Cognitive Function After Treatment for Alcohol Problems

Objective: The objective of this study was to assess cognitive function and the potential recovery in a group of patients with alcohol dependence (AD) in treatment for alcohol problems. Methods: Patients with AD, fulfilling the ICD-10 diagnostic criteria, were recruited consecutively over a 9-months period from an outpatient clinic at Hvidovre University Hospital, Denmark. Patients’ (n=74) cognitive function was repeatedly assessed within 100 days after start of treatment by means of two methods: The quick test of cognitive speed (AQT) and continuous reaction time (CRT). The association between days from start of alcohol treatment and cognitive function was assessed in linear generalized estimating equation models, taking account of correlation structure in data and incomplete follow-up. All analyses were adjusted for sex, years of alcohol dependence, days of high alcohol use 30 days before start of treatment, other drug use, relapse, use of psychoactive medicine, and psychiatric diagnosis. Results : At treatment start, 46 % of the patients displayed a normal score on both tests, 12 % of the patients had abnormal scores on both tests, and 42 % of the patients had an abnormal score on one test. Our results indicate a slight improvement of AQT reaction time over time, whereas the CRT test score was almost stable throughout the follow-up. Discussion : We found no clinically significant improvement of cognitive function among patients with AD treated for alcohol problems. Further research of alcohol related cognitive impairments and recovery is needed to guide clinical practice in treatment of AD and timing of cognitive behavioral therapy.


Introduction
Alcohol is the causal factor for more than 200 diseases and conditions (Rehm, et al., 2017) [1] and is one of the leading global risk factors for the overall disease burden (World Health Organization, 2018) [2]. Studies among patients with alcohol dependence (AD) have demonstrated an approximately 3-fold higher mortality compared to the general population (Holst, Tolstrup, Sorensen, & Becker, 2017) [3]. Further, alcohol may damage multiple brain regions and a range of non-selective cognitive functions, especially if chronically consumed, causing cognitive impairments and behavioral changes (Oscar-Berman, Shagrin, Evert, & Epstein, 1997; Stavro, Pelletier, & Potvin, 2013) [4,5].
The possibility of recovery of cognitive function after treatment for AD and cessation of drinking is an area that has not been extensively investigated and existing evidence is inconsistent. A study of cognitive function among long-term abstinent AD patients (abstained on average 6.7 years) showed that abstinent AD patients performed similarly to controls (George Fein, et al., 2006) [20]. Another study showed impaired cognitive function among AD patients as compared to controls, regardless of abstinence duration (Nowakowska, Jablkowska, & Borkowska, 2007) [21]. While a meta-analysis of cognitive deficits in alco-holism, suggests that cognitive function among AD patients do not appear within the normal range, until over a year of sobriety (Stavro, et al., 2013) [22].
Understanding how cognitive function among AD patients develops over time is important as it may add to evidence guiding clinical practice in treatment of AD, and timing of cognitive behavioral therapy.
The aim of the present study was to the assess the association between cognitive function (measured with AQT and CRT) and time since start of treatment for alcohol problems among AD patients.

Subjects
Patients with AD were recruited consecutively over a 9-months period from an outpatient clinic at Hvidovre Univer-

The Quick Test of Cognitive Speed (AQT)
AQT was designed to assess perceptual and cognitive speed from visual stimuli to verbal response (Nielsen, Wiig, Warkentin, & Minthon, 2004;Wiig, et al., 2002) [24,25]. The test has been used in the evaluation of patients with Alzheimer disease (Nielsen, et al., 2004) [24] and dementia evaluation in primary care (Kvitting, Wimo, Johansson, & Marcusson, 2013) [26]. In part 1 and 2 of the test one dimension is assessed at a time, thus the patient names forms (circles, squares, triangles, or rectangles) and colors (red, black, yellow, or blue) respectively. In part 3 overall cognitive speed is assessed using both dimensions, and the patient is asked to name colors and forms of the 40 visual stimuli. The main result is extracted from part 3 of the test and measured in seconds. A test result above 70 seconds is considered abnormal. AQT has shown to be independent of language, color blindness, education, age and gender (Kvitting, et al., 2013; Takahashi, Awata, Sakuma, Inagaki, & Ijuin, 2012) [26,27].

Continuous reaction time (CRT)
CRT is an approximately 10 minutes registration of motor reaction to audible stimuli, that measures and combines motor reactions speed, sustained attention, and inhibitory control.
CRT is used for the assessment of mild forms of hepatic encephalopathy and is used as a screening tool for minimal hepatic encephalopathy in Scandinavia (Lauridsen, et al., 2016 [20]). CRT is measured by means of a set of headphones, a trigger button, a laptop, and software (Lauridsen, Thiele, Kimer, & Vilstrup, 2013) [28] (in this study EKHO was applied). The patient must press a button as fast as possible in response to each audible stimulus in the headphones. During the test, the patient is exposed to 150 randomly occurring sound stimuli (90 dB and 500 mHz) with 2 to 6 seconds intervals. The CRT index (the ratio: 50 percentile/

Covariates
Information on age, sex, highest completed education, employment status, years of alcohol dependence, other drug use, use of psychoactive medicine, psychiatric diagnosis, days of a high alcohol use (≥5 drinks/day) 30 days before start of treatment, and weekly alcohol intake 30 days before start of treatment, was obtained through systematic interviews and registered in the Copenhagen Alcohol Cohort as described elsewhere (Holst, et al., 2017) [3].
Years of alcohol dependency (<14 years/≥14 years), and days of high alcohol use (≥5 drinks per day) 30 days before start of treatment (not every day/every day) were dichotomized based on the median. Other drug use was dichotomized (yes/no), and due to the size of the study population no distinction was made between type of drug(s) used. Patients were defined as users of psychoactive medicine if they used at least one of the following products: antipsychotic medicine, antidepressants, anti-anxiety agents (benzodiazepine), anti-abstinence agents, unspecific sedatives (neuroleptic), or hypnotics (sleeping pills). Patients that were intoxicated by alcohol under the conduction of a test or in between tests were classified as having relapse (yes/no). Patients were identified as having a psychiatric diagnosis (yes/no) if they had at least one psychiatric diagnosis.

Statistical methods
The potential association between days from start of al- Sensitivity analyses were conducted, to assess whether cognitive recovery varied depending on years of alcohol dependence, days of high alcohol use 30 days before start of treatment, other drug use, relapse, use of psychoactive medicine, and psychiatric diagnosis. Thus, stratified analyses were performed, and potential interactions between these factors and time since start of treatment on cognitive function were assessed.

Baseline characteristics
The study population consisted of 74 patients, 70 % were men, and the average age was 49 years (table 1). The majority had a short educational level (38 %), 20 % were employed, and consumed 100 drinks per week on average in the 30 days before start of treatment. At treatment start, 46 % of the patients displayed a normal

The Quick Test of Cognitive Speed (AQT) after treatment for alcohol problems
The association between time since start of treatment

Discussion
Our results show that 92 % of the AD patients in treatment for alcohol problems had a normal cognitive function, in at least one of the tests applied, while 54 % had an abnormal test score at either AQT or the CRT by start of treatment. The prevalence of cognitive abnormalities in our sample is relatively low compared to previous studies (Parsons & Nixon, 1993) [6]. we are interested in cognitive recovery after start of treatment, this selection bias is not of great concern.
In conclusion, we found no clinically significant im- Becker provided significant guidance and helped edit and write the manuscript.

Appendix 2
The black curves are cubic smooth splines illustrating the association between days since alcohol treatment start and CRT index for AD patients with respectively ≥14 years of alcohol dependence, ≥30 days of high alcohol use the month before start of treatment, user of other drugs, relapse, use of psychoactive medicine and psychiatric disorders. The grey curves are cubic smooth splines illustrating the association between days since alcohol treatment start and CRT index for AD patients with respectively <14 years of alcohol dependence, <30 days of high alcohol use the month before start of treatment, no use of other drugs, no relapse, no use of psychoactive medicine and no psychiatric disorders.
Appendix 2, Figure A: Test results of the Quick Test of Cognitive Speed (AQT) by days since alcohol treatment start, by years of alcohol dependence, by days of high alcohol use last 30 days, by other drug use, by relapse, by use of psychoactive medicine and by psychiatric diagnosis.