Inspired by Yang et al 2019 [1]
Have you heard of VCIND?
This paper attracted my attention principally because I had not come across this acronym before. VCIND stands for vascular cognitive impairment no dementia. VCI is the type of cognitive impairment that commonly accompanies stroke, and it can be a forerunner to the development of some forms of dementia.[2] There is a substantial overlap with Alzheimer’s Disease (AD), and the two may promote or unmask eachother.
In recent years there has been increasing interest in strategies for prevention of AD and other forms of dementia, since the burden on Society is substantial and growing hand in hand with an aging population.
Populations with VCIND are a potential target for prevention
Populations with VCIND are a potential target for prevention and since acupuncture is widely used in stroke rehabilitation in China and the neuroprotective potential of acupuncture has been demonstrated in numerous laboratory studies, it does seem reasonable to try it out. Research to date is tentatively positive but plagued by the usual high risk of bias (RoB) in open comparative studies against drugs.[3]
Despite this problem of high RoB, the authors of this paper effectively did the same thing, although they did do it well! They did not want to use sham acupuncture as a control because it is likely to be active, so instead chose a drug called citicoline, which has been shown to have neuroprotective properties.[4] Citicoline is the same as the endogenous molecule called CDP-choline (cytidine-5′-diphosphate choline), which is produced in the body and breaks down to cytidine and choline. Both are used in phospholipid production, required for neural membranes, and choline is a precursor of acetylcholine, a neurotransmitter with particular importance in AD. Loss of neural membranes is associated with VCI and AD, and the requirement for acetylcholine may exacerbate membrane loss.[4,5]
Citicoline has been found to be safe and potentially protective [by halting decline] in mild VCI,[6] so it does seem to be a useful pragmatic comparator for this population without dementia (VCIND). Citicoline in combination with acetylcholinesterase inhibitors (AChEIs) has also been found beneficial in AD when compared to AChEIs alone.[7]
Citicoline may be a good pragmatic comparator for acupuncture, but we are still left with the high RoB label from the strict explanatory view.[8] The latter approach does not allow for arguments, but in a blog no one is going to stop me use a bit of logic. In an open trial the key RoB comes from a form of detection bias – the possibility of systematic differences between groups derived from the knowledge of receiving a certain intervention rather than from the intervention itself. So in this case, the patient can see the acupuncture applied rather than taking the citicoline pills, and thus may be more convinced of improvement. But wait! What is the primary outcome? In this trial it was an assessment of cognitive function (ADAS-Cog) applied by a blinded assessor and handed over to a blinded statistician. So in order to create significant detection bias, the patient with cognitive impairment has to think themselves better in terms of cognitive performance just by seeing the acupuncture applied. Now that seems a little unlikely. Furthermore we already know that placebo responses [to pain] are extinguished in more severe forms of cognitive impairment [dementia].[9,10] Unfortunately expectation alone (from taking placebo pills) has proven to show some benefit in cognitive performance in healthy seniors, so we need to be cautious in this line of argument.[11]
Alzheimer’s Disease Assessment Scale – Cognitive (ADAS-Cog)
Next we need to look at ADAS-Cog, the primary outcome. ADAS-Cog stands for Alzheimer’s Disease Assessment Scale – Cognitive. It was first presented in 1984,[12] and has become perhaps the most recognised outcome measure in established AD.[13,14] It has been translated and validated in a number of different languages, including Chinese.[15] Increasingly it is being modified and used in pre-dementia populations.[14]
ADAS-Cog is a subscale of ADAS. The full ADAS takes about 45 minutes to perform. It is scored from 0 to 150, higher numbers associated with more severe AD. The cognitive subscale includes: Word Recall, Naming Objects and Fingers, Commands, Constructional Praxis, Ideational Praxis, Orientation, Word Recognition, and Language. This scale generally uses 11 tasks with a total score from 0 to 70, although the Chinese version appears to score up to 75.
Why all this detail? Well we are in the realm of what is clinically relevant change, how this has been established, with which versions of the scale and in what populations. Oh my, I am now wishing I never started this blog, I am already up to 15 refs!
A deterioration in the score of +3 points in mild AD has been suggested as a minimal clinically relevant change (MCRC), but the equivalent for improvement or for the difference between interventions has not been established.[13]
Acupuncture sessions were performed twice a week for 12 weeks, lasted 30 minutes and involved 16 points (circa 27 needles). The citicoline group were seen every week and given 100mg tablets to be taken three times a day for 3 months – compliance was tested by pill counting, and <80% compliance led to withdrawal. 216 patients were enrolled at the start, 213 were included in the intention to treat (ITT) analysis and 173 in the per protocol analysis.
At 3 and 6 months the acupuncture group improved (ie reduced score) by -2.33 and -2.61 on ADAS-Cog respectively (ITT). The results for the citicoline group at 3 and 6 months were -1.38 and -1.25. The differences were both statistically significant.
Now we can enter the discussion about clinical relevance and think about logistics and costs. At this point I really want to know what change would have occurred in an untreated group, but in the setting of this sort of trial I guess that might have been deemed unethical. The nearest I could find in the literature was a study charting longterm changes on ADAS-Cog in an AD population most of whom were taking drugs for the condition (AChEIs).[16] This study followed 346 AD patients over 18 months: 9% improved more than -2 points; 38% were stable ±2 points; 32% were moderately worse +2 to +7 points; and 21% had severe impairment with more than +7 points change on ADAS-Cog.
A quick look at some drug trials that used ADAS-Cog and I see that the total change score is generally not reported. So I added up the items and after 24 weeks of the highest dose patch of transdermal rivastigmine in an AD population and the change was about -1.6.[17] In a Parkinson’s disease dementia population in oral form, rivastigmine performs marginally better with a gain of -2.0.[18]
Liverot, an astonishingly smelly French cheese.
So finally I guess -2.61 for the acupuncture group in VCIND seems as though it might be worth pursuing along with eating lots of good lipids – personally I quite like Liverot, an astonishingly smelly French cheese.
References
1 Yang J-W, Shi G-X, Zhang S, et al. Effectiveness of acupuncture for vascular cognitive impairment no dementia: a randomized controlled trial. Clin Rehabil 2019;:269215518819050. doi:10.1177/0269215518819050
2 Gorelick PB, Scuteri A, Black SE, et al. Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the american heart association/american stroke association. Stroke 2011;42:2672–713. doi:10.1161/STR.0b013e3182299496
3 Min D, Xu-Feng W. An Updated Meta-Analysis of the Efficacy and Safety of Acupuncture Treatment for Vascular Cognitive Impairment Without Dementia. Curr Neurovasc Res 2016;13:230–8.
4 Gareri P, Castagna A, Cotroneo AM, et al. The role of citicoline in cognitive impairment: pharmacological characteristics, possible advantages, and doubts for an old drug with new perspectives. Clin Interv Aging 2015;10:1421–9. doi:10.2147/CIA.S87886
5 Pérez-Gálvez A, Jarén-Galán M, Garrido-Fernández J, et al. Activities, bioavailability, and metabolism of lipids from structural membranes and oils: Promising research on mild cognitive impairment. Pharmacol Res 2018;134:299–304. doi:10.1016/j.phrs.2018.07.013
6 Cotroneo AM, Castagna A, Putignano S, et al. Effectiveness and safety of citicoline in mild vascular cognitive impairment: the IDEALE study. Clin Interv Aging 2013;8:131–7. doi:10.2147/CIA.S38420
7 Gareri P, Castagna A, Cotroneo AM, et al. The Citicholinage Study: Citicoline Plus Cholinesterase Inhibitors in Aged Patients Affected with Alzheimer’s Disease Study. J Alzheimers Dis 2017;56:557–65. doi:10.3233/JAD-160808
8 Cummings M, White A. A Critical Approach to Randomised Controlled Trials of Acupuncture. In: Filshie J, White A, Cummings M, eds. Medical Acupuncture – A Western Scientific Approach. London: Elsevier 2016. 279–97.
9 Benedetti F. Can Low Placebo Responsiveness in Dementia be Exploited in Clinical Trials? Acupunct Med 2014;32:98–9. doi:10.1136/acupmed-2014-010537
10 Benedetti F, Arduino C, Costa S, et al. Loss of expectation-related mechanisms in Alzheimer’s disease makes analgesic therapies less effective. Pain 2006;121:133–44. doi:10.1016/j.pain.2005.12.016
11 Oken BS, Flegal K, Zajdel D, et al. Expectancy effect: impact of pill administration on cognitive performance in healthy seniors. J Clin Exp Neuropsychol 2008;30:7–17. doi:10.1080/13803390701775428
12 Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer’s disease. Am J Psychiatry 1984;141:1356–64. doi:10.1176/ajp.141.11.1356
13 Schrag A, Schott JM, Alzheimer’s Disease Neuroimaging Initiative. What is the clinically relevant change on the ADAS-Cog? J Neurol Neurosurg Psychiatry 2012;83:171–3. doi:10.1136/jnnp-2011-300881
14 Kueper JK, Speechley M, Montero-Odasso M. The Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog): Modifications and Responsiveness in Pre-Dementia Populations. A Narrative Review. J Alzheimers Dis 2018;63:423–44. doi:10.3233/JAD-170991
15 Wang H, Yu X, Li S, et al. The cognitive subscale of Alzheimer’s Disease Assessment Scale, Chinese version in staging of Alzheimer disease. Alzheimer Dis Assoc Disord 2004;18:231–5.
16 Vellas B, Andrieu S, Cantet C, et al. Long-term changes in ADAS-cog: what is clinically relevant for disease modifying trials in Alzheimer? J Nutr Health Aging 2007;11:338–41.
17 Grossberg GT, Schmitt FA, Meng X, et al. Reviews: Effects of transdermal rivastigmine on ADAS-cog items in mild-to-moderate Alzheimer’s disease. Am J Alzheimers Dis Other Demen 2010;25:627–33. doi:10.1177/1533317510385808
18 Schmitt FA, Aarsland D, Brønnick KS, et al. Evaluating rivastigmine in mild-to-moderate Parkinson’s disease dementia using ADAS-cog items. Am J Alzheimers Dis Other Demen 2010;25:407–13. doi:10.1177/1533317510367486
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