Early Daytime Sleepiness and Nighttime Slow-wave Sleep Disorganization in Progressive Macaque Model of Parkinson’s Disease

Parkinsonian patients often experience wake/sleep behavior disturbances, which can appear at an early stage of the disease in a way that is still not fully described. We aimed here at reproducing and characterizing these clinical signs in a progressive non-human primate model of the Parkinson’s disease to better understand the underlying physiopathology and to identify biomarkers of the disease. Three adult non-human primates (macaca fascicularis) were equipped with a polysomnographic telemetry system allowing the characterization of the wake/sleep behavior by long-term neurophysiological recordings and a modified multiple sleep latency test. Experiments were first performed in healthy animals and then during the progressive induction of a parkinsonian syndrome by chronic intramuscular injections of low doses of MPTP. We observed a significant early onset of wake/sleep behavior disturbances, before any motor symptoms, resulting in (i) a disorganization of nighttime sleep with more deep sleep and (ii) a disorganization of daytime naps with an excessive daytime sleepiness characterized by longer duration of naps, which occurred faster. These observations persisted and worsened in stable symptomatic state. In that latter state, we observed persistent excessive daytime sleepiness and more disorganized nighttime sleep architecture and continuity. Interpolating to the human condition, the present study suggests that nighttime and daytime sleep disorders may appear in early stage of the disease. They could thus be used as biomarkers of the disease for early stratification of patients who are at risk of developing Parkinson’s disease.

A Selective Review of the Excitatory-Inhibitory Imbalance in Schizophrenia: Underlying Biology, Genetics, Microcircuits, and Symptoms

Schizophrenia is a chronic disorder characterized by specific positive and negative primary symptoms, social behavior disturbances and cognitive deficits (e.g., impairment in working memory and cognitive flexibility). Mounting evidence suggests that altered excitability and inhibition at the molecular, cellular, circuit and network level might be the basis for the pathophysiology of neurodevelopmental and neuropsychiatric disorders such as schizophrenia. In the past decades, human and animal studies have identified that glutamate and gamma-aminobutyric acid (GABA) neurotransmissions are critically involved in several cognitive progresses, including learning and memory. The purpose of this review is, by analyzing emerging findings relating to the balance of excitatory and inhibitory, ranging from animal models of schizophrenia to clinical studies in patients with early onset, first-episode or chronic schizophrenia, to discuss how the excitatory-inhibitory imbalance may relate to the pathophysiology of disease phenotypes such as cognitive deficits and negative symptoms, and highlight directions for appropriate therapeutic strategies.

Insomnia as a benign presentation of fatal familial insomnia (FFI). A case report from Malaysia

Fatal familial insomnia (FFI) is an extremely rare autosomal dominant prion disease. The chief clinical features include an organic sleep disorder associated with sympathetic overdrive, motor and bulbar compromise as well as progressive cognitive decline. Death ensures in 100% of cases with a mean survival duration of 18 months from time of symptom onset. Treatment strategies in the management of FFI remains largely symptomatic with greater emphasis placed on palliative care services. We report a case of a 31-year old gentleman (Mr G) who presented with insomnia, sleep behavior disturbances, diplopia, myoclonus and transient global amnesia. A family history of a paternal aunt with similar presentation who passed away raised the suspicion of probable FFI, which was subsequently confirmed by genetic testing. Mr G is the first reported definitive FFI case of Malaysian Chinese descent. Standard MRI imaging and CSF analyses are insufficient in the workup of an individual with probable FFI. PET scan, polysomnogram and genetic studies are required for cases with high index of suspicion. In view of the rapid progression of the disease with significant cognitive impairment within months of symptom onset, we advocate for early diagnosis and a biopsychosocial patient-centered treatment approach.

COVID-19 Lockdown Effect on Not Institutionalized Patients with Dementia and Caregivers

SARS-COV-2 is a severe medical condition. Old patients are very vulnerable, but they have been studied only as institutionalized patients. During the lock-down, little attention is dedicated to old, demented patients who lived at home. This study wants to examine their behavioral reactions by video-phone follow-up. We conducted a longitudinal study in subcortical vascular dementia (sVAD) patients. We enrolled 221 sVAD, not institutionalized patients. We divided sVAD patients into low-medium grade sVAD (A) and severe sVAD (B), based on neuroimaging severity degree and executive alterations. At baseline, at the end of lock-down, and two months later, global behavioral symptoms were recorded for each patient. We found significantly higher scores of general behavioral deterioration, anxiety, delusions, hallucinations and apathy after controlling for sVAD severity. The direct consequence was a drastic increment of psychotropic drugs prescribed and employed during the lock-down. Moreover, caregivers’ stress has been evaluated, together with their anxiety and depression levels. During the lock-down, their scores increased and reflected a severe worsening of their behavior. Our data demonstrate that social isolation induces a severe perception of loneliness and abandonment; these fears can exacerbate behavior disturbances in old-aged frail persons. Thus, these can be considered as indirect victims of SARS-COV-2.

Neuropsychiatric Symptoms of Alzheimer’s Disease in Down Syndrome and Its Impact on Caregiver Distress

Background: Neuropsychiatric symptoms (NPS) are non-cognitive manifestations common to dementia and other medical conditions, with important consequences for the patient, caregivers, and society. Studies investigating NPS in individuals with Down syndrome (DS) and dementia are scarce. Objective: Characterize NPS and caregiver distress among adults with DS using the Neuropsychiatric Inventory (NPI). Methods: We evaluated 92 individuals with DS (≥30 years of age), divided by clinical diagnosis: stable cognition, prodromal dementia, and AD. Diagnosis was determined by a psychiatrist using the Cambridge Examination for Mental Disorders of Older People with Down’s Syndrome and Others with Intellectual Disabilities (CAMDEX-DS). NPS and caregiver distress were evaluated by an independent psychiatrist using the NPI, and participants underwent a neuropsychological assessment with Cambridge Cognitive Examination (CAMCOG-DS). Results: Symptom severity differed between-groups for delusion, agitation, apathy, aberrant motor behavior, nighttime behavior disturbance, and total NPI scores, with NPS total score being found to be a predictor of AD in comparison to stable cognition (OR for one-point increase in the NPI = 1.342, p = 0.012). Agitation, apathy, nighttime behavior disturbances, and total NPI were associated with CAMCOG-DS, and 62% of caregivers of individuals with AD reported severe distress related to NPS. Caregiver distress was most impacted by symptoms of apathy followed by nighttime behavior, appetite/eating abnormalities, anxiety, irritability, disinhibition, and depression (R2 = 0.627, F(15,76) = 8.510, p < 0.001). Conclusion: NPS are frequent and severe in individuals with DS and AD, contributing to caregiver distress. NPS in DS must be considered of critical relevance demanding management and treatment. Further studies are warranted to understand the biological underpinnings of such symptoms.

The gut microbiome and its metabolites are necessary for morphine reward

Recent evidence has demonstrated that the gut microbiome has marked effects on neuronal function and behavior. Disturbances to microbial populations within the gut have been linked to myriad models of neuropsychiatric disorders. However, the role of the microbiome in substance use disorders remains understudied. Here we show that animals with their gut microbiome depleted by non-absorbable antibiotics (Abx) exhibit decreased formation of morphine conditioned place preference and demonstrate marked changes in gene expression within the nucleus accumbens (NAc) in response to morphine. Replacement of short-chain fatty acid (SCFA) metabolites, which are reduced by microbiome knockdown, reversed the behavioral and transcriptional effects of microbiome depletion. This identifies SCFA as the crucial mediators of microbiome-brain communication responsible for the effects on morphine reward caused by microbiome knockdown. These studies add important new behavioral, molecular, and mechanistic insight to the role of gut-brain signaling in substance use disorders.

Electrophysiological dysfunction induced by anti-ribosomal P protein antibodies injection into the lateral ventricle of the rat brain

Objective Anti-ribosomal P antibodies (anti-P) are strongly associated with neuropsychiatric lupus. This study was designed to determine whether these antibodies are capable of causing electro-oscillogram (EOSG) and behavior alterations in rats. Methods IgG fraction anti-P positive and affinity-purified anti-P antibodies were injected intraventricularly in rats. Sequential cortical and subcortical EOSGs were analyzed during 30 days. IgG anti-Ro/SS-A and normal IgG were used as controls. Results All 13 animals injected with IgG anti-P demonstrated a high prevalence of polyspikes, diffusely distributed in hippocampal fields and cerebral cortex. These abnormalities persisted approximately a month. Remarkably, an identical electrical disturbance was observed with the inoculation of affinity-purified anti-P antibodies. The EOSG alterations were associated with behavioral disorders with varying degrees of severity in every animal injected with anti-P. In contrast, no changes in EOSG or behavioral disturbances were observed in the control group. Conclusion Our study indicates that anti-P antibodies can directly induce electrophysiological dysfunction in central nervous system particularly in hippocampus and cortex associated with behavior disturbances.