Neuroimaging Association Scores: reliability and validity of aggregate measures of brain structural features linked to mental disorders in youth.

In genetics, aggregation of many loci with small effect sizes into a single score improved prediction. Nevertheless, studies applying easily replicable weighted scores to neuroimaging data are lacking. Our aim was to assess the reliability and validity of the Neuroimaging Association Score (NAS), which combines information from structural brain features previously linked to mental disorders. Participants were 726 youth (aged 6-14) from two cities in Brazil who underwent MRI and psychopathology assessment at baseline and 387 at 3-year follow-up. Results were replicated in two samples: IMAGEN (n = 1627) and the Healthy Brain Network (n = 843). NAS were derived by summing the product of each standardized brain feature by the effect size of the association of that brain feature with seven psychiatric disorders documented by previous meta-analyses. NAS were calculated for surface area, cortical thickness and subcortical volumes using T1-weighted scans. NAS reliability, temporal stability and psychopathology and cognition prediction were analyzed. NAS for surface area showed high internal consistency and 3-year stability and predicted general psychopathology and cognition with higher replicability than specific symptomatic domains for all samples. They also predicted general psychopathology with higher replicability than single structures alone, accounting for 1-3% of the variance, but without directionality. The NAS for cortical thickness and subcortical volumes showed lower internal consistency and less replicable associations with behavioural phenotypes. These findings indicate the NAS based on surface area might be replicable markers of general psychopathology, but these links are unlikely to be causal or clinically useful yet.

Inclusion of the Symbol Digit Modalities Test in a revised assessment of 'no evidence of disease activity-4 (NEDA-4)' in Latin-American patients with multiple sclerosis.

BACKGROUND: In relapsing-remitting multiple sclerosis (RRMS), no evidence of disease activity-3 (NEDA-3) is defined as the absence of: (1) relapses; (2) disability progression; (3) MRI activity (new/enlarged T2 lesions and/or gadolinium-enhanced T1 lesions). NEDA-4 status is defined as meeting all NEDA-3 criteria plus having an annualized percentage brain volume change (a-PBVC) >-0.4%. In individual patients, brain volume assessment is confounded with normal aging, methodological limitations and fluid-shift related fluctuations in brain volume. Cognitive impairment has been proposed as another component that should be integrated into therapeutic algorithms for RRMS. We aim to determine the proportion of patients failing to meet NEDA-4 criteria and to appraise whether the Symbol Digit Modalities Test (SDMT) is capable of replacing a-PBVC as one of the components of NEDA-4. We hypothesize that NEDA-4 has the potential to capture the impact of DMT therapies in RRMS. METHODS: Forty-five patients were prospectively followed 1 and 2 years after their baseline assessment at the University of Chile Hospital. SIENA software was used to assess a-PBVC. RESULTS: At baseline, the patients had a mean age of 33.0 years (range 18-57), disease duration of 1.9 years (0.4-4), Expanded Disability Status Scale score of 1.3 (0-4), and 67% were female. The majority had RRMS (91% while 9% had clinically isolated syndrome (CIS)). Seventy-three percent were on the so-called first line DMTs such as interferons (53%), glatiramer acetate (13%), teriflunomide (9%), and 18% were on fingolimod. There was a serial decline in the proportion of NEDA: after 1 and 2 years of follow-up 60% and 47% met NEDA-3 status, and 38% and 27% met NEDA-4, respectively. At the last follow-up 21% remained on interferons, 47% were now on fingolimod, 4% on alemtuzumab and 2% on natalizumab. At year 1 and year 2, with the replacement of a-PBVC by SDMT, 53% and 40% of patients achieved a putative NEDA-4 status, respectively. CONCLUSION: Brain volumetric MRI has yet to be translated into clinical practice and SDMT may qualify as the fourth component of NEDA-4 definition. NEDA-4 has the potential to capture the impact of DMT therapies in RRMS earlier in the disease course of RRMS.

Prospective Assessment of No Evidence of Disease Activity-4 Status in Early Disease Stages of Multiple Sclerosis in Routine Clinical Practice.

Background: In relapsing-remitting multiple sclerosis, no evidence of disease activity-3 (NEDA-3) is defined as no relapses, no disability progression and no MRI activity. NEDA-4 status is defined as meeting all NEDA-3 criteria plus having an annualized brain volume loss (a-BVL) of ≤0.4%. Prospective real-world studies presenting data on NEDA-4 are scarce. Objective: To determine the proportion of patients failing to meet one or more NEDA-4 criteria and the contribution of each component to this failure. Methods: Forty-eight patients were followed for 12 months. Structural image evaluation, using normalization, of atrophy was used to assess a-BVL. Results: The patients had a mean age of 33.0 years (range 18-57), disease duration of 1.7 years (0.4-4) and Expanded Disability Status Scale score of 1.3 (0-4); 71% were women. All patients were on disease-modifying therapies. During follow-up, 21% of the patients had at least one relapse, 21% had disability progression, 8% had new T2 lesions, and 10% had gadolinium-enhanced lesions. Fifty-eight percent (28/48) achieved NEDA-3 status. a-BVL of >0.4% was observed in 52% (25/48). Only 29% (14/48) achieved NEDA-4 status. Conclusion: a-BVL is a good marker to detect subclinical disease activity. a-BVL is parameter to continue investigating for guiding clinical practice in relapsing-remitting multiple sclerosis.

Whole-Brain Atrophy Differences between Progressive Supranuclear Palsy and Idiopathic Parkinson's Disease.

BACKGROUND: The absence of markers for ante-mortem diagnosis of progressive supranuclear palsy (PSP), results in this disorder being commonly mistaken for other conditions, such as idiopathic Parkinson's disease (IPD). Such mistakes occur particularly in the initial stages, when "plus syndrome" has not yet clinically emerged. OBJECTIVE: To investigate the global brain volume and tissue loss in patients with PSP relative to patients with IPD and healthy controls and correlations between clinical parameters and magnetic resonance imaging (MRI)-derived brain volume estimates. METHODS: T1-weighted images were obtained from three groups of Chilean Latin American adults: 21 patients with IPD, 18 patients with PSP and 14 healthy controls. We used Structural Imaging Evaluation with Normalization of Atrophy (SIENAX) to assess white matter, gray matter and whole-brain volumes (normalized to cranial volume). Imaging data were used to analyze putative correlations with the clinical status of PSP and IPD patients using the Unified Parkinson's Disease Rating Scale Part III (UPDRS III), Hoehn and Yahr (H&Y), the Clinical Global Impression for Disease Severity Scale (CGI-S) and the Frontal Assessment Battery (FAB). RESULTS: PSP patients had significantly lower whole brain volume than both IPD patients and controls. Whole brain volume reduction in PSP patients was primarily attributable to gray matter volume reduction. We found a significant correlation between brain volume reduction and clinical status in the PSP group. CONCLUSIONS: At the group level, the whole brain and gray matter volumes differentiated patients with PSP from patients with IPD. There was also significant clinical-imaging correlations with motor disturbances in PSP.