Review: Cognitive Decline in CADASIL

The featured article is ‘Insidious Cognitive Decline in CADASIL’ by Amberla and colleagues and freely available (at the time of writing) here. The authors introduce CADASIL as a small-vessel disease involving mutations at the Notch3 gene with resulting accumulation of granular osmiophilic material (GOM) in the vascular smooth muscle cells. There is also a recognisable pattern of cognitive decline although the authors point out that there is little research characterising the nature of this decline before going onto summarise the literature there is in this area.

The authors choose a cross-sectional design involving 34 people with confirmed identical mutations in the NOTCH3 gene.  They divide up these people into those with and without dementia. For the latter group, they are compared with non-carriers of the mutation. The authors state that the non-carriers are from the same kindred. There are well established drawbacks to using a cross-sectional design for answering these kinds of questions – such designs do not establish causality but instead produce associations. In practical terms however, they can still provide useful information particularly for informing further studies. Other points include the relatively small sample size, the large number of potential confounders and the relevance of the gene mutations in terms of phenotype for those involved in the study.

DSM-III criteria were used for diagnosis and then a neuropsychological battery was undertaken which include a range of tests including those examining executive functioning and various types memory in some detail. The authors used ANOVA to compare the characteristics of the groups but the distribution of neuropsychological values in the  comparison groups is unclear and consequently it is also unclear if a mixed-effects, random effects or fixed effects model is being used.

The poststroke group is just under 10 years older on average than the prestroke group while the dementia group is roughly 15 years older on average than the prestroke group.  The dementia group has roughly half the number of years of formal education of the control group although the sample sizes are small e.g. the dementia group has 8 members.

The authors use a discriminant analysis to distinguish between the controls, pre-stroke and post-stroke groups. They find that the groups can be effectively discriminated using three tests – the Rey-Osterreith memory test (executive function mainly), digit span backwards (working memory mainly) and digit symbol (mental speed). They illustrate this with a scatter plot showing a small number of cases being misclassified but the majority of cases falling into one of three clusters corresponding to the three study groups (excluding the dementia group).

The pre-stroke group are described as having difficulties with strategy and task completion which meant they could be discriminated from the control group. The post-stroke group are described as having ‘mental slowing’ relative to the pre-stroke group. They also identify the relative preservation of verbal episodic memory but were surprised that the finger-tapping test was not effective in discrimination in view of previous research in this area.

Despite the limitations mentioned above this is a useful study which suggests a possible phenotypic expression of the NOTCH3 gene mutations identified in this study. Furthermore a sequential path of cognitive decline is suggested which would need to be explored using a longitudinal study.


Steps To Treatment (STT)

STT = Steps To Treatment. An estimate of the number of steps between the results and translation into practice i.e. treatment. This is an opinion.


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The comments made here represent the opinions of the author and do not represent the profession or any body/organisation. The comments made here are not meant as a source of medical advice and those seeking medical advice are advised to consult with their own doctor. The author is not responsible for the contents of any external sites that are linked to in this blog.


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