- Email: [email protected]
Validation of a rapid and easy-to-perform screening test for neurocognitive impairment in HIV+ patients
Journal Pre-proof Validation of a rapid and easy-to-perform screening test for neurocognitive impairment in HIV+ patients
Heloise Joly, Matteo Vassallo, Margaux Issaurat, Roxane Fabre, Christian Pradier, Christine Lebrun-Frenay PII:
S0022-510X(19)32429-3
DOI:
https://doi.org/10.1016/j.jns.2019.116664
Reference:
JNS 116664
To appear in:
Journal of the Neurological Sciences
Received date:
4 September 2019
Revised date:
2 December 2019
Accepted date:
27 December 2019
Please cite this article as: H. Joly, M. Vassallo, M. Issaurat, et al., Validation of a rapid and easy-to-perform screening test for neurocognitive impairment in HIV+ patients, Journal of the Neurological Sciences (2019), https://doi.org/10.1016/j.jns.2019.116664
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2019 Published by Elsevier.
Journal Pre-proof
Validation of a rapid and easy-to-perform screening test for neurocognitive impairment in HIV+ patients
Heloise Joly1*, Matteo Vassallo2*, Margaux Issaurat1, Roxane Fabre3, Christian Pradier4 and Christine Lebrun-Frenay 1
1 = Centre de Ressources et de Compétences sclérose en plaques (CRCSEP), Department of Neurology, Pasteur 2 Hospital, Côte d’Azur University of Nice, France
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2 = Service de Medicine Interne, Centre hospitalier de Cannes, Cannes, France 3 = Université Côte d'Azur, CoBTeK lab, Centre Hospitalier Universitaire de Nice, Department de Santé Publique, Nice, France
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4 = Université Côte d’Azur, Centre Hospitalier Universitaire de Nice, Département de
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Santé Publique, Nice, France
*These authors contributed equally to this work
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Corresponding author information: Dr Matteo Vassallo, Department of Internal Medicine, Cannes General Hospital. Telephone number: 0033493697211, Fax number:
ur
0033492183764 email: [email protected]
Jo
The statistical analysis was performed by R Fabre and C Pradier (Université Côte d’Azur, Centre Hospitalier Universitaire de Nice, Département de Santé Publique, Nice, France and Université Côte d'Azur, CoBTeK lab, Centre Hospitalier Universitaire de Nice, CMRR, Nice, France)
Word count: 1591 Title character count (including spaces): 103 Search terms: HIV Dementia, Cognitive neuropsychology in Dementia Study funding: none
Journal Pre-proof
This study did not receive any funding
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na
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All authors have no disclosures relevant to this manuscript
Journal Pre-proof
Abstract
Objective: Information Processing Speed (IPS) is one of the earliest cognitive domains impaired in both multiple sclerosis (MS) and HIV-infected patients. Our aim was to study whether the Computerized Speed Cognitive Test (CSCT), an ultra-rapid tool which detects IPS impairment and is already used in MS subjects, could also be useful to screen for HIVassociated neurocognitive disorders (HAND).
Methods: The Neuracog study was an open-label prospective trial conducted in Nice and
ro of
Cannes hospitals. Each patient performed a wide range of neuropsychological (NP) tests. Patients were defined as no-HAND or HAND. Groups were compared to measure
of CSCT for detecting HAND.
-p
sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV)
HAND was diagnosed in 67/86 patients.
re
Results: Eighty-six subjects were included (26 women, 60 men, mean age: 53.1 years).
lP
The CSCT z-score showed a highly significant difference between the no-HAND and the HAND groups (No HAND mean: -0.1, SD: 1.0 versus HAND mean: -1.1, SD: 1.6;
respectively
na
p=0.002),. The sensitivity, specificity, PPV and NPV were 81%, 53%, 86% and 43%,
Conclusions: the CSCT is an easy-to-perform test allowing detection of mild forms of
Jo
ur
HAND, to be considered among screening tools for neurocognitive impairment.
Journal Pre-proof
Introduction The prevalence of HIV-associated neurocognitive disorders (HAND) remains high despite the availability of combination antiretroviral therapies (cART). With the introduction of cART, the clinical phenotype of the disorders has switched from dementia to mild forms of impairment. HAND are associated with loss of quality of life, poorer adherence to treatment and higher mortality [1]. While this might require an adjustment of cART, it is sometimes difficult in clinical practice to diagnose mild forms of HAND, especially if
patients are asymptomatic. Neuropsychologists outside the research field are generally
ro of
limited in number and a detailed neuropsychological battery of tests requires at least one and a half hours per patient. Rapid tools for screening subjects requiring more in-depth evaluation would thus be particularly useful. .
-p
Several screening tools for the detection of HAND are currently used, including the HIVDementia Scale, the International HIV-Dementia Scale, the Mini Mental State Examination
re
(MMSE), the Montreal Cognitive Assessment (MoCA) and the Cognitive Assessment tool-
lP
rapid version (CAT-rapid) and the Neurocognitive (NEU) screen [2-3]. In general, these tools easily detect severe forms of HAND, but in cases of mild deficit they
na
either do not perform well or, in the case of the NEU screen, are too complex to be conducted by a non-neuropsychologist.
We recently showed that the combination of MoCA, the Isaac Set Test and Memory Span
ur
Test performed better than the majority of screening tools available for the detection of
Jo
mild forms of HAND [4]. These tests take about 20 minutes and can be administered by a psychologist but hardly by current medical providers. In Multiple Sclerosis (MS), a short test (90 seconds) evaluating Information Processing Speed (IPS) has been validated as a screening measure of cognitive dysfunction [5]. A
computerized version of this test, the CSCT (Computerized Speed Cognitive Test) was recently developed [6]. Cognitive deficits in MS and HIV infection share certain similarities, as they both show white matter inflammation and display a mainly sub-cortical phenotype of cognitive impairment. IPS is one of the most frequent and earliest impairments to appear in both MS and HAND. Our aim was to examine the relevance of the CSCT, an ultra-rapid and easy-to-perform tool, for detecting HAND.
Journal Pre-proof Methods The Neuracog study was an open-label prospective trial conducted in the Departments of Neurology in Nice Côte d’Azur University Hospital and of Internal Medicine/Infectious Diseases of the Cannes General Hospital in France. The study was approved by the Sud Méditerranée I Ethics Committee in France. Each HIV-1 infected patient over 18 years old and followed in the two Departments could be included, with the exception of subjects currently using illicit drugs, those with any severe neurological history or severe psychiatric disorder. There was no limit to the CD4 cell count or HIV-viral load. After providing written informed consent, each patient performed a wide range of
neuropsychological (NP) tests administered by a single trained neuropsychologist (MI).
ro of
The following cognitive domains were explored: Global cognitive functioning with the MoCA, attentional domain with the Paced Auditory Serial Audition (PASAT) 3 seconds which evaluates sustained attention and has already been validated in HIV population [7],
-p
and with the Trail Making Test (TMTA and B) time, long-term verbal memory with the RL/RI-16 (a French validated test evaluating verbal episodic memory were patients have
re
to learn 16 words with semantic index through an encoding phase, followed by three free
lP
and then indexed recalls, and one free and indexed differed recall after 20 minutes [8]), visual memory with the recall of the Rey figure, visuo-construction with the copy of the Rey
na
figure, executive functions with the copy of the Rey figure for planning, the TMTB-A time and the number of perseverative errors at the TMTB for mental shifting, and verbal fluency for language. The CSCT was used to evaluate IPS. In this test, patients had to associate a
ur
number with each symbol shown on a screen by referring to a model in front of them. They
Jo
gave their answers orally, which allowed control of the motor processing speed that may be impaired in this condition.
As the cut-off value for defining a pathological CSCT score in HIV-infected population is still unknown, we measured performance according to norms adjusted for age, sex and
socio-cultural level. Using Received Operating Characteristic (ROC)
curves, we then
calculated the potential cut-off for identifying subjects with pathological scores. The test results were converted into z-scores based on normative data. The normality of the variables was tested with the Shapiro test. According to the classification proposed by Antinori et al. [9], HAND was defined as impairment of at least two cognitive domains 1 SD below the mean. The CSCT scores were excluded from this definition as the aim of the study was to evaluate whether it is suitable for predicting cognitive impairment. The IADL scale was used to measure the
symptomatic versus asymptomatic aspects of cognitive impairment and allowed definition
Journal Pre-proof of the 3 following sub-groups of impairment: Asymptomatic Neurocognitive Impairment (ANI), Mild Neurocognitive Disorder (MND), and HIV-Associated Dementia (HAD). Subjects with normal tests were categorized as No-HAND. Groups were compared using Student’s t-test or the Wilcoxon-Mann-Whitney test for quantitative variables and with chisquare or Fisher’s tests for qualitative variables. A p value ≤ 0.05 was considered significant. Statistical analyses were performed with the R-3.5.1 free software. In addition to this analysis, we created a ROC curve with the ROCR library in order to identify a potential cut-off value for the CSCT which could be indicative of HAND. Data availability
All significant data about patients are included in the work. In case of necessity, data not
ro of
published in the article are available in a registry at the Department of Clinical Research in
-p
Nice University Hospital.
Results
re
Eighty-six subjects were included from March 2017 to October 2018 (26 women, 60 men,
lP
mean age: 53.1 years; SD=9.7). The characteristics of each group are shown in Table 1. All but two subjects (98%) had HIV-RNA viral load below < 50 copies/ml at inclusion.
na
Patients diagnosed with HAND numbered 67/86 (78%). Among subgroups of impairment, 60 subjects were considered as ANI, 2 subjects as MND and 5 subjects as HAD. The two groups differed significantly only in terms of sex with a higher percentage of women in the
ur
HAND group than in the No HAND group (p=0.03).
Jo
The CSCT z-score showed a statistically significant difference between the groups i.e. No HAND mean: -0.1, SD: 1.0 versus HAND mean: -1.1, SD: 1.6; p=0.002. Based on the statistical relevance, the threshold of 47 correct responses for the CSCT was used to define the predictive value of this test. Figure 1 shows the ROC curve for the predictive
value of the CSCT to detect HAND. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were the following: 81%, 53%, 86% and 43%, respectively. Results did not change when excluding subjects with HAD (79%, 53%, 84% and 43%, respectively). In order to reduce the risk of interference between HIV and alcohol abuse in the interpretation of Digit Symbol performance, we included the alcohol consumption in the analysis and we found that only 3 out of 84 subjects met criteria for alcohol abuse.
Journal Pre-proof Discussion The CSCT thus showed strong sensitivity to detect cognitive dysfunction in HIV patients both in severe and mild forms of HAND. ANI is the most frequent phenotype of impairment in the cART era and its diagnosis is currently one of the main challenges for clinicians, as patients have no symptom of impairment. The high prevalence of HAND in the present study could be explained by the open-label study design, where subjects were not randomly selected and those with suspected neurocognitive disorders were prioritized in the inclusions.
The CSCT is a computerized version of the Symbol Digit Modality Test (SDMT) which
ro of
exists in two versions: one where patients give their answer orally and the other with a written answer. The written SDMT has been shown to be a predictor of dementia, AIDS and death in the HIV-infected population [10]. However, the written SDMT results include
-p
the impact of motor slowing in its measure of IPS which is controlled in the oral version used with the CSCT. Furthermore, the present study has the advantage of discriminating
re
patients even with mild forms of HAND. In our previous work, we showed a similar
lP
performance for detecting HAND with a brief battery composed of MOCA, Isaac set test and Memory span test [4]. However, compared to CSCT, this brief battery takes longer
na
(approximatively 20 minutes) and requires preferably administration by a psychologist. The CSCT is much faster (2 minutes) and its simplicity could allow its administration also by other medical providers.
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In this study the sensitivity and PPV of the CSCT to detect HIV-related cognitive
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impairment was comparable to the performance of most screening tests. However, this test is extremely rapid and easy to perform, thus showing potential interest for reducing time and cost. It is particularly helpful in settings where neuropsychologists are scarce. In line with other screening tests, we found a low specificity and NPV for the CSCT. This
may be due to the overlapping aspect of IPS. Indeed, a slow IPS may have an impact on attention as well as on memory, language and executive performance. The lack of specificity and overlap may explain its high sensitivity for detection of cognitive impairment in HIV-infected patients. In conclusion, the CSCT is a short test that is easy for many medical providers to use in current clinical practice and is available online (https://csctcogms-bordeaux.fr/). It is a quick and efficient tool to assess whether an HIV-infected
patient requires more thorough cognitive evaluation.
Journal Pre-proof Table 1. Characteristics of HIV+ patients according to the No Hand versus HAND (ANI, HAD, MND) groups No HAND n=19
ANI / HAD / MND n=67
mean SD
mean SD
p-value
Age (Year)
53.6 [11.8]
53.0 [9.2]
0.825
Weight
74.5 [14.0]
69.1 [15.8]
0.190
Size
174.8 [6.4]
171.1 [9.3]
0.108
70.2 [12.5]
74.8 [13.1]
0.172
Years since HIV infection
15.4 [11.7]
16.9 [10.6]
0.593
CD4 at inclusion
696.7 [332.6]
CD8 at inclusion
917.9 [476.1]
Women
0.879
24 (35.8)
17 (89.5)
43 (64.2)
0 (0.0)
12 (17.9)
12 (63.2)
42 (62.7)
7 (36.8)
13 (19.4)
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0.034
2 (10.5)
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Educational level
University
937.7 [419.9]
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Men
College
0.278
n (%)
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Sex
Basic
800.4 [373.4]
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n (%)
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Heart rate
0.055
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Figure 1: Roc curve of the predictive value of the CSCT score to categorize HIV+ patients depending on the presence or absence of HAND and box plot of the distribution of the CSCT z-score depending on the threshold of 47 correct responses with the CSCT.
Journal Pre-proof Authors contributions: H Joly, M Vassallo, and C Lebrun were involved in planning the study, writing, and in the critical revision of the manuscript. M Issaurat performed NP testing and revised the manuscript. R Fabre and C Pradier were involved in planning the study, statistical analysis and critical revision of the manuscript Ackowledgements: We wish to thank Cassandre Landes, who provided valuable assistance for the administrative tasks required for such a project. We are grateful for the help of Sandrine DiPace and Dominique Hoffer, who participated in patient recruitment. A special thanks to Brigitte Dunais who provided helpful suggestions for improving this paper
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Study funding No targeted study funding reported
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Disclosure H Joly reports no disclosures relevant to the manuscript M Vassallo reports no disclosures relevant to the manuscript M Issaurat reports no disclosures relevant to the manuscript R Fabre reports no disclosures relevant to the manuscript C Pradier reports no disclosures relevant to the manuscript C Lebrun reports no disclosures relevant to the manuscript.
Journal Pre-proof References:
1. J.C. McArthur, J. Steiner, N. Sacktor, et al. Human Immunodeficiency virus associated neurocognitive disorders: mind the gap. Ann Neurol 67 (2010) 699–714. 2. K. A. Bottiggi, J.J Chang, F.A. Schmitt, et al. The HIV Dementia Scale: predictive power in mild dementia and HAART. J Neurol Sci 260 (2007) 11-5. 3. J.A. Joska, J. Witten, K.G. Thomas, et al. A Comparison of Five Brief Screening Tools for HIV-Associated Neurocognitive Disorders in the USA and South Africa.
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AIDS Behav 20 (2016) 1621-31 4. M. Vassallo, L. Barbaud, R. Fabre, et al. Evaluation of Three Brief Screening Tests for Older Patients with Mild HIV Associated Neurocognitive Disorders in the cART Era. J Neurol Neurophysiol 8 (2017) 421
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5. M.S. Deloire, M.C. Bonnet, E. Salort, et al. How to detect cognitive dysfunction at
re
early stages of multiple sclerosis? Mult Scler 12 (2006) 445-52 6. A. Ruet, M.S. Deloire, J. Charré-Morin, et al. A new computerised cognitive test for
Scler 19 (2013) 1665-72
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the detection of information processing speed impairment in multiple sclerosis. Mult
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7. M.C. Diehr, M. Cherner, T.J. Wolfson, et al. HIV Neurobehavioral Research Center Group. The 50 and 100-item short forms of the Paced Auditory Serial Addition Task
ur
(PASAT): demographically corrected norms and comparisons with the full PASAT in normal and clinical samples. J Clin Exp Neuropsychol 25 (2003) 571-85
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8. M. Van der Linden, F. Coyette, J. Poitrenaud et al. L’épreuve de rappel libre/rappel indicé à 16 items (RL/RI-16). In : M. Van der Linden, S. Adam, A. Agniel, et al. (Eds.). L’évaluation des troubles de la mémoire: Présentation de quatre tests de
mémoire épisodique (avec leur étalonnage). Solal, Marseille (2004) 25-47. 9. A. Antinori, G. Arendt, J.T. Becker, et al. Updated research nosology for HIVassociated neurocognitive disorders. Neurology 69 (2007) 1789–1799 10. N.C. Sacktor, H. Bacellar, D.R. Hoover, et al. Psychomotor slowing in HIV infection: a predictor of dementia, AIDS and death. J Neurovirol 2 (1996) 404-10
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Journal Pre-proof Highlights
CSCT could easily allow the detection of mild and severe forms of HAND
Its performance is similar to other screening tools but requires shorter time
This easy-to-use screening tool could be helpful especially in settings where
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neuropsychologists are scarce
Figure 1
Heloise Joly, Matteo Vassallo, Margaux Issaurat, Roxane Fabre, Christian Pradier, Christine Lebrun-Frenay PII:
S0022-510X(19)32429-3
DOI:
https://doi.org/10.1016/j.jns.2019.116664
Reference:
JNS 116664
To appear in:
Journal of the Neurological Sciences
Received date:
4 September 2019
Revised date:
2 December 2019
Accepted date:
27 December 2019
Please cite this article as: H. Joly, M. Vassallo, M. Issaurat, et al., Validation of a rapid and easy-to-perform screening test for neurocognitive impairment in HIV+ patients, Journal of the Neurological Sciences (2019), https://doi.org/10.1016/j.jns.2019.116664
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2019 Published by Elsevier.
Journal Pre-proof
Validation of a rapid and easy-to-perform screening test for neurocognitive impairment in HIV+ patients
Heloise Joly1*, Matteo Vassallo2*, Margaux Issaurat1, Roxane Fabre3, Christian Pradier4 and Christine Lebrun-Frenay 1
1 = Centre de Ressources et de Compétences sclérose en plaques (CRCSEP), Department of Neurology, Pasteur 2 Hospital, Côte d’Azur University of Nice, France
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2 = Service de Medicine Interne, Centre hospitalier de Cannes, Cannes, France 3 = Université Côte d'Azur, CoBTeK lab, Centre Hospitalier Universitaire de Nice, Department de Santé Publique, Nice, France
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4 = Université Côte d’Azur, Centre Hospitalier Universitaire de Nice, Département de
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Santé Publique, Nice, France
*These authors contributed equally to this work
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Corresponding author information: Dr Matteo Vassallo, Department of Internal Medicine, Cannes General Hospital. Telephone number: 0033493697211, Fax number:
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0033492183764 email: [email protected]
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The statistical analysis was performed by R Fabre and C Pradier (Université Côte d’Azur, Centre Hospitalier Universitaire de Nice, Département de Santé Publique, Nice, France and Université Côte d'Azur, CoBTeK lab, Centre Hospitalier Universitaire de Nice, CMRR, Nice, France)
Word count: 1591 Title character count (including spaces): 103 Search terms: HIV Dementia, Cognitive neuropsychology in Dementia Study funding: none
Journal Pre-proof
This study did not receive any funding
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All authors have no disclosures relevant to this manuscript
Journal Pre-proof
Abstract
Objective: Information Processing Speed (IPS) is one of the earliest cognitive domains impaired in both multiple sclerosis (MS) and HIV-infected patients. Our aim was to study whether the Computerized Speed Cognitive Test (CSCT), an ultra-rapid tool which detects IPS impairment and is already used in MS subjects, could also be useful to screen for HIVassociated neurocognitive disorders (HAND).
Methods: The Neuracog study was an open-label prospective trial conducted in Nice and
ro of
Cannes hospitals. Each patient performed a wide range of neuropsychological (NP) tests. Patients were defined as no-HAND or HAND. Groups were compared to measure
of CSCT for detecting HAND.
-p
sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV)
HAND was diagnosed in 67/86 patients.
re
Results: Eighty-six subjects were included (26 women, 60 men, mean age: 53.1 years).
lP
The CSCT z-score showed a highly significant difference between the no-HAND and the HAND groups (No HAND mean: -0.1, SD: 1.0 versus HAND mean: -1.1, SD: 1.6;
respectively
na
p=0.002),. The sensitivity, specificity, PPV and NPV were 81%, 53%, 86% and 43%,
Conclusions: the CSCT is an easy-to-perform test allowing detection of mild forms of
Jo
ur
HAND, to be considered among screening tools for neurocognitive impairment.
Journal Pre-proof
Introduction The prevalence of HIV-associated neurocognitive disorders (HAND) remains high despite the availability of combination antiretroviral therapies (cART). With the introduction of cART, the clinical phenotype of the disorders has switched from dementia to mild forms of impairment. HAND are associated with loss of quality of life, poorer adherence to treatment and higher mortality [1]. While this might require an adjustment of cART, it is sometimes difficult in clinical practice to diagnose mild forms of HAND, especially if
patients are asymptomatic. Neuropsychologists outside the research field are generally
ro of
limited in number and a detailed neuropsychological battery of tests requires at least one and a half hours per patient. Rapid tools for screening subjects requiring more in-depth evaluation would thus be particularly useful. .
-p
Several screening tools for the detection of HAND are currently used, including the HIVDementia Scale, the International HIV-Dementia Scale, the Mini Mental State Examination
re
(MMSE), the Montreal Cognitive Assessment (MoCA) and the Cognitive Assessment tool-
lP
rapid version (CAT-rapid) and the Neurocognitive (NEU) screen [2-3]. In general, these tools easily detect severe forms of HAND, but in cases of mild deficit they
na
either do not perform well or, in the case of the NEU screen, are too complex to be conducted by a non-neuropsychologist.
We recently showed that the combination of MoCA, the Isaac Set Test and Memory Span
ur
Test performed better than the majority of screening tools available for the detection of
Jo
mild forms of HAND [4]. These tests take about 20 minutes and can be administered by a psychologist but hardly by current medical providers. In Multiple Sclerosis (MS), a short test (90 seconds) evaluating Information Processing Speed (IPS) has been validated as a screening measure of cognitive dysfunction [5]. A
computerized version of this test, the CSCT (Computerized Speed Cognitive Test) was recently developed [6]. Cognitive deficits in MS and HIV infection share certain similarities, as they both show white matter inflammation and display a mainly sub-cortical phenotype of cognitive impairment. IPS is one of the most frequent and earliest impairments to appear in both MS and HAND. Our aim was to examine the relevance of the CSCT, an ultra-rapid and easy-to-perform tool, for detecting HAND.
Journal Pre-proof Methods The Neuracog study was an open-label prospective trial conducted in the Departments of Neurology in Nice Côte d’Azur University Hospital and of Internal Medicine/Infectious Diseases of the Cannes General Hospital in France. The study was approved by the Sud Méditerranée I Ethics Committee in France. Each HIV-1 infected patient over 18 years old and followed in the two Departments could be included, with the exception of subjects currently using illicit drugs, those with any severe neurological history or severe psychiatric disorder. There was no limit to the CD4 cell count or HIV-viral load. After providing written informed consent, each patient performed a wide range of
neuropsychological (NP) tests administered by a single trained neuropsychologist (MI).
ro of
The following cognitive domains were explored: Global cognitive functioning with the MoCA, attentional domain with the Paced Auditory Serial Audition (PASAT) 3 seconds which evaluates sustained attention and has already been validated in HIV population [7],
-p
and with the Trail Making Test (TMTA and B) time, long-term verbal memory with the RL/RI-16 (a French validated test evaluating verbal episodic memory were patients have
re
to learn 16 words with semantic index through an encoding phase, followed by three free
lP
and then indexed recalls, and one free and indexed differed recall after 20 minutes [8]), visual memory with the recall of the Rey figure, visuo-construction with the copy of the Rey
na
figure, executive functions with the copy of the Rey figure for planning, the TMTB-A time and the number of perseverative errors at the TMTB for mental shifting, and verbal fluency for language. The CSCT was used to evaluate IPS. In this test, patients had to associate a
ur
number with each symbol shown on a screen by referring to a model in front of them. They
Jo
gave their answers orally, which allowed control of the motor processing speed that may be impaired in this condition.
As the cut-off value for defining a pathological CSCT score in HIV-infected population is still unknown, we measured performance according to norms adjusted for age, sex and
socio-cultural level. Using Received Operating Characteristic (ROC)
curves, we then
calculated the potential cut-off for identifying subjects with pathological scores. The test results were converted into z-scores based on normative data. The normality of the variables was tested with the Shapiro test. According to the classification proposed by Antinori et al. [9], HAND was defined as impairment of at least two cognitive domains 1 SD below the mean. The CSCT scores were excluded from this definition as the aim of the study was to evaluate whether it is suitable for predicting cognitive impairment. The IADL scale was used to measure the
symptomatic versus asymptomatic aspects of cognitive impairment and allowed definition
Journal Pre-proof of the 3 following sub-groups of impairment: Asymptomatic Neurocognitive Impairment (ANI), Mild Neurocognitive Disorder (MND), and HIV-Associated Dementia (HAD). Subjects with normal tests were categorized as No-HAND. Groups were compared using Student’s t-test or the Wilcoxon-Mann-Whitney test for quantitative variables and with chisquare or Fisher’s tests for qualitative variables. A p value ≤ 0.05 was considered significant. Statistical analyses were performed with the R-3.5.1 free software. In addition to this analysis, we created a ROC curve with the ROCR library in order to identify a potential cut-off value for the CSCT which could be indicative of HAND. Data availability
All significant data about patients are included in the work. In case of necessity, data not
ro of
published in the article are available in a registry at the Department of Clinical Research in
-p
Nice University Hospital.
Results
re
Eighty-six subjects were included from March 2017 to October 2018 (26 women, 60 men,
lP
mean age: 53.1 years; SD=9.7). The characteristics of each group are shown in Table 1. All but two subjects (98%) had HIV-RNA viral load below < 50 copies/ml at inclusion.
na
Patients diagnosed with HAND numbered 67/86 (78%). Among subgroups of impairment, 60 subjects were considered as ANI, 2 subjects as MND and 5 subjects as HAD. The two groups differed significantly only in terms of sex with a higher percentage of women in the
ur
HAND group than in the No HAND group (p=0.03).
Jo
The CSCT z-score showed a statistically significant difference between the groups i.e. No HAND mean: -0.1, SD: 1.0 versus HAND mean: -1.1, SD: 1.6; p=0.002. Based on the statistical relevance, the threshold of 47 correct responses for the CSCT was used to define the predictive value of this test. Figure 1 shows the ROC curve for the predictive
value of the CSCT to detect HAND. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were the following: 81%, 53%, 86% and 43%, respectively. Results did not change when excluding subjects with HAD (79%, 53%, 84% and 43%, respectively). In order to reduce the risk of interference between HIV and alcohol abuse in the interpretation of Digit Symbol performance, we included the alcohol consumption in the analysis and we found that only 3 out of 84 subjects met criteria for alcohol abuse.
Journal Pre-proof Discussion The CSCT thus showed strong sensitivity to detect cognitive dysfunction in HIV patients both in severe and mild forms of HAND. ANI is the most frequent phenotype of impairment in the cART era and its diagnosis is currently one of the main challenges for clinicians, as patients have no symptom of impairment. The high prevalence of HAND in the present study could be explained by the open-label study design, where subjects were not randomly selected and those with suspected neurocognitive disorders were prioritized in the inclusions.
The CSCT is a computerized version of the Symbol Digit Modality Test (SDMT) which
ro of
exists in two versions: one where patients give their answer orally and the other with a written answer. The written SDMT has been shown to be a predictor of dementia, AIDS and death in the HIV-infected population [10]. However, the written SDMT results include
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the impact of motor slowing in its measure of IPS which is controlled in the oral version used with the CSCT. Furthermore, the present study has the advantage of discriminating
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patients even with mild forms of HAND. In our previous work, we showed a similar
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performance for detecting HAND with a brief battery composed of MOCA, Isaac set test and Memory span test [4]. However, compared to CSCT, this brief battery takes longer
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(approximatively 20 minutes) and requires preferably administration by a psychologist. The CSCT is much faster (2 minutes) and its simplicity could allow its administration also by other medical providers.
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In this study the sensitivity and PPV of the CSCT to detect HIV-related cognitive
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impairment was comparable to the performance of most screening tests. However, this test is extremely rapid and easy to perform, thus showing potential interest for reducing time and cost. It is particularly helpful in settings where neuropsychologists are scarce. In line with other screening tests, we found a low specificity and NPV for the CSCT. This
may be due to the overlapping aspect of IPS. Indeed, a slow IPS may have an impact on attention as well as on memory, language and executive performance. The lack of specificity and overlap may explain its high sensitivity for detection of cognitive impairment in HIV-infected patients. In conclusion, the CSCT is a short test that is easy for many medical providers to use in current clinical practice and is available online (https://csctcogms-bordeaux.fr/). It is a quick and efficient tool to assess whether an HIV-infected
patient requires more thorough cognitive evaluation.
Journal Pre-proof Table 1. Characteristics of HIV+ patients according to the No Hand versus HAND (ANI, HAD, MND) groups No HAND n=19
ANI / HAD / MND n=67
mean SD
mean SD
p-value
Age (Year)
53.6 [11.8]
53.0 [9.2]
0.825
Weight
74.5 [14.0]
69.1 [15.8]
0.190
Size
174.8 [6.4]
171.1 [9.3]
0.108
70.2 [12.5]
74.8 [13.1]
0.172
Years since HIV infection
15.4 [11.7]
16.9 [10.6]
0.593
CD4 at inclusion
696.7 [332.6]
CD8 at inclusion
917.9 [476.1]
Women
0.879
24 (35.8)
17 (89.5)
43 (64.2)
0 (0.0)
12 (17.9)
12 (63.2)
42 (62.7)
7 (36.8)
13 (19.4)
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0.034
2 (10.5)
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Educational level
University
937.7 [419.9]
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Men
College
0.278
n (%)
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Sex
Basic
800.4 [373.4]
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n (%)
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Heart rate
0.055
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Figure 1: Roc curve of the predictive value of the CSCT score to categorize HIV+ patients depending on the presence or absence of HAND and box plot of the distribution of the CSCT z-score depending on the threshold of 47 correct responses with the CSCT.
Journal Pre-proof Authors contributions: H Joly, M Vassallo, and C Lebrun were involved in planning the study, writing, and in the critical revision of the manuscript. M Issaurat performed NP testing and revised the manuscript. R Fabre and C Pradier were involved in planning the study, statistical analysis and critical revision of the manuscript Ackowledgements: We wish to thank Cassandre Landes, who provided valuable assistance for the administrative tasks required for such a project. We are grateful for the help of Sandrine DiPace and Dominique Hoffer, who participated in patient recruitment. A special thanks to Brigitte Dunais who provided helpful suggestions for improving this paper
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Study funding No targeted study funding reported
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Disclosure H Joly reports no disclosures relevant to the manuscript M Vassallo reports no disclosures relevant to the manuscript M Issaurat reports no disclosures relevant to the manuscript R Fabre reports no disclosures relevant to the manuscript C Pradier reports no disclosures relevant to the manuscript C Lebrun reports no disclosures relevant to the manuscript.
Journal Pre-proof References:
1. J.C. McArthur, J. Steiner, N. Sacktor, et al. Human Immunodeficiency virus associated neurocognitive disorders: mind the gap. Ann Neurol 67 (2010) 699–714. 2. K. A. Bottiggi, J.J Chang, F.A. Schmitt, et al. The HIV Dementia Scale: predictive power in mild dementia and HAART. J Neurol Sci 260 (2007) 11-5. 3. J.A. Joska, J. Witten, K.G. Thomas, et al. A Comparison of Five Brief Screening Tools for HIV-Associated Neurocognitive Disorders in the USA and South Africa.
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AIDS Behav 20 (2016) 1621-31 4. M. Vassallo, L. Barbaud, R. Fabre, et al. Evaluation of Three Brief Screening Tests for Older Patients with Mild HIV Associated Neurocognitive Disorders in the cART Era. J Neurol Neurophysiol 8 (2017) 421
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5. M.S. Deloire, M.C. Bonnet, E. Salort, et al. How to detect cognitive dysfunction at
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early stages of multiple sclerosis? Mult Scler 12 (2006) 445-52 6. A. Ruet, M.S. Deloire, J. Charré-Morin, et al. A new computerised cognitive test for
Scler 19 (2013) 1665-72
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the detection of information processing speed impairment in multiple sclerosis. Mult
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7. M.C. Diehr, M. Cherner, T.J. Wolfson, et al. HIV Neurobehavioral Research Center Group. The 50 and 100-item short forms of the Paced Auditory Serial Addition Task
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(PASAT): demographically corrected norms and comparisons with the full PASAT in normal and clinical samples. J Clin Exp Neuropsychol 25 (2003) 571-85
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8. M. Van der Linden, F. Coyette, J. Poitrenaud et al. L’épreuve de rappel libre/rappel indicé à 16 items (RL/RI-16). In : M. Van der Linden, S. Adam, A. Agniel, et al. (Eds.). L’évaluation des troubles de la mémoire: Présentation de quatre tests de
mémoire épisodique (avec leur étalonnage). Solal, Marseille (2004) 25-47. 9. A. Antinori, G. Arendt, J.T. Becker, et al. Updated research nosology for HIVassociated neurocognitive disorders. Neurology 69 (2007) 1789–1799 10. N.C. Sacktor, H. Bacellar, D.R. Hoover, et al. Psychomotor slowing in HIV infection: a predictor of dementia, AIDS and death. J Neurovirol 2 (1996) 404-10
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Journal Pre-proof Highlights
CSCT could easily allow the detection of mild and severe forms of HAND
Its performance is similar to other screening tools but requires shorter time
This easy-to-use screening tool could be helpful especially in settings where
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neuropsychologists are scarce
Figure 1