Limits to human neurogenesis – really?

Lucassen PJ, Toni N, Kempermann G, Frisen J, Gage FH, Swaab DF: Limits to human neurogenesis – really? Molecular Psychiatry [Epub ahead of print, January 7, 2019; doi: 10.1038/s41380-018-0337-5.].

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Abstract: “Genetic discoveries about human brain development and neuropsychiatric syndromes have changed the landscape of psychiatric research. The genotyping of hundreds of thousands of individuals has identified many hundreds of genomic regions that are associated with psychiatric diagnoses, and progress is being made in uncovering the specific genes that underlie these statistical associations, although most are still undetermined. While there are great expectations that such genetic discoveries will lead to novel treatments based on fundamental mechanisms of illness, there are important caveats. Individual risk-associated common variants explain only a tiny fraction of individual liability. The degree to which common risk variants represent “core” pathogenic insights is controversial. Individuals with rare and more penetrant risk variants are often intellectually disabled, which raises epistemological questions about classification. In clinical research, the application of polygenic risk scores—the cumulative sum of associated alleles in an individual genome—to prediction models of environmental influences and outcome is gaining enthusiasm because these scores explain more liability, but predictions are small and not yet actionable for individuals. Psychiatry is intertwined with genomic medicine, and our understanding of what we call schizophrenia and the possibilities of improving the lives of affected individuals have never seemed more promising. Yet the research challenges are daunting; psychiatric syndromes ultimately reflect how the brain mishandles environmental information, which at the systems level is far “downstream” of the effect of genes in cells.”

Weinberger DR: Thinking About Schizophrenia in an Era of Genomic Medicine. Amer. J. Psychiatry [Epub ahead of print, Jan.1,2019].

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Mitochondrial dysfunction has been implicated in a number of brain disorders. Traditionally, mitochondria and mitochondrial DNA (mtDNA) have been thought to be exclusively maternally inherited in humans. In this report, Luo and colleagues identified three unrelated multigeneration families with a high level of mtDNA heteroplasmy. A comprehensive exploration of mtDNA segregation in these families shows biparental mtDNA transmission with an autosomal dominant-like inheritance. The authors suggest that, while the central dogma of maternal inheritance of mtDNA remains valid, there are some exceptional cases where paternal mtDNA could be passed to the offspring.

Elucidating the molecular mechanism for this unusual mode of inheritance will provide new insights into how mtDNA is passed on from parent to offspring and may lead to development of new therapeutic treatments for pathogenic mtDNA transmission.

Luo S, Valencia CA, Zhang J, Lee NC, Slone J, Gui B, Wang X, Li Z, Dell S, Brown J, Chen SM, Chien YH, Hwu WL, Fan PC, Wong LJ, Atwal PS and Huang T: Biparental Inheritance of Mitochondrial DNA in Humans. Proc. Natl. Acad. Sci. USA 115(51): 13039-13044 (2018).

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Administration of the antidepressant fluoxetine to zebrafish, a common laboratory model, reduced levels of the stress hormone cortisol as well as exploratory behavior, effects that persisted across generations, according to a study by Vera-Chang and colleagues. They state that this may be a cause for concern given the high prescription rates of fluoxetine to pregnant women and the potential long-term negative impacts on humans exposed to these therapeutic drugs.

Vera-Chang MN, St-Jacques AD, Gagné R, Martyniuk CJ, Yauk CL, Moon TW and Trudeau VL: Transgenerational hypocortisolism and behavioral disruption are induced by the antidepressant fluoxetine in male zebrafish Danio rerio. Proc. Natl. Acad. Sci. USA 115(52):E12435-E12442 (2018).

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Cognitive impairment in major depressive disorder (MDD), including remitted major depressive disorder, raises the question whether these cognitive defects are part of preexisting vulnerability or a consequence of the disorder or its treatment. The purpose of this study was to compare (via meta-analysis) cognitive performance between individuals with and without family history of major depressive disorder.

.Across 284 measures of cognition in 54 non-overlapping samples including 3246 relatives of people with MDD and 5222 controls, relatives of people with MDD performed worse than controls across all measures of cognition. Domain-specific meta-analyses showed similar size of relative-control difference in most domains of cognition, including Full-Scale IQ, verbal intelligence, perceptual intelligence, memory, academic performance, and language.

The authors concluded that a general impairment in cognition is a feature of familial disposition for major depressive disorder. They suggest that cognition may contribute to early risk identification for depression and may represent a target for early intervention.

MacKenzie LE, Uher R and Pavolva B: Cognitive Performance in First-Degree Relatives of Individuals With vs Without Major Depressive Disorder: A Meta-analysis. JAMA Psychiatry [Epub ahead of print, Dec. 26, 2018; doi: 10.1001/jamapsychiatry.2018.3672.]

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“The ApoE ε4 allele is the most significant genetic risk factor for late-onset Alzheimer disease. The risk conferred by ε4, however, differs across populations, with populations of African ancestry showing lower ε4 risk compared to those of European or Asian ancestry. The cause of this heterogeneity in risk effect is currently unknown; it may be due to environmental or cultural factors correlated with ancestry, or it may be due to genetic variation local to the ApoE region that differs among populations.” To test these hypotheses, the authors analyzed ApoE genotypes and genome-wide array data in individuals from African American and Puerto Rican populations. They concluded that factors contributing to the lower risk effect in the ApoE gene ε4 allele are likely due to ancestry-specific genetic factors near ApoE rather than non-genetic ethnic, cultural, and environmental factors. Further exploration of these hypotheses may lead to novel, population-specific therapeutics and risk predictions.

Rajabli F, Feliciano BE, Celis K, Hamilton-Nelson KL, Whitehead PL, Adams LD, Bussies PL, Manrique CP, et al: Ancestral origin of ApoE  ε4 Alzheimer disease risk in Puerto Rican and African American populations. PLoS Genet. 2018 Dec 5;14(12):e1007791. doi: 10.1371/journal.pgen.1007791. eCollection 2018 Dec.

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Revealing the brain’s molecular architecture
The PsychENCODE Consortium
Science  14 Dec 2018:
Vol. 362, Issue 6420, pp. 1262-1263
DOI: 10.1126/science.362.6420.1262




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The following report describes how microglia in the brain might have a role in the cognitive impairment (“chemobrain”) seen after chemotherapy cancer treatment.

“…Some chemotherapies cause a lasting condition known as ‘chemobrain’, which is marked by deficiencies in attention, information processing and fine motor skills. …(Monje and colleagues) found that children and young adults treated with a chemotherapy called methotrexate had fewer oligodendrocyte-lineage cells — cells that help to form the crucial insulation around neurons — in their brains than those who had not been exposed to the drug.

Similarly, mice exposed to methotrexate had fewer of these cells than untreated controls. Six months after methotrexate treatment, these mice struggled to distinguish between novel and familiar objects. They also had increased numbers of active microglia.

After exposing the mice to chemotherapy, researchers gave the animals a drug that reduced the numbers of their microglia. This reversed methotrexate’s negative effects on both oligodendrocyte-lineage cells and the animals’ ability to discriminate between novel and familiar objects.”

Gibson EM, Nagaraja S, Ocampo A, Tam LT, Wood LS, Pallegar PN, Greene JJ et al.: Methotrexate Chemotherapy Induces Persistent Tri-glial Dysregulation that Underlies Chemotherapy-Related Cognitive Impairment. Cell [ Epub ahead of print, Nov. 13, 2018; pii: S0092-8674(18)31405-3. doi: 10.1016/j.cell.2018.10.049 ].

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Excerpts from article:

“The observation that higher rates of schizophrenia and other nonaffective psychotic disorders are associated with city living is robustly replicated across epidemiologic studies conducted throughout Northern Europe and North America. The weight of this evidence, combined with exhaustive investigations of potential bias, suggest that methodological artifacts are unlikely to explain such associations. Instead, they imply a causal role for underlying environmental factors more common in urban settings. Evidence from northern Europe strongly links social factors, including deprivation, inequality, and social isolation, to raised rates of nonaffective psychotic disorders in urban settings, and while mechanisms through which such factors influence psychosis remain uncharacterized, they may include effects of social stress and possibly exposure to socially distributed biological factors, such as poor nutrition, infections, and/or pollutants.

The first idea is consistent with emerging neurobiological evidence, which has found that healthy volunteers who live or grew up in more urban environments show heightened activity in the amygdala and perigenual anterior cingulate cortex, respectively, after stress. These 2 interconnected brain regions are involved in threat perception and social evaluative stress processing, which may be more demanding in response to city life, and which are associated with psychotic disorder. Nonetheless, a definitive statement about causality (or refutation of it) awaits results of ongoing efforts to produce convergent evidence that elucidates the exact mechanisms through which some or all of these factors account for differential rates of psychotic disorder in some urban populations.

It does not follow, however, that city living should be associated with psychotic disorders in all contexts. Indeed, recent data from southern Europe suggest that the association may not pertain even across European countries, while findings from rural England suggest urbanicity per se need not be the primary social construct driving increased incidence rates in some environments.

New data from the World Health Survey (WHS) published by DeVylder et al further expand our purview and underscore how mistaken it could be to assume that city living has the same meaning across the globe. Across 42 low- and middle-income countries (LMICs), they found no consistent pattern of urban-rural differences in the prevalence of subclinical psychotic experiences (PEs). However, as we expand the epidemiological horizon, we cannot afford to uncritically accept evidence that emerges on urban-rural differences. Studying PEs does not yield direct evidence about variation in psychotic disorders, given that PEs are relatively common, yet to be conclusively associated with polygenic risk for schizophrenia, and associated with risks for several other psychiatric disorders and have low positive predictive value for psychotic disorders. We must be even more cautious about WHS findings on psychotic disorders, which were based on a single-question item asking whether a physician had ever diagnosed survey participants with a psychotic disorder. In LMICs, access to clinical care is often very limited, and the diagnosis, communication, and understanding of the term psychotic disorder is likely to vary widely. Finally, WHS data are measures of prevalence rather than incidence. With respect to psychotic disorders in LMICs, where rural-to-urban migration has strongly contributed to rapid urbanization, urban-rural differences in prevalence could be influenced by reverse causation, if people who developed such disorders were less likely to migrate than their peers or more likely return home after psychosis onset.

The attempt to use the WHS data to study urban-rural differences in psychosis underscores the need for a new, global vista, long overdue in epidemiologic studies of city living and psychosis. Although these findings do not invalidate Northern European findings on urban living and associated risk of psychotic disorders, they do challenge us to investigate whether such gradients exist elsewhere and understand why or why not this may be the case.

Moreover, global investigations of PEs are important in their own right, given that they predict several adverse psychopathologies. In this regard, it is unfortunate that DeVylder et al were unable to contextualize cultural variation between and within these vastly different countries to explore reasons for the apparent heterogeneity in urban-rural differences in PE prevalence, instead favoring a meta-analytic approach which led to pooled, null effects. A multitude of factors may account for why PEs were more apparent in urban Laos, Estonia, and Mali and rural Vietnam, Hungary, and South Africa, which, given the large WHS sample sizes, were unlikely to be chance findings. For example, the social construction of urban environments in each of these countries is likely to vary, following complex historical, sociocultural morphologies that alter both the patterns of exposure to putative social or biological risk factors in such environments, as well as the very meaning of urban or rural living. More fundamentally, we know little about possible cross-cultural variation in endorsement of PEs between or within LMICs, which could have contributed to differential urban-rural patterns in the WHS data.

Despite these limitations, these results press us to build theory and collect in-depth empirical data that reveal the variety of meanings of city living across contexts, and explain how and why observed associations between city living and psychotic disorders differ across these contexts. A recent study of men in Chengdu, China, underscores how profoundly the meaning of city living might differ by sociocultural and historical context, where rapid urbanization has been driven by rural-to-urban labor migration over a single generation. Here, rural-to-urban labor migrants were not found to be at increased risk of severe psychotic symptoms indicative of likely disorder, but men born in more urban areas were. Such data allow us to generate new theories in this context. Perhaps internal migrants are a selectively resilient group relative to men born in Chinese cities, those left behind, and those who returned to rural areas. Perhaps early-life exposure to adversities in urban environments holds greater causative relevance for psychotic disorders than adulthood exposure. Perhaps settlement patterns for labor migrants in Chengdu foster strong bonding social capital, irrespective of material conditions.

Overcoming some of the challenges above will require us to expand carefully conducted incidence studies of psychotic disorder in LMIC settings. This could provide a falsifiable methodology for testing different causative theories in samples across different settings, with different patterns of genetic, social, and biological exposures. Such studies will also be vital for global public mental health, given the seismic shifts in population dynamics anticipated over the next 30 years; by 2050, the United Nations anticipates that two-thirds of the world’s population will live in cities, with 90% of this growth occurring in Africa and Asia. The WHS findings stimulate us to expand our scope of enquiry, and as such, they are important for psychosis research.

As with all public health issues, however, the costs of misinterpreting their results may have negative unintended consequences. Just as we should not expect a universal association between city living and psychotic disorders, nor should we infer from pooled results on PEs across heterogeneous, uncharacterized settings that such associations do not exist. Rather, we should anticipate and seek to understand the causes of heterogeneous associations between city living and psychotic disorders as we develop a global purview of the epidemiology of psychotic disorders in a fast-changing world.”

Kirkbride JB, Keyes KM, Susser E: City Living and Psychotic Disorders – Implications of Global Heterogeneity for Theory Development. JAMA Psychiatry 75(12):1211-1212 (2018).

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