Part II | Vascular risk factors for depression and apathy 125 7 whole-brain disease and the lesions it causes are probably more dynamic than earlier thought: regions without visible lesions on neuroimaging can actually dysfunction, while regions with visible lesions sometimes regenerate 4. In general though, it is a progressive disease 4 18. Also, although upon pathological examination of the brains of CSVD patients not all radiological lesions seem to represent actual lesions, most do 19. Furthermore, an increasing total CSVD burden or progression of WMH load does seem to reflect progression in CSVD severity 20 18. It is therefore plausible that radiologically observed CSVD manifests as pathological lesions in the brain and that these lesions can hinder brain circuitries. Imaging studies across patient populations (including populations of patients with neurodegenerative diseases, acquired brain injury, psychiatric disorders or Parkinson´s disease) have related apathy to white matter lesions in the frontal, striatal and anterior cingulate pathways, to basal ganglia lesions and to lesions in the parietal pathways 21 22 23. Pathway analyses revealed that network disruption mediated the relationship between CSVD markers and apathy 24. But how do lesions in these pathways lead to apathy? Diffusion tensor imaging and functional imaging studies in humans have shown that effort-based decision making tasks are related to the frontal and striatal regions, including the medial orbitofrontal cortex, the anterior cingulate cortex (ACC) and the basal ganglia including the ventral striatum 25. Connectivity in these pathways, which together are called the reward network, was reduced in CSVD patients with apathy (and connectivity was not reduced in motor or visual networks) 26. The link between this reward network and apathy would then be as follows: when, at the functional level, the process of effortbased decision making is disturbed, we see an apathy syndrome at the clinical level. And indeed, when behavioral paradigms were applied in CSVD patients, those with apathetic symptoms were less responsive to rewards and less inclined to investing efforts 27 28. The plausibility of a pathophysiological link between CSVD and apathy has thus been convincingly demonstrated. Strength and biological gradient What information do we have on the strength of a CSVD-apathy relationship and does the severity of CSVD predict the level of apathy? In a recent meta-analysis of apathy studies including healthy individuals, persons with cognitive deficits and/or stroke, larger WMH volumes were significantly associated with apathy, with an OR of 1.41 (95% CI 1.05-1.89) and a standard mean difference (SMD) in apathy scores on the Apathy Evaluation Scale (AES)29 between WMH severities (low or high) of 0.38 (95% CI 0.15-0.61) 30. In a large diffusion tensor imaging (DTI) study CSVD patients were significantly more apathetic than healthy controls, with the microstructural white matter changes in the CSVD sample showing a strong relationship with apathy 10. In older adults receiving treatment for depression evidence of an WMH-apathy association was less consistent than in the populations referred to earlier (healthy older adults and
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