Assessing White Matter Hyperintensities in the Cholinergic Pathway in Dementia


There is a paper by Bocti and colleagues titled “A New Visual Rating Scale to Assess Strategic White Matter Hyperintensities Within Cholinergic Pathway in Dementia” which is freely available here.  There is abundant evidence that Acetylcholine plays an important role in memory and this is the theoretical basis for a class of drugs Acetylcholinesterase Inhibitors that are used in Alzheimer’s Disease. The researchers in this study were interested in vascular injury to cholinergic pathways in the brains of people with Alzheimer’s Disease. An important cause of cognitive decline results from vascular injury in the brain. Broadly speaking causes of dementia are considered to occur in the ‘higher’ cortical areas and the Subcortical areas. Dementias that affect the cortical areas have very different qualities to the dementias that occur subcortically. Vascular Subcortical Dementias can be very subtle and there is much to learn about them. The researchers in this study wanted to understand whether Subcortical Vascular injury to the Cholinergic Pathway was associated with cognitive impairment and to validate a new rating scale – the Cholinergic Pathways HyperIntensities Scale (CHIPS – although the letters are out of order it serves as a handy mnemonic).

The researchers recruited 60 people with Alzheimer’s Disease with and without White Matter Hypeintensities (matched for age) and 15 controls. The subjects were part of a larger longitudinal study. They met the National Institute of Neurological Communicative Disorders and Stroke-Alzheimer Disease and Related Disorders Association (NINCDS-ADRDA) researcher criteria. The subjects underwent a battery of Neuropsychological tests

The researchers used the results of histopathological studies where the pathways had been identified using a special staining technique which enabled them to outline the course of the cholinergic neurons. Since these neurons pass close to other structures, the researchers mapped out the pathways in relation to these other structures. This was used as the basis for identifying the pathway on the T2 Weighted and proton-density MRI scans which do not show the cholinergic pathway directly. However by identifying these other structures, the researchers could work out the location of the Cholinergic pathway at each level that was visualised.

The researchers identified subjects with Alzheimer’s Disease where they thought it was likely to have developed from vascular injury to the Cholinergic pathway. These subjects were compared with subjects without White Matter Hyperintensities on the MRI. The researchers were careful to match these two groups on a number of variables including

  • Age
  • Education

However the former group had more vascular risk factors including a history of Hypertension and a past history of Stroke.

The researchers had refined an earlier version of their visual rating scale and used 4 slices as the basis for their scale

The researchers wanted to find out what happened when different raters used the scale to rate images. This is an important test and the researchers were looking for good agreement between raters. This is known as reliability. The researchers found that there was good agreement between raters – they used a special test of inter-rater reliability – the Intraclass Correlation Coefficient (ICC=0.97).

When the researchers compared the CHIPS score with another method of assessing lesions White Matter Hyperintensity volume they found that again there was a good agreement between the two. Thus the CHIPS seemed to be a very good tool for approximating the volume of the lesions in the pathway. (The researchers limited the White Matter Hyperintensity volume analysis to the region-of-interest which needed to coincide with that used for the CHIPS). Interestingly there was a strong correlation between the CHIPS score and performance on the Mattis Dementia Rating Scale with the CHIPS accounting for 12% of the variance.  The researchers suggested that this variance was mediated by attention and memory subscores although due caution must be exercised in this interpretation as this is a secondary analysis.

The researchers point out a number of shortcomings of the study

  • There was no direct correlation of CHIPS scores with CSF measured cholinergic marker levels
  • There were few anatomical landmarks that could be used to characterise the course of the Cholinergic Pathway above the Sylvian Fissure

Nevertheless the researchers suggest future improvements that can be made to the CHIPS and the visual rating scale fills an important need in investigating the relationship between Alzheimer’s Disease and Vascular lesions.

An index of the site can be found here. The page contains links to all of the articles in the blog in chronological order. Twitter: You can follow ‘The Amazing World of Psychiatry’ Twitter by clicking on this link. Podcast: You can listen to this post on Odiogo by clicking on this link (there may be a small delay between publishing of the blog article and the availability of the podcast). It is available for a limited period. TAWOP Channel: You can follow the TAWOP Channel on YouTube by clicking on this link. Responses: If you have any comments, you can leave them below or alternatively e-mail Disclaimer: 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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