Anatomically interpretable deep learning of brain age captures domain-specific cognitive impairment.

The gap between chronological age (CA) and biological brain age, as estimated from magnetic resonance images (MRIs), reflects how individual patterns of neuroanatomic aging deviate from their typical trajectories. MRI-derived brain age (BA) estimates are often obtained using deep learning models that may perform relatively poorly on new data or that lack neuroanatomic interpretability. This study introduces a convolutional neural network (CNN) to estimate BA after training on the MRIs of 4,681 cognitively normal (CN) participants and testing on 1,170 CN participants from an independent sample. BA estimation errors are notably lower than those of previous studies. At both individual and cohort levels, the CNN provides detailed anatomic maps of brain aging patterns that reveal sex dimorphisms and neurocognitive trajectories in adults with mild cognitive impairment (MCI, N = 351) and Alzheimer's disease (AD, N = 359). In individuals with MCI (54% of whom were diagnosed with dementia within 10.9 y from MRI acquisition), BA is significantly better than CA in capturing dementia symptom severity, functional disability, and executive function. Profiles of sex dimorphism and lateralization in brain aging also map onto patterns of neuroanatomic change that reflect cognitive decline. Significant associations between BA and neurocognitive measures suggest that the proposed framework can map, systematically, the relationship between aging-related neuroanatomy changes in CN individuals and in participants with MCI or AD. Early identification of such neuroanatomy changes can help to screen individuals according to their AD risk.

Neuroanatomical and clinical factors predicting future cognitive impairment.

Identifying cognitively normal (CN) older adults who will convert to cognitive impairment (CI) due to Alzheimer's disease is crucial for early intervention. Clinical and neuroimaging measures were acquired from 301 CN adults who converted to CI within 15 years of baseline, and 294 who did not. Regional volumes and brain age measures were extracted from T1-weighted magnetic resonance images. Linear discriminant analysis compared non-converters' characteristics against those of short-, mid-, and long-term converters. Conversion was associated with clinical measures such as hearing impairment and self-reported memory decline. Converters' brain volumes were smaller than non-converters' across 48 frontal, temporal, and subcortical structures. Brain age measures of 12 structures were correlated with shorter times to conversion. Conversion prediction accuracy increased from 81.5% to 90.5% as time to conversion decreased. Proximity to CI conversion is foreshadowed by anatomic features of brain aging that enhance the accuracy of predicting conversion.

Prediction of cognitive outcome after mild traumatic brain injury from acute measures of communication within brain networks.

A considerable but ill-defined proportion of patients with mild traumatic brain injury (mTBI) experience persistent cognitive sequelae; the ability to identify such individuals early can help their neurorehabilitation. Here we tested the hypothesis that acute measures of efficient communication within brain networks are associated with patients' risk for unfavorable cognitive outcome six months after mTBI. Diffusion and T1-weighted magnetic resonance imaging, alongside cognitive measures, were obtained to map connectomes both one week and six months post injury in 113 adult patients with mTBI (71 males). For task-related brain networks, communication measures (characteristic path length, global efficiency, navigation efficiency) were moderately correlated with changes in cognition. Taking into account the covariance of age and sex, more unfavorable communication within networks were associated with worse outcomes within cognitive domains frequently impacted by mTBI (episodic and working memory, verbal fluency, inductive reasoning, and processing speed). Individuals with more unfavorable outcomes had significantly longer and less efficient pathways within networks supporting verbal fluency (all t > 2.786, p < .006), highlighting the vulnerability of language to mTBI. Participants in whom a task-related network was relatively inefficient one week post injury were up to eight times more likely to have unfavorable cognitive outcome pertaining to that task. Our findings suggest that communication measures within task-related networks identify mTBI patients who are unlikely to develop persistent cognitive deficits after mTBI. Our approach and findings can help to stratify mTBI patients according to their expected need for follow-up and/or neurorehabilitation.

Identification and Connectomic Profiling of Concussion Using Bayesian Machine Learning.

Accurate early diagnosis of concussion is useful to prevent sequelae and improve neurocognitive outcomes. Early after head impact, concussion diagnosis may be doubtful in persons whose neurological, neuroradiological, and/or neurocognitive examinations are equivocal. Such individuals can benefit from novel accurate assessments that complement clinical diagnostics. We introduce a Bayesian machine learning classifier to identify concussion through cortico-cortical connectome mapping from magnetic resonance imaging in persons with quasi-normal cognition and without neuroradiological findings. Classifier features are generated from connectivity matrices specifying the mean fractional anisotropy of white matter connections linking brain structures. Each connection's saliency to classification was quantified by training individual classifier instantiations using a single feature type. The classifier was tested on a discovery sample of 92 healthy controls (HCs; 26 females, age µ ± σ: 39.8 ± 15.5 years) and 471 adult mTBI patients (158 females, age µ ± σ: 38.4 ± 5.9 years). Results were replicated in an independent validation sample of 256 HCs (149 females, age µ ± σ: 55.3 ± 12.1 years) and 126 patients with concussion (46 females, age µ ± σ: 39.0 ± 17.7 years). Classifier accuracy exceeds 99% in both samples, suggesting robust generalizability to new samples. Notably, 13 bilateral cortico-cortical connection pairs predict diagnostic status with accuracy exceeding 99% in both discovery and validation samples. Many such connection pairs are between prefrontal cortex structures, fronto-limbic and fronto-subcortical structures, and occipito-temporal structures in the ventral ("what") visual stream. This and related connectivity form a highly salient network of brain connections that is particularly vulnerable to concussion. Because these connections are important in mediating cognitive control, memory, and attention, our findings explain the high frequency of cognitive disturbances after concussion. Our classifier was trained and validated on concussed participants with cognitive profiles very similar to those of HCs. This suggests that the classifier can complement current diagnostics by providing independent information in clinical contexts where patients have quasi-normal cognition but where concussion diagnosis stands to benefit from additional evidence.

Increases in regional brain volume across two native South American male populations.

Industrialized environments, despite benefits such as higher levels of formal education and lower rates of infections, can also have pernicious impacts upon brain atrophy. Partly for this reason, comparing age-related brain volume trajectories between industrialized and non-industrialized populations can help to suggest lifestyle correlates of brain health. The Tsimane, indigenous to the Bolivian Amazon, derive their subsistence from foraging and horticulture and are physically active. The Moseten, a mixed-ethnicity farming population, are physically active but less than the Tsimane. Within both populations (N = 1024; age range = 46-83), we calculated regional brain volumes from computed tomography and compared their cross-sectional trends with age to those of UK Biobank (UKBB) participants (N = 19,973; same age range). Surprisingly among Tsimane and Moseten (T/M) males, some parietal and occipital structures mediating visuospatial abilities exhibit small but significant increases in regional volume with age. UKBB males exhibit a steeper negative trend of regional volume with age in frontal and temporal structures compared to T/M males. However, T/M females exhibit significantly steeper rates of brain volume decrease with age compared to UKBB females, particularly for some cerebro-cortical structures (e.g., left subparietal cortex). Across the three populations, observed trends exhibit no interhemispheric asymmetry. In conclusion, the age-related rate of regional brain volume change may differ by lifestyle and sex. The lack of brain volume reduction with age is not known to exist in other human population, highlighting the putative role of lifestyle in constraining regional brain atrophy and promoting elements of non-industrialized lifestyle like higher physical activity.

Regional Neuroanatomic Effects on Brain Age Inferred Using Magnetic Resonance Imaging and Ridge Regression.

The biological age of the brain differs from its chronological age (CA) and can be used as biomarker of neural/cognitive disease processes and as predictor of mortality. Brain age (BA) is often estimated from magnetic resonance images (MRIs) using machine learning (ML) that rarely indicates how regional brain features contribute to BA. Leveraging an aggregate training sample of 3 418 healthy controls (HCs), we describe a ridge regression model that quantifies each region's contribution to BA. After model testing on an independent sample of 651 HCs, we compute the coefficient of partial determination R¯p2 for each regional brain volume to quantify its contribution to BA. Model performance is also evaluated using the correlation r between chronological and biological ages, the mean absolute error (MAE ) and mean squared error (MSE) of BA estimates. On training data, r=0.92, MSE=70.94 years, MAE=6.57 years, and R¯2=0.81; on test data, r=0.90, MSE=81.96 years, MAE=7.00 years, and R¯2=0.79. The regions whose volumes contribute most to BA are the nucleus accumbens (R¯p2=7.27%), inferior temporal gyrus (R¯p2=4.03%), thalamus (R¯p2=3.61%), brainstem (R¯p2=3.29%), posterior lateral sulcus (R¯p2=3.22%), caudate nucleus (R¯p2=3.05%), orbital gyrus (R¯p2=2.96%), and precentral gyrus (R¯p2=2.80%). Our ridge regression, although outperformed by the most sophisticated ML approaches, identifies the importance and relative contribution of each brain structure to overall BA. Aside from its interpretability and quasi-mechanistic insights, our model can be used to validate future ML approaches for BA estimation.

White matter degradation near cerebral microbleeds is associated with cognitive change after mild traumatic brain injury.

To explore how cerebral microbleeds (CMBs) accompanying mild traumatic brain injury (mTBI) reflect white matter (WM) degradation and cognitive decline, magnetic resonance images were acquired from 62 mTBI adults (imaged ∼7 days and ∼6 months post-injury) and 203 matched healthy controls. On average, mTBI participants had a count of 2.7 ± 2.6 traumatic CMBs in WM, located 6.1 ± 4.4 mm from cortex. At ∼6-month follow-up, 97% of CMBs were associated with significant reductions (34% ± 11%, q < 0.05) in the fractional anisotropy of WM streamlines within ∼1 cm of CMB locations. Male sex and older age were significant risk factors for larger reductions (q < 0.05). For CMBs in the corpus callosum, cingulum bundle, inferior and middle longitudinal fasciculi, fractional anisotropy changes were significantly and positively associated with changes in cognitive functions mediated by these structures (q < 0.05). Our findings distinguish traumatic from non-traumatic CMBs by virtue of surrounding WM alterations and challenge the assumption that traumatic CMBs are neurocognitively silent. Thus, mTBI with CMB findings can be described as a clinical endophenotype warranting longitudinal cognitive assessment.

Older age, male sex, and cerebral microbleeds predict white matter loss after traumatic brain injury.

Little is known on how mild traumatic brain injury affects white matter based on age at injury, sex, cerebral microbleeds, and time since injury. Here, we study the fractional anisotropy of white matter to study these effects in 109 participants aged 18-77 (46 females, age µ ± σ = 40 ± 17 years) imaged within [Formula: see text] 1 week and [Formula: see text] 6 months post-injury. Age is found to be linearly associated with white matter degradation, likely due not only to injury but also to cumulative effects of other pathologies and to their interactions with injury. Age is associated with mean anisotropy decreases in the corpus callosum, middle longitudinal fasciculi, inferior longitudinal and occipitofrontal fasciculi, and superficial frontal and temporal fasciculi. Over [Formula: see text] 6 months, the mean anisotropies of the corpus callosum, left superficial frontal fasciculi, and left corticospinal tract decrease significantly. Independently of other predictors, age and cerebral microbleeds contribute to anisotropy decrease in the callosal genu. Chronically, the white matter of commissural tracts, left superficial frontal fasciculi, and left corticospinal tract degrade appreciably, independently of other predictors. Our findings suggest that large commissural and intra-hemispheric structures are at high risk for post-traumatic degradation. This study identifies detailed neuroanatomic substrates consistent with brain injury patients' age-dependent deficits in information processing speed, interhemispheric communication, motor coordination, visual acuity, sensory integration, reading speed/comprehension, executive function, personality, and memory. We also identify neuroanatomic features underlying white matter degradation whose severity is associated with the male sex. Future studies should compare our findings to functional measures and other neurodegenerative processes.

The Indigenous South American Tsimane Exhibit Relatively Modest Decrease in Brain Volume With Age Despite High Systemic Inflammation.

Brain atrophy is correlated with risk of cognitive impairment, functional decline, and dementia. Despite a high infectious disease burden, Tsimane forager-horticulturists of Bolivia have the lowest prevalence of coronary atherosclerosis of any studied population and present few cardiovascular disease (CVD) risk factors despite a high burden of infections and therefore inflammation. This study (a) examines the statistical association between brain volume (BV) and age for Tsimane and (b) compares this association to that of 3 industrialized populations in the United States and Europe. This cohort-based panel study enrolled 746 participants aged 40-94 (396 males), from whom computed tomography (CT) head scans were acquired. BV and intracranial volume (ICV) were calculated from automatic head CT segmentations. The linear regression coefficient estimate ß^T of the Tsimane (T), describing the relationship between age (predictor) and BV (response, as a percentage of ICV), was calculated for the pooled sample (including both sexes) and for each sex. ß^T was compared to the corresponding regression coefficient estimate ß^R of samples from the industrialized reference (R) countries. For all comparisons, the null hypothesis ß T = ß R was rejected both for the combined samples of males and females, as well as separately for each sex. Our results indicate that the Tsimane exhibit a significantly slower decrease in BV with age than populations in the United States and Europe. Such reduced rates of BV decrease, together with a subsistence lifestyle and low CVD risk, may protect brain health despite considerable chronic inflammation related to infectious burden.

Acute cognitive deficits after traumatic brain injury predict Alzheimer's disease-like degradation of the human default mode network.

Traumatic brain injury (TBI) and Alzheimer's disease (AD) are prominent neurological conditions whose neural and cognitive commonalities are poorly understood. The extent of TBI-related neurophysiological abnormalities has been hypothesized to reflect AD-like neurodegeneration because TBI can increase vulnerability to AD. However, it remains challenging to prognosticate AD risk partly because the functional relationship between acute posttraumatic sequelae and chronic AD-like degradation remains elusive. Here, functional magnetic resonance imaging (fMRI), network theory, and machine learning (ML) are leveraged to study the extent to which geriatric mild TBI (mTBI) can lead to AD-like alteration of resting-state activity in the default mode network (DMN). This network is found to contain modules whose extent of AD-like, posttraumatic degradation can be accurately prognosticated based on the acute cognitive deficits of geriatric mTBI patients with cerebral microbleeds. Aside from establishing a predictive physiological association between geriatric mTBI, cognitive impairment, and AD-like functional degradation, these findings advance the goal of acutely forecasting mTBI patients' chronic deviations from normality along AD-like functional trajectories. The association of geriatric mTBI with AD-like changes in functional brain connectivity as early as ~6 months post-injury carries substantial implications for public health because TBI has relatively high prevalence in the elderly.

Post-Traumatic Cerebral Microhemorrhages and their Effects Upon White Matter Connectivity in the Aging Human Brain.

Cerebral microbleeds (CMBs), a common manifestation of mild traumatic brain injury (mTBI), have been sporadically implicated in the neurocognitive deficits of mTBI victims but their clinical significance has not been established adequately. Here we investigate the longitudinal effects of post-mTBI CMBs upon the fractional anisotropy (FA) of white matter (WM) in 21 older mTBI patients across the first ~6 months post-injury. CMBs were segmented automatically from susceptibility-weighted imaging (SWI) by leveraging the intensity gradient properties of SWI to identify CMB-related hypointensities using gradient-based edge detection. A detailed diffusion magnetic resonance imaging (dMRI) atlas of WM was used to segment and cluster tractography streamlines whose prototypes were then identified. The correlation coefficient was calculated between (A) FA values at vertices along streamline prototypes and (B) topological (along-streamline) distances between these vertices and the nearest CMB. Across subjects, the CMB identification approach achieved a sensitivity of 97.1% ± 4.7% and a precision of 72.4% ± 11.0% across subjects. The correlation coefficient was found to be negative and, additionally, statistically significant for 12.3% ± 3.5% of WM clusters (p <; 0.05, corrected), whose FA was found to decrease, on average, by 11.8% ± 5.3% across the first 6 months post-injury. These results suggest that CMBs can be associated with deleterious effects upon peri-lesional WM and highlight the vulnerability of older mTBI patients to neurovascular injury.