Introduction to age-related cognitive-behavioural changes.

Despite the many neuroimaging studies that suggest gray matter volume reductions in schizophrenia, there is no compelling postmortem evidence to suggest neuronal loss, nor is there a distinctive or specific signature of gray matter abnormalities in schizophrenia. Instead, there appears to be no observed focal lesion that characterizes gray matter pathology in schizophrenia. This state of affairs has led to a movement away from conceptualizing schizophrenia as resulting from a single lesion, to conceptualizing schizophrenia as arising from abnormal communication between brain regions. Abnormal connectivity between brain regions is not a new concept, as Bleuler (1911) postulated such abnormalities. What is new, however, is an appreciation that brain regions that are not spatially proximal may be connected functionally into neural networks and that to understand altered neural connectivity we need to have a better understanding of the connections between brain regions which are made possible by white matter, the main infrastructure in the brain that makes possible long distance communication among neurons. Accordingly, a focus on white matter connections in the brain has become increasingly of interest in schizophrenia, particularly in the areas of imaging studies, postmortem studies, and new animal models of schizophrenia. This special issue focuses on schizophrenia and oligodendrocytes, the latter a class of neuroglia that give rise to myelin. The primary aim of this special issue is to understand and to clarify further white matter pathology in schizophrenia and how it may contribute to disconnectivity among brain regions, which results in the observed cognitive, behavioral, and clinical symptoms in this disorder. The first paper begins with a description of the theory that schizophrenia reflects a disorder of connectivity. The proposition put forth is that schizophrenia is, at least in part, the result of abnormal communication between brain regions that may be spatially distant but nonetheless functionally connected. As white matter is the main infrastructure for brain connectivity, this paper focuses on the use of a magnetic resonance imaging (MRI) technique called diffusion tensor imaging (DTI) to gain insight into the role of white matter abnormalities in schizophrenia. This paper also focuses on the functional implications of white matter abnormalities, particularly with regard to the possible role of myelin in modulating the transmission velocity of neural discharges. The paper ends with a speculative hypothesis about the relationship between gray matter and white matter abnormalities in schizophrenia. The second paper also focuses on altered neuronal connectivity. Here, however, the focus is on altered connectivity and impaired myelination in a postmortem study of schizophrenia and normal controls, where electron microscopy is used to study myelinated fibers and oligodendrocytes. This morphometric study examines myelinated fibers in the prefrontal cortex in both gray and white matter. Six types of abnormal fibers and ultrastructural alterations are described in the schizophrenia sample. The study reveals increased pathological fibers in gray matter in both young and elderly patients that are associated with positive symptoms, while in elderly patients, the frequency of pathological fibers in white matter is increased and these changes are associated with more negative symptoms. The key implication here is that altered myelinated fibers in white matter in schizophrenia likely follow alterations of myelinated fibers in gray matter that occur earlier in the course of illness. The third paper is a postmortem study on age-related changes in the number of oligodendrocytes in prefrontal cortex in schizophrenia, bipolar disorder and major depression. The study reveals an age-related increase in numerical density of oligodendrocytes in layer VI and adjacent white matter of BA9 and 10 that is seen only in normal controls and not in schizophrenia or in mood disorders. The absence of the normal age-related increase in oligodendrocytes in patients suggests that this aspect of normal brain development is dysregulated in schizophrenia and in mood disorders, and confirms postmortem and imaging data, further highlighting the fact that the absence of a normal age-related increase in oligodendrocytes is a key shared feature in these psychiatric populations. The fourth paper reviews white matter abnormalities in schizophrenia, including imaging and postmortem findings on the disconnectivity theory of schizophrenia, a major theme that underlies the three previous papers in this special issue. This paper then reviews some of the white matter diseases that commonly lead to psychotic symptoms and then reviews transgenic and mutant mouse models of schizophrenia. More specifically, genetic mouse models such as Plp1 transgenic mice and mutant mice heterogeneous for either NRG1 or its receptor erbB4, as well as Nogo-A- deficient mice are reviewed. This is followed by a focus on the myelin toxicity model of mice fed cuprizone. In the early stage (the second and third week) of the cuprizone feeding, mice show higher dopamine levels and lower norepinephrine levels in their prefrontal cortex, along with behavioral changes indicative of increased CNS activity. In the late stage (weeks 4–6), when demyelination and oligodendrocyte loss are obvious, mice display cognitive deficits as well as deficits in social interactions that are reminiscent of social withdrawal seen in patients with schizophrenia. Importantly, this cuprizone-feeding mouse may be used as an in vivo platform for psychopharmacological studies testing the effects of antipsychotic drugs on white matter alterations and associated behavioral changes, in addition to providing a new animal model of schizophrenia. The fifth and final paper of this special issue focuses on abnormal behavior and microstructural changes in juvenile mice that are repeatedly exposed to nonneurotoxic levels of amphetamine. These mice are compared with nonamphetamine treated mice. Oligodendrocyte numbers and three proteins expressed in mature oligodendrocytes are investigated in these young male mice at sacrifice. Treated mice showed higher locomotion and impaired spatial working memory, along with lowered Noga-A and GST-pi proteins, and lower MBP proteins, in frontal cortex and hippocampus and fewer mature oligodendrocytes in frontal cortex and corpus callosum, as well as lower MBP staining in frontal cortex, corpus callosum, and hippocampus, than untreated mice. These differences suggest that in wild-type mice late developing white matter is vulnerable to amphetamine and may lead to compromised white matter with increased dopamine in specific brain regions. Not only do these findings explain well the increased locomotion and impaired spatial working memory observed in amphetamine-treated mice, but also may serve as a principle for the amphetamine-treated mouse being used as a novel animal model of schizophrenia. To summarize, compared to the focus on gray matter and neurons, research on white matter and myelin/glial has been sparse in schizophrenia. In this special issue, neuroimaging findings are presented that suggest that myelin abnormalities in schizophrenia may underlie the white matter abnormalities observed using diffusion tensor imaging techniques. Data from postmortem studies also confirm the presence of oligodendrocyte and myelin abnormalities in schizophrenia as well as mood disorders. Oligodendrocytes provide protection and improve communication between brain regions and the oligodendroglia-producing myelin is approaching maturity in the same time frame as the onset of symptoms. Further, normal age-related white matter increases and related gray matter changes that likely predate the white matter changes are dysregulated in schizophrenia and may contribute to the clinical symptomatology of the disease. Finally, the recently developed animal models are not only of help in understanding connectivity abnormalities in schizophrenia but also provide novel platforms to test novel therapeutic approaches for schizophrenic patients. Treatments specifically targeting white matter, for example, may improve on the efficacy of those treatments currently in use. Martha E. Shenton Haiyun Xu Vahram Haroutunian George Bartzokis

For many group-living animals, acquiring adult dominance rank is an important social transition. In species with maternal rank “inheritance,” juveniles appear to acquire their adult rank by receiving coalitionary support from kin and by altering patterns of aggressive behavior as they age. Previous studies of rank acquisition, however, have focused on species with high rates of aggression and coalitionary support. We studied rank acquisition in blue monkeys, a species with relatively low aggression and coalition rates, hypothesizing that individualistic changes in agonistic behavior would accompany rank acquisition while the presence of potential coalition partners would be relatively unimportant. Focusing on juvenile females in a wild population, we evaluated latency to reach maternal status and assessed how agonistic behavior changed with age. We also compared rank acquisition in orphaned vs. non-orphaned juveniles. Females from higher ranking matrilines and those in larger groups took longer to reach their maternal status and having more kin did not accelerate rank acquisition. As they aged, subjects were more likely to show aggression to individuals that they were expected to outrank as adults. Female juveniles also appeared to work their way up the hierarchy by overturning ranks with groupmates sequentially. Most orphans reached their matrilineal rank, though orphans were less likely to reach their matrilineal rank than non-orphans, suggesting that in some cases mothers do play an important role in rank acquisition. Orphans with more or high-ranking kin were not more likely to reach their matrilineal rank. These results support the hypothesis that age-related changes in agonistic behavior accompany rank acquisition in blue monkeys while the availability of kin as coalition partners often has little effect on the process. Behavioral mechanisms underlying maternal rank acquisition may vary between closely related species in conjunction with other patterns of social behavior, such as aggression and coalition rates. In group-living animals with matrilineal hierarchies, individuals are born low-ranking, but eventually acquire a rank similar to their mother’s. In species with high rates of aggression and coalition formation, juveniles reach their mother’s rank by receiving support from kin in aggressive interactions, and by selectively directing aggression to groupmates from lower ranking families. We studied maternal rank acquisition in blue monkeys, hypothesizing that the process might occur differently in a species with low rates of aggression and coalitions. Indeed, the availability of kin appeared to have limited effects on rank acquisition. Maternal rank acquisition was, however, associated with age-related changes in juvenile behavior. We concluded that in some species with matrilineal hierarchies, rank acquisition might occur relatively independent of support from kin.

The relationship between age-related changes in brain structural connectivity (SC) and functional connectivity (FC) with cognition is not well understood. Furthermore, it is not clear whether cognition is represented via a similar spatial pattern of FC and SC or instead is mapped by distinct sets of distributed connectivity patterns. To this end, we used a longitudinal, within-subject, multimodal approach aiming to combine brain data from diffusion-weighted MRI (DW-MRI), and functional MRI (fMRI) with behavioral evaluation, to better understand how changes in FC and SC correlate with changes in cognition in a sample of older adults. FC and SC measures were derived from the multimodal scans acquired at two time points. Change in FC and SC was correlated with 13 behavioral measures of cognitive function using Partial Least Squares Correlation (PLSC). Two of the measures indicate an age-related change in cognition and the rest indicate baseline cognitive performance. FC and SC—cognition correlations were expressed across several cognitive measures, and numerous structural and functional cortical connections, mainly cingulo-opercular, dorsolateral prefrontal, somatosensory and motor, and temporo-parieto-occipital, contributed both positively and negatively to the brain-behavior relationship. Whole-brain FC and SC captured distinct and independent connections related to the cognitive measures. Overall, we examined age-related function-structure associations of the brain in a comprehensive and integrated manner, using a multimodal approach. We pointed out the behavioral relevance of age-related changes in FC and SC. Taken together, our results highlight that the heterogeneity in distributed FC and SC connectivity patterns provide unique information about the variable nature of healthy cognitive aging.

Canine cognitive dysfunction (CCD) is becoming increasingly recognized in veterinary medicine, as dogs live longer and with CCD being highly prevalent among the elderly dog population. Various studies have shown that diet and dietary supplementation can positively influence the clinical signs of CCD, especially if given at an early stage. The aim of this study was to investigate owner use of dietary supplements (DSs) in dogs with age-related behavioral changes. An observational study based on an online questionnaire for owners of dogs with age-related behavioral changes was performed. Out of a total of 394 owners who completed the survey, after noticing age-related behavioral changes, over half of the dogs received DSs (54%), whereas only 8% reported changing their dog's base diet. The most used DS was fish oil (48%). The use of DSs should be discussed with and monitored by veterinary surgeons since many geriatric patients have multi-morbidities, may have specific nutritional requirements and receive multi-faceted medications.

MRI-based finite element analysis (MRI-FEA) is the only method able to assess microstructural and whole-bone mechanical properties of the hip in vivo. To examine whether MRI-FEA is capable of discriminating age-related changes in whole-bone mechanical performance and micromechanical behavior of the proximal femur, particularly considering the most common hip fracture-related sideways fall loading. Retrospective. A total of nine younger (27 ± 3.2 years) and nine elderly (61 ± 3.9 years) healthy volunteers. 3T; 3D fast field echo sequence. The left proximal femurs were scanned and FE models created. FEA was performed to simulate sideways fall and stance loading for each femoral model. Apparent stiffness and high-risk (90th percentile) tensile and compressive strains of the proximal femur as well as the average strains within cubic regions of the femoral neck and greater trochanter were assessed. Paired and unpaired t-tests. Compared to the young group, the femoral stiffness of the elderly decreased by 39% and 40% (both P < 0.05) under the sideways fall and stance conditions, respectively. Accordingly, the high-risk tensile and compressive stains were elevated with aging (40% and 23% for sideways fall, 23% and 11% for stance conditions; all P < 0.05). However, the loading configuration-induced difference was only observed in the elderly group for the high-risk strains (22% for tension and 12% for compression; both P < 0.05). Additionally, compared to the stance condition, the sideways fall increased the average tensile (young: 108%, elderly: 123%; both P < 0.05) and compressive strains (young: 631%, elderly: 617%, both P < 0.05) within the greater trochanter rather than the femoral neck region. In vivo MRI-FEA is capable of capturing age-related changes in both apparent-level stiffness and tissue-level micromechanical behavior of the proximal femur. However, the effect of sideways fall loading might be better reflected by tissue-level micromechanics rather than apparent stiffness. 3 TECHNICAL EFFICACY STAGE: 1.

High reproductive performance is the key attribute of male fitness, especially due to the high reproductive skew among the males of most animal species. Males of long-lived iteroparous species have opportunities to improve upon their previous reproductive attempts with increasing age. We collected individual-specific reproductive behaviour and age data on a cyprinid fish, the asp (Leuciscus aspius), from 2015 to 2019. We tested whether males changed their performance over time using a unique dataset where individual performance was recorded yearly with passive telemetry. Individual fish behaviour was tracked from one to five reproductive seasons at least a year after the tagging. Fish were scored by measures of quality (first arrival time, number of visits and time spent in the reproductive grounds, and encountered proportion of males to all adult fish). In general, fish improved in the first three metrics with age, suggesting a shift towards behaviours likely to enhance reproductive success as individuals aged. A larger size at tagging was predictive of earlier fish arrival on the spawning ground in subsequent years. Our study therefore demonstrates the importance of age as a factor when considering the potential reproductive success of long-lived fish species.Significance statementHigh reproductive performance is the key attribute of male fitness. Males of long-lived species reproducing multiple times in their life have opportunities to improve upon their previous reproductive performance with increasing age. In this 5-year study, we tracked a large cyprinid fish with telemetry systems during their reproduction. We investigated the age-related behavioural changes in males and demonstrated the improvement of male reproductive timing and length of stay with potential repercussions for male’s reproductive output. We emphasize the importance of old and experienced individuals among the fish population, which are often targeted and selectively removed from the human-managed waters.

Background and Purpose: Behavioral abnormalities account for much of the morbidity of vascular dementia (VaD) and Alzheimer’s disease (AD). The goals of the study were to compare the behavioral changes in patients with VaD associated with ischemic white matter subcortical changes and lacunar infarctions (VaD-WSI) to those in patients with AD. Methods: Thirty outpatients with VaD and multiple lacunar infarctions in the periventricular white matter and 30 AD patients, matched for age and severity of dementia, were enrolled in this prospective study. The behavioral abnormalities of these patients were assessed by interviewing their caregivers with the Neuropsychiatric Inventory. Results: A similar spectrum of noncognitive behavioral changes was found in AD and WSI patients. In VaD-WSI, the severity of delusions, hallucinations, aggression, irritability, aberrant motor behavior, nighttime behavior and appetite changes was correlated with cognitive decline, whereas depression, apathy, anxiety and euphoria were unrelated to the severity of dementia. In AD, none of the behavioral changes correlated with the severity of dementia. Conclusion: Behavioral changes are frequent in VaD-WSI and are present regardless of the severity of the cognitive decline. It is therefore important to assess behavioral as well as cognitive changes at early stages of the illness, to ensure appropriate treatment.

BackgroundMaternal immune activation (MIA) during gestation can increase the later risk of schizophrenia in adult offspring. Neuroinflammation is believed to underlie this process. Postmortem brain studies have found changes in the neuroimmune systems of patients with schizophrenia. However, little is known about the dynamic changes in cerebral inflammation and behavior during the course of the disease.MethodsHere, the prepulse inhibition (PPI) test was conducted in adolescent and adult Sprague–Dawley rats prenatally challenged with polyriboinosinic–polyribocytidylic acid (Poly I:C) on gestational day 9 to determine the behavioral trajectory triggered by early exposure to Poly I:C. Brain immune changes were determined in the prefrontal cortex (PFC) and hippocampus (HC) at both ages. The status of the microglia and astrocytes was determined with immunohistochemical staining. The levels of IL-6, IL-1β, and TNF-α in both brain regions were evaluated with enzyme-linked immunosorbent assays.ResultsDisrupted PPI, the core phenotype of schizophrenia, only emerged in adulthood. Behavioral changes during puberty and adulthood were both accompanied by the activation of microglia (PFC and HC). Astrocytes were only activated at PN60. The levels of proinflammatory cytokines (IL-1β, IL-6, and TNF-α) in the offspring of the Poly I:C-exposed mothers differed with brain region and time, with more cytokines elevated during periadolescence than during adulthood.ConclusionsOur findings indicate that immune activation emerged before symptom manifestation in the offspring of MIA rats. We conclude that early prenatal Poly I:C challenge can lead to age-related behavioral and neuroinflammatory changes. These data provide new insight into the neuroinflammatory and neuropathological mechanisms underlying the development of schizophrenia. They also suggest that periadolescence could be more important than adulthood in the prevention and treatment of schizophrenia.

ObjectivesThe present study aimed to identify immune, metabolic, and hematological biomarkers, among those commonly monitored in clinical practice, that are predictive of age-related behavioral and cognitive changes in clinically healthy elderly cats, with the objective of highlighting potential patterns of inflammaging.MethodsA cross-sectional observational study was conducted at two veterinary institutions and involved 90 clinically healthy, privately owned domestic cats aged 7–16 years. All cats underwent physical examinations, laboratory, and behavioral screenings. Serum concentrations of the pro-inflammatory cytokine interleukin-1beta (IL-1β) and the anti-inflammatory cytokine IL-10 were measured using ELISA as markers of peripheral inflammation. Behavioral and cognitive changes were assessed using the Feline Behavioral Assessment and Research Questionnaire and Feline Cognitive Dysfunction Rating Chart, respectively. Multivariate regression analysis was used to assess the association between behavioral and cognitive outcomes and immune, metabolic, and biochemical predictors (p < 0.05).ResultsSignificant associations were identified between immune, hematological, and metabolic phenotypes indicative of chronic inflammation and cognitive changes assessed using the FCDRS Sleep–wake cycle disturbances were strongly and positively predicted by increased body condition score (BCS), alanine aminotransferase (ALT), creatinine, white blood cells (WBCs), globulin, and IL-1β levels, and negatively predicted by albumin and neutrophils. Anxiety was positively associated with higher BCS, creatinine, and IL-10, and negatively associated with IL-1β. Activity levels were positively predicted by IL-10. Altered social interactions and house-soiling were significantly associated with increased BCS.Conclusion and relevanceFindings suggest that changes in physiological parameters describing patterns of chronic inflammation are associated with measurable cognitive changes in aging cats, in the absence of overt clinical disease, which is consistent with the concept of inflammaging. Routine monitoring of standard bloodwork and BCS may offer an accessible means of tracking chronic subclinical inflammation and predicting cognitive aging in senior feline patients. These results highlight the importance of proactive cognitive screening and client education to preserve welfare and the human-animal bond in aging cats.

New models in which aging-related neurodegeneration more closely resembling the combination of pathologies that develop in aging humans, are needed. The fish Nothobranchius, which naturally develops such pathologies over the course of its short lifespan, is one such model. This review compares the lifespans and pathologies of different Nothobranchius strains to those of current vertebrate models of aging. Furthermore, existing data pertaining to neurodegeneration in these fish is discussed in the context of their reported neuropathologies, along with open questions related to mammalian chronopathologies. Specifically, the evidence for a Parkinson's disease-like pathology is discussed. Neurogenesis and age-related changes therein are discussed in the context of siRNA and neurodegeneration. We also discuss changes in the expression of neuropeptide Y in relation to the brain-gut axis and how these change with age. Age-related behavioral changes are discussed, along with the assays used in their evaluation. Genetic discoveries are outlined and discussed with a view on DJ-1/NRF2 signaling in N. furzeri, and insights gained from comparative genomics and siRNA studies. Finally, research focus areas are highlighted, and a case is made for the utility of these fish in the study of aging-related neurodegeneration, and to screen for environmental risk factors of aging-related neuropathology.

To investigate age-related behavioral changes with the administration of cocaine, young (6-10 mo), middle-aged (12-18 mo), young-old (21-24 mo), and old (25-36 mo) rats that had been trained on a 2-choice, discrete trial vigilance task were tested under different doses of cocaine. The young and middle-aged rats exhibited significantly increased accuracy and decreased choice latencies following 2.5 mg/kg cocaine. A 15.0 mg/kg dose increased variability in these measures and increased food retrieval latencies. The young-old and old rats exhibited no significant changes in accuracy or choice latency to 1.25, 2.5, and 5.0 mg/kg cocaine; however, a dose of 15.0 mg/kg significantly reduced accuracy in both these groups and increased choice latencies in the old animals. Also, doses of 5.0 and 15.0 mg/kg tended to increase food retrieval latencies more in the two older groups than in the two younger groups. These results indicate that, rather than a simple increase or decrease in sensitivity, there is a qualitative change in cocaine's behavioral effects as rats age. These findings may reconcile long-standing discrepancies in the literature regarding age-related changes in the behavioral effects of amphetamine, with actions and effects very similar to those of cocaine.

Self-injurious behaviour (SIB) is a common problem among individuals with intellectual and developmental disabilities (IDDs) with important impacts on quality of life. Although some evidence suggests that SIB may increase with age, perhaps in a curvilinear pattern, this is primarily based on cross-sectional studies. Therefore, the purpose of the current study was to conduct a prospective, longitudinal analysis of age-related changes in a high-risk cohort of children with developmental disabilities/delays. A total of 110 participants, between 2 and 12 years of age at enrolment (70% male), were followed for between 2 and 4 years. Caregivers completed the RBS-EC SIB subscale annually, for a total of 317 assessments. The SIB total score, SIB interference ratings and endorsement of specific topographies were selected as dependent measures. Generalised linear models evaluating linear, quadratic and cubic age-related changes and differences by intellectual disability (ID) status (no or mild ID vs. moderate to profound ID) were created for each outcome. For SIB total scores, the model suggested complex developmental patterns that varied by degree of ID. For SIB interference ratings, the model suggested that individuals with moderate to profound ID showed relatively high and stable levels of SIB interference across ages, whereas individuals with no or mild ID showed an increasing trend with age. Patterns varied across the specific SIB topographies. The results suggest that age-related changes in SIB are complex and may vary across topographies. Overall, the results are concerning in that they indicate a potentially increasing trend in frequency of SIB and its impact on daily activities as individuals approach adolescence, indicating the need for further longitudinal work across the lifespan.

The effect of breed on age-related changes in behavior and disease prevalence in cognitively normal older community dogs, Canis lupus familiaris

Brain Aging (Normal): Behavioral, Cognitive, and Personality Consequences

Age-related changes in behavior and sensory perception have been observed in a wide variety of animal species. In ants and other eusocial insects, workers often progress through an ordered sequence of olfactory-driven behavioral tasks. Notably, these behaviors are plastic, and workers adapt and rapidly switch tasks in response to changing environmental conditions. In the Florida carpenter ant, smaller minors typically perform most of the work needed to maintain the colony, while the larger majors are specialized for nest defense and rarely engage in these routine tasks. Here, we investigate the effects of age and task group on olfactory responses to a series of odorant blends in minor and major worker castes. Consistent with their respective roles within the colony, we observed significant age-associated shifts in the olfactory responses of minors as they transitioned between behavioral states, whereas the responses of majors remained consistently low regardless of age. Furthermore, we have identified a unitary compound, 3-methylindole, which elicited significantly higher responses and behavioral aversion in minor nurses than in similarly aged foragers suggesting that this compound may play an important role in brood care. Taken together, our results suggest that age- and task-associated shifts in olfactory physiology may play a critical role in the social organization of ant colonies.