An NIMH Workshop on Non-Affective Psychosis in Midlife and Beyond: Research Agenda on Phenomenology, Clinical Trajectories, Underlying Mechanisms, and Intervention Targets.

We present a review of the state of the research in the phenomenology, clinical trajectories, biological mechanisms, aging biomarkers, and treatments for middle-aged and older people with schizophrenia (PwS) discussed at the NIMH sponsored workshop "Non-affective Psychosis in Midlife and Beyond." The growing population of PwS has specific clinical needs that require tailored and mechanistically derived interventions. Differentiating between the effects of aging and disease progression is a key challenge of studying older PwS. This review of the workshop highlights the recent findings in this understudied clinical population and the critical gaps in knowledge and consensus for research priorities. This review showcases the major challenges and opportunities for research to advance clinical care for this growing and understudied population.

Hippocampal α-Synuclein in Dementia with Lewy Bodies Contributes to Memory Impairment and Is Consistent with Spread of Pathology.

Despite considerable research to uncover them, the anatomic and neuropathologic correlates of memory impairment in dementia with Lewy bodies (DLB) remain unclear. While some studies have implicated Lewy bodies in the neocortex, others have pointed to α-synuclein pathology in the hippocampus. We systematically examined hippocampal Lewy pathology and its distribution in hippocampal subfields in 95 clinically and neuropathologically characterized human cases of DLB, finding that α-synuclein pathology was highest in two hippocampal-related subregions: the CA2 subfield and the entorhinal cortex (EC). While the EC had numerous classic somatic Lewy bodies, CA2 contained mainly Lewy neurites in presumed axon terminals, suggesting the involvement of the EC → CA2 circuitry in the pathogenesis of DLB symptoms. Clinicopathological correlations with measures of verbal and visual memory supported a role for EC Lewy pathology, but not CA2, in causing these memory deficits. Lewy pathology in CA1-the main output region for CA2-correlated best with results from memory testing despite a milder pathology. This result indicates that CA1 may be more functionally relevant than CA2 in the context of memory impairment in DLB. These correlations remained significant after controlling for several factors, including concurrent Alzheimer's pathology (neuritic plaques and neurofibrillary tangles) and the interval between time of testing and time of death. Our data suggest that although hippocampal Lewy pathology in DLB is predominant in CA2 and EC, memory performance correlates most strongly with CA1 burden.SIGNIFICANCE STATEMENT This study provides a detailed neuropathologic analysis of hippocampal Lewy pathology in human patients with autopsy-confirmed dementia with Lewy bodies. The approach-informed by regional molecular markers, concurrent Alzheimer's pathology analysis, and relevant clinical data-helps tease out the relative contribution of Lewy pathology to memory dysfunction in the disease. Levels of Lewy pathology were found to be highest in the hippocampal CA2 subregion and entorhinal cortex, implicating a potentially overlooked circuit in disease pathogenesis. However, correlation with memory performance was strongest with CA1. This unexpected finding suggests that Lewy pathology must reach a critical burden across hippocampal circuitry to contribute to memory dysfunction beyond that related to other factors, notably coexisting Alzheimer's disease tau pathology.

Executive functioning trajectories and their prospective association with inflammatory biomarkers in schizophrenia and non-psychiatric comparison participants.

BACKGROUND AND HYPOTHESIS: Cognitive change in people with schizophrenia (PwS) is challenging to assess, but important to understand. Previous studies with limited age ranges and follow-up were subject to practice effects. Controlling for practice effects in a well-established cohort, we examined executive functioning trajectories and their association with inflammatory biomarkers, hypothesizing that PwS will have worsening executive functioning over time compared to non-psychiatric comparison participants (NCs), predicted by higher baseline inflammation with a stronger relationship in PwS than NCs. STUDY DESIGN: Executive functioning was assessed in 350 participants (n = 186 PwS, 164 NCs) at 12-16-month intervals (0 to 7 follow-up visits). Inflammatory biomarkers at baseline included high sensitivity C-Reactive Protein (hs-CRP), Interferon-gamma, Tumor Necrosis Factor (TNF)-alpha, and Interleukin(IL)-6, -8, and - 10. Executive functioning trajectories across diagnostic groups were estimated using a linear mixed-effects model controlling for age, sex, race/ethnicity, and education level, with additional models to assess prediction by baseline inflammation. STUDY RESULTS: Over 4.4 years average follow-up, improvements in executive functioning were attenuated in PwS and older participants. Controlling for practice effects negated improvements, revealing declines among highly educated participants regardless of diagnosis. Higher baseline hs-CRP predicted worse executive functioning only among NCs, while TNF-alpha was predictive of change in all participants only after controlling for practice effects. Only the main effect of hs-CRP on executive function was significant after adjusting for multiple comparisons. None of the other inflammatory biomarkers predicted executive functioning or trajectories of performance among study participants. CONCLUSIONS: Systemic inflammation as reflected by baseline inflammatory biomarker levels did not predict longitudinal declines in executive functioning. Additional studies examining the temporal dynamics of inflammation and cognition in PwS will help further clarify their relationship and associated mechanisms.

Dementia among older people with schizophrenia: an update on recent studies.

PURPOSE OF REVIEW: This narrative review examines recently published research that examines the prevalence, underlying causes, and treatments for dementia among people with schizophrenia. RECENT FINDINGS: People with schizophrenia have high rates of dementia, compared with the general population, and cognitive decline has been observed 14 years prior to onset of psychosis with accelerated decline in middle age. Underlying mechanisms of cognitive decline in schizophrenia include low cognitive reserve, accelerated cognitive aging, cerebrovascular disease and medication exposure. Although pharmacologic, psychosocial and lifestyle interventions show early promise for preventing and mitigating cognitive decline, few studies have been conducted in older people with schizophrenia. SUMMARY: Recent evidence supports accelerated cognitive decline and brain changes in middle-aged and older people with schizophrenia, relative to the general population. More research in older people with schizophrenia is needed to tailor existing cognitive interventions and develop novel approaches for this vulnerable and high-risk group.

Associations between inflammatory marker profiles and neurocognitive functioning in people with schizophrenia and non-psychiatric comparison subjects.

BACKGROUND: Cognitive dysfunction in schizophrenia is the key predictor of functional disability and drives economic burden. Inflammation has been increasingly implicated in the pathogenesis of schizophrenia, yet its role in cognitive decline has not been evaluated. This study explores the association between inflammation and cognitive functioning in persons with schizophrenia. METHODS: Participants included 143 persons with schizophrenia (PwS) and 139 non-psychiatric comparison subjects (NCs) from an ongoing study of aging. Cognitive assessments included validated measures for executive functioning, processing speed, and visuospatial skills. Plasma levels of nine biomarkers associated with inflammation (high sensitivity C-reactive protein, intercellular adhesion molecule 1, serum amyloid A, interleukin-6, interleukin-8, interferon gamma-induced protein-10, monocyte chemotactic protein-1, fractalkine, and brain-derived neurotrophic factor) were quantified using commercially available, enzyme-linked immunosorbent assays. Partial least squares regression was used to develop a composite "inflammatory profile" to maximize correlations with the cognitive outcomes. We then constructed a best-fit model using these composites and their interactions with diagnosis and sex as the predictors, controlling for covariates. RESULTS: The biomarker composite, which best correlated with scores on cognitive testing, included high sensitivity C-reactive protein, intercellular adhesion molecule 1, serum amyloid A, interleukin-6, and brain-derived neurotrophic factor, for a 5-biomarker "inflammatory profile." The best-fit model showed a significant biomarker composite by diagnosis by sex three-way interaction, for executive function and processing speed, but not visuospatial skill. CONCLUSIONS: This approach to building an "inflammatory profile" may provide insight into inflammatory pathways affecting brain function and potential targets for anti-inflammatory interventions to improve cognition in schizophrenia.

Efficient Generation of CA3 Neurons from Human Pluripotent Stem Cells Enables Modeling of Hippocampal Connectivity In Vitro.

Despite widespread interest in using human induced pluripotent stem cells (hiPSCs) in neurological disease modeling, a suitable model system to study human neuronal connectivity is lacking. Here, we report a comprehensive and efficient differentiation paradigm for hiPSCs that generate multiple CA3 pyramidal neuron subtypes as detected by single-cell RNA sequencing (RNA-seq). This differentiation paradigm exhibits characteristics of neuronal network maturation, and rabies virus tracing revealed synaptic connections between stem cell-derived dentate gyrus (DG) and CA3 neurons in vitro recapitulating the neuronal connectivity within the hippocampus. Because hippocampal dysfunction has been implicated in schizophrenia, we applied DG and CA3 differentiation paradigms to schizophrenia-patient-derived hiPSCs. We detected reduced activity in DG-CA3 co-culture and deficits in spontaneous and evoked activity in CA3 neurons from schizophrenia-patient-derived hiPSCs. Our approach offers critical insights into the network activity aspects of schizophrenia and may serve as a promising tool for modeling diseases with hippocampal vulnerability. VIDEO ABSTRACT.

Propagation of tau pathology in a model of early Alzheimer's disease.

Neurofibrillary tangles advance from layer II of the entorhinal cortex (EC-II) toward limbic and association cortices as Alzheimer's disease evolves. However, the mechanism involved in this hierarchical pattern of disease progression is unknown. We describe a transgenic mouse model in which overexpression of human tau P301L is restricted to EC-II. Tau pathology progresses from EC transgene-expressing neurons to neurons without detectable transgene expression, first to EC neighboring cells, followed by propagation to neurons downstream in the synaptic circuit such as the dentate gyrus, CA fields of the hippocampus, and cingulate cortex. Human tau protein spreads to these regions and coaggregates with endogenous mouse tau. With age, synaptic degeneration occurs in the entorhinal target zone and EC neurons are lost. These data suggest that a sequence of progressive misfolding of tau proteins, circuit-based transfer to new cell populations, and deafferentation induced degeneration are part of a process of tau-induced neurodegeneration.

Soluble tau species, not neurofibrillary aggregates, disrupt neural system integration in a tau transgenic model.

Neurofibrillary tangles are a feature of Alzheimer disease and other tauopathies, and although they are generally believed to be markers of neuronal pathology, there is little evidence evaluating whether tangles directly impact neuronal function. To investigate the response of cells in hippocampal circuits to complex behavioral stimuli, we used an environmental enrichment paradigm to induce expression of an immediate-early gene, Arc, in the rTg4510 mouse model of tauopathy. These mice reversibly overexpress P301L tau and exhibit substantial neurofibrillary tangle deposition, neuronal loss, and memory deficits. Using fluorescent in situ hybridization to detect Arc messenger RNA, we found that rTg4510 mice have impaired hippocampal Arc expression both without stimulation and in response to environmental enrichment; this likely reflects the combination of functional impairments of existing neurons and loss of neurons. However, tangle-bearing cells were at least as likely as non-tangle-bearing neurons to exhibit Arc expression in response to enrichment. Transgene suppression with doxycycline for 6 weeks resulted in increased percentages of Arc-positive cells in rTg4510 brains compared with untreated transgenics, restoring enrichment-induced Arc messenger RNA levels to that of wild-type controls despite the continued presence of neurofibrillary pathology. We interpret these data to indicate that soluble tau contributes to impairment of hippocampal function, although tangles do not preclude neurons from responding in a functional circuit.