Intertwined depressive and cognitive trajectories and the risk of dementia and death in older adults: a competing risk analysis.

Background: Depressive symptoms and cognitive impairment often interact, rendering their associations controversial. To date, their joint trajectories and associations with dementia and death remain underexplored. Aims: To explore the interactions between depressive symptoms and cognitive function, their developmental trajectories and the associations with all-cause dementia, Alzheimer's disease (AD) and all-cause death in older adults. Methods: Data were from the Health and Retirement Study. Depressive symptoms and cognitive function were measured using the 8-item Centre for Epidemiologic Studies Depression Scale and the Telephone Interview of Cognitive Status, respectively. All-cause dementia and AD were defined by self-reported or proxy-reported physician diagnoses. All-cause death was determined by interviews. The restricted cubic spline, group-based trajectory modelling and subdistribution hazard regression were used. Results: Significant interactions between depressive symptoms and cognitive function in 2010 in their association with new-onset all-cause dementia and AD from 2010 to 2020 were found, especially in women (p for interaction <0.05). Independent trajectory analysis showed that emerging or high (vs no) depressive trajectories and poor or rapidly decreased cognitive trajectories (vs very good) from 1996 to 2010 were at significantly higher risk of subsequent all-cause dementia, AD and all-cause death. 15 joint trajectories of depressive symptoms and cognitive function from 1996 to 2010 were determined, where rapidly decreased cognitive function was more common in those with no depressive symptoms. Compared with older adults with the trajectory of no depressive symptoms and very good cognitive function, those with the trajectory of no depressive symptoms but rapidly decreased cognitive function were much more likely to develop new-onset all-cause dementia and death, with subdistribution hazard ratios (95% confidence intervals) of 4.47 (2.99 to 6.67) and 1.84 (1.43 to 2.36), especially in women. Conclusions: To effectively mitigate the risk of dementia and death, it is crucial to acknowledge the importance of preventing cognitive decline in older adults without depressive symptoms, particularly in women.

Neuroanatomical and prognostic associations of depression in Parkinson's disease.

BACKGROUND: Depression is reported as a risk factor, prodromal feature and late consequence of Parkinson's disease (PD). We aimed to evaluate the timing, neuroanatomy and prognostic implications of depression in PD. METHODS: We used data from 434 023 participants from UK Biobank with 14.1 years of follow-up. Multivariable regression models established associations of depression with incident PD and regional brain volumes. Cox proportional hazards models assessed prognostic associations of depression in PD with incident dementia and all-cause mortality. RESULTS: Of 2632 individuals with incident PD, 539 (20.5%) were diagnosed with depression at some point. Depression was associated with an increased risk of subsequent PD (risk ratio 1.53, 95% CI 1.37 to 1.72). Among incident PD cases, depression prevalence rose progressively from 10 years pre-PD diagnosis (OR 2.10, 95% CI 1.57 to 2.83) to 10 years postdiagnosis (OR 3.51, 95% CI 1.33 to 9.22). Depression severity in PD was associated with reduced grey matter volume in structures including the thalamus and amygdala. Depression prior to PD diagnosis increased risk of dementia (HR 1.47, 95% CI 1.05 to 2.07) and mortality (HR 1.30, 95% CI 1.07 to 1.58). CONCLUSIONS: This large-scale prospective study demonstrated that depression prevalence increases from 10 years before PD diagnosis and is a marker of cortical and subcortical volume loss. Depression before PD diagnosis signals a worse prognosis in terms of dementia and mortality. This has clinical implications in stratifying people with poorer cognitive and prognostic trajectory in PD.

Cerebrospinal fluid amyloid-ß and cerebral microbleed are associated with distinct neuropsychiatric sub-syndromes in cognitively impaired patients.

BACKGROUND: Neuropsychiatric symptoms (NPS) are prevalent in cognitively impaired individuals including Alzheimer's disease (AD) dementia and mild cognitive impairment (MCI). Whereas several studies have reported the associations between NPS with AD pathologic biomarkers and cerebral small vessel disease (SVD), but it remains unknown whether AD pathology and SVD contribute to different sub-syndromes independently or aggravate same symptoms synergistically. METHOD: We included 445 cognitively impaired individuals (including 316 MCI and 129 AD) with neuropsychiatric, cerebrospinal fluid (CSF) biomarkers (Aß42, p-tau, and t-tau) and multi-model MRI data. Psychiatric symptoms were accessed by using the Neuropsychiatric Inventory (NPI). Visual assessment of SVD (white matter hyperintensity, microbleed, perivascular space, lacune) on MRI images was performed by experienced radiologist. Linear regression analyses were conducted to test the association between neuropsychiatric symptoms with AD pathology and CSVD burden after adjustment for age, sex, education, apolipoprotein E (APOE) ε4 carrier status, and clinical diagnosis. RESULTS: The NPI total scores were related to microbleed (estimate 2.424; 95% CI [0.749, 4.099]; P =0.005). Considering the sub-syndromes, the hyperactivity was associated with microbleed (estimate 0.925; 95% CI [0.115, 1.735]; P =0.025), whereas the affective symptoms were correlated to CSF level of Aß42 (estimate -0.006; 95% CI [-0.011, -0.002]; P =0.005). Furthermore, we found the apathy sub-syndrome was associated with CSF t-tau/Aß42 (estimate 0.636; 95% CI [0.078, 1.194]; P =0.041) and microbleed (estimate 0.693; 95% CI [0.046, 1.340]; P =0.036). In addition, we found a significant interactive effect between CSF t-tau/Aß42 and microbleed (estimate 0.993; 95% CI [0.360, 1.626]; P =0.019) on severity of apathy sub-syndrome. CONCLUSION: Our study showed that CSF Aß42 was associated with affective symptoms, but microbleed was correlated with hyperactivity and apathy, suggesting the effect of AD pathology and SVD on different neuropsychiatric sub-syndromes.

Adolescent patient with post traumatic stress disorder due atypical stressor: Case report.

INTRODUCTION: Post-traumatic stress disorder (PTSD) is characterised by intrusive, anxious, and avoidant symptoms that are triggered after a stressful experience and affect the mood. The definition of a stressor that generates PTSD has been debated in recent years, as a clinical picture compatible with the disorder can occur after exposure to stressors that do not meet the criteria A1 of the DSM V; these stressors have been defined in the literature as "of low magnitude, uncommon, unusual or atypical". CLINICAL CASE: We present the clinical case of a paediatric patient who developed PTSD after being exposed to an atypical stressor. CONCLUSIONS: The literature shows these stressors to be more frequently documented in the paediatric population. We therefore suggest that cases should be analysed as a complex interweaving of variables, where one of the most important is each patient's interpretation of the event according to their life history and social context, and not because of an inherent characteristic of the stressor itself.

Increased apathy post-interstitial laser capsulotomy for refractory obsessive-compulsive disorder.

BACKGROUND: MRI guided laser interstitial thermal therapy (M-LITT) capsulotomy has proven to be efficacious in decreasing refractory obsessive-compulsive disorder (OCD) related symptomatology yet capsulotomy either via radiosurgery or radiofrequency ablation has in some patients led to increased apathy following surgery. The current case series aims to investigate objective patient-reported change in apathy, disinhibition, depression, and executive dysfunction following anterior capsulotomy via M-LITT for OCD. METHODS: Ten consecutive patients pre- and post-M-LITT completed measures of OCD, apathy, disinhibition, executive dysfunction, and depression (Mtime between = 1.3 years; 0.42-3.7 years). Reliable Change Index (RCI) was used to evaluate change in pre- and post-M-LITT. OCD symptom response was evaluated using percent change (Y-BOCS scores: 24-34 % reduction indicating partial response; ≥35% reduction indicating full response). RESULTS: Positive post-surgical change was noted in OCD symptomatology with >65% reporting a partial or full response. However, six patients endorsed increased apathy with half of the non-responders (e.g., less than <24% score reduction on Y-BOCS) reporting increases in apathy. Patients reported relatively stable disinhibition and executive dysfunction, while over half reported a decrease in depression symptoms. Two of the non-responders and one responder endorsed increased apathy despite stable or improved depression symptoms, disinhibition, and executive dysfunction. CONCLUSIONS: Most patients in the current cohort achieved full-or-partial OCD recovery. Yet, 60% of patients also reported significant increases in apathy, despite experiencing a decrease in depression symptoms, with stable disinhibition and executive dysfunction. Despite these promising improvements in OCD symptomatology following M-LITT, further investigations of the impact of surgery and lesion location on apathy levels is clearly warranted using objective, quantifiable methods.

Anxiety and school avoidance in an 8-year-old child with epilepsy.

Anxiety is ubiquitous in school age children. Co-occurring medical illness adds to the complexity of identifying pathologic anxiety as opposed to that of typical development such as with social interactions or academic pressures. Anxiety may also occur in the context of cognitive difficulties or inattention, both of which may be exacerbated by epilepsy or by anti-seizure medicines themselves. Treatment strategies may require patience and long-term observations to account for the typical range of stressors that may be expected with disease progression or with development through childhood. This section illustrates the challenge of diagnosis and management of anxiety in the context of epilepsy in a school aged child and addresses nuances that neurology clinicians need to consider. Practical strategies for management including stepwise options for pharmacologic treatment will be emphasized.

Resolution of severe neurobehavioral difficulties in an individual with Primrose syndrome with sertraline.

Primrose syndrome (PS) is a rare genetic disease characterized by developmental delay, intellectual disability, sensorineural hearing loss, and dysmorphic features. PS is caused by de novo pathogenic variants in the ZBTB20 gene, which encodes a transcription factor modulating neurogenesis. We describe resolution with sertraline of neurobehavioral difficulties in a 17-year-old Hispanic male with PS with de novo heterozygous c.1916G > A (p.C639Y) variant of ZBTB20. Neurobehavioral difficulties included aggression towards self and others, irritability, tearfulness, and mood liability that did not respond to behavioral interventions or aripiprazole. Treatment with sertraline, a medication indicated for psychiatric disorders including anxiety and depression, led to the resolution of neurobehavioral difficulties after 2 weeks of initiation of medication. The treatment course suggests that selective serotonin reuptake inhibitors, such as sertraline, may be a useful tool for neurobehavioral difficulties in PS over antipsychotics that are accompanied by complex side effect profiles, and suggest that anxiety is the primary cause of the neurobehavioral difficulties in this patient.

Steroid-induced mania in a patient with previously well-controlled organic bipolar 1-like affective disorder secondary to acquired brain injury: case report and literature review.

Steroid-induced neuropsychiatric sequelae are common, and pose significant risks to people usually receiving glucocorticoids in the context of physical illness. Steroid-induced mania and hypomania are the most common of the acute complications, yet despite great progress in understandings in neurophysiology there are no recent studies which review the factors which might predict who will experience this severe complication, nor are there consensus guidelines on management. We report the unusual case of a woman in her 50s admitted to a psychiatric unit with steroid-induced mania despite compliance with two mood stabilisers, several days after the administration of a Dexamethasone and Docetaxel chemotherapy regime adjunctive to lumpectomy for breast cancer. She had previously been diagnosed with an organic affective disorder (with classical bipolar 1 pattern) following severe ventriculitis related to ventricular drain insertion for obstructive hydrocephalus secondary to a colloid cyst. She had no psychiatric illness before this brain injury, but has a maternal history of idiopathic bipolar 1 affective disorder. Her episode of steroid-induced mania resolved following use of sedative medications, continuation of her existing mood stabilisers, and reductions of the steroid dosing in collaboration with her oncology team, which also protected her from further manic relapses during continued chemotherapy. Established mental illness, a family history, and acquired brain injury may reflect risk factors for steroid-induced mania through currently unclear pathways. Future epidemiological studies could better confirm these observations, and basic neuroscience may look to further explore the role of extrinsic glucocorticoids in the pathophysiology of affective disorders.

The Impact of C-3 Side Chain Modifications on Kynurenic Acid: A Behavioral Analysis of Its Analogs in the Motor Domain.

The central nervous system (CNS) is the final frontier in drug delivery because of the blood-brain barrier (BBB), which poses significant barriers to the access of most drugs to their targets. Kynurenic acid (KYNA), a tryptophan (Trp) metabolite, plays an important role in behavioral functions, and abnormal KYNA levels have been observed in neuropsychiatric conditions. The current challenge lies in delivering KYNA to the CNS owing to its polar side chain. Recently, C-3 side chain-modified KYNA analogs have been shown to cross the BBB; however, it is unclear whether they retain the biological functions of the parent molecule. This study examined the impact of KYNA analogs, specifically, SZR-72, SZR-104, and the newly developed SZRG-21, on behavior. The analogs were administered intracerebroventricularly (i.c.v.), and their effects on the motor domain were compared with those of KYNA. Specifically, open-field (OF) and rotarod (RR) tests were employed to assess motor activity and skills. SZR-104 increased horizontal exploratory activity in the OF test at a dose of 0.04 µmol/4 µL, while SZR-72 decreased vertical activity at doses of 0.04 and 0.1 µmol/4 µL. In the RR test, however, neither KYNA nor its analogs showed any significant differences in motor skills at either dose. Side chain modification affects affective motor performance and exploratory behavior, as the results show for the first time. In this study, we showed that KYNA analogs alter emotional components such as motor-associated curiosity and emotions. Consequently, drug design necessitates the development of precise strategies to traverse the BBB while paying close attention to modifications in their effects on behavior.

Post-stroke emotionalism: Diagnosis, pathophysiology, and treatment.

BACKGROUND: Post-stroke emotionalism affects one in five stroke sufferers 6 months after their stroke, but despite its frequency remains a poorly understood stroke symptom. The literature is limited, especially compared to other frequently observed neurological conditions such as aphasia and visual neglect. AIM AND METHODS: This narrative review presents a summary of the post-stroke emotionalism literature, to inform clinical practice and future research. We cover discussion of definitions, prevalence, neurobiology, predisposing and precipitating factors, and treatment. RESULTS: Increasing evidence suggests that damage to specific areas functionally linked to emotion expression or regulation processes, disruption to structural pathways and those related to serotonin production and modulation individually or in concert give rise to emotionalism-type presentations. A range of emotionalism measurement tools have been used in research contexts making between study comparisons difficult. Testing for Emotionalism after Recent Stroke-Questionnaire (TEARS-Q) has recently been developed to allow standardized assessment. Treatment options are limited, and there have been few adequately powered treatment trials. Antidepressants may reduce severity, but more trial data are required. There have been no randomized-controlled trials of non-pharmacological interventions. CONCLUSIONS: More research is needed to improve recognition and treatment of this common and disabling symptom. We conclude with research priorities and recommendations for the field.

Exploring Brain and Heart Interactions during Electroconvulsive Therapy with Point-of-Care Ultrasound.

BACKGROUND: Electroconvulsive therapy (ECT) is a procedure commonly used to treat a number of severe psychiatric disorders, including pharmacologic refractory depression, mania, and catatonia by purposefully inducing a generalized seizure that results in significant hemodynamic changes as a result of an initial transient parasympathetic response that is followed by a marked sympathetic response from a surge in catecholamine release. While the physiologic response of ECT on classic hemodynamic parameters such as heart rate and blood pressure has been described in the literature, real-time visualization of cardiac function using point-of-care ultrasound (POCUS) during ECT has never been reported. This study utilizes POCUS to examine cardiac function in two patients with different ages and cardiovascular risk profiles undergoing ECT. METHODS: Two patients, a 74-year-old male with significant cardiovascular risks and a 23-year-old female with no significant cardiovascular risks presenting for ECT treatment, were included in this study. A portable ultrasound device was used to obtain apical four-chamber images of the heart before ECT stimulation, after seizure induction, and 2 min after seizure resolution to assess qualitative cardiac function. Two physicians with expertise in echocardiography reviewed the studies. Hemodynamic parameters, ECT settings, and seizure duration were recorded. RESULTS: Cardiac standstill was observed in both patients during ECT stimulation. The 74-year-old patient with a significant cardiovascular risk profile exhibited a transient decline in cardiac function during ECT, while the 23-year-old patient showed no substantial worsening of cardiac function. These findings suggest that age and pre-existing cardiovascular conditions may influence the cardiac response to ECT. Other potential contributing factors to the cardiac effects of ECT include the parasympathetic and sympathetic responses, medication regimen, and seizure duration with ECT. This study also demonstrates the feasibility of using portable POCUS for real-time cardiac monitoring during ECT. CONCLUSION: This study reports for the first time cardiac standstill during ECT stimulation visualized using POCUS imaging. In addition, it reports on the potential differential impact of ECT on cardiac function based on patient-specific factors such as age and cardiovascular risks that may have implications for ECT and perioperative anesthetic management and optimization.

Catatonia: A deep dive into its unfathomable depths.

This editorial addresses catatonia, a complex neuropsychiatric syndrome characterised by a spectrum of psychomotor disturbances. The editorial seeks to clarify the ambiguous aspects of catatonia, integrating recent research findings, including global studies and diagnostic advancements. It discusses catatonia's clinical manifestations, prevalence, and associated psychiatric and medical conditions, with particular emphasis on its frequent co-occurrence with schizophrenia and mood disorders. The prevalence of catatonia, which varies across psychiatric populations, is illustrated by a significant study conducted in Nelson Mandela Bay, South Africa. This study provides valuable insights into the effectiveness of the Bush-Francis Screening Instrument compared to the Diagnostic and Statistical Manual 5 criteria in diagnosing catatonia. The editorial evaluates treatment approaches, primarily focusing on benzodiazepines and electroconvulsive therapy, and discusses emerging therapeutic strategies. It underscores the importance of robust diagnostic frameworks and early intervention in managing catatonia, as recommended by the latest evidence-based consensus guideline. Furthermore, it suggests future research directions, particularly in exploring the neurobiological and genetic factors of catatonia, to enhance our understanding and improve treatment outcomes. This editorial succinctly aims to demystify catatonia and provide valuable insights for clinicians and researchers in mental health care.

Experiencia Del Abordaje Multidisciplinar Aplicado En El Hospital De Día De Neuropsiquiatría Del Hospital Mare De Déu De La Mercè (Años 2015 A 2022) / [Experience of the Multidisciplinary Approach Applied in the Neuropsychiatry Day Hospital of the Mare De Déu Hospital of La Mercè (Years 2015 to 2022)]

Introducción: El hospital de día de Neuropsiquiatría del Hospital Mare de Déu de la Mercè es un recurso sanitario especializado suprasectorial de régimen diurno, que atiende a personas adultas entre los 18 y 65 años de edad, con deterioro cognitivo debido a un daño cerebral sobrevenido, a uso de sustancias, enfermedad de Huntington o demencias neurodegenerativas de inicio precoz. La duración del ingreso es de 90 días y el objetivo principal es rehabilitador. Las terapias impartidas incluyen estimulación cognitiva, manejo de agenda, adaptación al déficit, manejo de la autonomía, terapia física e inclusión social. El objetivo del manuscrito es presentar la experiencia del abordaje multidisciplinar aplicado durante los años 2015 a 2022, y describir su capacidad resolutiva, entendiéndola como la capacidad para mejorar las habilidades cognitivas, la conducta, el equilibrio físico y la funcionalidad de las personas atendidas.Métodos: La información ha sido obtenida a partir de las valoraciones realizadas según los protocolos de evaluación multidisciplinar del hospital. Se ha realizado una estadística descriptiva y se ha utilizado la prueba t para medias de dos muestras emparejadas para evaluar diferencias significativas entre las valoraciones al ingreso y al alta. La muestra es de 435 personas, con una media de edad de 51.54 años, de las cuales 185 (42.53%) son mujeres. Como instrumentos de medida se han utilizado pruebas de despistaje cognitivo, de evaluación de la conducta, de equilibrio y funcionalidad, y un cuestionario de calidad de vida. Resultados: Se incluyeron un total de 435 personas con los siguientes perfiles diagnósticos: daño cerebral sobrevenido (n = 199), deterioro cognitivo asociado a uso de sustancias (n = 103), enfermedad de Huntington (n = 41), demencias degenerativas de inicio precoz (n = 32), deterioro cognitivo asociado al VIH (n = 2) y deterioro cognitivo no especificado (n = 58). ... (AU)

Introduction: The Neuropsychiatry day hospital of the Mare de Déu de la Mercè Hospital is a specialized suprasectorial daytime health resource, which cares for adults between 18 and 65 years of age, with cognitive impairment due to acquired brain damage, substance use, Huntington's disease, and early-onset neurodegenerative dementias. The duration of admission is 90 days and the main objective is rehabilitation. The therapies provided include cognitive stimulation, agenda management, deficit adaptation, autonomy management, physical therapy and social inclusion. The objective of the manuscript is to present the experience of the multidisciplinary approach applied during the years 2015 to 2022, and describe its resolution capacity, understanding it as the ability to improve the cognitive skills, behavior, physical balance and functionality of the people cared for.Methods: The information has been obtained from the assessments carried out according to the hospital's multidisciplinary evaluation protocols. Descriptive statistics were performed and the t test for means of two paired samples was used to evaluate significant differences between the assessments at admission and at discharge. The sample consists of 435 people, with an average age of 51.54 years, of which 185 (42.53%) were women. Cognitive screening tests, behavioral assessment tests, balance and functionality tests, and a quality of life questionnaire have been used as measurement instruments. Results: A total of 435 people were included with the following diagnostic profiles: acquired brain damage (n = 199), cognitive impairment associated with substance use (n = 103), Huntington's disease (n = 41), early-onset degenerative dementias (n = 32), HIV-associated cognitive impairment (n = 2) and unspecified cognitive impairment (n = 58). ... (AU)

Brain function in classic galactosemia, a galactosemia network (GalNet) members review.

Classic galactosemia (CG, OMIM #230400, ORPHA: 79,239) is a hereditary disorder of galactose metabolism that, despite treatment with galactose restriction, affects brain function in 85% of the patients. Problems with cognitive function, neuropsychological/social emotional difficulties, neurological symptoms, and abnormalities in neuroimaging and electrophysiological assessments are frequently reported in this group of patients, with an enormous individual variability. In this review, we describe the role of impaired galactose metabolism on brain dysfunction based on state of the art knowledge. Several proposed disease mechanisms are discussed, as well as the time of damage and potential treatment options. Furthermore, we combine data from longitudinal, cross-sectional and retrospective studies with the observations of specialist teams treating this disease to depict the brain disease course over time. Based on current data and insights, the majority of patients do not exhibit cognitive decline. A subset of patients, often with early onset cerebral and cerebellar volume loss, can nevertheless experience neurological worsening. While a large number of patients with CG suffer from anxiety and depression, the increased complaints about memory loss, anxiety and depression at an older age are likely multifactorial in origin.

Anatomical correlates of apathy and impulsivity co-occurrence in early Parkinson's disease.

BACKGROUND: Although apathy and impulse control disorders (ICDs) are considered to represent opposite extremes of a continuum of motivated behavior (i.e., hypo- and hyperdopaminergic behaviors), they may also co-occur in Parkinson's disease (PD). OBJECTIVES: We aimed to explore the co-occurrence of ICDs and apathy and its neural correlates analyzing gray matter (GM) changes in early untreated PD patients. Moreover, we aimed to investigate the possible longitudinal relationship between ICDs and apathy and their putative impact on cognition during the first five years of PD. METHODS: We used the Parkinson's Progression Markers Initiative (PPMI) database to identify the co-occurrence of apathy and ICDs in 423 early drug-naïve PD patients at baseline and at 5-year follow-up. Baseline MRI volumes and gray matter changes were analyzed between groups using voxel-based morphometry. Multi-level models assessed the longitudinal relationship (across five years) between apathy and ICDs and cognitive functioning. RESULTS: At baseline, co-occurrence of apathy and ICDs was observed in 23 patients (5.4%). This finding was related to anatomical GM reduction along the cortical regions involved in the limbic circuit and cognitive control systems. Longitudinal analyses indicated that apathy and ICDs were related to each other as well as to the combined use of levodopa and dopamine agonists. Worse apathetic and ICDs states were associated with poorer executive functions. CONCLUSIONS: Apathy and ICDs are joint non-exclusive neuropsychiatric disorders also in the early stages of PD and their co-occurrence was associated with GM decrease in several cortical regions of the limbic circuit and cognitive control systems.

Psychiatric manifestations of neurosyphilis over past two decades: Findings from a tertiary care neuropsychiatric hospital in south India.

OBJECTIVE: To assess presentation of neurosyphilis with a focus on the psychiatric aspects. METHOD: File review of the cases with a positive cerebrospinal fluid venereal disease research laboratory test between 1999 to 2020. RESULTS: Medical records of 143 neurosyphilis patients were analysed. Hallucinations, delusions, and catatonia were the commonest psychiatric symptoms. Brain atrophy was the commonest neuroimaging finding. The number of neurosyphilis patients and the proportion with delirium or catatonia declined during the second decade (2010-2020). CONCLUSION: Atypical presentation of psychiatric symptoms around the fifth decade, with associated neurological symptoms or brain imaging changes, should prompt evaluation for neurosyphilis.

The impact of psychiatric comorbidity on Parkinson's disease outcomes: a systematic review and meta-analysis.

Background: The burden of psychiatric symptoms in Parkinson's disease includes depression, anxiety, apathy, psychosis, and impulse control disorders. However, the relationship between psychiatric comorbidities and subsequent prognosis and neurological outcomes is not yet well understood. In this systematic review and meta-analysis, in individuals with Parkinson's disease, we aimed to characterise the association between specific psychiatric comorbidities and subsequent prognosis and neurological outcomes: cognitive impairment, death, disability, disease progression, falls or fractures and care home admission. Methods: We searched MEDLINE, Embase, PsycINFO and AMED up to 13th November 2023 for longitudinal observational studies which measured disease outcomes in people with Parkinson's disease, with and without specific psychiatric comorbidities, and a minimum of two authors extracted summary data. Studies of individuals with other parkinsonian conditions and those with outcome measures that had high overlap with psychiatric symptoms were excluded to ensure face validity. For each exposure-outcome pair, a random-effects meta-analysis was conducted based on standardised mean difference, using adjusted effect sizes-where available-in preference to unadjusted effect sizes. Study quality was assessed using the Newcastle-Ottawa Scale. Between-study heterogeneity was assessed using the I2 statistic and publication bias was assessed using funnel plots. PROSPERO Study registration number: CRD42022373072. Findings: There were 55 eligible studies for inclusion in meta-analysis (n = 165,828). Data on participants' sex was available for 164,514, of whom 99,182 (60.3%) were male and 65,460 (39.7%) female. Study quality was mostly high (84%). Significant positive associations were found between psychosis and cognitive impairment (standardised mean difference [SMD] 0.44, [95% confidence interval [CI] 0.23-0.66], I2 30.9), psychosis and disease progression (SMD 0.46, [95% CI 0.12-0.80], I2 70.3%), depression and cognitive impairment (SMD 0.37 [95% CI 0.10-0.65], I2 27.1%), depression and disease progression (SMD 0.46 [95% CI 0.18-0.74], I2 52.2), depression and disability (SMD 0.42 [95% CI 0.25-0.60], I2 7.9%), and apathy and cognitive impairment (SMD 0.60 [95% CI 0.02-1.19], I2 27.9%). Between-study heterogeneity was moderately high. Interpretation: Psychosis, depression, and apathy in Parkinson's disease are all associated with at least one adverse outcome, including cognitive impairment, disease progression and disability. Whether this relationship is causal is not clear, but the mechanisms underlying these associations require exploration. Clinicians should consider these psychiatric comorbidities to be markers of a poorer prognosis in people with Parkinson's disease. Future studies should investigate the underlying mechanisms and which treatments for these comorbidities may affect Parkinson's disease outcomes. Funding: Wellcome Trust, UK National Institute for Health Research (NIHR), National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust and King's College London, National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at University College London Hospitals NHS Foundation Trust, National Brain Appeal.