Antipsychotic Treatment in People at Clinical High Risk for Psychosis: A Narrative Review of Suggestions for Clinical Practice.

PURPOSE: 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.

Prodromal Phase of Idiopathic Generalized Epilepsy: A Register-Based Case Control Study.

BACKGROUND AND OBJECTIVES: Idiopathic generalized epilepsy (IGE) is associated with distinct behavioral traits, symptoms of frontal lobe dysfunction, and psychiatric comorbidity. Whether psychiatric symptoms are part of the IGE endophenotype or secondary to the burden of chronic disease is unknown. In this study, we aimed at describing the sequence of appearance of psychiatric and epilepsy symptoms in patients with IGE. METHODS: Inclusion criteria for this cohort study were diagnosis of IGE with age at diagnosis at 10-25 years. We created 2 mutually exclusive cohorts, 1 based on ICD-10 codes in Danish registers with a first IGE diagnosis from January 1, 2005, to December 31, 2018, and a second patient cohort treated at Odense University Hospital and the Danish Epilepsy Centre in the same period. Each case was matched with 10 age-matched, sex-matched, and geography-matched normal population controls from the Danish registers. We compared social status, health care utilization, and psychiatric diagnoses between the groups in the 5 years preceding epilepsy diagnosis, at diagnosis, and at the end of the study period using the Wilcoxon rank-sum test and confirmatory logistic regression models. RESULTS: We identified 1,009 patients for the register-based cohort (55.1% female; mean age at diagnosis [SD]: 15.9 [±3.8] years) and 402 patients for the hospital-based cohort (56.2% female; mean age at diagnosis [SD]: 18.3 [±7.4] years) and matched them to 10,090 and 4,020 controls, respectively. IGE cohorts and controls did not differ at birth. In the 5 years before their IGE diagnosis, register patients had an increasing number of contacts with hospitals (mean visits [SD]: cases: 8.3 [±5.6], controls: 6.6 [±4.5]) and their general practitioners (mean visits [SD]: cases: 48.7 [±26.3], controls: 45.3 [±24.5]) and received more prescriptions for psychiatric medications (prescriptions: cases: 4.2%, controls: 2.5%, p = 0.003) compared with controls. Patients had a higher rate of psychiatric comorbidity (comorbidity: cases: 26.5%, controls: 17.8%, p < 0.0001) at the end of the study than controls. Data were similar in the hospital-based cohort. DISCUSSION: Our data suggest a prodromal phase of IGE detectable approximately 5 years before the first seizure characterized by increased health care utilization and greater use of prescription medicine for psychiatric symptoms.

Path Integration Detects Prodromal Alzheimer's Disease and Predicts Cognitive Decline.

Background: The entorhinal cortex is the very earliest involvement of Alzheimer's disease (AD). Grid cells in the medial entorhinal cortex form part of the spatial navigation system. Objective: We aimed to determine whether path integration performance can be used to detect patients with mild cognitive impairment (MCI) at high risk of developing AD, and whether it can predict cognitive decline. Methods: Path integration performance was assessed in 71 patients with early MCI (EMCI) and late MCI (LMCI) using a recently developed 3D virtual reality navigation task. Patients with LMCI were further divided into those displaying characteristic brain imaging features of AD, including medial temporal lobe atrophy on magnetic resonance imaging and posterior hypoperfusion on single-photon emission tomography (LMCI+), and those not displaying such features (LMCI-). Results: Path integration performance was significantly lower in patients with LMCI+than in those with EMCI and LMCI-. A significantly lower performance was observed in patients who showed progression of MCI during 12 months, than in those with stable MCI. Path integration performance distinguished patients with progressive MCI from those with stable MCI, with a high classification accuracy (a sensitivity of 0.88 and a specificity of 0.70). Conclusions: Our results suggest that the 3D virtual reality navigation task detects prodromal AD patients and predicts cognitive decline after 12 months. Our navigation task, which is simple, short (12-15 minutes), noninvasive, and inexpensive, may be a screening tool for therapeutic choice of disease-modifiers in individuals with prodromal AD.

Are factors that predict conversion to psychosis associated with initial transition to a high risk state? An adolescent brain cognitive development study analysis.

OBJECTIVE: Previous work suggests that cognitive and environmental risk factors may predict conversion to psychosis in individuals at clinical high risk (CHRs) for the disorder. Less clear, however, is whether these same factors are also associated with the initial emergence of the high risk state in individuals who do not meet current threshold criteria for being considered high risk. METHOD: Here, using data from the Adolescent Brain Cognitive Development (ABCD) study, we examined associations between factors previously demonstrated to predict conversion to psychosis in CHRs with transition to a "high risk" state, here defined as having a distress score between 2 and 5 on any unusual thought content question in the Prodromal Questionnaire-Brief Child version. Of a sample of 5237 children (ages 11-12) studied at baseline, 470 transitioned to the high-risk state the following year. A logistic regression model was evaluated using age, cognition, negative and traumatic experiences, decline in school performance, and family history of psychosis as predictors. RESULTS: The overall model was significant (χ2 = 100.89, R2 = 0.042, p < .001). Significant predictors included number of negative life events, decline in school performance, number of trauma types, and verbal learning task performance. CONCLUSIONS: These results suggest that factors that predict conversion in CHR teenagers are also associated with initial emergence of a "high-risk" state in preadolescents. Limitations regarding the degree to which model factors and outcome in this study parallel those used in previous work involving psychosis risk in older teenagers are discussed.

Sleep disturbance, suicidal ideation and psychosis-risk symptoms in individuals at clinical high risk for psychosis.

Insomnia and suicidal ideation (SI) are common in schizophrenia, including in individuals at clinical high-risk for psychosis (CHR-P). Previous studies have found associations between sleep disturbance, SI, and psychopathology in schizophrenia. We explored these associations in a CHR-P cohort. We leveraged data from CHR-P individuals in the North American Prodrome Longitudinal Studies (NAPLS-3) (n = 688) cohort. We investigated relationships between sleep disturbance (Scale of Prodromal Symptoms [SOPS]; Calgary Depression Scale for Schizophrenia [CDSS], and the Pittsburgh Sleep Quality Index [PSQI]), suicidal ideation (CDSS), and psychosis-risk symptoms. The prevalence of terminal insomnia, sleep disturbance, and SI in NAPLS3 was 25 %, 69 %, and 29 %, respectively. After controlling for potential confounders, multiple indices of sleep disturbance (SOPS, PSQI: OR = 1.05-1.40) were significant indicators of concurrent SI. Terminal insomnia was not associated with conversion to psychosis. Multiple indices of sleep problems were associated with higher total and subscale psychosis-risk symptom scores (ß = 0.09-0.39). Sleep problems are prevalent and associated with SI and more severe psychosis-risk symptoms in CHR-P individuals. These findings underscore the importance of designing longitudinal intervention studies to investigate whether the treatment of sleep disturbances may reduce suicidality and symptoms in this population.

α-Synuclein in speculative neuronal extracellular vesicles: A marker for Parkinson's disease risk?

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.

Functional and structural abnormalities of thalamus in individuals at early stage of schizophrenia.

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. TRIAL REGISTRATION: ClinicalTrials.govNCT03965598; https://clinicaltrials.gov/ct2/show/NCT03965598.

Occasional cannabis use is associated with higher premorbid functioning and IQ in youth at clinical high-risk (CHR) for psychosis: Parallel findings to psychosis cohorts.

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. DISCUSSION: 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.

Novel N100 area reliably captures aberrant sensory processing and is associated with neurocognition in early psychosis.

BACKGROUND: Despite findings from translational and genetic studies in the event-related potential (ERP) literature, the validity and reliability of P50 suppression as a schizophrenia spectrum endophenotype has been questioned. Here, we aimed to examine sensory registration and gating measures derived from P50 and N100 amplitude, as well as N100 area-a novel approach proposed herein-in early psychosis versus health. METHODS: Individuals at clinical high risk for psychosis (CHR; n = 77), first-episode psychosis (FE; n = 52), and healthy controls (HC; n = 65) were assessed in a paired-click auditory ERP paradigm. Eight CHR converted to psychosis (CHRC) and 39 did not (CHR-NC) by 24 months, while 30 CHR were lost to follow-. Group differences, test-retest reliability, and associations with neurocognitive function were assessed in nine ERP measures. RESULTS: Significant differences were observed in N100 S1 amplitude, S1 area, and area difference between HC and FE, as well as in N100 S1 area between HC and CHR, among the total population. Furthermore, significant differences were found in N100 S1 area between HC and CHR-NC (Cliff's delta, Δ = 0.32), as well as in N100 area difference between HC and CHR-C (Δ = 0.55). Both N100 S1 area and area difference demonstrated moderate to acceptable reliability (intraclass correlation coefficients: 0.61-0.78). Processing speed negatively correlated with both N100 S1 area and area difference, while executive function negatively correlated with N100 S1 area alone in CHR and FE. CONCLUSION: Among the ERP measures studied, N100 area measures may serve as a reliable biomarker of aberrant sensory processing and neurocognition in early psychosis.

Neurocognition in adolescents and young adults at clinical high risk for psychosis: Predictive stability for social and role functioning.

The prodromal phase of schizophrenia provides an optimal opportunity to mitigate the profound functional disability that is often associated with fully expressed psychosis. Considerable evidence supports the importance of neurocognition in the development of interpersonal (social) and academic (role) skills. Further findings from adolescents and young adults at clinical high risk for developing psychosis (CHRP) suggest that treatment for functioning might be most effective when targeting early and specific neurocognitive deficits. The current study addresses this critical intervention issue by examining the potential of neurocognitive deficits at intake for predicting social and role functioning over time in CHR-P youth. The study included 345 CHR-P participants from the second phase of the North American Prodrome Longitudinal Study (NAPLS2) with baseline neurocognition and 2-year follow-up data on social and role functioning. Slower baseline processing speed consistently predicted poor social functioning over time, while attention deficits predicted poor role functioning at baseline and follow-up. In addition, the impact of processing speed and attention impairments on social and role functioning, respectively, persisted even when adjusting the regression models for attenuated positive, negative, and disorganized symptoms, and transition status. The current study demonstrates for, arguably the first time, that processing speed and attention are strongly predictive of social and role functioning over time, respectively, above and beyond the impact of symptoms and those CHR-P individuals that develop psychosis over the course of the study. These findings imply that early neurocognition is a critical treatment target linked to the developmental trajectory of social and role functioning.

Sex differences in clinical presentation in youth at high risk for psychosis who transition to psychosis.

Sex differences have been observed in individuals with schizophrenia and for those at clinical high risk (CHR) for psychosis. However, specific differences in CHR individuals who transition to psychosis remain inconsistent and understudied. This study aimed to investigate sex differences in 156 CHR individuals who made the transition to psychosis. A wide range of demographics, positive and negative symptoms, depression, anxiety, social and role functioning, trauma, and substance use were assessed at baseline and symptoms and diagnoses at the time of transition. Fluctuations in positive and negative symptoms and different medications were also assessed. No sex differences were observed at baseline for those who later transitioned to psychosis. At transition, males were significantly more likely to be diagnosed as having schizophrenia or schizophreniform disorder and through the course of the study, males were more likely to be taking stimulants. Limitations in this study was the lack of longitudinal follow-up post transition. The study highlights the need for further research on sex differences in individuals who transition to psychosis. Understanding these differences can have implications for treatment and monitoring of CHR individuals.

Nutrition guidance within a multimodal intervention improves diet quality in prodromal Alzheimer's disease: Multimodal Preventive Trial for Alzheimer's Disease (MIND-ADmini).

BACKGROUND: Multimodal lifestyle interventions can benefit overall health, including cognition, in populations at-risk for dementia. However, little is known about the effect of lifestyle interventions in patients with prodromal Alzheimer's disease (AD). Even less is known about dietary intake and adherence to dietary recommendations within this population making it difficult to design tailored interventions for them. METHOD: A 6-month MIND-ADmini pilot randomized controlled trial (RCT) was conducted among 93 participants with prodromal AD in Sweden, Finland, Germany, and France. Three arms were included in the RCT: 1) multimodal lifestyle intervention (nutritional guidance, exercise, cognitive training, vascular/metabolic risk management, and social stimulation); 2) multimodal lifestyle intervention + medical food product; and 3) regular health advice (control group). Adherence to dietary advice was assessed with a brief food intake questionnaire by using the Healthy Diet Index (HDI) and Mediterranean Diet Adherence Screener (MEDAS). The intake of macro- and micronutrients were analyzed on a subsample using 3-day food records. RESULTS: The dietary quality in the intervention groups, pooled together, improved compared to that of the control group at the end of the study, as measured with by HDI (p = 0.026) and MEDAS (p = 0.008). The lifestyle-only group improved significantly more in MEDAS (p = 0.046) and almost significantly in HDI (p = 0.052) compared to the control group, while the lifestyle + medical food group improved in both HDI (p = 0.042) and MEDAS (p = 0.007) during the study. There were no changes in macro- or micronutrient intake for the intervention groups at follow-up; however, the intakes in the control group declined in several vitamins and minerals when adjusted for energy intake. CONCLUSION: These results suggest that dietary intervention as part of multimodal lifestyle interventions is feasible and results in improved dietary quality in a population with prodromal AD. Nutrient intakes remained unchanged in the intervention groups while the control group showed a decreasing nutrient density. TRIAL REGISTRATION: ClinicalTrials.gov NCT03249688, 2017-07-08.

Clinical High-Risk for Psychosis (CHR-P) circa 2024: Synoptic analysis and synthesis of contemporary treatment guidelines.

The construct of Clinical-High Risk for Psychosis (CHR-P) identifies young help-seeking subjects in putative prodromal stages of psychosis and is a central component of the Early Intervention (EI) paradigm in Mental Health, aimed at facilitating rapid entry into appropriate care pathways to prevent the onset of psychosis or mitigate is biopsychosocial consequences. This approach, which promotes an innovative culture of care for early, at risk situations, is inspired by a clinical staging concept as a guide to optimal treatment. The objective of this article is to map the existing guidelines in the field of CHR-P treatment recommendations, examine overlaps and differences, and critically evaluate blind spots to be addressed in future guideline updated. The search identified 9 guidelines focused on CHR-P or schizophrenia and other psychotic conditions but containing a specific section on CHR-P or prodromal psychosis. All guidelines acknowledge that psychosis is preceded by more or less pronounced prodromal stages, and most detail CHR-P criteria. Among guidelines, 8 out of 9 indicate cognitive-behavioural therapy as the best psychotherapeutic option and 7 out of 9 suggest that antipsychotics can be prescribed as second option in case psychosocial and/or other pharmacological interventions prove insufficient or inadequate in reducing clinical severity and subjective suffering. Antidepressants, mood stabilizers, and benzodiazepines were considered for the treatment of comorbid disorders. Only the European Psychiatric Association Guidance paper distinguished treatment recommendations for adults and minors. Agreements in treatment guidelines were discussed in light of recent meta-analytical evidences on pharmacological and non-pharmacological treatments for CHR-P, suggesting the need to provide an updated, age-sensitive consensus on how to manage CHR-P individuals.

Left Frontoparietal Control Network Connectivity Moderates the Effect of Amyloid on Cognitive Decline in Preclinical Alzheimer's Disease: The A4 Study.

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. OBJECTIVES: We investigated whether these networks are associated with longitudinal CR to AD biomarkers of beta-amyloid (Aß). DESIGN: Longitudinal mixed. SETTING: 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. PARTICIPANTS: A sample of 1,021 cognitively unimpaired older adults (mean age = 71.2 years [SD = 4.7 years], 61% women, 42% APOEε4 carriers, 52% Aß positive). MEASUREMENTS: Global cognitive performance (Preclinical Alzheimer's Cognitive Composite) was assessed over an average 5.4 year follow-up period (SD = 2 years). Cortical Aß 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 Aß on cognitive change (p = .025) such that stronger connectivity was associated with reduced Aß-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 Aß-related cognitive decline.

Greater White Matter Hyperintensity Volume Is Associated with the Number of Microhemorrhages in Preclinical Alzheimer's Disease.

BACKGROUND: Increased white matter hyperintensity (WMH) volume visible on MRI is a common finding in Alzheimer's disease (AD). We hypothesized that WMH in preclinical AD is associated with the presence of advanced vessel amyloidosis manifested as microhemorrhages (MCH). OBJECTIVES: 1) To assess the relationship between baseline WMH volume and baseline MCH. 2) To assess the relationship between longitudinal WMH accumulation and last MRI MCH during the double-blind phase of the A4 trial. DESIGN: A multicenter, randomized, double-blind, placebo-controlled, Phase 3 study comparing solanezumab with placebo given as infusions once every 4 weeks over 4.5 years in subjects with preclinical AD, defined as having evidence of elevated brain amyloid before the stage of clinically evident cognitive impairment, with an optional open-label extension period. SETTING: Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study. PARTICIPANTS: A sample of 1157 cognitively unimpaired older adults (mean age = 71.9 years [SD = 4.8 years], 59% women, 59% APOE ε4 carriers). MEASUREMENTS: A linear regression model was used to assess the impact of baseline MCH amount (0, 1, 2+) on WMH volume. A linear mixed-effects model was used to assess the impact of last MRI MCH on longitudinal WMH. All models were corrected for age, sex, grey matter volume, cortical amyloid PET, APOE ε4 status, and treatment group. RESULTS: Baseline WMH volume was greater in individuals with more than one MCH compared to those with no MCH (t=4.8, p<0.001). The longitudinal increase in WMH amongst individuals with one (t=2.3, p=0.025) and more than one MCH (t=6.7, p<0.001) at the last MRI was greater than those with no MCH. CONCLUSION: These results indicate a strong association between WMH and MCH, a common manifestation of cerebral amyloid angiopathy and ARIA-H. These results suggest that increased WMH volume may represent an early sign of vessel amyloidosis, likely prior to the emergence of MCH.

Pre-Randomization Predictors of Study Discontinuation in a Preclinical Alzheimer's Disease Randomized Controlled Trial.

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. DESIGN: 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). SETTING: The trial was conducted across 67 study sites in the United States, Canada, Japan and Australia through the global COVID-19 pandemic. PARTICIPANTS: The sample consisted of all 1169 A4 trial randomized participants. MEASUREMENTS: 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.

Foveolar Drusen Decrease Fixation Stability in Pre-Symptomatic AMD.

Purpose: This study aims at linking subtle changes of fixational eye movements (FEM) in controls and in patients with foveal drusen using adaptive optics retinal imaging in order to find anatomo-functional markers for pre-symptomatic age-related macular degeneration (AMD). Methods: We recruited 7 young controls, 4 older controls, and 16 patients with presymptomatic AMD with foveal drusen from the Silversight Cohort. A high-speed research-grade adaptive optics flood illumination ophthalmoscope (AO-FIO) was used for monocular retinal tracking of fixational eye movements. The system allows for sub-arcminute resolution, and high-speed and distortion-free imaging of the foveal area. Foveal drusen position and size were documented using gaze-dependent imaging on a clinical-grade AO-FIO. Results: FEM were measured with high precision (RMS-S2S = 0.0015 degrees on human eyes) and small foveal drusen (median diameter = 60 µm) were detected with high contrast imaging. Microsaccade amplitude, drift diffusion coefficient, and ISOline area (ISOA) were significantly larger for patients with foveal drusen compared with controls. Among the drusen participants, microsaccade amplitude was correlated to drusen eccentricity from the center of the fovea. Conclusions: A novel high-speed high-precision retinal tracking technique allowed for the characterization of FEM at the microscopic level. Foveal drusen altered fixation stability, resulting in compensatory FEM changes. Particularly, drusen at the foveolar level seemed to have a stronger impact on microsaccade amplitudes and ISOA. The unexpected anatomo-functional link between small foveal drusen and fixation stability opens up a new perspective of detecting oculomotor signatures of eye diseases at the presymptomatic stage.

"Back to Braak": Role of Nucleus Reuniens and Subcortical Pathways in Alzheimer's Disease Progression.

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. OBJECTIVES: 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). DESIGN: Investigating between-group differences in the volumetric features of distinct thalamic nuclei across the AD spectrum. SETTING: Prodromal and clinical stages of AD. PARTICIPANTS: 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. MEASUREMENTS: 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.