Cognitive profile in CADASIL patients

Short abstract

Age is an important predictor of clinical deterioration in CADASIL patients

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) often starts with silent lacunar infarcts or white matter changes in the third decade of life and cognitive or other neurological signs become apparent within the next 10 years. In the following 20 years, dementia and psychiatric disturbances become more and more apparent and death frequently occurs in the sixth decade of life.¹,²,³

Age is an important predictor of clinical deterioration, with an odds ratio of 1.10⁴ per year starting at the age of 24. Cognitive impairment affects about 60% of CADASIL patients, and psychiatric disturbances nearly 30%. Cognitive impairment initially manifests through mild executive and visuospatial deficits, psychomotor slowing, and apathy.⁵ Working and short term memory defects also appear insidiously⁶; later on, abulia and other executive dysfunctions are the main manifestations of CADASIL. Two thirds of CADASIL patients are dependent and have dementia by the time they die.¹ Dementia is more apparent if the patient has a lower educational level.⁶

In the paper by Buffon et al in this issue of the journal (see pages 175–80), the cognitive profile of 42 CADASIL patients is described. The authors conclude that executive dysfunction dominates the pattern of cognitive impairment in CADASIL, followed by visuo‐constructive memory impairment. With aging, other cognitive dysfunctions become more and more evident, denoting a diffuse cognitive impairment, except for the relative preservation of the encoding process in episodic memory.

This paper replicates the results of previous studies²,⁵,⁶ and confirms that the cognitive profile of CADASIL is similar to that presented by patients with subcortical ischaemic vascular dementia. In fact, CADASIL can be considered a pure form of subcortical ischaemic vascular dementia.

A limitation of the paper by Buffon et al is the design of the neuropsychological evaluation. Inferences concerning the role of age on cognitive impairment are drawn from a cross sectional evaluation of CADASIL patients of different age groups.

Much more robust conclusions would result from a longitudinal neuropsychological evaluation of CADASIL patients, starting in their third decade and repeated, in parallel with neuroimaging, for instance, every 5 or 10 years. To achieve adequate statistical power, such a longitudinal study would need to involve many centres and countries, because of the limited number of CADASIL patients available in individual regions. The harmonisation of a neuropsychological battery to be used in different languages is a difficult but achievable task.⁷ This longitudinal study would elucidate the relative role of lacunes and white matter changes, their localisation and their influence on the development of cognitive impairment, mood changes, and movement performance in CADASIL patients.

As CADASIL is a pure subcortical ischaemic vascular dementia, it is a good model for pilot clinical trials for this type of dementia. Antiplatelets or statins to prevent progression of the disease are unlikely to be effective, as CADASIL is mainly a disease of the arterial media. Other candidate drugs to be tested with the aim of improving cognition are cholinergic agents, memantine, and antidepressants.