Vascular risk factors for depression and apathy | Part II 126 older adults with cognitive impairment and/or stroke). One study did find an association 31, one did not 32, and in a severely depressed population the WMH-apathy association was established in participants with late-onset depression only 33. Other CSVD biomarkers than WMH could not be systematically analyzed, due to the large heterogeneity with respect to CSVD biomarkers, apathy scales and research designs across studies. In those investigating the association between lacunes and apathy, some reported confirmatory 34 35 and some negative results 26 36. As to subcortical infarcts, most studies supported a clinically significant association with apathy, but because of the heterogeneity in their designs the strength of the association remains unclear. Finally, no evidence was found to suggest that microbleeds or perivascular spaces are associated with apathy 37 38 26 36. While most research uses WMH as a biomarker of CSVD, this might not be the best index since CSVD causes widespread disruptions in cerebral connections. Given that CSVD concerns a whole- brain disease, studies focusing on a particular type of MRI finding (for instance only WMH) might thus miss the larger picture, where the use of a composite score -which combines information on CSVD neuroimaging biomarkers- might be more informative 20 4. A high total CSVD burden raised the odds of having apathy in post-stroke patients (OR 3.61; 95% CI 1.34-9.68) 39 and in a CSVD sample apathy was associated with the total CSVD burden (R2=0.332; t=4.134; p<0.00) 40. Numerous studies only examined whether CSVD markers such as WMH predicted apathy, without looking for evidence of a dose-response effect 26 41 42 37 36 43 44 45 46 47 48 49 10 31 32. The studies that did do so are summarized here to evaluate the support for a biological gradient. In healthy older adults the WMH grade was found to correlate with apathy 50. In geriatric outpatients WMH volume was related to apathy 51. In a study of Alzheimer’s disease patients WMH volume was not related to apathy as measured by NPI score 52, while in a small study in patients with probable Alzheimer’s disease frontal WMH volume was related to apathy 53. In patients diagnosed with subcortical vascular cognitive impairment each additional lacuna and higher WMH volumes were both related to the severity of apathy 35, while in another cohort of subcortical vascular patients with mixed cognitive status higher lacunar volume in WMH was related to the presence of apathy 34. In stroke patients the periventricular white matter hyperintensity score and the number of pontine infarcts were associated with apathy 54, while a gradient between total CSVD burden and risk of apathy was established in another cohort of stroke patients 39. Finally, the extent of the total CSVD burden predicted apathy in CSVD patients 40. In two cohort-studies of SVD patients whitematter connectivitymeasures were significantly associated with apathy, while WMH volume or the number of lacunar infarcts (when depression and cognition were corrected for) were not, suggesting it might be large-scale white matter network disruption specifically which is associated with apathy 24 26.
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