalized to baseline was defined as plasticity effect. All measures were repeated in two visits for examining test-retest reliability. RESULTS: SI1mV were lower in aMCI compared to HC, while there was no difference between AD and HC. RMT and SI1mV showed excellent test-retest reliability in all groups. PASLTP indiscriminately did not induce LTP-like plasticity in any of the groups, and expressed poor test-retest reliability. CONCLUSIONS: aMCI shows corticospinal hyperexcitability, consistent with glutamatergic excitotoxicity in early-stage AD. Possible abnormalities of LTP-like plasticity could not be reliably tested with the standard PASLTP protocol due to massive inter-subject variability even in HC, and poor test-retest reliability. SIGNIFICANCE: Findings indicate corticospinal hyperexcitability in prodromal AD, and reliability of single-pulse TMS measures for identifying such abnormality. In contrast, the standard PASLTP protocol may not be suitable for assessing LTP-like motor cortical plasticity, given its overall nil effect and poor test-retest reliability.

Evaluation of [18F]-JNJ-64326067-AAA tau PET tracer in humans.

The [18F]-JNJ-64326067-AAA ([18F]-JNJ-067) tau tracer was evaluated in healthy older controls (HCs), mild cognitive impairment (MCI), Alzheimer's disease (AD), and progressive supranuclear palsy (PSP) participants. Seventeen subjects (4 HCs, 5 MCIs, 5 ADs, and 3 PSPs) received a [11C]-PIB amyloid PET scan, and a tau [18F]-JNJ-067 PET scan 0-90 minutes post-injection. Only MCIs and ADs were amyloid positive. The simplified reference tissue model, Logan graphical analysis distribution volume ratio, and SUVR were evaluated for quantification. The [18F]-JNJ-067 tau signal relative to the reference region continued to increase to 90 min, indicating the tracer had not reached steady state. There was no significant difference in any bilateral ROIs for MCIs or PSPs relative to HCs; AD participants showed elevated tracer relative to controls in most cortical ROIs (P < 0.05). Only AD participants showed elevated retention in the entorhinal cortex. There was off-target signal in the putamen, pallidum, thalamus, midbrain, superior cerebellar gray, and white matter. [18F]-JNJ-067 significantly correlated (p < 0.05) with Mini-Mental State Exam in entorhinal cortex and temporal meta regions. There is clear binding of [18F]-JNJ-067 in AD participants. Lack of binding in HCs, MCIs and PSPs suggests [18F]-JNJ-067 may not bind to low levels of AD-related tau or 4 R tau.

Neurogranin as biomarker in CSF is non-specific to Alzheimer's disease dementia.

We aimed to evaluate the specificity of neurogranin (Ng) for Alzheimer's disease (AD) in a dementia cohort. Cerebrospinal fluid (CSF) Ng was measured (ELISA) in two independent cohorts: (1) clinical (n = 116; age 72±11 years): AD, non-AD (+high T-tau), and controls; and (2) autopsy-confirmed (n = 97; age 71±11 years): AD and non-AD, and 50 controls (age 60±6 years). In 16 autopsy-confirmed AD and 8 control subjects, Ng was measured in tissue (BA6+BA22). Ng was compared across diagnostic groups or neuropathological staging using multilinear regression models. Median[IQR] Ng concentrations were elevated in AD (414[315-499]pg/mL) and non-AD (464[319-699]pg/mL) compared to controls (260[193-306]pg/mL), but highest in AD-high-T-tau (874[716, 1148] pg/mL) and Creutzfeldt-Jakob disease (CJD; 828[703-1373]pg/mL) in cohort 1 (p < 0.01), but not in cohort 2: AD: 358[249-470]pg/mL; non-AD:245[137-416]pg/mL; controls: 259[193-370]pg/mL. Ng and tau biomarkers strongly correlated (r = 0.4-0.9, p < 0.05), except in CJD. CSF Ng concentrations were not associated with neuropathological AD hallmarks, nor with tissue Ng concentrations. CSF Ng is a general biomarker for synaptic degeneration, strongly correlating with CSF tau, but without added value for AD differential diagnosis.

Discovery of Atabecestat (JNJ-54861911): A Thiazine-Based ß-Amyloid Precursor Protein Cleaving Enzyme 1 Inhibitor Advanced to the Phase 2b/3 EARLY Clinical Trial.

Accumulation of amyloid ß peptides (Aß) is thought to be one of the causal factors of Alzheimer's disease (AD). The aspartyl protease ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the rate-limiting protease for Aß production, and therefore, BACE1 inhibition is a promising therapeutic approach for the treatment of AD. Starting with a dihydro-1,3-thiazine-based lead, Compound J, we discovered atabecestat 1 (JNJ-54861911) as a centrally efficacious BACE1 inhibitor that was advanced into the EARLY Phase 2b/3 clinical trial for the treatment of preclinical AD patients. Compound 1 demonstrated robust and dose-dependent Aß reduction and showed sufficient safety margins in preclinical models. The potential of reactive metabolite formation was evaluated in a covalent binding study to assess its irreversible binding to human hepatocytes. Unfortunately, the EARLY trial was discontinued due to significant elevation of liver enzymes, and subsequent analysis of the clinical outcomes showed dose-related cognitive worsening.

The ß-Secretase BACE1 in Alzheimer's Disease.

BACE1 (beta-site amyloid precursor protein cleaving enzyme 1) was initially cloned and characterized in 1999. It is required for the generation of all monomeric forms of amyloid-ß (Aß), including Aß42, which aggregates into bioactive conformational species and likely initiates toxicity in Alzheimer's disease (AD). BACE1 concentrations and rates of activity are increased in AD brains and body fluids, thereby supporting the hypothesis that BACE1 plays a critical role in AD pathophysiology. Therefore, BACE1 is a prime drug target for slowing down Aß production in early AD. Besides the amyloidogenic pathway, BACE1 has other substrates that may be important for synaptic plasticity and synaptic homeostasis. Indeed, germline and adult conditional BACE1 knockout mice display complex neurological phenotypes. Despite BACE1 inhibitor clinical trials conducted so far being discontinued for futility or safety reasons, BACE1 remains a well-validated therapeutic target for AD. A safe and efficacious compound with high substrate selectivity as well as a more accurate dose regimen, patient population, and disease stage may yet be found. Further research should focus on the role of Aß and BACE1 in physiological processes and key pathophysiological mechanisms of AD. The functions of BACE1 and the homologue BACE2, as well as the biology of Aß in neurons and glia, deserve further investigation. Cellular and molecular studies of BACE1 and BACE2 knockout mice coupled with biomarker-based human research will help elucidate the biological functions of these important enzymes and identify their substrates and downstream effects. Such studies will have critical implications for BACE1 inhibition as a therapeutic approach for AD.