A high-resolution transcriptomic and spatial atlas of cell types in the whole mouse brain.

The mammalian brain consists of millions to billions of cells that are organized into many cell types with specific spatial distribution patterns and structural and functional properties1-3. Here we report a comprehensive and high-resolution transcriptomic and spatial cell-type atlas for the whole adult mouse brain. The cell-type atlas was created by combining a single-cell RNA-sequencing (scRNA-seq) dataset of around 7 million cells profiled (approximately 4.0 million cells passing quality control), and a spatial transcriptomic dataset of approximately 4.3 million cells using multiplexed error-robust fluorescence in situ hybridization (MERFISH). The atlas is hierarchically organized into 4 nested levels of classification: 34 classes, 338 subclasses, 1,201 supertypes and 5,322 clusters. We present an online platform, Allen Brain Cell Atlas, to visualize the mouse whole-brain cell-type atlas along with the single-cell RNA-sequencing and MERFISH datasets. We systematically analysed the neuronal and non-neuronal cell types across the brain and identified a high degree of correspondence between transcriptomic identity and spatial specificity for each cell type. The results reveal unique features of cell-type organization in different brain regions-in particular, a dichotomy between the dorsal and ventral parts of the brain. The dorsal part contains relatively fewer yet highly divergent neuronal types, whereas the ventral part contains more numerous neuronal types that are more closely related to each other. Our study also uncovered extraordinary diversity and heterogeneity in neurotransmitter and neuropeptide expression and co-expression patterns in different cell types. Finally, we found that transcription factors are major determinants of cell-type classification and identified a combinatorial transcription factor code that defines cell types across all parts of the brain. The whole mouse brain transcriptomic and spatial cell-type atlas establishes a benchmark reference atlas and a foundational resource for integrative investigations of cellular and circuit function, development and evolution of the mammalian brain.

Connectome-based predictive modelling of cognitive reserve using task-based functional connectivity.

Cognitive reserve supports cognitive function in the presence of pathology or atrophy. Functional neuroimaging may enable direct and accurate measurement of cognitive reserve which could have considerable clinical potential. The present study aimed to develop and validate a measure of cognitive reserve using task-based fMRI data that could then be applied to independent resting-state data. Connectome-based predictive modelling with leave-one-out cross-validation was applied to predict a residual measure of cognitive reserve using task-based functional connectivity from the Cognitive Reserve/Reference Ability Neural Network studies (n = 220, mean age = 51.91 years, SD = 17.04 years). This model generated summary measures of connectivity strength that accurately predicted a residual measure of cognitive reserve in unseen participants. The theoretical validity of these measures was established via a positive correlation with a socio-behavioural proxy of cognitive reserve (verbal intelligence) and a positive correlation with global cognition, independent of brain structure. This fitted model was then applied to external test data: resting-state functional connectivity data from The Irish Longitudinal Study on Ageing (TILDA, n = 294, mean age = 68.3 years, SD = 7.18 years). The network-strength predicted measures were not positively associated with a residual measure of cognitive reserve nor with measures of verbal intelligence and global cognition. The present study demonstrated that task-based functional connectivity data can be used to generate theoretically valid measures of cognitive reserve. Further work is needed to establish if, and how, measures of cognitive reserve derived from task-based functional connectivity can be applied to independent resting-state data.

Age-related normative changes in cerebral perfusion: Data from The Irish Longitudinal Study on Ageing (TILDA).

OBJECTIVE: To establish normative reference values for total grey matter cerebral blood flow (CBFGM) measured using pseudo-continuous arterial spin labelling (pCASL) MRI in a large cohort of community-dwelling adults aged 54 years and older. BACKGROUND: Quantitative assessment of CBFGM may provide an imaging biomarker for the early detection of those at risk of neurodegenerative diseases, such as Alzheimer's and dementia. However, the use of this method to differentiate normal age-related decline in CBFGM from pathological reduction has been hampered by the lack of reference values for cerebral perfusion. METHODS: The study cohort comprised a subset of wave 3 (2014-2015) participants from The Irish Longitudinal Study on Ageing (TILDA), a large-scale prospective cohort study of individuals aged 50 and over. Of 4309 participants attending for health centre assessment, 578 individuals returned for 3T multi-parametric MRI brain examinations. In total, CBFGM data acquired from 468 subjects using pCASL-MRI were included in this analysis. Normative values were estimated using Generalised Additive Models for Location Shape and Scale (GAMLSS) and are presented as percentiles, means and standard deviations. RESULTS: The mean age of the cohort was 68.2 ± 6.9 years and 51.7% were female. Mean CBFGM for the cohort was 36.5 ± 8.2 ml/100 g/min. CBFGM decreased by 0.2 ml/100 g/min for each year increase in age (95% CI = -0.3, -0.1; p ≤ 0.001) and was 3.1 ml/100 g/min higher in females (95% CI = 1.6, 4.5; p ≤ 0.001). CONCLUSIONS: This study is by far the largest single-site study focused on an elderly community-dwelling cohort to present normative reference values for CBFGM measured at 3T using pCASL-MRI. Significant age- and sex-related differences exist in CBFGM.

Impaired orthostatic heart rate recovery is associated with smaller thalamic volume: Results from The Irish Longitudinal Study on Aging (TILDA).

The thalamus is a central hub of the autonomic network and thalamic volume has been associated with high-risk phenotypes for sudden cardiac death. Heart rate response to physiological stressors (e.g., standing) and the associated recovery patterns provide reliable indicators of both autonomic function and cardiovascular risk. Here we examine if thalamic volume may be a risk marker for impaired heart rate recovery in response to orthostatic challenge. The Irish Longitudinal Study on Aging involves a nationally representative sample of older individuals aged ≥50 years. Multimodal brain magnetic resonance imaging and orthostatic heart rate recovery were available for a cross-sectional sample of 430 participants. Multivariable regression and linear mixed-effects models were adjusted for head size, age, sex, education, body mass index, blood pressure, history of cardiovascular diseases and events, cardiovascular medication, diabetes mellitus, smoking, alcohol intake, timed up-and-go (a measure of physical frailty), physical exercise and depression. Smaller thalamic volume was associated with slower heart rate recovery (-1.4 bpm per 1 cm3 thalamic volume, 95% CI -2.01 to -0.82; p < .001). In multivariable analysis, participants with smaller thalamic volumes had a mean heart rate recovery -2.7 bpm slower than participants with larger thalamic volumes (95% CI -3.89 to -1.61; p < .001). Covariates associated with smaller thalamic volume included age, history of diabetes, and heavy alcohol consumption. Thalamic volume may be an indicator of the structural integrity of the central autonomic network. It may be a clinical biomarker for stratification of individuals at risk of autonomic dysfunction, cardiovascular events, and sudden cardiac death.

Plasma concentrations of vitamin B12 and folate and global cognitive function in an older population: cross-sectional findings from The Irish Longitudinal Study on Ageing (TILDA).

The uncertainty surrounding high intakes of folic acid and associations with cognitive decline in older adults with low vitamin B12 status has been an obstacle to mandatory folic acid fortification for many years. We estimated the prevalence of combinations of low/normal/high vitamin B12 and folate status and compared associations with global cognitive function using two approaches, of individuals in a population-based study of those aged ≥50 years in the Republic of Ireland. Cross-sectional data from 3781 men and women from Wave 1 of The Irish Longitudinal Study on Ageing were analysed. Global cognitive function was assessed by the Mini Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). Prevalence estimates for combinations of vitamin B12 (plasma vitamin B12 < or ≥258 pmol/l) and folate (plasma folate ≤ or >45·3 nmol/l) concentrations were generated. Negative binomial regression models were used to investigate the associations of vitamin B12 and folate status with global cognitive function. Of the participants, 1·5 % (n 51) had low vitamin B12 (<258 pmol/l) and high folate (>45·3 nmol/l) status. Global cognitive performance was not significantly reduced in these individuals when compared with those with normal status for both B-vitamins (n 2433). Those with normal vitamin B12/high folate status (7·6 %) had better cognitive performance (MMSE: incidence rate ratio (IRR) 0·82, 95 % CI 0·68, 0·99; P = 0·043, MoCA: IRR 0·89, 95 % CI 0·80, 0·99; P = 0·025). We demonstrated that high folate status was not associated with lower cognitive scores in older adults with low vitamin B12 status. These findings provide important safety information that could guide fortification policy recommendations in Europe.

The association between frontal lobe perfusion and depressive symptoms in later life.

BACKGROUND: Deficits in frontal lobe perfusion have been demonstrated in late-life depression; however, studies to date have generally involved small numbers, used neuroimaging rather than bedside testing and have not controlled for important covariates.AimsWe aimed to examine the association between depressive symptoms and frontal lobe perfusion during standing, in a large cohort of community-dwelling older people. METHOD: Participants aged ≥50 years underwent continuous measurement of orthostatic blood pressure by finometry, and frontal lobe perfusion by near-infrared spectroscopy. Depressive symptoms were assessed by the eight-item Centre for Epidemiological Studies Depression Scale. Real-time frontal lobe cerebral oxygenation was measured by the Portalite System, detecting changes in frontal lobe perfusion and reporting a tissue saturation index score. RESULTS: Almost 8% (209 out of 2616) had clinically significant depressive symptoms. Multilevel models demonstrated a significantly lower tissue saturation index in participants with depressive symptoms at both 60 and 90 s post-stand, with coefficients of -0.43 (95% CI -0.63 to -0.22) and -0.37 (95% CI -0.57 to -0.16), respectively. Controlling for relevant covariates did not significantly attenuate these associations. After addition of systolic blood pressure this association was no longer significant, suggesting lower blood pressure may modify this relationship. CONCLUSIONS: This study demonstrates that lower frontal lobe perfusion, related to lower values of baseline systolic blood pressure, is associated with clinically significant depressive symptoms in a cohort of community-dwelling older people. Given the recognised longitudinal association between lower blood pressure and depression in older people, this may represent a potential therapeutic target for prevention of incident depression.Declaration of interestNone.

Fear of falling: A manifestation of executive dysfunction?

OBJECTIVE: Fear of falling (FoF) may be an early marker of decline in global cognitive functioning, but associations with specific domains of cognitive functioning are unclear. The aim was to examine associations between FoF and 4-year decline in memory, processing speed, and executive functioning in adults aged 50 years and older. METHODS: Data were from 5174 participants (mean age = 62.6 ± 8.9 years, range = 50-91, 54.5% female) in The Irish Longitudinal Study on Ageing, a population-based study. MEASUREMENTS: FoF was self-reported in 2009 to 2011. Immediate and delayed recall, Colour Trails 1 and 2, choice reaction time, sustained attention to response task, and verbal fluency were measured in 2009 to 2011 and 2014 to 2015. Prospective associations between FoF and domains of cognitive functioning were examined using linear mixed modelling. Adjustment was made for demographic and health factors. Interactions with age were examined. RESULTS: In 2009 to 2011, 20.6% of participants reported FoF. No statistically significant interaction of FoF with age was found for any of the associations (P ≥ .06). Participants with FoF had greater decline on delayed recall (B = -0.19; 95% CI, -0.32 to -0.06), verbal fluency (B = -0.52; 95% CI, -0.88 to -0.18); and the ln-transformed scores for the Colour Trails 1 test (B = -0.04; 95% CI, -0.07 to -0.01) and the Colour Trails 2 test (B = -0.04; 95% CI, -0.06 to -0.02) than participants without FoF. No statistically significant associations were found for any of the other outcomes. CONCLUSIONS: FoF may be an indicator of decline in domains of cognitive functioning, particularly those related to executive function and processing speed. However, studies with longer follow-up and/or higher average age are required to confirm this.

Syntroph diversity and abundance in anaerobic digestion revealed through a comparative core microbiome approach.

Anaerobic digestion is an important biotechnology treatment process for conversion of waste to energy. In this study, a comparative core microbiome approach, i.e., determining taxa that are shared in functioning digesters but not shared in non-functioning digesters, was used to determine microbial taxa that could play key roles for effective anaerobic digestion. Anaerobic digester functions were impaired by adding the broad-spectrum antimicrobial triclosan (TCS) or triclocarban (TCC) at different concentrations, and the core microbiomes in both functioning and non-functioning anaerobic digesters were compared. Digesters treated with high (2500 mg/kg) or medium (450 mg/kg) TCS and high (850 mg/kg) TCC concentrations lost their function, i.e., methane production decreased, effluent volatile fatty acid concentrations increased, and pH decreased. Changes in microbial community diversity and compositions were assessed using 16S rRNA gene amplicon sequencing. Microbial richness decreased significantly in non-functioning digesters (p < 0.001). Microbial community compositions in non-functioning digesters significantly differed from those in functioning digesters (p = 0.001, ANOSIM). Microbes identified as potentially key taxa included previously known fatty acid-degrading syntrophs and amino acid-degrading syntrophs. A diverse group of syntrophs detected in this study had low relative abundance in functioning digesters, suggesting the importance of rare microbes in anaerobic digester operation. The comparative microbiome approach used in this study can be applied to other microbial systems where a community-driven biological phenomena can be observed directly.

Quantitative MRI provides markers of intra-, inter-regional, and age-related differences in young adult cortical microstructure.

Measuring the structural composition of the cortex is critical to understanding typical development, yet few investigations in humans have charted markers in vivo that are sensitive to tissue microstructural attributes. Here, we used a well-validated quantitative MR protocol to measure four parameters (R1, MT, R2*, PD*) that differ in their sensitivity to facets of the tissue microstructural environment (R1, MT: myelin, macromolecular content; R2*: myelin, paramagnetic ions, i.e., iron; PD*: free water content). Mapping these parameters across cortical regions in a young adult cohort (18-39 years, N = 93) revealed expected patterns of increased macromolecular content as well as reduced tissue water content in primary and primary adjacent cortical regions. Mapping across cortical depth within regions showed decreased expression of myelin and related processes - but increased tissue water content - when progressing from the grey/white to the grey/pial boundary, in all regions. Charting developmental change in cortical microstructure cross-sectionally, we found that parameters with sensitivity to tissue myelin (R1 & MT) showed linear increases with age across frontal and parietal cortex (change 0.5-1.0% per year). Overlap of robust age effects for both parameters emerged in left inferior frontal, right parietal and bilateral pre-central regions. Our findings afford an improved understanding of ontogeny in early adulthood and offer normative quantitative MR data for inter- and intra-cortical composition, which may be used as benchmarks in further studies.

Point-to-point overlay of a 100Gb/s DP-QPSK channel in LR-PONs for urban and rural areas.

The continuing growth in information demand from fixed and mobile end-users, coupled with the need to deliver this content in an economically viable manner, is driving new innovations in access networks. In particular, it is becoming increasingly important to find new ways to enable the coexistence of heterogeneous services types which may require different signal modulation formats over the same fiber infrastructure. For example, the same physical layer can potentially be used to deliver shared 10Gb/s services to residential customers, dedicated point-to-point (P2P) 100Gb/s services to business customers, and wireless fronthaul, in a highly cost-effective manner. In this converged scenario, the performance of phase modulated signals can be heavily affected by nonlinear crosstalk from co-propagating on-off-keying (OOK) channels. In this paper, the overlay of a 100G P2P dual-polarization quadrature phase-shift keying (DP-QPSK) channel in a long-reach passive optical network (LR-PON) in the presence of co-propagating 10Gb/s OOK neighboring channels is studied for two different PON topologies. The first LR-PON topology is particularly suited for densely populated areas while the second is aimed at rural, sparsely populated areas. The experimental results indicate that with an emulated load of 40 channels the urban architecture can support up to 100km span and 512 users, while the rural architecture can support up to 120km span and 1024 users. Finally, a system model is developed to predict the system performance and system margins for configurations different from the experimental setups and to carry out design optimization that could in principle lead to even more efficient and robust schemes.

What is the Longitudinal Relationship between Gait Abnormalities and Depression in a Cohort of Community-Dwelling Older People? Data From the Irish Longitudinal Study on Ageing (TILDA).

OBJECTIVE: Does baseline gait disturbance predict incident depression in a cohort of community-dwelling older people? METHODS: This is a longitudinal study, embedded within the Irish Longitudinal Study on Ageing (TILDA), examining the association between baseline depression and incident gait abnormalities, as well as between baseline gait abnormalities and incident depression at 2 year follow-up. Depression was defined as a score of ≥16 on the Centre for Epidemiological Studies Depression Scale (CES-D). Gait abnormality was defined as a Timed Up and Go Test (TUG) ≥12 seconds. Assessments were carried out at baseline and at 2 year follow-up. RESULTS: 7% (179/2,638) had baseline depression and 11% (296/2,638) had a gait abnormality at baseline. The incidence of new-onset depression and gait abnormality at Wave 2 was 4% (95/2,364) and 13% (308/2,342) respectively. Logistic regression models demonstrated that baseline gait abnormality was a significant predictor of incident depression with an Incidence Rate Ratio (IRR) of 2.00 (95% CI: 1.18 - 3.40, p =0.010, t =2.57, df =625), which was not attenuated after controlling for covariates. Baseline depression was a predictor of incident gait abnormality at Wave 2 with an IRR of 1.68 (95% CI: 1.16 - 2.43, p =0.006, t =2.75, df =625) but this association was no longer statistically significant when analysis was adjusted for clinical variables. CONCLUSIONS: This study demonstrates that baseline gait disturbance, measured by TUG, predicts incident depression, defined by CES-D, in a population-representative cohort of community-dwelling older people. Possible biological mechanisms for this relationship include white matter disease and executive dysfunction.

Voluntary fortification is ineffective to maintain the vitamin B12 and folate status of older Irish adults: evidence from the Irish Longitudinal Study on Ageing (TILDA).

Mandatory fortification of staple grains with folic acid and/or vitamin B12 (B12) is under debate in many countries including Ireland, which has a liberal, but voluntary, fortification policy. Older adults can be at risk of both deficiency and high folate status, although little is known on the actual prevalence and the major predictors. Population prevalence estimates from older adults (n 5290 ≥50 years) from the Irish Longitudinal Study on Ageing (TILDA) (Wave 1) are presented here. Measures included plasma total vitamin B12 and folate, whereas predictors included detailed demographic, socio-economic, geographic, seasonal and health/lifestyle data. The prevalence of deficient or low B12 status (45 nmol/l) was observed in 8·9 %, whereas high B12 status was observed in 3·1 % (>601 pmol/l). The largest positive predictor of B12 concentration was self-reported B12 injection and/or supplement use (coefficient 51·5 pmol/; 95 % CI 9·4, 93·6; P=0·016) followed by sex and geographic location. The largest negative predictor was metformin use (-33·6; 95 % CI -51·9, -15·4; P<0·0001). The largest positive predictor of folate concentration was folic acid supplement use (6·0; 95 % CI 3·0, 9·0 nmol/l; P<0·001) followed by being female and statin medications. The largest negative predictor was geographic location (-5·7; 95 % CI -6·7, -4·6; P<0·0001) followed by seasonality and smoking. B-vitamin status in older adults is affected by health and lifestyle, medication, sampling period and geographic location. We observed a high prevalence of low B12 and folate status, indicating that the current policy of voluntary fortification is ineffective for older adults.

Vocal Tract Images Reveal Neural Representations of Sensorimotor Transformation During Speech Imitation.

Imitating speech necessitates the transformation from sensory targets to vocal tract motor output, yet little is known about the representational basis of this process in the human brain. Here, we address this question by using real-time MR imaging (rtMRI) of the vocal tract and functional MRI (fMRI) of the brain in a speech imitation paradigm. Participants trained on imitating a native vowel and a similar nonnative vowel that required lip rounding. Later, participants imitated these vowels and an untrained vowel pair during separate fMRI and rtMRI runs. Univariate fMRI analyses revealed that regions including left inferior frontal gyrus were more active during sensorimotor transformation (ST) and production of nonnative vowels, compared with native vowels; further, ST for nonnative vowels activated somatomotor cortex bilaterally, compared with ST of native vowels. Using test representational similarity analysis (RSA) models constructed from participants' vocal tract images and from stimulus formant distances, we found that RSA searchlight analyses of fMRI data showed either type of model could be represented in somatomotor, temporal, cerebellar, and hippocampal neural activation patterns during ST. We thus provide the first evidence of widespread and robust cortical and subcortical neural representation of vocal tract and/or formant parameters, during prearticulatory ST.

Functional and Quantitative MRI Mapping of Somatomotor Representations of Human Supralaryngeal Vocal Tract.

Speech articulation requires precise control of and coordination between the effectors of the vocal tract (e.g., lips, tongue, soft palate, and larynx). However, it is unclear how the cortex represents movements of and contact between these effectors during speech, or how these cortical responses relate to inter-regional anatomical borders. Here, we used phase-encoded fMRI to map somatomotor representations of speech articulations. Phonetically trained participants produced speech phones, progressing from front (bilabial) to back (glottal) place of articulation. Maps of cortical myelin proxies (R1 = 1/T1) further allowed us to situate functional maps with respect to anatomical borders of motor and somatosensory regions. Across participants, we found a consistent topological map of place of articulation, spanning the central sulcus and primary motor and somatosensory areas, that moved from lateral to inferior as place of articulation progressed from front to back. Phones produced at velar and glottal places of articulation activated the inferior aspect of the central sulcus, but with considerable across-subject variability. R1 maps for a subset of participants revealed that articulator maps extended posteriorly into secondary somatosensory regions. These results show consistent topological organization of cortical representations of the vocal apparatus in the context of speech behavior.

Functional brain outcomes of L2 speech learning emerge during sensorimotor transformation.

Sensorimotor transformation (ST) may be a critical process in mapping perceived speech input onto non-native (L2) phonemes, in support of subsequent speech production. Yet, little is known concerning the role of ST with respect to L2 speech, particularly where learned L2 phones (e.g., vowels) must be produced in more complex lexical contexts (e.g., multi-syllabic words). Here, we charted the behavioral and neural outcomes of producing trained L2 vowels at word level, using a speech imitation paradigm and functional MRI. We asked whether participants would be able to faithfully imitate trained L2 vowels when they occurred in non-words of varying complexity (one or three syllables). Moreover, we related individual differences in imitation success during training to BOLD activation during ST (i.e., pre-imitation listening), and during later imitation. We predicted that superior temporal and peri-Sylvian speech regions would show increased activation as a function of item complexity and non-nativeness of vowels, during ST. We further anticipated that pre-scan acoustic learning performance would predict BOLD activation for non-native (vs. native) speech during ST and imitation. We found individual differences in imitation success for training on the non-native vowel tokens in isolation; these were preserved in a subsequent task, during imitation of mono- and trisyllabic words containing those vowels. fMRI data revealed a widespread network involved in ST, modulated by both vowel nativeness and utterance complexity: superior temporal activation increased monotonically with complexity, showing greater activation for non-native than native vowels when presented in isolation and in trisyllables, but not in monosyllables. Individual differences analyses showed that learning versus lack of improvement on the non-native vowel during pre-scan training predicted increased ST activation for non-native compared with native items, at insular cortex, pre-SMA/SMA, and cerebellum. Our results hold implications for the importance of ST as a process underlying successful imitation of non-native speech.

Triclocarban Influences Antibiotic Resistance and Alters Anaerobic Digester Microbial Community Structure.

Triclocarban (TCC) is one of the most abundant organic micropollutants detected in biosolids. Lab-scale anaerobic digesters were amended with TCC at concentrations ranging from the background concentration of seed biosolids (30 mg/kg) to toxic concentrations of 850 mg/kg to determine the effect on methane production, relative abundance of antibiotic resistance genes, and microbial community structure. Additionally, the TCC addition rate was varied to determine the impacts of acclimation time. At environmentally relevant TCC concentrations (max detect = 440 mg/kg), digesters maintained function. Digesters receiving 450 mg/kg of TCC maintained function under gradual TCC addition, but volatile fatty acid concentrations increased, pH decreased, and methane production ceased when immediately fed this concentration. The concentrations of the mexB gene (encoding for a multidrug efflux pump) were higher with all concentrations of TCC compared to a control, but higher TCC concentrations did not correlate with increased mexB abundance. The relative abundance of the gene tet(L) was greater in the digesters that no longer produced methane, and no effect on the relative abundance of the class 1 integron integrase encoding gene (intI1) was observed. Illumina sequencing revealed substantial community shifts in digesters that functionally failed from increased levels of TCC. More subtle, yet significant, community shifts were observed in digesters amended with TCC levels that did not inhibit function. This research demonstrates that TCC can select for a multidrug resistance encoding gene in mixed community anaerobic environments, and this selection occurs at concentrations (30 mg/kg) that can be found in full-scale anaerobic digesters (U.S. median concentration = 22 mg/kg, mean = 39 mg/kg).

Examining the Impact of Socioeconomic Position Across the Life Course on Cognitive Function and Brain Structure in Healthy Aging.

This study explores the relationship of life-course intergenerational social mobility with cognitive function and brain structure in older adults using Diagonal Reference Models. Data from the Irish Longitudinal Study on Ageing, a population-based cohort of adults aged 50 years and older (N = 4 620 participants; mean age: 66.1; standard deviation: 9.1; 55% female) was used for analysis. Brain magnetic resonance imaging data were available for 464 participants. Social mobility was characterized as the difference between childhood socioeconomic position (SEP; ie, father's occupation) and adulthood SEP (ie, own occupation). The Montreal Cognitive Assessment (MoCA), the Mini-Mental State Examination (MMSE), cortical thickness, and total gray matter volume (GMV) served as global cognitive and brain measures. Exploratory analyses included the volumes of the ventromedial prefrontal cortex (vmPFC), anterior cingulate (AC), hippocampus, and amygdala. A social gradient in cognitive function was observed among the intergenerationally stable; brain structure was not as clearly socially patterned. Adulthood SEP was significantly associated with MoCA (weight = 0.76; p < .001), MMSE (weight = 0.91; p < .001), GMV (weight = 0.77; p = .002), and AC volume (weight = 0.76; p < .001), whereas childhood SEP was associated with vmPFC volume (weight = 1.00; p = .003). There was no independent association of social mobility with any of the outcomes. Together our results suggest that both childhood and adulthood SEP are important in shaping later-life brain health, but that adulthood SEP predominates in terms of its influence. This is potentially an important insight as it suggests that brain health may be modifiable if socioeconomic circumstances change.

Relationship between hippocampal subfield volumes and cognitive decline in healthy subjects.

We examined the relationship between hippocampal subfield volumes and cognitive decline over a 4-year period in a healthy older adult population with the goal of identifying subjects at risk of progressive cognitive impairment which could potentially guide therapeutic interventions and monitoring. 482 subjects (68.1 years +/- 7.4; 52.9% female) from the Irish Longitudinal Study on Ageing underwent magnetic resonance brain imaging and a series of cognitive tests. Using K-means longitudinal clustering, subjects were first grouped into three separate global and domain-specific cognitive function trajectories; High-Stable, Mid-Stable and Low-Declining. Linear mixed effects models were then used to establish associations between hippocampal subfield volumes and cognitive groups. Decline in multiple hippocampal subfields was associated with global cognitive decline, specifically the presubiculum (estimate -0.20; 95% confidence interval (CI) -0.78 - -0.02; p = 0.03), subiculum (-0.44; -0.82 - -0.06; p = 0.02), CA1 (-0.34; -0.78 - -0.02; p = 0.04), CA4 (-0.55; -0.93 - -0.17; p = 0.005), molecular layer (-0.49; -0.87 - -0.11; p = 0.01), dentate gyrus (-0.57; -0.94 - -0.19; p = 0.003), hippocampal tail (-0.53; -0.91 - -0.15; p = 0.006) and HATA (-0.41; -0.79 - -0.03; p = 0.04), with smaller volumes for the Low-Declining cognition group compared to the High-Stable cognition group. In contrast to global cognitive decline, when specifically assessing the memory domain, cornu ammonis 1 subfield was not found to be associated with low declining cognition (-0.14; -0.37 - 0.10; p = 0.26). Previously published data shows that atrophy of specific hippocampal subfields is associated with cognitive decline but our study confirms the same effect in subjects asymptomatic at time of enrolment. This strengthens the predictive value of hippocampal subfield atrophy in risk of cognitive decline and may provide a biomarker for monitoring treatment efficacy.

Tooth loss and regional grey matter volume.

OBJECTIVES: To investigate whether tooth loss was associated with regional grey matter volume (GMV) in a group of community dwelling older men and women from Ireland. METHODS: A group of 380 dementia-free men and women underwent a dental examination and had a Magnetic Resonance Imaging (MRI) scan as part of The Irish Longitudinal Study of Aging (TILDA). Cortical parcellation was conducted using Freesurfer utilities to produce volumetric measures of gyral based regions of interest. Analysis included multiple linear regression to investigate the association between tooth loss and regional GMVs with adjustment for various confounders. RESULTS: The mean age of participants was 68.1 years (SD 7.3) and 51.6% of the group were female. 50 (13.2%) of the participants were edentulous, 148 (38.9%) had 1-19 teeth, and 182 (47.9%) had ≥20 teeth. Multiple liner regression analysis with adjustment for a range of potential confounders showed associations between the number of teeth and GMVs in the paracentral lobule and the cuneus cortex. In the paracentral lobule, comparing participants with 1-19 teeth versus edentates there was an increase in GMV of ß=323.0mm3 (95% Confidence Interval [CI] 84.5, 561.6) and when comparing participants with ≥20 teeth to edentates there was an increase of ß=382.3mm3 (95% CI 126.9, 637.7). In the cuneus cortex, comparing participants with ≥20 teeth to edentates there was an increase in GMV of ß=380.5mm3 (95% CI 69.4, 691.5). CONCLUSIONS: In this group of older men and women from Ireland, the number of teeth was associated with GMVs in the paracentral lobule and the cuneus cortex independent of various known confounders. CLINICAL SIGNIFICANCE: Although not proof of causation, the finding that tooth loss was associated with regional reduced GMV in the brain may represent a potential explanatory link to the observed association between tooth loss and cognitive decline.

Structural brain signatures of frailty, defined as accumulation of self-reported health deficits in older adults.

Background: Frailty in older adults has been associated with reduced brain health. However, structural brain signatures of frailty remain understudied. Our aims were: (1) Explore associations between a frailty index (FI) and brain structure on magnetic resonance imaging (MRI). (2) Identify the most important FI features driving the associations. Methods: We designed a cross-sectional observational study from a population-based study (The Irish Longitudinal Study on Aging: TILDA). Participants aged ≥50 years who underwent the wave 3 MRI sub-study were included. We measured cortex, basal ganglia, and each of the Desikan-Killiany regional volumes. Age-and sex-adjusted correlations were performed with a 32-item self-reported FI that included conditions commonly tested for frailty in research and clinical settings. A graph theory analysis of the network composed by each FI item and cortex volume was performed. White matter fiber integrity was quantified using diffusion tensor imaging (DTI). Results: In 523 participants (mean age 69, 49% men), lower cortex and thalamic volumes were independently associated with higher FI. Sensory and functional difficulties, diabetes, polypharmacy, knee pain, and self-reported health were the main FI associations with cortex volume. In the network analysis, cortex volume had a modest influence within the frailty network. Regionally, higher FI was significantly associated with lower volumes in both orbitofrontal and temporal cortices. DTI analyses revealed inverse associations between the FI and the integrity of some association bundles. Conclusion: The FI used had a recognizable but subtle structural brain signature in this sample. Only some FI deficits were directly associated with cortex volume, suggesting scope for developing FIs that include metrics more specifically related with brain health in future aging neuroscience studies.