Renée Baelde
5661145
Masterscriptie
Programmagroep Brein en Cognitie
Begeleider:
Sieberen van der Werf
09-07-2015
E
XPLORING WHITE MATTER INTEGRITY
AND COGNITIVE DYSFUNCTION IN
ABSTRACT
Currently, HIV is known as a chronic disease, affecting a widespread spectrum of cognitive domains: information processing speed, attention, memory, executive functioning and motor skills. The cognitive disorders related to HIV are termed HIV-associated
neurocognitive disorders (HAND) and can occur in any combination. These symptoms may be attributable to the damage HIV eventually causes to white matter. Predominantly the white matter in the basal ganglia and frontal regions are thought to be affected. The aim of this study is to examine the degree of white matter damage of two tracts (a frontostriatal tract and a motorstriatal tract) in HIV patients with an increased risk of HAND, and correlate this with the degree of cognitive impairment present. No correlation was found between the white matter impairment and cognition impairment. However, patients with HAND did display significantly lower white matter integrity than patients without HAND, which could suggest that the degree of white matter integrity preludes HAND. Interestingly, previous research found this effect in the frontostratial areas. Whereas the present study could only find a strong effect on the motorstriatal tracts, which is not yet associated with HAND.
TABLE OF CONTENTS Abstract 2 Introduction 4 Present study 9 Methods 10 Subjects 10 Procedure 11 Neuropsychological Measurements 12 Motor Functioning 12 Executive functioning 13 HAND 14
DTI Data Acquisition 15
Image Processing 16
Statistical Analysis 17
Results 17
Participants 17
White Matter and Cognition 18
White Matter in HAND 20
Discussion 21 Limitations 24 Further Research 25 References 25 Appendices A NPA measurements 30 B interview 32
Exploring white matter integrity and cognitive dysfunction in patients with HIV
Introduction
The Human Immunodeficiency Virus (HIV) is a global epidemic, affecting roughly 33 million people worldwide (WHO, UNAIDS & UNICEF 2010). Shortly after infection, HIV-1 enters the central nervous system (CNS) in mononuclear cells (Davis et al., 1992), destructing CD4 T-cells, causing decline of the functional immune system. This progressive disorder of the immune system is called Acquired Immune Deficiency Syndrome (AIDS), which
eventually leads to death through an increased risk of opportunistic infection (Orenstein, Fox, & Wahl, 1997).
In the final stages of aids, HIV-patients developed severe progressive cognitive and motor impairment (Schouten, Cinque, Gisslen, Reiss, & Portegies, 2011). This clinical syndrome was termed AIDS dementia complex (ADC) (Navia, Jordan & Price, 1986). ADC is characterized by impairment in three areas: cognition, motor functioning and behaviour. Cognitive impairment is characterised by mental slowness, memory and concentration problems. Motor symptoms include a loss of fine motor control leading to clumsiness, poor balance and tremors. Behavioural changes may include apathy, lethargy and diminished emotional responses and spontaneity. This impairment is deemed to be due to the production of viral and inflammatory proteins resulting from immune activation (Schouten et al., 2011).
Presently, the course of the disease has changed dramatically, due to the introduction of highly active combined antiretroviral therapy (cART). This is not a cure for HIV. Rather, it combines different drugs into regimens that attack viral replication at multiple targets and on different stages of the infection cycle (Koczor & Lewis, 2010), thus controlling the replication of the virus. Since the introduction of cART, morbidity and mortality rates among
HIV-patients have been substantially lower (Cysique & Brew, 2009). Also, the diagnosis ADC became a rare complication.
However, after 1996, the American Academy of Neurology revised and updated the terminology of HIV-associated cognitive diagnoses into a broader clinical spectrum of neurocognitive impairment(Antinori et al., 2007; American Academy of Neurology, 1996), resulting in diagnoses of milder neurocognitive impairment in HIV patients. The prevalence of milder neurocognitive impairment has since been estimated to be between 15 and 50 percent (Cysique & Brew, 2009; Valcour, Sithinamsuwan, Letendre, & Ances, 2011). Also, previous research show that milder neurocognitive impairment may even be prevalent in patients with well-controlled infection using cART (Simioni et al., 2010). The revised classification system of HIV associated neurocognitive disorders (HAND) is shown in Table 1. HIV-Associated Dementia (HAD) is the most severe form of injury and is comparable to ADC. Mild Neurocognitive Disorder (MND) represents a milder form of impairment, which still impacts the activities of daily living. Asymptomatic Neurocognitive Impairment (ANI) is the mildest form of HAND. It is based on the observation that some individuals have
demonstrable, usually mild, cognitive impairment, without any apparent abnormality in everyday functioning (Antinori et al., 2007). The last two subcategories have been criticized by researchers, as the corresponding criteria are milder than those usually applied when diagnosing impaired cognitive abilities.
The cognitive impairment seen in HAND may affect multiple domains, including executive functioning, motor skills, attention, information processing, memory and language. Despite its prevalence and impact, the widespread profile of impairment is not fully
characterized and the neural basis of cognitive impairments in HAND remains uncertain. Patterns of cognitive dysfunctions are equally variable. Patients with a pattern of impairment predominantly mediated by frontal-striatal structures exist, yet impairment in the partial or
temporal lobe can also be found (Chen et al., 2009). This heterogeneity is thought to be attributed to diverse underlying mechanisms of HAND. These underlying mechanisms are not yet clearly understood, although available evidence suggests that shortly after systemic
infection, HIV enters the brain by using a “Trojan horse” mechanism; infected macrophage-monocyte cells help the virus cross the Blood-Brain Barrier (BBB) (Ances & Ellis, 2007). Entry to the CNS is (to some extent) restricted for antiretroviral drugs by the BBB and the blood-cerebrospinal fluid barrier (Edén et al., 2010), resulting in ongoing viral replication within this compartment. This unparalleled course between systematic and CNS-infection in HIV-patients is called ‘viral escape’ (Garvey, Everitt, Winston, Mackie, & Benzie, 2009) and is thought to be responsible for HIV associated cognitive impairment.
Table 1
Criteria for HAND
Asymptomatic Neurocognitive Impairment (ANI) Impairment in cognitive functioning, involving at least two cognitive domains, of which performance is at least 1 standard deviation below the mean. The cognitive impairment does not interfere with everyday functioning.
Mild Neurocognitive Disorder (MND) Impairment in cognitive functioning, involving at least two cognitive domains, of which performance is at least 1 standard deviation below the mean. The cognitive impairment produces at least mild interference in daily functioning.
HIV-Associated Dementia (HAD) Impairment in cognitive functioning, involving at least two cognitive domains, of which performance is at least 2 standard deviation below the mean. The cognitive impairment produces marked interference with day-to-day functioning.
Structural magnetic resonance (MR) imaging has been utilized to get more insight in underlying mechanisms of HIV. Studies with MR imaging reveal that HIV often coincides with global grey matter atrophy (Ances & Ellis, 2007), callosal and cortical thinning (Thompson et al., 2005), ventricular enlargement (Ances & Ellis, 2007), macrostructural
white matter integrity, as evidenced by white matter hyperintensities (Thurnher et al., 2005), and reduced white matter volume (Tucker et al., 2004).
Diffusion Tensor Imaging (DTI) has been proven useful in this field, for it can detect small abnormalities in normal appearing white matter on standard MRI examination by mapping the diffusion process of molecules, mainly water, in biological tissues in vivo. Molecular diffusion refers to the random translational motion of molecules (also called Brownian motion). In a free medium, molecules travel randomly in space. This is referred to as isotropic diffusion, which is the case in grey matter and cerebrospinal fluid. The movement of hydrogen molecules in white matter is directionally dependent or anisotropic. An intact white matter tract will show mostly anisotropic diffusion, whereas damaged white matter tracts will show mostly isotropic diffusion. The degree of anisotropy is represented by a Fractional Anisotropy-value (FA-value), ranging from 0 to 1. A value of zero means that diffusion is isotropic, and a value of one indicates that diffusion occurs only along one axis and is fully restricted along all other directions. When examining HIV patients, the FA value is thought to reflect the degree of myelinisation in white matter, thus the degree of
connectivity between structures.
DTI techniques have revealed CNS abnormalities in patients with normal findings on a standard MRI examination, suggesting that microstructural brain alterations may prelude more prominent structural abnormalities (Stebbins et al., 2007). DTI studies measuring whole brain white matter integrity have demonstrated widespread white matter abnormalities in multiple regions (Chen et al., 2009). These abnormalities occur in all HIV patients, including those with undetectable HIV (Pomara et al., 2001), but more severe abnormalities were found in patients with more severe cognitive disorders (Chen et al., 2009). Frequently, abnormalities in the corpus callosum (Leite et al., 2013), including splenium (Filippi, Ulug, Ryan, Ferrando, & van Gorp, 2001), genu (Thurnher et al., 2005), frontal lobes (Chen et al., 2009; Pomara et
al., 2001), and capsula interna (Leite et al., 2013; Pomara et al., 2001) have been found in HIV patients. In HIV patients, increased FA-values were found in the genu and capsula interna, although in frontal lobes the FA-values tend to be reduced. In patients suffering from HAND, white matter abnormalities are found to be consistent with findings from proton magnetic resonance spectography (MRS) studies, which used a non-invasive technique to examine metabolic changes in diseases affecting the brain. Metabolic changes due to HIV include abnormal rates of N-acetyl aspartate NAA, choline and creatine metabolite in the capsula interna (Lopez-Villegas et al., 1997). Also, the white matter abnormalities in the capsula interna are consistent with findings of high HIV viral loads in this structure (Kumar, Borodowsky, Fernandez, Gonzalez, & Kumar, 2007), suggesting the capsula interna to be a prominent structure affected by HIV, that can mediate the underlying mechanisms of HAND.
Some research even suggests that the whole Fronto-Striatal-Thalamic-Cortico (FSTC) circuit is affected due to HIV infection (Melrose, Tinaz, Castelo, Courtney, & Stern, 2008). The circuit reciprocally links the prefrontal cortex to the striatum, to structures such as the capsula interna, to the thalamus and back to the prefrontal cortex (Stuss, 2000). It is involved in cognitive domains as executive functioning, including disturbance in abstraction, speeded information processing, verbal fluency, decision making, various aspects of attention and memory (Ellis, Langford, & Masliah, 2007), which are all domains that can be impaired in HAND. Moreover, the separate components are deemed to be affected by HIV, as described above. Thus, it could be likely that the FSTC circuit mediates HIV-associated cognitive decline.
However, research is ambiguous about the brain regions and cognitive domains involved. This could be due to the fact that impairment in HAND is diverse and mostly mild, and the supposed underlying white matter abnormalities found are also diverse and mostly small. Tate et al. (2010) found an association between abnormal white matter integrity and
cognitive functioning in patients with HIV, in particular in the domains of speed of
processing, fine motor control/speed, and executive function. Also, it was found that white matter abnormalities in frontal white matter, in combination with abnormalities in the capsula interna, the anterior part of the corona radiate and cingulate gyrus, relate to dysfunction in attention and executive functioning domains in non-HIV patients (Gongvatana, 2008;
Kinnunen et al., 2011; Zheng et al., 2014). The present study will try to examine this relation in HIV patients. Furthermore, the posterior limb of the internal capsula has been described to contain corticospinal fibers (Kretschmann, 1988). Damage to such white matter tracts would be consistent with motor deficits that can be observed in patients with HIV dementia or former AIDS patients. Also, volume loss in the premotor cortices can be found in these patients (Thompson et al., 2005), which suggest a motor-striatal tract could be affected in
patients with HIV.
Present study
CNS complications are frequently observed in HIV-infected individuals. Most research shows that mainly the frontal lobes and basal ganglia are affected by HIV. The current study aims to find supporting evidence of these white matter injuries. Therefore, the present study selected two white matter tracts for examination: the prefrontal tract, initiating from the anterior part of the internal capsule on to the prefrontal cortex, and the motor tract, initiating from the posterior part of the internal capsule on to the (pre-)motor cortex. Few HIV studies focussed on the selected motor tract. It was selected for its robustness, the motor tract commonly only activates when motor (and motor-associated) function is involved and motor skills tests, commonly only test motor skills. Also, impairment of motor functioning was a prominent characteristic of ADC. The present study used DTI to examine the relationship between measures of white matter integrity (FA values) in the two selected tracts and performance in two distinct cognitive domains (executive function and motor skills). FA
values are used as a measure of diffusion in the white matter tracts, for they are deemed to be more sensitive to white matter abnormalities resulting from HIV than other DTI measures.
The present study uses a sample of HIV-patients with a high risk of HAND. Therefore, we expect that patients will show varying degrees of mild cognitive impairment and mild white matter abnormalities. First, we hypothesized that white matter abnormalities in the distinct tracts will be associated with the degree of cognitive impairment in congruent domain. Secondly, we hypothesized that patients fulfilling the criteria of HAND generally display lower white matter integrity in the examined tracts.
Methods Subjects
Participants were recruited at the HIV outpatient clinic of the Academic Medical Centre of Amsterdam (AMC) as part of the AgeIV Cohort Study, approved by a certified medical ethics committee. This is a multidisciplinary prospective study on comorbidity and aging in HIV-patients. All participants were informed of the AgeIV Cohort Study protocol prior to enrolment, and all had given written informed consent. At the start of the cohort study, participants were screened for HAND with the HDS and MMSE. A cut-off score of respectively 10 and 24 was applied. All of the participants who performed below cut-off on one or both screening tests were referred to the AMC memory clinic, where they received a personal interview, 100 min of eye examinations, 60 min MRI-examinations (plus preparations), Lumbar puncture and blood examination and 120 min of neuropsychological assessment (NPA).Some data of this group of the cohort study were made available for the present study. The data for this study were collected during February and March 2012. In total 33 HIV patients were included in this study. Exclusion criteria for the present study were current or past opportunistic infections or tumours of the CNS, non-HIV-related major neurological or psychiatric disorders, current use of illicit drugs or sedative-hypnotics, as
these may interfere with DTI images and performance on the NPA. After applying these criteria, the test group consisted of 29 eligible participants. After acquisition, five more participants were excluded for not having received a DTI-scan, and six were excluded as their NPA results were evaluated as unreliable, on account of either insufficient knowledge of the English or Dutch language, not enough motivation or too little education. After inclusion, 18 participants were eligible. Figure 1. shows a flow chart of participants in the present study.
Figure 1. Flow chart of participants.
Procedure
The scope of the present study extends to data of the NPA, the DTI components of the MRI examination and personal interviews. These components were all conducted in the AMC on the same day, by a trained neuropsychologist (or psychologist in training). In the personal
Present Study
HIV+ participants of the AgeIV cohort study recruited in February and March of 2012. All participants have an HDS-score below 10 an/or a MMSE score below 25 and are referred to the memory clinic of the AMC. (n = 33)
interview, participants were asked questions about their socio-demographical characteristics, medication and habits, activities and daily living, as can be seen in appendix A. Afterwards, they underwent an NPA (specified below) and a DTI examination. In the five hours prior to examination, participants were not allowed to consume any caffeine, alcohol or drugs, as this might influence the imaging. Usually, participants first completed the NPA and then the MRI examination, yet due to planning issues some participants finished MRI examination first or after only one hour of NPA examination.
Neuropsychological Measures
For the AgeIV study an comprehensive neuropsychological assessment (NPA) was performed. A selection was made containing two domains: the motor functioning domain and executive functioning domain.These domains are shown to be associated with white matter integrity in the examined prefrontal and motor tract (Kodl et al., 2008; Kraus et al., 2007; Kubicki et al., 2004; Murphy et al., 2006; O’Sullivan et al, 2001; Warner et al., 2006).
Motor functioning. Motor functioning was examined using the Finger Tapping Test (Halstead, 1947) and the Grooved Pegboard Test (Kløve, 1963). These tests were selected as a measure of motor functioning with relatively minimal loading on components of complex cognitive processing. The Finger Tapper is an instrument which requires participants to tap as fast as possible on a tapping device. It measures the number of taps made within a limited time. Both hands were measured (FT dominant and FT non-dominant). The Grooved Pegboard requires participants to place small metal key-shaped pegs into a metal board with key-shaped slots. Measured is the time acquired to put all pegs in their slots. Also, both hands are measured separately (GP dominant and GP non-dominant). Next, these measures were transformed into distinct measures for the right hand and the left hand, so they can be related to congruent motor tract (right hand is related to the motor tract in the left hemisphere and vice versa). Furthermore, a weighted domain scores (SumM) was composed for the motor
domain, using normative T-scores from the grooved pegboard and Fingertapping. All four outcome measures divided by four is he weighted domain score.
Executive functioning. Cognitive processes that regulate, control, and manage other cognitive processes are part of the umbrella term ‘executive functions’. Examples of
executive functions are planning, working memory, problem solving, verbal reasoning, inhibition, mental flexibility, task switching, initiation, and monitoring of actions. In the current study, executive functioning was represented using tests measuring the suppression of an overlearned simple tendency over the performance of a task of greater difficulty (e.g. Stroop Colour and Word Test), and task switching (e.g. Trailmaking Part B) or problem solving (e.g Wisconsin Card Sorting Test). The present study will compare the normalized outcome variables of these tests to FA values of frontostriatal white matter tracts.
The Stroop Colour and Word Test (Stroop, 1935) is a timed task in which participants need to name the colour of the ink in which words are written (yellow, blue, red, green) as quickly as possible, while the words are printed in an incongruous colour ink. Figure 2 shows part of the Colour-Word card. The recorded variable used in this study was the interference score, which is the time spent on the Colour-Word task given the time spent on the Stroop
Colour naming task (Stroop). The colour naming task requires participants to name the colour of the presented pars as quickly as possible.
The Trailmaking Test (Part B; Reitan, 1958) is a paper and pencil procedure which requires participants to connect alternating letters and numbers in an
ascending and alphabetical order. For examining executive functioning, the interference score was used: time spent on Part B given the time spent on Part A (TMT BA).
Figure 2.
Incongruent colour-words of the
The Wisconsin Card Sorting Test (WCST; Berg, 2010) is a computerized task, which is used to assess problem solving ability. It presents a number of stimulus cards to the participant, who is told to match the cards to four possible open cards, without knowing on what principle they should match (colour, number, shape). However,
participants are told whether a particular match is right or wrong. Figure 3. shows an example of how to match the cards. In this example the sorting principle that should be followed is sorting by number. Recorded variables are the number of categories completed (WCST cat), number of perseverative responses (WCST pers) and number of perseverative errors (WCST errors).
Furthermore, a weighted domain scores (SumEF) was composed for the executive functioning domain, using normative T-scores from the each tests. Because the WCST has three outcome measures these were divided by three before adding to the domain score. The sum of the three tests used in this domain (TMT, Stroop and WCST) divided by three makes the weighted domain score.
HAND. The validated normative T-scores were also applied classifying patient with HAND. For this classification the results of an exhaustive NPA are needed. In our study we examined six domains of cognitive abilities that are most likely to be impaired in HAND: information processing speed, attention, language fluency, memory, motor functioning and executive functioning (Antinori et al., 2007; Woods et al., 2004). Appendix B shows the whole test battery used in the present study. The tests were selected on previous research supporting their
Figure 3. Example of the WCST sorting principle: sorting by number.
sensitivity to early HIV-related neurocognitive changes. Table 1 shows the Antinori et al. (2007) criteria for HAND that were used in this study. Each domain was measured by at least two tests. If patients perform 1 SD below the mean on more than half of the tests representing a domain, that domain is deemed ‘impaired’. To measure functional decline, self-reports of the Instrumental Activities of Daily Living (IADL) and an interview were utilized. The conducted interview is shown in Appendix B. Mild interference in daily functioning requires at least two of the following: less efficiency/productivity during day-to-day tasks and inability to perform some aspects former employment. Major functional decline requires at least two of the following: participants needing substantially greater assistance with two or more IADL’s, unable to maintain former employment and self-reports of great difficulty in four of six cognitive domains (Antinori et al., 2007). Using these criteria, the participants were divided into either the group with HAND or in the group without HAND.
DTI Data Acquisition
All neuroimaging scans were performed on an Intera 3 Tesla imager at the AMC in Amsterdam, with a phased array SENSE 8-channel receiver head coil. DTI data for all included participants were acquired using multi-slice spin echo single-shot echo-planar imaging set at the following parameters: TE/TR = 92/7725 ms; flip angle 90˚; diffusion sensitivities of b=0 and b=1000 s/mm2; field of view = 224x224x120 mm2, 55-60 continuous (no inter-slice gap) slices in sagittal direction, slice thickness 2 mm, field of view 224x120x224 mm2; acquisition matrix 112×112 mm; voxel size 2×2×2 mm2. Diffusion-weighted images were acquired in 64 diffusion directions and DTI scan time for a complete brain was approximately 8-9 minutes, depending on the number of slices used. The current study is part of a larger study. Therefore, subjects underwent the DTI scan additional to other MRI scans used in the AgeIV cohort study. The total scan duration was approximately 60 minutes.
Image Processing
All data was anonymised prior to analysis, and assessed qualitatively to check for radiological abnormalities outside of the normal range. Participants with such abnormalities were excluded from the study, as described above. Data pre-processing was performed using software developed in-house, written in Matlab (The MathWorks, Natick, MA, USA), and conducted on the Dutch Lifescience Grid to transform data to DTI and co-registered T1 scans on which probabilistic tractography could be performed, using the fMRIB software library
(http://www.fmrib.ox.ac.uk/fsl/index.html) (Giesbertz, 2012).
After consulting an experienced neurosurgeon, two tracts were selected for examination. These tracts were chosen for respectively their association with executive functioning (Tate et al., 2010) and motor ability (Tate et al., 2010; Werring et al., 1998), as well as their association with HIV-1 (Pomara et al., 2001). The tract deemed to be associated with executive functioning is part of the FSTC. The prefrontal tract that the present study researches begins in the caudate nucleus and extends to the prefrontal cortex (PFC). The motor tract begins in the posterior part of the capsula interna and extends into the motor cortex (MC). Using Matlab, the mean fractional anisotropy (FA) values per patient were calculated over each tract and hemisphere, resulting in the tracts shown in figure 4. The FA values represent the degree of diffusion in fibres. Using DTI we can measure in which direction diffusion occurs and the degree of diffusion. FA values can lie between 0 and 1, where 0 corresponds to unrestricted diffusion in all directions and 1 corresponds to restricted diffusion in one direction due to barriers (as is expected in white matter fibres). Roughly said, low FA values correspond with low connectivity between areas, whereas high FA-values corresponds with good connectivity between areas.
Figure 4. Probabilistic fibretracking. Mean FA of all participants in the selected motor tracts (red-yellow) and the PFC-tracts (blue-purple).
Statistical Analysis
The data were analysed using SPSS 20.0 for Windows. Non-parametric tests were used, as the current data set is small (n = 18). The data set was split into two groups, participants diagnosed with neurocognitive impairment (HAND group) and participants without neurocognitive impairment (non-HAND). The Mann-Whitney test was applied to test for differences in FA-values between the two groups. Significance was accepted at the level of p < 0.05. For each participant, a summary score of FA-values was made for each tract.
Spearman’s Rho was applied to examine the correlation between the summary FA-values per tract and the congruent weighted domain score. Significance was accepted at the level of p < 0.05.
Results Participants
The examined subjects all have a heightened risk of HAND, as none of them passed the screening tests. All subjects are older than 45 years old, most are men and have Dutch as their mother tongue. Sample characteristics are displayed in Table 2. When examining the NPA results, a variation in degree of impairment on cognitive- and motor tests can be seen.
Table 2
Demographic characteristics of the sample.
Variable M (SD)/N, %
Age Male
Education in years Mother tongue Dutch Handedness, right 54.1 (7.7) 16, 88.9% 12.8 (3.6) 11, 61.1 % 15, 83.3%
White Matter Integrity and Cognition
When correlating the Mean FA values of the prefrontal tract with the tests of the Executive Functioning domain, no relation was found. This is shown in Figure 5. This scatterplot has no recognizable direction. Also, no correlation was found between the Mean FA values of the motor tract and the tests regarding the motor domain. This relation was also shown in Figure 5. However, when correlating the separate FA tracts with the separate tests in both domains some correlation are found. These correlations are shown in Tables 3 and 4. The Mean FA values of the prefrontal tracts did correlate with an EF test: the WCST error (r = - 0.58, p<0.05) and the WSCT categories (r = -0.88, p<0.05).
Most of the expected correlations were found: both the prefrontal and motor tracts correlated highly with each other. Also, the weighted summary scores correlated with the tests contained within, as shown in Table 3 and 4. Table 4 also shows that most of the motor
Figure 5. Relation between the weighted domain scores of the motor domain and the executive functioning domain and Mean FA values of the corresponding tract.
Table 3
Correlation Matrix of the FA values of the PFC tracts and the corresponding executive functioning tests .
Mean PFC PFC r PFC l SumEF W error W pers W cat TMT Stroop
Mean PFC PFC r PFC l SumEF W error W pers W cat TMT Stroop 0.87b 0.91b 0.59a -0.15 0.01 -0.09 -0.58a -0.64a -0.33 0.52a -0.39 -0.39 -0.23 0.70b 0.85b -0.87b -0.80b -0.70b 0.39 0.85b 0.66b 0.32 0.29 0.50 0.54a -0.14 -0.05 -0.25 0.20 0.44 -0.07 0.48a -0.12 0.09 -0.23 0.06
NOTE: Mean PFC = Mean FA values of the striatal-prefrontalcortical tract, PFC r = FA values of the right striatal-prefrontalcortical tract, PFC l = FA values of the left striatal-prefrontalcortical tract, SumEF = summary score of the Executive functioning domain, W error = T-score of the Wisconsin Card Sorting Test (WSCT) errors, W pers= T- score of the WSCT perseverations, W cat = T-score of the WSCT categories, TMT = T-score of the interference score B|A, Stroop = T-score of the interference score card 3|2.
a
significance at p<0.05
b
Table 4
Correlation Matrix of the FA values of the Motor tracts and the corresponding motor tests .
NOTE: Mean Motor = Mean FA values of the striatal-premotoric tracts, Motor r = FA values of the right striatal-premotoric tract, Motor l = FA values of the left striatal-premotoric tract, Sum M = summary score of the motor domain, GP r = T-score of Grooved Pegboard executed with the right hand, GP l = T-score of Grooved Pegboard executed with the left hand, FT r = T-score of FingerTapping test executed with the right hand, FT l = T-score of FingerTapping test executed with the left hand.
a
significance at p<0.05
b
significance at p<0.01
White Matter in HAND
As shown in Figures 5 and 6, the FA values of both tracts differ slightly, when
splitting the group in two: one group with cognitive impairment by the criteria of HAND and one without, non-HAND. The HAND group shows lower FA-values than the non-HAND group throughout both tracts. Comparing the mean FA value of the motor tracts between groups, the HAND group (M = .403) has lower FA than the non-HAND group (M = .435), U = 12.00 , p < .05 (2-tailed). Although, as seen in Figure 6, the error bars of the motor tract of both groups have a slight overlap. This will make distinguishing the groups solely with DTI measures difficult. The mean FA values of the prefrontal tracts do not differ between the two groups.
Mean Motor Motor r Motor l Sum M GP r GP l FT r FT l
Mean Motor Motor r Motor l Sum M GP r GP l FT r FT l 0.86b 0.95b 0.71b -0.03 -0.03 -0.08 -0.12 -0.03 -0.15 0.89b -0.01 0.21 -0.08 0,83b 0.89b -0.11 -0.38 -0.19 0,47 0,14 -0.01 0.25 0.24 0.18 0.74b 0.53a 0.50 0.43
Figure 5. The mean FA values in 10 points on the two tracts.
Figure 6. Mean of the FA values of both white matter tracts for patients with HAND and HIV patients without HAND. Error bars indicate a 95% confidence interval.
Discussion
The aim of this study was to gain insight in specific white matter pathways, the striatal-prefrontal and the striatal-motor tract, in patients at risk of HAND. Current results
suggest no relation between the pathways and respectively executive and motor functioning. However, it was found that patients suffering from HAND did have slightly lower white matter integrity on the motor tracts. This finding may be considered robust, as it was found in a small sample. This may suggest that the white matter abnormalities in this tract is a prelude to HAND. Yet, it should be taken into account that the differences found in the present study are very small and these exact same white matter measures are not likely to be reproduced, as DTI testing is very specific and difficult to exactly reproduce. The current results will be discussed further in the next paragraphs.
No relation between abnormalities in the examined white matter tracts and cognitive and motoric functioning was found. However, when looking at the correlations between the DTI tracts and separate cognition and motor tests, a relation was found. The white matter integrity of the prefrontal tracts and the right motor tract shows a relation with parts of the WCST (an executive test). Yet, unexpectedly, this relation has a negative direction, thus a better test score relates to less white matter integrity. Possibly, the sample size of our study is too small to find a relation between the motor tract and motor tests. Additionally, we should take into account the multiple comparisons that were done when examining the relation between the tracts and the separate tests. Incorrectly rejecting the null hypothesis is likely to occur by chance when many comparisons are made. Correcting for multiple testing may be done by maintaining a more stringent significance level. When alpha is reduced to 0,01, only the expected correlations remain.
In accordance with previous results, the present study shows that patients who meet the criteria of HAND show less white matter integrity than patients who do not meet the criteria of HAND. Yet, current results only show this holds true for the researched motor tracts, which, to my knowledge, have not been examined in relation to HAND before. In the current study, no patients with severe motor functioning impairments were present, which
may suggest that the found white matter impairment might be a prelude for cognitive impairment. The current study, however, cannot reveal if the found effect is due to HIV.
Previous research found that patients classified with HAND show less white matter integrity in the prefrontal tract than patients without HAND. The results of the present study do not support this finding. Also, present results do not show an increase of white matter integrity in the capsula interna, as previous studies do. It is possible that without the power of a big sample size, a small difference will not be observed. It is also possible that the patients used in our study did not show a large enough cognitive impairment spread, to show a noticeable difference in white matter integrity between patients with HAND and without HAND. In the present sample, the participants without HAND did not pass the conducted cognitive screening tests, which might indicate lower cognitive abilities than in a regular control group. Also, the patients with HAND were only eligible for the milder forms of HAND. A greater spread in cognitive impairment and white matter integrity may be achieved in a bigger sample, with a pure control group, and a patient group with more severe forms of HAND.
However, in previous, larger studies, also only small differences were found in FA values of white matter tracts between patients with HAND and control groups (Chen et al., 2009; Pomara et al., 2001; Ragin et al., 2008; Thurnher et al., 2005). Between studies, FA values for the same region may differ greatly. Also, between studies, the area associated with HAND differs. These differences may be due to various elements. For instance, not all studies use the same DTI method. Additionally, studies use diverse criteria when defining regions. Also, studies use different ways of applying the criteria for HAND (how many tests per domain are used). Lastly, the degree of comorbidity in the HIV sample differs between studies. The present study applies strict criteria for HAND (as can be seen in the methods section), and has very strict exclusion criteria, which results in a pure sample size without
somatic or psychiatric comorbidities or unreliable NPA’s. Due to these strict exclusion criteria, the sample size of the present study is small, leading to a lack of power of the study. The difference between patients with and without HAND in white matter integrity in the frontal tract and the increased white matter integrity in the capsula interna that was found in previous studies, was not supported by the present results. This may be a result of this lack of power. Possibly, however, no difference may be found in this tract when using a pure sample. Limitations
As stated earlier, this study uses a small sample size, which limits the power of the analysis. In small studies, a greater risk of type II error occurs, resulting in failure to reject a false null-hypothesis, and obscuring the presence of weaker relations. Also, the sample does not contain a non-HIV control group, making it impossible to interpret if results can be attributed to the HIV virus.
Furthermore, current results show all FA values as lower than normal. This is likely caused by the probabilistic way of tracking. The mean FA value over all voxels of a tract was calculated, including voxels located on the edges of the fibres. These edge-voxels have lower FA values, which results in generally lower FA values in the tracts. This might be problematic for the current data, as FA values below 0.2 are deemed to become very sensitive to image noise and the estimated major eigenvector direction becomes less accurate (Jellison et al., 2004). Ideally, FA values of at least 0.4 are needed to overcome these problems, while the FA values of the examined tracts lie around 0.3 and 0.4 for respectively the prefrontal and motor tract.
Finally, the current results show that aspects of the WCST relate to prefrontal white matter integrity, contrary to what was expected. This may be due to the way our experiment was set up. The day the NPA took place, patients had to fulfil four hours of different
were not allowed to drink coffee or tea or have chocolate on the day of the experiment. This situation was experienced as cumbersome. The WCST itself is a somewhat tedious test, as the patient is not informed how to perform the test. This sometimes leads to frustration among patients taking the test, which may result in poor performance on the test.
Further Research
Further research is recommended, to better understand the expression of HAND, as many questions on this subject still remain. The causal relation between specific white matter regions and HIV should be further examined through a longitudinal study with a control group matched for demography and lifestyle. In the light of the current results, it is
recommended to examine the striatal-motor tracts among other regions. This research may answer questions about whether white matter abnormalities increase over time and whether the underlying mechanisms of increasing white matter damage may be attributed to normal aging or HIV infection. Also, further research might shed some light on the test-retest reliability of DTI methods. This is advisable, as the differences in FA values between the control groups and HAND groups are small. FA values vary greatly between studies, also when the same DTI method is used. More insight in these matters may show if DTI will produce a helpful biomarker for HAND.
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Appendix A
Measurements of NPA and questionnaires used in present study.
Cognitive Domain Test Measures Duration
Montreal Cognitive Assessment Screens cognitive impairment 10 min Instrumental Activities of Daily Living (IADL)
Functional impact of impairment
5 min
Beck’s Depression Inventory (BDI) Depression 5 min Cognitive Failure Questionnaire behavioral problems associated with attentiveness and memory 5 min
Language Fluency Groninger Intelligentie Test (GIT) (animals, professions)
Semantic fluency 2 min
GIT Letter fluency Phonemic fluency 3 min
Memory Rey’s Auditory Verbal
Learning Test (RAVL)
Verbal Memory 20 min
Wechsler Memory Scale III (WMS-III)
Visual Memory 15 min
Information Processing Speed
Wechsler Adult Intelligence Scale (WAIS-III) (Digit symbol test, Symbol Substitution)
Scanning speed, motor and mental speed.
7 min
Trail Making Test (TMT) part A
Motor speed 2 min
Stroop Colour Naming Mentals speed 2 min
Executive Functioning
Wisconsin Cart Sorting Test (WCST) (categories, errors,
Mental flexibility, set-shifting
perseverations)
Stroop Colour Word Selective attention 3 min
TMT part B Dividing attention 3 min
Attention/Working Memory
Paced Auditory Serial Addition Test Auditory working memory 10 min WAIS-III Letter-Number sequencing
Attention, concentration 3 min
Motor Skills Grooved Peg Board Fine motoric
movements, motoric speed
10 min
Appendix B
Interview that is used by the AgeIV cohort study. Present study uses components of this interview, the questions below marked in bold.
ANAMNESE: Demografisch/Psychosociaal Ik ga u nu een aantal algemene vragen stellen.
1) Hoe oud bent u (controleer door uitvragen geboortedatum)? Noteer leeftijd:
2) Heeft u nu werk? Ja / Nee
3) Wat voor soort werk heeft u? (beroep) Noteer: In welk soort bedrijf of industrie werkt u? Noteer:
4) Heeft u hobby’s? Hoe besteedt u uw vrije tijd?
Ja…………(1) Noteer:
Nee………(2) Wat doet u zoal overdag? Noteer:
5) Hoeveel jaar school heeft u afgemaakt? Noteer: Wat is uw hoogst behaalde graad (diploma gehaald)? Noteer:
Verhage-score: Noteer:
6) Dominante hand? Rechts……...(1) Links……..….(2)
7) Is Nederlands uw moedertaal? Ja / Nee
Indien ‘Nee’, Is er sprake van voldoende beheersing van de NL taal? Ja / Nee Indien ‘Ja’, Spreekt u thuis gewoonlijk Nederlands? Ja / Nee Indien ‘Nee’, Hoe oud was u toen u Nederlands begon te spreken? Noteer:
ANAMNESE: Cognitie & stemming
Tijdens uw deelname aan de cohort studie (hoofdstudie) zijn uw mentale functies zoals geheugen en concentratie kort (globaal) onderzocht.
Vandaag zullen we in het neuropsychologisch onderzoek dit uitgebreider onderzoeken. Maar eerst wil ik een aantal vragen over uw geheugen en concentratie stellen.
1) Hoe vindt u zelf uw geheugen?
Goed / Functioneert hetzelfde als voorheen……….………(1) Functioneert iets minder dan voorheen / Geringe achteruitgang.………...(2) Functioneert veel minder dan voorheen / Duidelijke achteruitgang.……..(3) Slecht / Zeer duidelijke achteruitgang………...(4)
2) Kunt u voorbeelden geven van uw geheugenklachten/vergeetachtigheid? Noteer:
Beloop:
3) Kunt u mij iets uit het recente nieuws vertellen?
Noteer: Correct:
4) Hoe vindt u uw concentratie? Kunt u uw aandacht er goed bij houden? Bv. bij uw werk / bij het lezen van een boek / bij het lezen van de krant / bij het kijken naar een film / tv-programma.
Noteer: Beloop:
5) Kunt u datgene wat u gelezen of gezien hebt navertellen (aan bijvoorbeeld uw partner)? Noteer:
Beloop:
6) Hoe is uw fysieke conditie? Hoe is uw lichamelijke toestand? Noteer:
Tijdens uw deelname aan de cohort studie (hoofdstudie), heeft u ook een vragenlijst over uw stemming beantwoord. Na het neuropsychologische onderzoek zal ik u vragen een aantal vragenlijsten in te vullen, waaronder een andere vragenlijst over uw stemming. Maar eerst ga ik u hierover een aantal vragen stellen.
7) Hoe vindt u uw stemming? Hoe voelt u zich? (gedurende de afgelopen maand) Noteer:
Beloop:
- Wanneer is het begonnen? / Wanneer is het u voor het eerst opgevallen dat er iets mis was? / Wanneer voelde u zich voor het laatst in orde? (Gewoon uzelf?).
- Is dit iets nieuws of is het de terugkeer van iets dat u wel eens eerder heeft gehad? - Wat gebeurde er in uw leven toen dit alles begon? Is er iets gebeurd of veranderd vlak
voordat dit alles is begonnen.(Denkt u dat het iets te maken heeft met uw huidige ziekte?)
8) Bent u momenteel onder behandeling bij een psycholoog of psychiater?
Ja…………(1) Noteer soort behandelaar: Reden:
Soort behandeling: Nee……….(2)
9) Gebruikt u momenteel medicijnen voor psychische aandoeningen?
Ja…………(1) Noteer:
Nee……….(2)
ANAMNESE: Intoxicaties
Ik ga u nu een aantal vragen stellen over het gebruik van cafeïne, tabak, alcohol en drugs.
1) Rookt u tabak?
Ja…………(1) sigaretten of shag / sigaren / pijp / snuif- of pruimtabak
Hoeveel: Laatste inname (< 2 uur?):
2) Drinkt u koffie of andere cafeïnehoudende dranken of heeft u cacao bevattende voedingsmiddelen genuttigd?
Ja…………(1) (A-B) Welke: Hoevee/per wk: Nee……….(2) (B)
A) Heeft u gisteravond of vandaag cafeïne-houdende dranken (bijvoorbeeld koffie, zwarte thee, cola of cafeïne-houdende energie-dranken) genuttigd?
Tijdstippen van inname: Totaal:
Hoeveelheid van inname: Totaal:
< 5 uur laatste inname? Ja / Nee
B) Heeft u gisteravond of vandaag cacao-bevattende consumpties (bijvoorbeeld chocolade, chocolademelk) genuttigd?
Tijdstippen van inname: Totaal:
Hoeveelheid van inname: Totaal:
< 5 uur laatste inname? Ja / Nee
3) Drinkt u alcoholhoudende consumpties?
Ja…………(1) (A-C) Welke? Momenten van inname:
Hoeveelheid/per wk: Afgelopen 6/12 maanden:
Nee……….(2)
A) Heeft u gisteravond > 3 alcohol-bevattende consumpties genuttigd ? Ja…………(1) Welke: Hoeveel:
Nee……….(2)
B) Heeft u vandaag alcohol-bevattende consumpties genuttigd ? Ja…………(1) Welke: Hoeveel:
Nee……….(2)
4) Gebruikt u drugs? (cannabis (wiet, marihuana, hasj), speed, amphetamine, heroine, cocaïne, XTC, poppers, anders namelijk).
Ja…………(1) (A-C) Welke: Momenten van inname:
Hoeveelheid per wk: Lifetime: Nee……….(2)
A) Heeft u in de afgelopen 2 weken drugs gebruikt? Ja…………(1) Welke: Hoeveel: Nee……….(2)
B) Heeft u vandaag drugs gebruikt?
Ja…………(1) Welke: Hoeveel: Nee……….(2)
C) Data/Tijdstip laatste inname: Welke: Dagen/Uren:
D)
ANAMNESE: AFSLUITING
Ik heb u veel vragen gesteld over uw huidige situatie (psychosociale situatie: partner, werk, woonsituatie), mogelijke geheugen- en emotionele problemen uw gewoontes (alcohol-, tabak- en drugsgebruik). Het kan zijn dat ik iets ben vergeten te vragen dat voor u belangrijk is.
1) Heeft u nu nog andere problemen waar ik naar had moeten vragen, maar niet gedaan hebt?
Zijn er nog andere dingen die u wilt vertellen waarvan u denkt dat het belangrijk is dat ik daarvan af weet?
