Table 2.

Neuroimaging studies assessing the relationship between markers of diffuse damage in NAGM and clinical disability and cognitive impairment.

Study	Method	Number of patients	Relevant findings
Rovaris et al. 2002 [70]	Cross sectional 1.5T; DTI	34 RRMS	Average gray matter mean diffusivity correlates with cognitive impairment measured by the Symbol Digit Modality Test (SDMT).
Ranjeva et al. 2005 [71]	Cross sectional 1.5T; MTR	18 CIS 18 HC	Decreased MTR in the parietal lobe (BA40) correlates with poorer performance on Paced Auditory Serial Addition Test (PASAT).
Agosta et al. 2006 [72]	8-year longitudinal 1.5T; MTR	73 MS (34 RRMS, 19 SPMS) 20 CIS 16 HC	Lower gray matter MTR-peak height at baseline is an independent predictor of accumulation of disability over 8 years as measured by the Expanded Disability Status Scale (EDSS).
Rovaris et al. 2006 [73]	5-year longitudinal 1.5T; DTI	55 PPMS	Average gray matter mean diffusivity was an independent predictor of clinical deterioration as measured by EDSS.
Khaleeli et al. 2007 [74]	Cross sectional 1.5T; MTR	46 PPMS 23 HC	Lower MTR in the right primary motor cortex correlated with disability as measured by EDSS. Lower MTR in the right parietal and occipital cortices correlated with poorer performance on PASAT.
Amato et al. 2008 [75]	Cross sectional 1.5T; MTR	47 Benign MS 24 HC	Reduced cortical MTR correlated with a variety of measures of cognitive impairment.
Fisniku et al. 2009 [76]	Cross sectional 1.5T; MTR	41 MS (31 RRMS, 10 SPMS) 28 CIS 19 HC	Reduced gray matter peak height MTR is the best independent predictor of disability as measured by EDSS, and only independent predictor of cognitive impairment as measured by the Multiple Sclerosis Functional Composite (MSFC).
Tovar-Moll et al. 2009 [77]	Cross sectional 3T; DTI	24 MS (13 RRMS, 11 SPMS) 24 HC	Elevated mean diffusivity within the thalamus correlated with performance on PASAT and EDSS.
Crespy et al. 2011 [78]	Cross sectional 1.5T; MTR	88 CIS 44 HC	Gray matter MTR decrease is significantly associated with worse EDDS scores. (R 2 = 0.135, P = 0.002).