Cerebellar Plasticity in Health and Disease

The cerebellum helps fine-tuning movements by evaluating disparities between intention and action, in order to adjust the execution of movements ‘online’, and to keep movements calibrated in the long term. The cerebellar capacity to store information, which provides the ‘memory’ needed for the recalibration of movements, the learning of new motor skills, and associative learning, is provided by modifications in the strength of synaptic couplings between neurons in the cerebellar circuitry (‘synaptic plasticity’). Cerebellar coordination and motor learning can be affected by degenerative processes, such as paraneoplastic cerebellar ataxia (PCA). This is a severe side effect of certain forms of cancer, usually characterized by the degeneration of Purkinje cells, which provide the sole output of the cerebellar cortex. PCA is associated with the expression of antineuronal autoantibodies. In chapters 2 and 3 we describe two patients with Hodgkin’s disease and PCA associated with a previously undescribed autoantibody against the metabotropic glutamate receptor type 1 (mGluR1). This autoantibody directly interferes with receptor function in vitro, affecting synaptic transmission and spontaneous Purkinje neuronal firing behavior, as well as inhibiting the induction of long-term depression of the parallel fiber to Purkinje cell synapse (PF-LTD), a form of synaptic plasticity widely associated with motor learning. Infusion of these anti-mGluR1 autoantibodies into the cerebellum of mice causes severe, reversible ataxia, indicating that PCA autoantibodies can directly affect Purkinje neuronal function by blocking receptors. Post-mortem analysis of one mGluR1-PCA patient’s cerebellum reveals a reduction in the number of Purkinje cells after chronic exposition to anti-mGluR1 autoantibodies. Together these results indicate that the anti-mGluR1 autoantibodies can cause ataxia by acutely interfering with neuronal function and synaptic plasticity, as well as through a chronic degenerative effect on cerebellar Purkinje cells. The block of PF-LTD by the anti-mGluR1 autoantibodies was also shown to affect the patients’ ability to recalibrate motor output. Cerebellar motor learning in the patients was assessed using a saccade adaptation paradigm, in which the amplitude of voluntary fast eye movements (‘saccades’) is gradually changed by systematically displacing a target during a series of consecutive saccades. Although their saccade performance was within the normal range, the capability to gradually adapt saccade amplitude was impaired in the patients with anti-mGluR1 autoantibodies, adding to the body of evidence that PF-LTD underlies forms of motor learning. In chapter 4, further analysis of saccade adaptation characteristics in humans indicates that this form of motor learning conforms to learning rules similar to those of cerebellar synaptic plasticity processes. The time course of induction and the error-based character of saccade adaptation are in line with the properties of cerebellar synaptic plasticity forms, such as PF-LTD. In chapters 5 and 6, the cellular mechanisms putatively underlying cerebellar motor learning were further explored by studying synaptic plasticity in vitro. PF-LTD can be induced by coactivation of parallel fiber (PF) and climbing fiber (CF) input at low frequencies, and is expressed as a reduction in AMPA glutamate receptors on the postsynaptic membrane. This selectively decreases the effect of glutamate released by the PFs that were concurrently active with the CF. In order to prevent synapse saturation and to allow reversal of motor learning, this reduction of PF-Purkinje cell synaptic strength must be counterbalanced by a form of potentiation that is also expressed postsynaptically. This modification, called long-term potentiation of the PF – Purkinje cell synapse (PF-LTP), can be induced by tetanizing only the PF at low frequencies. CF¬evoked calcium transients into the Purkinje cell are shown to be the polarity switch factor making the difference between PF-LTD and PF-LTP induction. Long-term depression of synaptic strength can also be induced at the CF – Purkinje cell synapse (CF-LTD), by high-frequent CF activity. CF-LTD reduces the amplitude of the CF¬evoked calcium transient, which is shown to inhibit the induction of PF-LTD. The concept arises that the cerebellar circuitry uses multiple interacting mechanisms to calibrate its output

Growing up with Fragile X Syndrome: Concerns and Care Needs of Young Adult Patients and Their Parents

Little is known about care needs of young adults with Fragile X Syndrome (FXS). Patient-driven information is needed to improve understanding and support of young adults with FXS. A qualitative study was performed in 5 young adult patients (aged 18–30), and 33 parents of young adults. Concerns and care needs were categorized using the International Classifcation of Functioning, Disability, and Health. Results indicated concerns on 14 domains for males, and 13 domains for females, including physical, psychological and socio-economical issues. In both groups parents reported high stress levels and a lack of knowledge of FXS in adult care providers. This study revealed concerns on various domains, requiring gender-specifc, multidisciplinary trans

Early recognition and treatment of neuropsychiatric symptoms to improve quality of life in early Alzheimer's disease

__Background:__ Neuropsychiatric symptoms (NPS) are very common in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD) dementia and are associated with various disadvantageous clinical outcomes including a negative impact on quality of life, caregiver burden, and accelerated disease progression. Despite growing evidence of the efficacy of (non)pharmacological interventions to reduce these symptoms, NPS remain underrecognized and undertreated in memory clinics. The BEhavioural symptoms in Alzheimer's disease Towards early Identification and Treatment (BEAT-IT) study is developed to (1) investigate the neurobiological etiology of NPS in AD and (2) study the effectiveness of the Describe, Investigate, Create, Evaluate (DICE) approach to structure and standardize the current care of NPS in AD. By means of the DICE method, we aim to improve the quality of life of AD patients with NPS and their caregivers who visit the memory clinic. This paper describes the protocol for the intervention study that incorporates the latter aim. __Methods:__ We aim to enroll a total of 150 community-dwelling patients with MCI or AD and their caregivers in two waves. First, we will recruit a control group who will receive care as usual. Next, the second wave of participants will undergo the DICE method. This approach consists of the following steps: (1) describe the context in which NPS occur, (2) investigate the possible causes, (3) create and implement a treatment pl

Candidate CSPG4 mutations and induced pluripotent stem cell modeling implicate oligodendrocyte progenitor cell dysfunction in familial schizophrenia

Schizophrenia is highly heritable, yet its underlying pathophysiology remains largely unknown. Among the most well-replicated findings in neurobiological studies of schizophrenia are deficits in myelination and white matter integrity; however, direct etiological genetic and cellular evidence has thus far been lacking. Here, we implement a family-based approach for genetic discovery in schizophrenia combined with functional analysis using induced pluripotent stem cells (iPSCs). We observed familial segregation of two rare missense mutations in Chondroitin Sulfate Proteoglycan 4 (CSPG4) (c.391G > A [p.A131T], MAF 7.79 × 10−5 and c.2702T > G [p.V901G], MAF 2.51 × 10−3). The CSPG4A131T mutation was absent from the Swedish Schizophrenia Exome Sequencing Study (2536 cases, 2543 controls), while the CSPG4V901G mutation was nominally enriched in cases (11 cases vs. 3 controls, P = 0.026, OR 3.77, 95% CI 1.05–13.52). CSPG4/NG2 is a hallmark protein of oligodendrocyte progenitor cells (OPCs). iPSC-derived OPCs from CSPG4A131T mutation carriers exhibited abnormal post-translational processing (P = 0.029), subcellular localization of mutant NG2 (P = 0.007), as well as aberrant cellular morphology (P = 3.0 × 10−8), viability (P = 8.9 × 10−7), and myelination potential (P = 0.038). Moreover, transfection of healthy non-carrier sibling OPCs confirmed a pathogenic effect on cell survival of both the CSPG4A131T (P = 0.006) and CSPG4V901G (P = 3.4 × 10−4) mutations. Finally, in vivo diffusion tensor imaging of CSPG4A131T mutation carriers demonstrated a reduction of brain white matter integrity compared to unaffected sibling and matched general population controls (P = 2.2 × 10−5). Together, our findings provide a convergence of genetic and functional evidence to implicate OPC dysfunction as a candidate pathophysiological mechanism of familial schizophrenia

Cerebellar motor learning deficits in medicated and medication-free men with recent-onset schizophrenia

Background: The notion that cerebellar deficits may underlie clinical symptoms in people with schizophrenia is tested by evaluating 2 forms of cerebellar learning in patients with recent-onset schizophrenia. A potential medication effect is evaluated by including patients with or without antipsychotics. Methods: We assessed saccadic eye movement adaptation and eyeblink conditioning in men with recentonset schizophrenia who were taking antipsychotic medication or who were antipsychotic-free and in age-matched controls. Results: We included 39 men with schizophrenia (10 who were taking clozapine, 16 who were taking haloperidol and 13 who were antipsychoticfree) and 29 controls in our study. All participants showed significant saccadi

Music to prevent deliriUm during neuroSurgerY (MUSYC) Clinical trial

Introduction Delirium is a neurocognitive disorder characterised by an acute and temporary decline of menta

Neuropsychiatric and Cognitive Symptoms Across the Alzheimer Disease Clinical Spectrum: Cross-sectional and Longitudinal Associations

BACKGROUND AND OBJECTIVES: To investigate the prevalence and trajectories of neuropsychiatric symptoms (NPS) in relation to cognitive functioning in a cohort of β-amyloid-positive (A+) individuals across the Alzheimer disease (AD) clinical spectrum.  METHODS: In this single-center observational study, we included all individuals who visited the Alzheimer Center Amsterdam and had a clinical diagnosis of subjective cognitive decline (SCD), mild cognitive impairment (MCI), or probable AD dementia and were A+. We measured NPS with the Neuropsychiatric Inventory (NPI), examining total scores and the presence of specific NPI domains. Cognition was assessed across 5 cognitive domains and with the Mini-Mental State Examination (MMSE). We examined trajectories including model-based trends for NPS and cognitive functioning over time. We used linear mixed models to relate baseline NPI scores to cognitive functioning at baseline (whole-sample) and longitudinal time points (subsample n = 520, mean 1.8 [SD 0.7] years follow-up).  RESULTS: We included 1,524 A+ individuals from the Amsterdam Dementia Cohort with A+ SCD (n = 113), A+ MCI (n = 321), or A+ AD dementia (n = 1,090). NPS were prevalent across all clinical AD stages (≥1 NPS 81.4% in SCD, 81.2% in MCI, 88.7% in dementia; ≥1 clinically relevant NPS 54.0% in SCD, 50.5% in MCI, 66.0% in dementia). Cognitive functioning showed a uniform gradual decline; while in contrast, large intraindividual heterogeneity of NPS was observed over time across all AD groups. At baseline, we found associations between NPS and cognition in dementia that were most pronounced for NPI total scores and MMSE (range β = -0.18 to -0.11, false discovery rate [FDR]-adjusted p < 0.05), while there were no cross-sectional relationships in SCD and MCI (range β = -0.32 to 0.36, all FDR-adjusted p > 0.05). There were no associations between baseline NPS and cognitive functioning over time in any clinical stage (range β = -0.13 to 0.44, all FDR-adjusted p > 0.05).  DISCUSSION: NPS and cognitive symptoms are both prevalent across the AD clinical spectrum, but show a different evolution during the course of the disease