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The disruption of brain energy metabolism, leading to alterations in synaptic signaling, neural circuitry, and neuroplasticity, has been implicated in severe mental illnesses such as schizophrenia, bipolar disorder, and major depressive disorder. The therapeutic potential of ketogenic interventions in these disorders suggests a link between metabolic disturbances and disease pathology; however, the precise mechanisms underlying these metabolic disturbances, and the therapeutic effects of metabolic ketogenic therapy, remain poorly understood. In this study, we conducted an in silico analysis of transcriptomic data to investigate perturbations in metabolic pathways in the brain across severe mental illnesses via gene expression profiling. We also examined dysregulation of the same pathways in rodent or cell culture models of ketosis, comparing these expression profiles to those observed in the disease states. Our analysis revealed significant perturbations across all metabolic pathways, with the greatest perturbations in glycolysis, the tricarboxylic acid (TCA) cycle, and the electron transport chain (ETC) across all three disorders. Additionally, we observed some discordant gene expression patterns between disease states and ketogenic intervention studies, suggesting a potential role for ketone bodies in modulating pathogenic metabolic changes. Our findings highlight the importance of understanding metabolic dysregulation in severe mental illnesses and the potential therapeutic benefits of ketogenic interventions in restoring metabolic homeostasis. This study provides insights into the complex relationship between metabolism and neuropsychiatric disorders and lays the foundation for further experimental investigations aimed at appreciating the implications of the present transcriptomic findings as well as developing targeted therapeutic strategies.

BACKGROUND: Impulse control disorders (ICDs) are known psychiatric conditions in Parkinson\'s disease (PD), especially as a side effect of antiparkinsonian therapy. Screening for vulnerable patients and avoiding high-risk treatments can be an effective approach to reduce the ICD burden in patients with PD. Thus, our goal was to identify risk factors for ICDs in PD in the Swedish total population.
METHODS: Our longitudinal study was based on records of all patients with PD in the Swedish National Patient Registries and the Prescribed Drug Register (n=55 235). Patients with incident gambling disorder and other ICDs were compared with a control group on demographic factors, psychiatric comorbidity, antiparkinsonian dopaminergic treatment and therapies for advanced disease. Potential risk factors were analysed using logistic regressions and relative frequency comparisons (Fisher\'s exact test).
RESULTS: Main predictors for incident gambling disorder were treatment with dopamine agonists (Frequency ratio 1.4, p=0.058), monoamine oxidase B (MAO-B) inhibitors (Frequency ratio 1.8, p=0.006) and a prescription for drugs used in addictive disorders (OR 5.85, 95% CI 2.00 to 17.10). Main predictors for other ICDs were dopamine agonist treatment (frequency ratio 1.6, p=0.003), anxiety disorders (OR 7.04, 95% CI 2.96 to 16.71) and substance use disorders other than alcohol (OR 5.66, 95% CI 1.75 to 18.23).
CONCLUSIONS: Our results support possible risk factors for incident ICDs that had previously been identified, like dopamine agonist treatment and raise additional attention for risk factors like MAO-B inhibitor treatment and specific psychiatric comorbidities. These findings enable tailoring antiparkinsonian therapy to individual patient-specific risk profiles.

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Activity-dependent modulations of N-methyl-D-aspartate glutamate receptor (NMDAR) trapping at synapses regulate excitatory neurotransmission and shape cognitive functions. Although NMDAR synaptic destabilization has been associated with severe neurological and psychiatric conditions, tuning NMDAR synaptic trapping to assess its clinical relevance for the treatment of brain conditions remains a challenge. Here, we report that ketamine (KET) and other clinically relevant NMDAR open channel blockers (OCBs) promote interactions between NMDAR and PDZ-domain-containing scaffolding proteins and enhance NMDAR trapping at synapses. We further show that KET-elicited trapping enhancement compensates for depletion in synaptic receptors triggered by autoantibodies from patients with anti-NMDAR encephalitis. Preventing synaptic depletion mitigates impairments in NMDAR-mediated CaMKII signaling and alleviates anxiety- and sensorimotor-gating-related behavioral deficits provoked by autoantibodies. Altogether, these findings reveal an unexpected dimension of OCB action and stress the potential of targeting receptor anchoring in NMDAR-related synaptopathies.

Biallelic (autosomal recessive) pathogenic variants in ATP13A2 cause a form of juvenile-onset parkinsonism, termed Kufor-Rakeb syndrome. In addition to motor symptoms, a variety of other neurological and psychiatric symptoms may occur in affected individuals, including supranuclear gaze palsy and cognitive decline. Although psychotic symptoms are often reported, response to antipsychotic therapy is not well described in previous case reports/series. As such, we describe treatment response in an individual with Kufor-Rakeb syndrome-associated psychosis. His disease was caused by a homozygous novel loss-of-function ATP13A2 variant (NM_022089.4, c.1970_1975del) that was characterized in this study. Our patient exhibited a good response to quetiapine monotherapy, which he has so far tolerated well. We also reviewed the literature and summarized all previous descriptions of antipsychotic treatment response. Although its use has infrequently been described in Kufor-Rakeb syndrome, quetiapine is commonly used in other degenerative parkinsonian disorders, given its lower propensity to cause extrapyramidal symptoms. As such, quetiapine should be considered in the treatment of Kufor-Rakeb syndrome-associated psychosis when antipsychotic therapy is deemed necessary.

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Dementia limits timely revascularization in individuals with acute myocardial infarction (AMI). However, it remains unclear whether dementia affects prognosis negatively in older individuals with AMI in the intensive care unit (ICU). This research aimed to evaluate the dementia effect on the outcomes in individuals with AMI in ICU.Data from 3,582 patients aged ≥ 65 years with AMI in ICU from the Medical Information Mart for Intensive Care IV (MIMIC IV) database were evaluated. The independent variable was dementia at baseline, and the primary finding was death from any cause during follow-up. A 1:1 propensity score matching (PSM) showed 208 participants with and without dementia. The correlation between dementia and poor prognosis of AMI was verified using a double-robust estimation method.In the PSM cohort, the 30-day all-cause mortality was 37.50% and 33.17% in the dementia and non-dementia groups (P = 0.356), respectively, and the 1-year all-cause mortality was 61.06% and 51.44%, respectively (P = 0.048). Cox regression analysis showed no association between dementia and elevated 30-day (hazard ratio [HR] 1.15, 95% confidence interval [CI] 0.84, 1.60) and 1-year (HR 1.28, 95% CI 0.99, 1.66) all-cause mortality after AMI. Similarly, dementia was not connected with in-hospital mortality, bleeding, or stroke after AMI. Interaction analysis showed that 1-year all-cause mortality was 48.00% higher in individuals with dementia and diabetic complications than in those without diabetic complications.Dementia is not an independent risk factor for adverse outcomes in AMI. Thus, it may be inappropriate to include dementia as a contraindication for invasive AMI therapy.

BACKGROUND: Hereditary transthyretin amyloidosis, caused by transthyretin gene mutations, progresses with systemic impact and often presents peripheral neuropathy. Recent research reveals central nervous system involvement, marked by leptomeningeal amyloid accumulation and transient focal neurological episodes displaying cortical dysfunction.
METHODS: A 47-year-old Caucasian man with hereditary transthyretin amyloidosis presented with motor aphasia, right hemiparesis, fever, and an altered state of consciousness. Tests ruled out stroke or infection. While improving, the patient reported an ongoing auditory repetition phenomenon for 48 hours despite efforts to shift focus or introduce new stimuli.
CONCLUSIONS: This represents the first known case report documenting palinacousis in hereditary transthyretin amyloidosis attributed to central nervous system involvement. This case highlights the complexities in assessment and management of patients when neurological and psychiatric symptoms overlap.

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