Cerebrospinal fluid neurofilament light predicts longitudinal diagnostic change in patients with psychiatric and neurodegenerative disorders.

OBJECTIVE: People with neuropsychiatric symptoms often experience delay in accurate diagnosis. Although cerebrospinal fluid neurofilament light (CSF NfL) shows promise in distinguishing neurodegenerative disorders (ND) from psychiatric disorders (PSY), its accuracy in a diagnostically challenging cohort longitudinally is unknown. METHODS: We collected longitudinal diagnostic information (mean = 36 months) from patients assessed at a neuropsychiatry service, categorising diagnoses as ND/mild cognitive impairment/other neurological disorders (ND/MCI/other) and PSY. We pre-specified NfL > 582 pg/mL as indicative of ND/MCI/other. RESULTS: Diagnostic category changed from initial to final diagnosis for 23% (49/212) of patients. NfL predicted the final diagnostic category for 92% (22/24) of these and predicted final diagnostic category overall (ND/MCI/other vs. PSY) in 88% (187/212), compared to 77% (163/212) with clinical assessment alone. CONCLUSIONS: CSF NfL improved diagnostic accuracy, with potential to have led to earlier, accurate diagnosis in a real-world setting using a pre-specified cut-off, adding weight to translation of NfL into clinical practice.

Plasma neurofilament light in behavioural variant frontotemporal dementia compared to mood and psychotic disorders.

OBJECTIVE: Blood biomarkers of neuronal injury such as neurofilament light (NfL) show promise to improve diagnosis of neurodegenerative disorders and distinguish neurodegenerative from primary psychiatric disorders (PPD). This study investigated the diagnostic utility of plasma NfL to differentiate behavioural variant frontotemporal dementia (bvFTD, a neurodegenerative disorder commonly misdiagnosed initially as PPD), from PPD, and performance of large normative/reference data sets and models. METHODS: Plasma NfL was analysed in major depressive disorder (MDD, n = 42), bipolar affective disorder (BPAD, n = 121), treatment-resistant schizophrenia (TRS, n = 82), bvFTD (n = 22), and compared to the reference cohort (Control Group 2, n = 1926, using GAMLSS modelling), and age-matched controls (Control Group 1, n = 96, using general linear models). RESULTS: Large differences were seen between bvFTD (mean NfL 34.9 pg/mL) and all PPDs and controls (all < 11 pg/mL). NfL distinguished bvFTD from PPD with high accuracy, sensitivity (86%), and specificity (88%). GAMLSS models using reference Control Group 2 facilitated precision interpretation of individual levels, while performing equally to or outperforming models using local controls. Slightly higher NfL levels were found in BPAD, compared to controls and TRS. CONCLUSIONS: This study adds further evidence on the diagnostic utility of NfL to distinguish bvFTD from PPD of high clinical relevance to a bvFTD differential diagnosis, and includes the largest cohort of BPAD to date. Using large reference cohorts, GAMLSS modelling and the interactive Internet-based application we developed, may have important implications for future research and clinical translation. Studies are underway investigating utility of plasma NfL in diverse neurodegenerative and primary psychiatric conditions in real-world clinical settings.

"Keeping our distance": Older adults' experiences during year one of the COVID-19 pandemic and lockdown in Australia.

The first year of the COVID-19 pandemic had a profound impact on everyday life in Australia despite relatively low infection rates. Lockdown restrictions were among the harshest in the world, while older adults were portrayed as especially vulnerable by politicians and the media. This study examines the perceptions and experiences of the pandemic and lockdowns among 31 older Australians. We investigated how participants perceived their own vulnerability, their attitudes towards lockdowns and protective behaviors, and how the pandemic affected everyday life. We found that participants were cautious about COVID-19 and vigilant observers of physical distancing. Despite approving of public health guidelines and lockdowns, participants raised concerns about weakening social ties and prolonged social isolation. Those living alone or lacking strong family ties were most likely to report increased loneliness. Most participants nonetheless regarded themselves as "fortunate": they perceived older age as affording them financial, emotional, and relational stability, which insulated them from the worst impacts of the coronavirus pandemic. In their views, financial independence and post-retirement lifestyles helped them adapt to isolation and the disruption of lockdowns.

Differential involvement of the anterior and posterior hippocampus, parahippocampus, and retrosplenial cortex in making precise judgments of spatial distance and object size for remotely acquired memories of environments and objects.

The hippocampus is known to support processing of precise spatial information in recently learned environments. It is less clear, but crucial for theories of systems consolidation, to know whether it also supports processing of precise spatial information in familiar environments learned long ago and whether such precision extends to objects and numbers. In this fMRI study, we asked participants to make progressively more refined spatial distance judgments among well-known Toronto landmarks (whether landmark A is closer to landmark B or C) to examine hippocampal involvement. We also tested whether the hippocampus was similarly engaged in estimating magnitude regarding sizes of familiar animals and numbers. We found that the hippocampus was only engaged in spatial judgment. Activation was greater and lasted longer in the posterior than anterior hippocampus, which instead showed greater modulation as discrimination between spatial distances became more fine grained. These findings suggest that the anterior and posterior hippocampus have different functions which are influenced differently by estimation of differential distance. Similarly, parahippocampal-place-area and retrosplenial cortex were involved only in the spatial condition. By contrast, activation of the intraparietal sulcus was modulated by precision in all conditions. Therefore, our study supports the idea that the hippocampus and related structures are implicated in retrieving and operating even on remote spatial memories whenever precision is required, as posted by some theories of systems consolidation.

The impact of strict lockdowns on the mental health and well-being of people living in Australia during the first year of the COVID-19 pandemic.

BACKGROUND: There are limited longitudinal studies on the effects of the COVID-19 pandemic on mental health and well-being, including the effects of imposed restrictions and lockdowns. AIMS: This study investigates how living in a pandemic, and related lockdowns and restrictions, affected the mental health of people living in Australia during the first year of the COVID-19 pandemic. METHOD: A total of 875 people living in Australia participated in a longitudinal survey from 27 May to 14 December 2020. This time period includes dates that span pre-, during and post-wave 2 lockdowns in Australia, with strict and sustained public health measures. Linear mixed models were fitted to investigate the effect of lockdown on depression and anxiety symptoms. RESULTS: Symptoms of depression and anxiety improved over time, during and after lockdowns. More adverse mental health symptoms were observed for people with a history of medical or mental health problems, caring responsibilities, more neurotic personality traits or less conscientiousness, and for people who were younger. People who reported being more conscientious reported better mental health. CONCLUSIONS: Despite notoriously strict lockdowns, participants did not experience a deterioration of mental health over time. Results suggest a lack of significant adverse effects of lockdown restrictions on mental health and well-being. Findings highlight cohorts that could benefit from targeted mental health support and interventions, so that public policy can be better equipped to support them, particularly if future strict public health measures such as lockdowns are being considered or implemented for the COVID-19 pandemic and other disasters.

The Text4HealthyAging Program: An Evidence-Based Text Messaging Innovation to Support Healthy Urban Aging in Canada and Australia.

Age-friendly cities are crucial to achieve the WHO goal of healthy aging. Such cities promote opportunities for health, participation, and security, thus enhancing quality of life as people age. Older people commonly experience psychosocial challenges such as anxiety, depression, substance abuse, loss of autonomy, grief, fear, and loneliness. Australian and Canadian cities continue to seek innovation to improve healthy urban aging and create more age-friendly environments for older adults. There is increasing evidence on the effectiveness and feasibility of mobile technology in health promotion and closing psychological treatment gaps. Older adults have been demonstrated to engage frequently with mobile devices, particularly text messaging. In this article, we conceptualize the Text4HealthyAging, an evidence-based text messaging innovation to support healthy urban aging in Canadian and Australian cities.

Recalling the firedog: Individual differences in associative memory for unitized and nonunitized associations among older adults.

Memory deficits in aging are characterized by impaired hippocampus-mediated relational binding-the formation of links between items in memory. By reducing reliance on relational binding, unitization of two items into one concept enhances associative recognition among older adults. Can a similar enhancement be obtained when probing memory with recall? This question has yet to be examined, because recall has been assumed to rely predominantly on relational binding. Inspired by recent evidence challenging this assumption, we investigated individual differences in older adults' recall of unitized and nonunitized associations. Compared with successfully aging individuals, older adults with mild memory deficits, typically mediated by the hippocampus, were impaired in recall of paired-associates in a task which relies on relational binding (study: "PLAY-TUNNEL"; test: PLAY-T?). In stark contrast, the two groups showed similar performance when items were unitized into a novel compound word (study: "LOVEGIGGLE"; test: LOVEG?). Thus, boosting nonrelational aspects of recall enhances associative memory among aging individuals with subtle memory impairments to comparable levels as successfully aging older adults.

Eye Movement Reinstatement and Neural Reactivation During Mental Imagery.

Half a century ago, Donald Hebb posited that mental imagery is a constructive process that emulates perception. Specifically, Hebb claimed that visual imagery results from the reactivation of neural activity associated with viewing images. He also argued that neural reactivation and imagery benefit from the re-enactment of eye movement patterns that first occurred at viewing (fixation reinstatement). To investigate these claims, we applied multivariate pattern analyses to functional MRI (fMRI) and eye tracking data collected while healthy human participants repeatedly viewed and visualized complex images. We observed that the specificity of neural reactivation correlated positively with vivid imagery and with memory for stimulus image details. Moreover, neural reactivation correlated positively with fixation reinstatement, meaning that image-specific eye movements accompanied image-specific patterns of brain activity during visualization. These findings support the conception of mental imagery as a simulation of perception, and provide evidence consistent with the supportive role of eye movement in neural reactivation.

Superior Memory Reduces 8-year Risk of Mild Cognitive Impairment and Dementia But Not Amyloid ß-Associated Cognitive Decline in Older Adults.

OBJECTIVE: To prospectively examine 8-year risk of clinical disease progression to mild cognitive impairment (MCI)/dementia in older adults ≥60 with superior episodic memory (SuperAgers) compared to those cognitively normal for their age (CNFA). Additionally, to determine the extent to which SuperAgers were resilient to the negative effects of elevated amyloid-beta (Aß+) on cognition. METHOD: Participants were classified as SuperAgers based on episodic memory performance consistent with younger adults aged 30-44 and no impairment on non-memory tests (n = 179), and were matched with CNFA on age, sex, education, and follow-up time (n = 179). Subdistribution hazard models examined risk of clinical progression to MCI/dementia. Linear mixed models assessed the effect of Aß on cognition over time. RESULTS: Prevalence of Aß+ and APOE ε4 was equivalent between SuperAgers and CNFA. SuperAgers had 69%-73% reduced risk of clinical progression to MCI/dementia compared to CNFA (HR: 0.27-0.31, 95% CI: 0.11-0.73, p < .001). Aß+ was associated with cognitive decline in verbal memory and executive function, regardless of SuperAger/CNFA classification. In the absence of Aß+, equivalent age-related changes in cognition were observed between SuperAgers and CNFA. CONCLUSIONS: SuperAgers displayed resilience against clinical progression to MCI/dementia compared to CNFA despite equivalent risk for Alzheimer's disease (AD); however, SuperAgers had no greater protection from Aß+ than CNFA. The deleterious effects of Aß on cognition persist regardless of baseline cognitive ability. Thus, superior cognitive performance does not reflect resistance against the neuropathological processes associated with AD, and the observed resilience for SuperAgers may instead reflect neuropsychological criteria for cognitive impairment.

Rates of age- and amyloid ß-associated cortical atrophy in older adults with superior memory performance.

INTRODUCTION: Superior cognitive performance in older adults may reflect underlying resistance to age-associated neurodegeneration. While elevated amyloid ß (Aß) deposition (Aß+) has been associated with increased cortical atrophy, it remains unknown whether "SuperAgers" may be protected from Aß-associated neurodegeneration. METHODS: Neuropsychologically defined SuperAgers (n = 172) and cognitively normal for age (n = 172) older adults from the Australian Imaging, Biomarkers and Lifestyle study were case matched. Rates of cortical atrophy over 8 years were examined by SuperAger classification and Aß status. RESULTS: Of the case-matched SuperAgers and cognitively normal for age older adults, 40.7% and 40.1%, respectively, were Aß+. Rates of age- and Aß-associated atrophy did not differ between the groups on any measure. Aß- individuals displayed the slowest rates of atrophy. DISCUSSION: Maintenance of superior memory in late life does not reflect resistance to age- or Aß-associated atrophy. However, those individuals who reached old age without cognitive impairment nor elevated Aß deposition (i.e. Aß-) displayed reduced rates of cortical atrophy.

Relationship Between Amyloid-ß Positivity and Progression to Mild Cognitive Impairment or Dementia over 8 Years in Cognitively Normal Older Adults.

BACKGROUND: Preclinical Alzheimer's disease (AD) is defined by cerebral amyloid-ß positivity (Aß+) in cognitively normal (CN) older adults. OBJECTIVE: To estimate the risk of progression to the symptomatic stages of AD due to PET Aß+ and the extent that progression was influenced by other demographic, genetic, and clinical characteristics in a large prospective study. METHODS: Fine-Gray subdistribution modeling was used to examine the risk of progression from CN to MCI/dementia due to Aß+, APOEɛ4 carriage, and their interaction in the Australian Imaging, Biomarkers and Lifestyle (AIBL) flagship study of aging CN cohort (n = 599) over 8 years. RESULTS: 17.7% Aß+ and 8.1% Aß-progressed over 8 years (OR: 2.43). Risk of progression for Aß+ was 65-104% greater than Aß-. Aß+ APOEɛ4 carriers were at 348% greater risk than all other participants. Significant risk factors of progression in Aß+ were age (HR: 1.05), PET SUVR (HR: 2.49) and APOE ɛ4 carriage (HR: 2.63); only age was a significant risk factor in Aß-(HR: 1.09). Aß-progressors were not near the threshold for Aß+. These relationships were not moderated by hypertension, diabetes, obesity, or stroke/TIA. CONCLUSION: Aß+ is an important prognostic marker for progression from CN to MCI/dementia in older adults and APOEɛ4 carriage provides further predictive value in the presence of Aß+. These data suggest that Aß-associated clinical progression is consistent with clinical-pathological models of AD, whereas progression in the absence of elevated Aß deposition may be the result of neuropathological processes other than AD that accumulate with age.

Estimates of age-related memory decline are inflated by unrecognized Alzheimer's disease.

Cognitive decline is considered an inevitable consequence of aging; however, estimates of cognitive aging may be influenced negatively by undetected preclinical Alzheimer's disease (AD). This study aimed to determine the extent to which estimates of cognitive aging were biased by preclinical AD. Cognitively normal older adults (n = 494) with amyloid-ß status determined from positron emission tomography neuroimaging underwent serial neuropsychological assessment at 18-month intervals over 72 months. Estimates of the effects of age on verbal memory, working memory, executive function, and processing speed were derived using linear mixed models. The presence of preclinical AD and clinical progression to mild cognitive impairment or dementia during the study were then added to these models as covariates. Initially, age was associated with decline across all 4 cognitive domains. With the effects of elevated amyloid-ß and clinical progression controlled, age was no longer associated with decline in verbal or working memory. However, the magnitude of decline was reduced only slightly for executive function and was unchanged for processing speed. Thus, considered together, the results of the study indicate that undetected preclinical AD negatively biases estimates of age-related cognitive decline for verbal and working memory.

Correction: Unhealthy habits persist: The ongoing presence of modifiable risk factors for disease in women.

[This corrects the article DOI: 10.1371/journal.pone.0173603.].

Unhealthy habits persist: The ongoing presence of modifiable risk factors for disease in women.

OBJECTIVES: Vascular disease remains a leading cause of death. There are several vascular risk factors identified that can mitigate development of disease in ageing. We examine reported rates of modifiable risk factors in women responding to an online health questionnaire advertised by popular media. METHODS: A sample of 26 620 women aged over 18 was examined in 2015 with a cross-sectional health questionnaire. The questionnaire included self-reported health, mood, lifestyle and vascular risk factors. RESULTS: There remains high rates of modifiable risk factors present in women. The vast majority of women (80%) reported not eating enough fruit and vegetables. Compared to the guidelines for health, the majority did not perform enough weekly physical activity (70%) and more than half the participants were overweight (54%). Sufficient fruit, vegetables, fish, legumes and physical activity were reported in less than 30% of women! CONCLUSIONS: Women continue to report low rates of physical activity, fruit and vegetable intake and higher BMI than recommended for good health, despite worldwide health promotion activities aimed at changing these lifestyle factors. Programs to support healthy living need to be reviewed and revised to reduce the burden of vascular disease and dementia in women. Previous guidelines are not having the important impact they should, particularly in women.