[Characteristics of psychoses in adolescence-Longitudinal data of integrated care]. / Charakteristika von Psychosen in der Adoleszenz ­ longitudinale Daten der Integrierten Versorgung.

BACKGROUND: Integrated care according to the Hamburg model combines therapeutic assertive community treatment (TACT) with initiatives for early detection and early treatment of schizophrenia and affective psychoses. The aim of this study was to identify the clinical characteristics of adolescents in comparison to adult patients and to derive knowledge for transition-specific treatment approaches. METHODOLOGY: Sociodemographic and clinical variables as well as treatment performance and clinical outcome were investigated over a period of 12 months in 167 patients with psychoses (16-25 years, n = 88; and >25 years, n = 79). RESULTS: Patients with psychosis in adolescence had significantly more outpatient treatment contacts (3.5/week vs. 1.6/week; p < 0.001), while adults were hospitalized for twice as long (10 days vs. 21 days; p = 0.003). The duration of untreated psychoses was significantly shorter in the adolescent group than in adults (122 weeks vs. 208 weeks; p = 0.002). The proportion of comorbid mental disorders was significantly higher in the adolescent group (87% vs. 63%; p < 0.001). In addition, the adolescence patients already showed greater impairment of daily functions and a higher severity of illness at the start of treatment. DISCUSSION: The treatment of psychoses in adolescence was characterized by a particularly high need for flexibility across all sectors and support systems, taking comorbid problem areas into account. Care models for adolescents and young adults with psychoses should therefore combine treatment approaches for severely ill patients with transition psychiatric interventions to avoid breaks in care and to meet the complex requirements of young patients with severe mental illnesses.

Autoantibody-associated psychiatric syndromes in children: link to adult psychiatry.

Studies show that psychiatric symptoms in adults and children are sometimes associated with serum neural autoantibodies. The significance of serum neural autoantibodies associated with psychiatric symptoms in children remains often unclear, but might be relevant for the extent and occurrence of psychiatric disease manifestation in later life, as well as therapy and outcome. For this narrative review, we sought articles listed in PubMed and published between 1988 and 2020 addressing the maternal-fetal transfer of neural autoantibodies and psychiatric disorders associated with serum neural autoantibodies. We identified six major subgroups of psychiatric disorders in children that are associated with serum neural autoantibodies: patients with attentional deficit hyperactivity disorder, autism spectrum disorder, obsessive compulsive disorder, Gilles de la Tourette syndrome, psychosis and catatonia. Furthermore, we summarized study findings from maternal-fetal transfer of Contactin-associated protein-like 2, N-methyl-D-aspartate receptor and fetal brain autoantibodies associated with behavioral effects in animals and humans. We hypothesize that the maternal transfer of serum neuronal autoantibodies during or after birth could result (1) in the ignition of an autoimmune-mediated inflammation having neurodevelopmental consequences for their children (autoimmune-priming-attack hypothesis) and (2) has a potential impact on the later manifestation of psychiatric disorders. Through this narrative review, we propose a diagnostic pathway for the clinical diagnosis of a potentially autoimmune origin of psychiatric symptoms in children while considering recent guidelines.

The use of long-acting Aripiprazole in a multi-center, prospective, uncontrolled, open-label, cohort study in Germany: a report on global assessment of functioning and the WHO wellbeing index.

BACKGROUND: In this non-interventional study, the functionality and well-being of patients with schizophrenia with aripiprazole once-monthly (AOM) was evaluated under real-life conditions in a naturalistic population. METHODS: This non-interventional, prospective, multicenter 6-month study included 242 predominantly symptomatically stable patients (mean age 43.1 ± 15.1 years, 55% male) who switched their treatment to AOM after 9.7 (± 22.3) months of oral treatment. Outcome parameters included functionality (Global Assessment of Functioning, GAF), patient's wellbeing (WHO-5 Well-Being Index, WHO-5), and both patient's and clinician's assessment of efficacy and tolerability of AOM. Treatment emergent adverse events (TRAE) were also recorded. RESULTS: At baseline, the mean GAF score was 47.0 (±13.9), indicating that patients experienced serious impairment in functioning. A continuous increase to 60.2 (±17.0) during treatment was found, with a robust and significant increase already after 4 weeks. At study start, patients reported diminished wellbeing, with a mean score of 10.6 (±5.6) on the WHO-5 scale. During treatment, patient wellbeing increased continuously with strong and significant improvements even after 4 weeks and an overall improvement of 4.8 (±6.9) over the course of 6 months with an endpoint of 15.4 (±5.5). Stratification of these results showed that more pronounced effects were achieved in younger patients ≤35 years (p<0.05 for GAF). The effectiveness and tolerability of AOM was rated good/very good by most patients (89.2 and 93.7%) and physicians (91.4 and 96.8%). Only few TRAEs occurred. CONCLUSIONS: Our results show a significant positive effect after initiation of AOM treatment in predominantly stable patients with schizophrenia on their functioning and wellbeing, which was even more pronounced in patients aged ≤35 years, thereby supporting previous randomized controlled findings under routine conditions in clinical practice.

Factors Influencing Staff's Attitude Toward Electroconvulsive Therapy: A Comparison of New Versus Experienced Electroconvulsive Therapy Clinics.

OBJECTIVES: Despite being a highly effective treatment, electroconvulsive therapy (ECT) is still stigmatized even among professionals. The aim of this study was to identify factors associated with a positive attitude toward ECT among health care workers. METHODS: We investigated staff's attitude and their self-assessment of knowledge while introducing ECT in 3 German psychiatric clinics. Furthermore, we compared this data to that of a clinic where ECT has been applied with a long tradition. An anonymous questionnaire was answered by n = 182 employees in the ECT-introducing clinics (novices) and n = 68 employees in the clinic with a long history of ECT (experts). RESULTS: Irrespective of the clinical history, the majority of participants approved the application of ECT in their clinic. Factors associated with a positive attitude were (a) profession (physicians presented a more positive mindset about ECT than nursing staff), (b) subjective feeling of being adequately informed, and (c) having had contact to patients undergoing ECT. Interestingly, the general attitude toward ECT did not differ between subjects who reported to have seen an ECT and those who had not. CONCLUSIONS: When introducing ECT as a new treatment into a clinic, formal information should be adapted to the needs of each profession with a special emphasis on nurses. To further increase acceptance, contact to ECT-experienced patients (professionals taught by patients) might result in a more positive attitude toward ECT than participation in an ECT treatment itself.

Effectiveness of aripiprazole once-monthly in schizophrenia patients pretreated with oral aripiprazole: a 6-month, real-life non-interventional study.

BACKGROUND: In this study, the treatment of schizophrenia patients with aripiprazole once-monthly (AOM) was evaluated under real-life conditions in a naturalistic setting. METHODS: This multicenter, prospective, non-interventional study included 242 patients (age = 43.1 ± 15.1 years, 55.0% male) who were monitored during 6 months of AOM treatment. Endpoints included measurements of psychopathology (Brief Psychiatric Rating Scale, BPRS) and severity of illness scales (Clinical Global Impressions-Severity, CGI-S, and -Improvement, CGI-I). Furthermore, treatment-related adverse events (TRAEs) were recorded. RESULTS: At baseline, the mean BPRS total score was 54.1 ± 15.6, the mean CGI-S was 4.8 ± 0.8 and the most frequent illness category was 'markedly ill' (41.7%). Patients had been pretreated with oral aripiprazole for a mean duration of 9.7 months (SD: 22.3) and 87.9% were deemed by their clinician as "clinically stable" and for a mean of 5.9 months. The difference in global BPRS after 6 months was - 13.8 (SD: 16.0; 95% CI: [- 15.9; - 11.7]; p < 0.001). The proportion of patients with high CGI-S scores decreased and the proportion of patients with low scores increased significantly (p < 0.001, respectively). BPRS scores improved numerically especially well in younger patients ≤35 years, CGI-S scores decreased significantly more in this population. TRAEs were rare, with low incidences of extrapyramidal symptoms (2.9%) or weight increase (0.4%). CONCLUSIONS: Treatment with AOM showed satisfying effectiveness in outpatients with further improvement of psychopathology after oral aripiprazole treatment for a considerable duration and even after having achieved clinically judged "stability". Our findings indicate a robust therapeutic effect of AOM and substantiate previous results from randomized controlled trials under real-world routine conditions.

Correction to: Effectiveness of aripiprazole once-monthly in schizophrenia patients pretreated with oral aripiprazole: a 6-month, real-life non-interventional study.

Following publication of the original article.

Stepped, evidence-based and integrated care service model vs. usual care for mental disorders: A randomized controlled trial (RECOVER).

Stepped, evidence-based and integrated care service models have the potential to be used as a reference for mental health services. RECOVER aimed to evaluate cost savings, effectiveness, and cost-effectiveness of such a model within a two arm, assessor- and data analysist-blinded RCT in Hamburg, Germany. Participants aged 16-79 years with mental disorders were randomly assigned either to RECOVER or treatment as usual (TAU). Primary outcomes comprised costs, effectiveness (combined symptoms, functioning, quality of life), and cost-effectiveness, hierarchically ordered. Outcomes were evaluated according to the ITT principle, group differences regarding costs with adjusted generalized linear models, effectiveness with ANCOVA models, and cost-effectiveness with the incremental cost-effectiveness ratio (ICER) and cost-effectiveness acceptability curves (CEACs). Between 1/1/2018 and 12/31/2020, n = 891 were finally included (n = 477 in RECOVER, n = 444 in TAU). RECOVER was associated with significantly lower annual total costs (-22 %), health and social care costs (-25 %) and hospital costs (-50 %). Effectiveness analyses showed a significantly better outcome for RECOVER with the fully imputed data . The CEACs descriptively demonstrated that RECOVER was cost-effective with a probability of >95 %. Treatment in RECOVER resulted in substantial cost reductions with better cost-effectiveness. RECOVER can be recommended as a reference model for comprehensive and integrated mental health services.

Remission with or without comorbid substance use disorders in early psychosis: long-term outcome in integrated care (ACCESS III study).

Introduction: Schizophrenia-Spectrum-Disorders are associated with poor long-term outcome as well as disability and often severely affect the lives of patients and their families often from symptom onset. Up to 70% of first episode psychosis (FEP) patients suffer from comorbid substance use disorders (SUD). We aimed at studying the course of illness in FEP patients within evidence-based care, with and without comorbid SUD, to examine how decreased, remitted or persistent substance use impacted rates of a combined symptomatic and functional long-term recovery compared with patients without SUD. Methods: ACCESS III is an integrated care model for FEP or patients in the early phase of non-affective and affective psychotic disorders. Treatment trajectories of patients, who had been in ACCESS care for 1 year, with and without SUD were compared with regard to the course of illness and quality of life using Mixed Model Repeated Measures (MMRM) and recovery rates were compared using binary logistic regression. Change in substance use was coded as either persistent, decreased/remitted or no use. Results: ACCESS III was a prospective 1-year study (N = 120) in patients aged 12-29 years. Of these, 74 (61.6%) had a comorbid SUD at admission. There were no group differences regarding the course of illness between patients with or without comorbid SUD or between patients with a substance abuse or substance dependence. The only outcome parameter that was affected by SUD was quality of life, with larger improvement found in the group without substance use (p = 0.05) compared to persistent and remitted users. Using LOCF, 44 patients (48.9%) fulfilled recovery criteria at the endpoint; recovery did not differ based on substance use status. Discussion: SUD and especially substance dependence are common in psychotic disorders even in FEP patients. Evidence-based integrated care led to long-term improvement in patients with comorbid SUD and rate of recovery did not differ for patients with substance use.

Mediators of quality of life change in people with severe psychotic disorders treated in integrated care: ACCESS II study.

BACKGROUND: Patients with severe psychotic disorders exhibit a severely reduced quality of life (QoL) at all stages of the disease. Integrated care often led to an improvement in QoL. However, the specific mediators of QoL change are not yet well understood. METHODS: The ACCESS II study is a prospective, long-term study investigating the effectiveness of an integrated care program for people with severe psychotic disorders (IC-TACT) that includes Therapeutic Assertive Community Treatment within a care network of in- and outpatient services at the University Medical Center Hamburg-Eppendorf, Germany. We examined longitudinal associations between QoL and the hypothesized mediators of change (i.e., negative symptoms, depression, and anxiety), using cross-lagged panel models. RESULTS: The sample includes 418 severely ill patients treated in IC-TACT for at least 1 year. QoL increased, whereas symptom severity decreased significantly from baseline to 6-month follow-up (p-values ≤ 0.001), and remained stable until 12-month follow-up. QoL and symptom severity demonstrated significant auto-correlated effects and significant cross-lagged effects from QoL at baseline to negative symptoms (6 months, ß = -0.20, p < 0.001) to QoL (12 months, ß = -0.19, p < 0.01) resulting in a significant indirect, mediated effect. Additionally, negative symptoms after 6 months had a significant effect on the severity of depression after 12 months (ß = 0.13, p < 0.05). CONCLUSIONS: Negative symptoms appear to represent an important mechanism of change in IC-TACT indicating that improvement of QoL could potentially be achieved through optimized intervention on negative symptoms. Moreover, this may lead to a reduction in the severity of depression after 12 months.

Autoantibody-associated psychiatric symptoms and syndromes in adults: A narrative review and proposed diagnostic approach.

BACKGROUND: Autoimmune-mediated encephalitis is a disease that often encompasses psychiatric symptoms as its first clinical manifestation's predominant and isolated characteristic. Novel guidelines even distinguish autoimmune psychosis from autoimmune encephalitis. The aim of this review is thus to explore whether a wide range of psychiatric symptoms and syndromes are associated or correlate with autoantibodies. METHODS: We conducted a PubMed search to identify appropriate articles concerning serum and/or cerebrospinal fluid (CSF) autoantibodies associated with psychiatric symptoms and syndromes between 2000 and 2020. Relying on this data, we developed a diagnostic approach to optimize the detection of autoantibodies in psychiatric patients, potentially leading to the approval of an immunotherapy. RESULTS: We detected 10 major psychiatric symptoms and syndromes often reported to be associated with serum and/or CSF autoantibodies comprising altered consciousness, disorientation, memory impairment, obsessive-compulsive behavior, psychosis, catatonia, mood dysfunction, anxiety, behavioral abnormalities (autism, hyperkinetic), and sleeping dysfunction. The following psychiatric diagnoses were associated with serum and/or CSF autoantibodies: psychosis and schizophrenia spectrum disorders, mood disorders, minor and major neurocognitive impairment, obsessive-compulsive disorder, autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD), anxiety disorders, eating disorders and addiction. By relying on these symptom clusters and diagnoses in terms of onset and their duration, we classified a subacute or subchronic psychiatric syndrome in patients that should be screened for autoantibodies. We propose further diagnostics entailing CSF analysis, electroencephalography and magnetic resonance imaging of the brain. Exploiting these technologies enables standardized and accurate diagnosis of autoantibody-associated psychiatric symptoms and syndromes to deliver early immunotherapy. CONCLUSIONS: We have developed a clinical diagnostic pathway for classifying subgroups of psychiatric patients whose psychiatric symptoms indicate a suspected autoimmune origin.

Reduction of Involuntary Admissions in Patients With Severe Psychotic Disorders Treated in the ACCESS Integrated Care Model Including Therapeutic Assertive Community Treatment.

Objective: The ACCESS treatment model offers assertive community treatment (ACT) embedded in an integrated care program to patients with severe psychotic disorders. Compared to standard care, it proved to be more effective in terms of service disengagement and other outcomes in patients with psychotic disorders over 12, 24, and 48 months. Many patients with severe mental disorders experience involuntary admissions which can be potentially traumatic. In this study, we assessed the effect of ACT on reducing involuntary admissions over an observation period of 4 years. Method: One hundred seventy-one patients treated in ACCESS were included in this study. The primary outcome was rate of involuntary admissions during 48 months. Secondary outcomes were differences between those with and without involuntary admissions in the 2 years prior to ACCESS regarding change of psychopathology, severity of illness, psychosocial functioning, quality of life, satisfaction with care, medication non-adherence, and service-disengagement. Results: Of 171 patients, 58 patients (33.9%) were involuntarily admitted to hospital in the past 2 years before entry. During the 4 years of treatment, 16 patients (9.4%) were involuntarily admitted to hospital which was a significantly lower rate compared to the 2 years before inclusion in ACCESS (p < .001). Comparing the two groups, larger improvements in severity of illness (p = .004) and functional status (p = .043) were detected in the group with no history of involuntary admissions. At 4-year follow-up, of the remaining patients, 69.2% (n = 81) were full adherent (p < .001), compared to 18.9% (n = 31) at baseline with no differences between the two groups over the study period (p = .25). Over 4 years, only 13 patients (13.2%) were service-disengaged due to non-practical reasons. Conclusions: In this long-term study, we were able to demonstrate a reduction in involuntary admissions in four treatment years compared to the 2 years prior to admission to the ACCESS model in patients with severe and mostly multiphase schizophrenia spectrum disorders and affective disorders with psychotic features. This may help prevent patients from suffering from a potentially traumatic experience during treatment in the psychiatric system. Clinical Trial Registration:www.ClinicalTrials.gov, identifier NCT01888627.

Comorbidity of chronic somatic diseases in patients with psychotic disorders and their influence on 4-year outcomes of integrated care treatment (ACCESS II study).

BACKGROUND: People with psychotic disorders fulfilling criteria of a severe and persistent mental illness (SPMI) display a high risk of somatic comorbidity (SC). METHODS: ACCESS II is a prospective, long-term study examining the effectiveness of Integrated Care for people with psychotic disorders fulfilling SPMI criteria. Chronic comorbid somatic disorders were systematically assessed according to ICD-10-GM criteria. Patients treated for ≥4years in ACCESS were categorized as early psychosis (treatment: ≤2years) or non-early psychosis (treatment: >2years) patients. RESULTS: Of 187 patients treated in ACCESS for ≥4years (mean age=41.8years, males=44.4%), 145 (77.5%) had SC, (mean=2.1±2.1). Overall, 55 different diseases from 15 different ICD-10-GM disease areas were identified. Prevalence of ≥1 SC (p=0.09) and specific types of SC (p=0.08-1.00) did not differ between early and non-early psychosis patients, but non-early psychosis patients had a higher mean number of SC (2.3±2.2 vs. 1.3±1.3, p=0.002). SC patients had higher rates of comorbid mental disorders (93% vs. 81%, p=0.002), specifically posttraumatic stress disorder (23% vs. 7%, p=0.002), and suicide attempts (43% vs. 19%, p<0.001). At the 4-year endpoint, both patients with and without comorbidity displayed major improvements in psychopathology, severity of illness, functioning, quality of life and satisfaction with care. CONCLUSIONS: SC is frequent in patients with severe psychotic disorders, even in the early psychosis phase. The magnitude of the problem underlines the need for regular screening, comprehensive assessment, preventive pharmacotherapy, and targeted SC management.

Effectiveness of integrated care including therapeutic assertive community treatment in severe schizophrenia-spectrum and bipolar I disorders: Four-year follow-up of the ACCESS II study.

The ACCESS-model offers integrated care including assertive community treatment to patients with psychotic disorders. ACCESS proved more effective compared to standard care (ACCESS-I study) and was successfully implemented into clinical routine (ACCESS-II study). In this article, we report the 4-year outcomes of the ACCESS-II study. Between May 2007 and December 2013, 115 patients received continuous ACCESS-care. We hypothesized that the low 2-year disengagement and hospitalization rates and significant improvements in psychopathology, functioning, and quality of life could be sustained over 4 years. Over 4 years, only 10 patients disengaged from ACCESS. Another 23 left for practical reasons and were successfully transferred to other services. Hospitalization rates remained low (13.0% in year 3; 9.1% in year 4). Involuntary admissions decreased from 35% in the 2 years prior to ACCESS to 8% over 4 years in ACCESS. Outpatient contacts remained stably high at 2.0-2.4 per week. We detected significant improvements in psychopathology (effect size d = 0.79), illness severity (d = 1.29), level of functioning (d = 0.77), quality of life (d = 0.47) and stably high client satisfaction (d = 0.02) over 4 years. Most positive effects were observed within the first 2 years with the exception of illness severity, which further improved from year 2 to 4. Within continuous intensive 4-year ACCESS-care, sustained improvements in psychopathology, functioning, quality of life, low service disengagement and re-hospitalization rates, as well as low rates of involuntary treatment, were observed in contrast to other studies, which reported a decline in these parameters once a specific treatment model was stopped. Yet, stronger evidence to prove these results is required. TRIAL REGISTRATION: Clinical Trial Registration Number: NCT01888627.

Early detection and integrated care for adolescents and young adults with severe psychotic disorders: rationales and design of the Integrated Care in Early Psychosis Study (ACCESS III).

AIM: The Integrated Care in Early Psychosis (ACCESS III) Study examined the efficacy and cost-effectiveness of a combined intervention consisting of strategies to improve early detection and quality of care (integrated care including therapeutic assertive community treatment) in adolescents and young adults in the early phase of a severe psychotic disorder from 2011 to 2014. METHODS: This is a prospective, single-centre, 1-year cohort study comparing an intervention condition (early detection plus integrated care, n = 120) to the historical control condition (standard care, SC, n = 105) for adolescents and young adults aged 12-29 years suffering from a severe, early-phase psychotic disorder (i.e. within 2 years of treatment). RESULTS: Primary outcome is the rate of combined symptomatic (i.e. Positive and Negative Syndrome Scale (PANSS) criteria) and functional (i.e. Global Assessment of Functioning scale (GAF) ≥ 60 points criterion) remission over at least 6 months at study endpoint. Secondary outcome comprises the comparison of the reduction in the duration of untreated psychosis within the 4-year study duration between integrated care and SC, course of psychopathology, functioning, quality of life, satisfaction with care, cost and quality-adjusted life years (QALYs) in comparison to a historical control group. CONCLUSION: To the authors' knowledge, this is the first study assessing the efficacy and cost-effectiveness of a combined intervention consisting of early detection strategies and strategies to improve quality of care in both adolescents and young adults with early-phase psychosis. The results will be published in 2016.

Post-injection delirium/sedation syndrome in patients treated with olanzapine pamoate: mechanism, incidence, and management.

Second-generation antipsychotics (SGAs) are a mainstay in the treatment of patients with schizophrenia. However, continuity in intake of the prescribed medication has been one of the greatest challenges in these patients. One option to improve medication adherence is to prescribe depot or long-acting injectable formulations (LAIs) of antipsychotics. Following risperidone, several other SGAs have been introduced as LAIs. Olanzapine pamoate, paliperidone palmitate, and aripiprazole are the new-generation LAIs, which are available for 2- to 4-week intervals of application in many countries. The literature shows a clear advantage of these drugs over placebo regarding symptom reduction and relapse prevention. LAIs show a similar safety profile to oral formulations of the relevant drug, with the exception of olanzapine pamoate, which can lead to rare cases of post-injection delirium/sedation syndrome (PDSS). PDSS is characterized by heavy sedation (possibly including coma) and/or delirium after injection. During PDSS events, patients show higher plasma concentrations of olanzapine, leading to the assumption that unintended partial intravascular injection or blood vessel injury during the injection is causative of PDSS. Therefore, a risk-management plan proposing an observation period of 3 h was introduced. In August 2013, a new proposal by the European Medicines Agency terminated the requirement to accompany these patients to their next destination, although this requirement remains in place according to US FDA recommendations.

Neurocognitive deficits are relevant for the jumping-to-conclusions bias, but not for delusions: A longitudinal study.

Patients with delusions exhibit an increased tendency to arrive at decisions based on very limited evidence (jumping-to-conclusions; JTC), making this reasoning bias relevant for the treatment of delusions. Neurocognitive deficits contribute to JTC, but it is not known whether this has any bearing on the clinical syndrome of delusions. We addressed this question by reanalyzing data from an efficacy study of non-pharmacological interventions as adjunctive treatments in schizophrenia. We investigated the longitudinal associations of cognitive functioning, JTC and delusions in patients with psychotic disorders receiving either a metacognitive intervention addressing reasoning biases (n = 59), or cognitive remediation (n = 58). Both interventions improved JTC; in the cognitive remediation group, tentative evidence suggested that better neurocognitive performance contributed to this improvement. However, JTC gains were associated with delusion improvement only in the metacognitive intervention group, suggesting a content-specific mechanism of action.

A novel presenilin 1 mutation (Ala275Val) as cause of early-onset familial Alzheimer disease.

Mutations in the presenilin 1 (PS1) gene (PSEN1) are associated with familial Alzheimer disease (FAD). Here, we report on a 50-year-old patient presenting with progressive deterioration of his short-term memory and a family history of early-onset dementia. Diagnostic workup included a neuropsychological examination, structural magnetic resonance (MR) imaging, cerebrospinal fluid (CSF) biomarkers including total tau, phosphorylated tau, and Aß42 levels, as well as sequencing relevant fragments of the genes PSEN1, PSEN2, and APP. Additionally, we were able to obtain archival paraffin-embedded cerebellar tissue from the patient's father for cosegregation analysis. Clinical, neuropsychological and MR imaging data were indicative of early-onset Alzheimer disease. Furthermore, CSF biomarkers showed a typical pattern for Alzheimer disease. DNA sequencing revealed a heterozygous nucleotide transition (c.824C>T) in exon 8 of PSEN1, leading to an amino acid change from alanine to valine at codon 275 (Ala275Val). The same mutation was found in an archival brain specimen of the patient's demented father, but not in a blood sample of the non-demented mother. This mutation alters a conserved residue in the large hydrophilic loop of PS1, suggesting pathogenic relevance. Cosegregegation analysis and the structural as well as the presumed functional role of the mutated and highly conserved residue suggest FAD causing characteristics of the novel PSEN1 mutation Ala275Val.