In this study, we found that: (i) the cognitive profile in CADASIL patients is heterogeneous and involves only a few cognitive domains at the onset of the disease, while it is homogeneous after the age of 60 with significant deficits in all cognitive domains; (ii) patients with dementia have additional impairment in skills such as reasoning compared to subjects without dementia; and (iii) memory impairment even at the late stage of the disorder does not involve the encoding process (retrieval significantly improved with cues) which is relatively preserved compared to that reported in other types of dementia with degeneration of the hippocampus.
The pattern of cognitive impairment clearly differs between younger patients and those more than 60 years of age. In the youngest individuals, the results of this study are in line with previous reports of early cognitive impairment in CADASIL predominately involving executive skills.5
Alteration of executive functions was the most frequent cognitive deficit in patients under 50 years of age and was globally detected in almost 90% of individuals in the present series. In the youngest patients, this deficit was frequently associated with a decline in attention and memory performance compatible with some degree of dysfunction in subcortical‐frontal networks.24,25,26
In subjects more than 60 years of age (60% of whom had dementia), cognitive impairment appeared more homogeneous than in younger subjects, with significant alterations in all cognitive domains. This extension of cognitive deficits cannot be ascribed only to the deterioration of executive skills affecting functions such as reasoning through the loss of attention, working memory, planning capacities, abstraction, or categorisation. The high frequency of associated impairment in instrumental activities such as language (vocabulary) or in visuospatial abilities in patients older than 60 suggests a diffuse cortical dysfunction well beyond the subcortical‐frontal circuits.
In this series, dementia was diagnosed in almost one third of patients and most with dementia were older than 60 years of age. The results showed that by then cognitive impairment was extensive involving not only executive functions, attention and memory but also reasoning and language performance. Dementia was also strongly associated with severe motor disability at the late stage of CADASIL as previously reported.28,29,30
Altogether, these data support the view that dementia occurs after years of accumulation of subcortical ischaemic insults leading to widespread secondary effects on different cortical networks and functions. Interestingly, we observed that a clinical history of stroke was not associated with dementia but only with visuospatial disability.5
In the present series, the number of strokes varied between 0 and 4, both in patients with and without dementia. This confirms that dementia can occur in CADASIL without stroke, and that the number of symptomatic ischaemic event is not a causal factor as already reported in one third of patients with other types of subcortical vascular dementia.31
Other mechanisms are therefore probably involved. The accumulation of so called “silent” infarcts, detected in both asymptomatic and symptomatic CADASIL patients,2
has been recently identified as a major risk factor for dementia in longitudinal studies of healthy elderly people.32
Vermeer et al
suggested that their location might be of crucial importance since they observed that silent thalamic infarcts were associated with a delayed decline in memory performances while infarcts outside the thalamus were related to a decrease in psycho‐motor speed.33
Alternative hypotheses are progressive increase in axonal loss within abnormal white matter as well as secondary degeneration occurring after focal ischaemic lesions in the subcortical grey matter34
or within heteromodal cortical areas. Previous imaging studies suggested a strong correlation between the degree of microstructural loss in subcortical areas and cognitive status in CADASIL. This issue cannot be settled by this study without imaging studies performed at the time of cognitive evaluation. Other investigations will help to assess the complex relationships between the number of infarcts, their location, the degree of white matter loss, the severity of cortical atrophy, and cognitive status in this small vessel disease.35
In the present study, we observed that the profile of memory impairment did not significantly change according to the age of patients. It is noteworthy that with the Grober and Buschke tests, negative mean z scores were obtained for immediate and delayed free recalls in the different age categories, but positive z scores were always found for delayed cued recall. Interestingly, the frequency of impairment in free recall was increased among patients with dementia but never reached 100%. Moreover, improvement of recall with cues in the same evaluation, present in all individuals without dementia, was also observed in about two thirds of patients with dementia. These results suggest that the encoding process is preserved during most stages of the disease. This is observed also with relative preservation of recognition and semantic memory. Such a pattern of memory impairment is clearly distinct from that detected in Alzheimer's disease.27,36,37
It is now recognised that cortical degeneration and atrophy may contribute to dementia and memory impairment in patients with subcortical infarcts and white matter lesions.26,38,39,40
Mesulam et al
reported that important cholinergic denervation predominated in frontal and parietal cortices and but relatively spared the mesio‐temporal cortex in a young CADASIL patient with dementia.41
The results of the present study also suggest that hippocampal regions are relatively spared in most patients with CADASIL, even those with dementia and significant memory impairment. Thus, the pattern of memory disturbance as detected in most CADASIL patients appears to be mainly subcortical. This is possibly related to interruption of frontal‐subcortical loops which can occur at different stages of the disorder with accumulation of ischaemic lesions in strategic areas.40
There are various limitations to this study: (i) some data are missing for patients with the most severe dementia for whom complete testing was not possible; this may have led to an underestimation of the mean z scores in the oldest patients; (ii) tests for memory were modified during the study period (the Grober and Buschke procedure was only used in two thirds of patients), but this heterogeneity may have been compensated for by the overall analysis by large cognitive domains in the study; (iii) the segmentation of large cognitive domains chosen to help understanding of the data is arbitrary and can lead to redundancies and/or artificial divisions of the cognitive process; (iv) we used control data from the literature which were obtained in different samples for the calculation of z scores, which may limit the interpretation of z scores within the different domains; and (v) finally, the study was cross‐sectional and did not include a detailed MRI evaluation thus restricting interpretation of the neuropsychological data.
Despite these limitations, we think that the results obtained provide a general picture of the spectrum of cognitive deficits in CADASIL from early cognitive impairment with predominant executive dysfunction to late dementia with impairment in multiple cognitive domains and demonstrate that the profile of memory impairment in most cases of CADASIL is clearly distinct from that observed in degenerative disorders primarily involving the mesio‐temporal cortex.