OBJECTIVE: The \"early intervention\" paradigm in psychiatry holds significant promise for preventing psychosis. Recent evidence showed that individuals at clinical high risk for psychosis (CHR-P) with antipsychotic (AP) prescription at baseline have higher psychosis transition rates compared with those without AP, although the underlying cause remains unclear. In this article, we reviewed international guidelines on early intervention in CHR-P people, paying specific attention to clinical recommendations on AP treatment. Then, we comment on these suggestions in the light of recent empirical evidence examining AP prescription in CHR-P populations within \"real-world\" clinical settings.
METHODS: This search was conducted on PubMed/MEDLINE, PsycINFO, EMBASE, and Google, looking for both \"Guidelines AND CHR-P OR UHR OR Early Psychosis.\"
RESULTS: International guidelines generally recommend not using AP as first-line treatment, but only when psychosocial interventions have failed. CHR-P people with AP drug showed high prevalence rates and had more severe clinical picture at entry. Is this a \"warning signal\" for potentially higher psychosis transition risk? Is it a direct AP iatrogenic effect? Is it possible to detect specific CHR-P subgroup that may benefit from AP? These are the questions that this article seeks to explore.
CONCLUSIONS: The current framework for identifying CHR-P subjects has defined psychometric criteria mainly based on positive symptoms. In our opinion, this is reductive, especially for evaluating therapeutic outcomes and prognosis. A more comprehensive assessment considering quality of life, psychiatric comorbidity, persistent negative symptoms, subjective experience of CHR-P psychopathology, and social/personal recovery is thus needed.

BACKGROUND: Increasing evidence suggests that impairments of spatial navigation, orientation and memory may represent one of the earliest features Alzheimer\'s disease (AD), preceding deficits in other cognitive domains. This is consistent with early pathological tau and amyloid deposition in temporal and parietal brain regions implicated in spatial processing. However, it remains unclear which metrics and spatial behaviours can i) differentiate high-risk, preclinical or prodromal AD individuals, and ii) may be captured with digital devices suitable for future deployment at scale in clinical practice. We addressed this knowledge gap with a systematic review.
METHODS: Two databases (PubMed/Web of Science) were searched following PRISMA guidelines. Medical subheading keywords for different dementia types were combined with prodromal, preclinical and genetic or disorder risk factor terms. We included studies published until October 2022 that collected digital or physical objective measures of egocentric or allocentric processing (wayfinding, orientation, reference frame translation, route learning or path integration). We excluded diagnoses of other conditions or dementia, cross-sectional MCI studies without biomarkers, young adults, case studies, interventional studies or studies without appropriate controls.
RESULTS: 25 articles were included from 316 identified abstracts. None investigated non-AD dementias. 131 metrics were extracted from 38 different tasks, of which 31 where digital (81%). 82 metrics showed differentiation of predementia AD groups (63%). We harmonised these into 21 distinct summary metrics covering four domains of active or passively tracked spatial behaviours. Across all domains, metrics capturing decreased navigation efficiency (i.e. distance or time required to find goals) and accuracy (i.e. distance or angle from goal) were most frequently reported, but egocentric better differentiated prodromal than preclinical groups. Metrics for path integration and passive tracking of everyday GPS data were promising but relatively under-explored.
CONCLUSIONS: For future clinical use, spatial tests will require standardisation and validation against established markers of disease. These review data will inform the selection of digital tools to assess spatial behaviours in at-risk, preclinical and prodromal AD populations as part of the EDoN Initiative.

This opinion piece describes major limitations of using α-synuclein in speculative neuronally enriched for diagnosing or predicting Parkinson\'s disease risk from prodromal conditions such as REM behaviour disorder. It concludes that such an approach is unreliable and recommends that future researchers divert away to more widely accepted approaches such as seed amplification assays.

BACKGROUND: Neurocognitive deficits have been widely reported in clinical high-risk for psychosis (CHR) populations. Additionally, rates of cannabis use are high among CHR youth and are associated with greater symptom severity. Cannabis use has been sometimes shown to be associated with better neurocognition in more progressed psychosis cohorts, therefore in this study we aimed to determine whether a similar pattern was present in CHR.
METHODS: CHR participants ages 12-30 from the North American Prodromal Longitudinal Study (NAPLS-3) (N = 698) were grouped according to: \"minimal to no cannabis use\" (n = 406), \"occasional use\" (n = 127), or \"frequent use\" (n = 165). At baseline, cannabis use groups were compared on neurocognitive tests, clinical, and functional measures. Follow-up analyses were used to model relationships between cannabis use frequency, neurocognition, premorbid, and social functioning.
RESULTS: Occasional cannabis users performed significantly better than other use-groups on measures of IQ, with similar trend-level patterns observed across neurocognitive domains. Occasional cannabis users demonstrated better social, global, and premorbid functioning compared to the other use-groups and less severe symptoms compared to the frequent use group. Follow-up structural equation modeling/path analyses found significant positive associations between premorbid functioning, social functioning, and IQ, which in turn was associated with occasional cannabis use frequency.
CONCLUSIONS: Better premorbid functioning positively predicts both better social functioning and higher IQ which in turn is associated with a moderate cannabis use pattern in CHR, similar to reports in first-episode and chronic psychosis samples. Better premorbid functioning likely represents a protective factor in the CHR population and predicts a better functional outcome.

BACKGROUND: Thalamic abnormalities in schizophrenia are recognized, alongside cognitive deficits. However, the current findings about these abnormalities during the prodromal period remain relatively few and inconsistent. This study applied multimodal methods to explore the alterations in thalamic function and structure and their relationship with cognitive function in first-episode schizophrenia (FES) patients and ultra-high-risk (UHR) individuals, aiming to affirm the thalamus\'s role in schizophrenia development and cognitive deficits.
METHODS: 75 FES patients, 60 UHR individuals, and 60 healthy controls (HC) were recruited. Among the three groups, gray matter volume (GMV) and functional connectivity (FC) were evaluated to reflect the structural and functional abnormalities in the thalamus. Pearson correlation was used to calculate the association between these abnormalities and cognitive impairments.
RESULTS: No significant difference in GMV of the thalamus was found among the abovementioned three groups. Compared with HC individuals, FES patients had decreased thalamocortical FC mostly in the thalamocortical triple network, including the default mode network (DMN), salience network (SN), and executive control network (ECN). UHR individuals had similar but milder dysconnectivity as the FES group. Furthermore, FC between the left thalamus and right putamen was significantly correlated with execution speed and attention in the FES group.
CONCLUSIONS: Our findings revealed decreased thalamocortical FC associated with cognitive deficits in FES and UHR subjects. This improves our understanding of the functional alterations in thalamus in prodromal stage of schizophrenia and the related factors of the cognitive impairment of the disease.
BACKGROUND: ClinicalTrials.govNCT03965598; https://clinicaltrials.gov/ct2/show/NCT03965598.

BACKGROUND: Few studies have assessed whether neuropathological markers of AD in the preclinical and prodromal stages are associated with polysomnographic changes and obstructive sleep apnea (OSA).
METHODS: This was a cross-sectional, case-control study of older adults (≥60 years) without relevant clinical and psychiatric comorbidities selected randomly from a cohort of individuals without dementia in a tertiary university hospital in São Paulo, Brazil. They underwent neuropsychological evaluation for clinical diagnosis and were allocated into two samples: cognitively unimpaired (CU) and mild cognitive impairment (MCI). Also, they underwent PET-PiB to determine the amyloid profile and all-night in-lab polysomnography. For each sample, we compared polysomnographic parameters according to the amyloid profile (A+ vs A-).
RESULTS: We allocated 67 participants (mean age 73 years, SD 10,1), 70 % females, 14 ± 5 years of education, into two samples: CU (n = 28, 42.4 %) and MCI (n = 39, 57.6 %). In the CU sample, the group A+ (n = 9) showed worse sleep parameters than A- (n = 19) (lower total sleep time (p = 0.007), and sleep efficiency (p = 0.005); higher sleep onset latency (p = 0.025), wake time after sleep onset (p = 0.011), and arousal index (AI) (p = 0.007)), and changes in sleep structure: higher %N1 (p = 0.005), and lower %REM (p = 0.006). In the MCI sample, MCI A-had higher AI (p = 0.013), respiratory disturbance index (p = 0.025, controlled for age), and higher rates of severe OSA than A+.
CONCLUSIONS: The amyloid profile was associated with polysomnographic markers of worse sleep quality in individuals with preclinical AD but not with prodromal AD, probably due to the higher frequencies of severe OSA.

BACKGROUND: The existing research has mainly focused on exploring how the duration of untreated psychosis effects the further course of the disease. By contrast, the duration of an untreated illness (DUI) in youth depression and its impact on the further course of the disease has remained scarcely investigated.
OBJECTIVE: The current study aims to determine how the duration of untreated illness affects the severity of the symptoms during the first depressive episode and the degree to which the symptoms are reduced after treatment.
METHODS: Fifty-two young male patients (15-29 years old) were examined. First, they were hospitalized with a severe without psychotic symptoms (F32.2) and moderate (F32.1) depressive episode. The Hamilton Depression Rating Scale (HDRS), the Scale of Prodromal Symptoms (SOPS), and the Scale for Assessment of Negative Symptoms (SANS) were used to achieve the research goals. The examination was conducted twice at the time of patient admission to the hospital and before discharge. Our statistical analysis was carried out with the Statistica 12 software. The Mann-Whitney U test was used to compare the differences between two independent groups. The Spearman\'s rank correlation coefficient was used to uncover any correlation between how long the illness has remained untreated and the severity of its clinical symptoms.
RESULTS: All patients were hospitalized at the first depressive episode. The average duration of an untreated illness was 35.8±17.0 months. The patients were divided into two groups: the first group (59.6%, n=31), with a duration of the untreated illness of more than 36 months, and the second group (40.4%, n=21), with a duration of the untreated illness of less than 36 months. A cross-group comparison between the participants showed that the reduction of HDRS scores was significantly higher in the second group (p=0.019) at the time of discharge, with no differences in the severity of depressive symptoms (p=0.544) at the time of admission. Comorbidity was detected in 83.9% of the patients in the first group and in 42.9% of the patients in the second group. A greater therapy effectiveness was found to exist in the second group, as the depressive symptoms score on the HDRS scale (p=0.016; U=196.0) and prodromal symptoms score on the SOPS disorganization subscale (p=0.046; U=218.0) were found to have been reduced significantly.
CONCLUSIONS: The study showed that DUI has an impact on the reduction of depressive, negative symptoms and symptoms of disorganization in youth patients at the first depressive episode. A high level of comorbidity has been uncovered, confirming that a variety of non-psychotic and psychotic disorders in youth manifest themselves in depression at a prodromal stage, causing difficulties in establishing diagnoses and requiring subsequent verification. Future research might need to focus on exploring depressive symptoms as predictors of mental disorders in youth patients.
UNASSIGNED: В настоящее время большинство исследований сфокусированы на изучении влияния длительности нелеченого психоза на дальнейшее течение заболевания. В отношении длительности нелеченого заболевания при депрессии таких работ значительно меньше.
UNASSIGNED: Целью данного исследования является: установить влияние длительности нелеченого заболевания на тяжесть симптомов депрессии, на степень их редукции за время лечения.
UNASSIGNED: Обследованы 52 больных мужского пола 15–29 лет, впервые госпитализированных по поводу депрессивного эпизода тяжелой степени без психотических симптомов (F32.2) и средней степени тяжести (F32.1). Применялись Шкала оценки депрессивных симптомов (HDRS), Шкала оценки продромальных симптомов (SOPS) и Шкала оценки негативных симптомов (SANS). Обследование проводилось дважды: на момент поступления пациента в стационар и на этапе редукции психопатологических расстройств перед выпиской. Статистический анализ проводился с помощью программы Statistica 12. Для сравнения различий между двумя независимыми группами применялся непараметрический метод Манна — Уитни и ранговый коэффициент Спирмена для оценки взаимосвязей между длительностью нелеченного заболевания и тяжестью клинических симптомов.
UNASSIGNED: Выборка включала больных, впервые госпитализированных с диагнозом «Депрессивный эпизод», средняя длительность нелеченого заболевания составила 35.8±17.0 месяцев. Пациенты были разделены на две группы: 1 группа (59.6%, n=31) с длительностью нелеченого заболевания более 36 месяцев, 2 группа (40.4%, n=21) — менее 36 месяцев. Межгрупповые сравнения показали, что редукция баллов по шкале HDRS к моменту выписки была значительно выше во второй группе (р=0.019) при отсутствии различий по степени выраженности депрессии при поступлении (р=0.544). Коморбидность отмечалась у 83.9% пациентов первой группы и у 42.9% — у второй. Лучший эффект терапии был установлен у больных второй группы по степени выраженности депрессивных симптомов (p=0.016; U=196.0) и продромальных симптомов, оцененных по подшкале симптомов дезорганизации шкалы SOPS (p=0.046; U=218.0) при выписке.
UNASSIGNED: Исследование показало влияние длительности нелеченого заболевания на степень редукции депрессивных, негативных симптомов и симптомов дезорганизации у молодых людей с первым депрессивным эпизодом. Также была установлена большая степень коморбидности, подтверждающая, что различные непсихотические психические расстройства, а также психотические заболевания на продромальных стадиях могут проявляться депрессивной симптоматикой, что затрудняет диагностику юношеских депрессий и требует последующей верификации диагноза. Будущие исследования должны быть направлены на определение предикторной значимости юношеских депрессий в отношении развития психических расстройств в юношеском возрасте.

BACKGROUND: Patients with Alzheimer\'s Disease (AD) exhibit structural alterations of the thalamus that correlate with clinical symptoms. However, given the anatomical complexity of this brain structure, it is still unclear whether atrophy affects specific thalamic nuclei and modulates the clinical progression from a prodromal stage, known as Mild Cognitive Impairment (MCI), to full-fledged AD.
OBJECTIVE: To characterize the structural integrity of distinct thalamic nuclei across the AD spectrum, testing whether MCI patients who convert to AD (c-MCI) show a distinctive pattern of thalamic structural alterations compared to patients who remain stable (s-MCI).
METHODS: Investigating between-group differences in the volumetric features of distinct thalamic nuclei across the AD spectrum.
METHODS: Prodromal and clinical stages of AD.
METHODS: We analyzed data from 84 healthy control subjects (HC), 58 individuals with MCI, and 102 AD patients. The dataset was obtained from the AD Neuroimaging Initiative (ADNI-3) database. The MCI group was further divided into two subgroups depending on whether patients remained stable (s-MCI, n=22) or progressed to AD (s-MCI, n=36) in the 48 months following the diagnosis.
METHODS: A multivariate analysis of variance (MANOVA) assessed group differences in the volumetric features of distinct thalamic nuclei obtained from magnetic resonance (MR) images. A stepwise discriminant function analysis identified which feature most effectively predicted the conversion to AD. The corresponding predictive performance was evaluated through a Receiver Operating Characteristic approach.
RESULTS: AD and c-MCI patients showed generalized atrophy of thalamic nuclei compared to HC. In contrast, no significant structural differences were observed between s-MCI and HC subjects. Compared to s-MCI, c-MCI individuals displayed significant atrophy of the nucleus reuniens and a trend toward significant atrophy in the anteroventral and laterodorsal nuclei. The discriminant function analysis confirmed the nucleus reuniens as a significant predictor of AD conversion, with a sensitivity of 0.73 and a specificity of 0.69.
CONCLUSIONS: In line with the pathophysiological relevance of the nucleus reuniens proposed by seminal post-mortem studies on patients with AD, we confirm the pivotal role of this nucleus as a critical hub in the clinical progression to AD. We also propose a theoretical model to explain the evolving dysfunction of subcortical brain networks in the disease process.

BACKGROUND: Stronger resting-state functional connectivity of the default mode and frontoparietal control networks has been associated with cognitive resilience to Alzheimer\'s disease related pathology and neurodegeneration in smaller cohort studies.
OBJECTIVE: We investigated whether these networks are associated with longitudinal CR to AD biomarkers of beta-amyloid (Aβ).
METHODS: Longitudinal mixed.
METHODS: The Anti-Amyloid Treatment in Asymptomatic Alzheimer\'s Disease (A4) study and its natural history observation arm, the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study.
METHODS: A sample of 1,021 cognitively unimpaired older adults (mean age = 71.2 years [SD = 4.7 years], 61% women, 42% APOEε4 carriers, 52% Aβ positive).
METHODS: Global cognitive performance (Preclinical Alzheimer\'s Cognitive Composite) was assessed over an average 5.4 year follow-up period (SD = 2 years). Cortical Aβ and functional connectivity (left and right frontoparietal control and default mode networks) were estimated from fMRI and PET, respectively, at baseline. Covariates included baseline age, APOEε4 carrier status, years of education, adjusted gray matter volume, head motion, study group, cumulative treatment exposure, and cognitive test version.
RESULTS: Mixed effects models revealed that functional connectivity of the left frontoparietal control network moderated the negative effect of Aβ on cognitive change (p = .025) such that stronger connectivity was associated with reduced Aβ-related cognitive decline.
CONCLUSIONS: Our results demonstrate a potential protective effect of functional connectivity in preclinical AD, such that stronger connectivity in this network is associated with slower Aβ-related cognitive decline.

BACKGROUND: Participant discontinuation from study treatment in a clinical trial can leave a trial underpowered, produce bias in statistical analysis, and limit interpretability of study results. Retaining participants in clinical trials for the full study duration is therefore as important as participant recruitment.
OBJECTIVE: This analysis aims to identify associations of pre-randomization characteristics of participants with premature discontinuation during the blinded phase of the Anti-Amyloid treatment in Asymptomatic AD (A4) Study.
METHODS: All A4 trial randomized participants were classified as having prematurely discontinued study during the blinded period of the study for any reason (dropouts) or completed the blinded phase of the study on treatment (completers).
METHODS: The trial was conducted across 67 study sites in the United States, Canada, Japan and Australia through the global COVID-19 pandemic.
METHODS: The sample consisted of all 1169 A4 trial randomized participants.
METHODS: Pre-randomization demographic, clinical, amyloid PET and genetic predictors of study discontinuation were evaluated using a univariate generalized linear mixed model (GLMM), with discontinuation status as the binary outcome, each predictor as a fixed effect, and site as a random effect to account for differences among study sites in the trial. Characteristics significant at p<0.10 were then included in a multivariable GLMM.
RESULTS: Among randomized participants, 339 (29%) discontinued the study during the blinded period (median follow-up time in trial: 759 days). From the multivariable analysis, the two main predictors of study discontinuation were screening State-Trait Anxiety Inventory (STAI) scores (OR = 1.07 [95%CI = 1.02; 1.12]; p=0.002) and age (OR = 1.06 [95%CI = 1.03; 1.09]; p<0.001). Participants with a family history of dementia (OR = 0.75 [95%CI = 0.55; 1.01]; p=0.063) and APOE ε4 carriers (OR = 0.79 [95%CI = 0.6; 1.04]; p=0.094) were less likely to discontinue from the study, with the association being marginally significant. In these analyses, sex, race and ethnicity, cognitive scores and amyloid/tau PET scores were not associated with study dropout.
CONCLUSIONS: In the A4 trial, older participants and those with higher levels of anxiety at baseline as measured by the STAI were more likely to discontinue while those who had a family history of dementia or were APOE ε4 carriers were less likely to drop out. These findings have direct implications for future preclinical trial design and selection processes to identify those individuals at greatest risk of dropout and provide information to the study team to develop effective selection and retention strategies in AD prevention studies.