Background: Duchenne Muscular Dystrophy (DMD) is a fatal muscular dystrophy of pediatric population coupled with other secondary comorbidities including mental retardation and neuropsychological impairments. Mutation location in the dystrophin gene, have been associated with neuropsychological functioning in DMD. Purpose: We investigated temporal changes in the neuropsychological functioning of DMD subjects, hitherto understudied. Methods: Subjects with suspected DMD were enrolled according to the ethical guidelines. Genetic confirmation by Multiplex Ligation Dependent Probe Amplification was carried out to identify pathogenic deletion or duplication in dystrophin gene. Intellectual and neuropsychological functioning was assessed by using standardized batteries. Investigated neuropsychological domains included visual, verbal and working memory, selective and sustained attention, executive functioning, verbal fluency, and visuo-constructive and visuo-spatial abilities. The assessments were carried out at baseline and followed for one time point in 30 cases. Result: The follow-up assessment revealed that neuropsychological functioning did not worsen with time. Improvements were seen in block designing task (p = 0.050), serial positioning primacy effect (p = 0.002), Stroop incongruent task (p = 0.006), visual long-term memory (p = 0.003) and attention (p = 0.001). DMD cases with mutation location affecting short dystrophin isoform (Dp140) also showed improvement in these domains. Conclusion: No temporal alterations were found in DMD subjects, though improvements in few domains were observed. Neuropsychological rehabilitation may be useful in improving the quality of life in DMD subjects. Keywords DMD, neuropsychology, cognition, longitudinal, follow-up, dystrophin In addition to skeletal muscle pathology and loss Introduction of physical strength, a subset of children with DMD is characterized by global cognitive impairment. Previous Duchenne muscular dystrophy (DMD) is a fatal X-linked works suggest that in DMD patients, intelligence quotient genetic neuromuscular disorder, characterized clinically by (IQ) distribution is downshifted one standard deviation with a rapidly progressive and disabling muscle weakness, present from lower verbal IQ than performance IQ. It is reported that DMD birth and exclusively occurring in males. DMD is caused by an patients might also have specific neuropsychological deficits X-linked recessive frameshift mutation in the dystrophin gene that ensues absent or non-functional muscle dystrophin protein and resultant muscle fibre degeneration, leading to chronic peripheral Neuroscience Research Lab, Department of Neurology, Postgraduate inflammation. Dystrophin functions as a direct signalling molecule Institute of Medical Education and Research, Chandigarh, India. Department of General Medicine, Kamineni Institute of Medical Sciences, and connects the extracellular matrix to the cytoskeleton. It is a 2,3 Narketpally, Nalgonda, Telangana, India. part of the dystrophin-associated glycoprotein complex. It is the Department of Neurosurgery, Postgraduate Institute of Medical Education most common childhood muscular dystrophy with an estimated and Research, Chandigarh, India. incidence of 200 per million male live births. By the age of 3, Corresponding author: patients with DMD exhibit motor inabilities in such as walking, Manju Mohanty, Department of Neurosurgery, Postgraduate Institute of Medical Education and Research, Chandigarh, India. running, climbing, jumping, waddling gait, difficulty in standing, E-mail: firstname.lastname@example.org followed by upper limb weakness and pseudohypertrophy by Co-corresponding author: the age of 5. This is followed by progressive worsening of the Akshay Anand, Neuroscience Research Lab, Department of Neurology, symptoms and with death due to respiratory failure or cardiac Postgraduate Institute of Medical Education and Research, Chandigarh, India. arrhythmia before the third decade of life. E-mail: email@example.com Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution- NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-Commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). Tyagi et al. 43 including poor performance in working memory, executive often have problems in short-term verbal working memory function, attention deficits, and impaired reading and language and increased risk of learning disability resulting from poor 1,6 phonological awareness/processing. They often encounter acquisition skills. Previous studies have led to hypothesis problems with reading as discussed in a study, whereby 40% that these specific neuropsychological deficits resonate with of boys with DMD have been shown to have reading prob- cerebellar lesions due to similarity in cognitive impairments. lems. It is also found that they have lower academic achieve- Even though dystrophin is often characterized in muscles, it is ment scores than expected of their level of cognitive func- also found in various other tissues including the brain. Multiple tioning. In addition to academic performance, they also face studies have shown the association between the loss of poor health-related global quality of life potentially posing dystrophin and cognitive impairments. Multiple studies from 17,18 them at risk of depression, anxiety and stress. A successful both clinical and animal models attribute the lack of dystrophin care of DMD patients thus requires comprehensive, multidis- expression in the brain to the development of the cognitive and 8–10 ciplinary plan including psychosocial care, in addition to a behavioural alterations in DMD. Some patients with DMD pharmacological approach. also have a higher incidence of neurobehavioral disorders In order to plan clinical trials to establish efficacy of inter - including attention-deficit/hyperactivity disorder (ADHD), ventions targeting different neuropsychological impairments, anxiety disorder, autism spectrum disorders (ASD), epilepsy longitudinal studies in DMD patients are required. This will and obsessive-compulsive disorder. Experimental studies help to explore how, over the course of time, neuropsycholog- have found that dystrophin is expressed in neurons within ical function changes with progression of DMD. Additionally, specific brain regions including the cortex, cerebellar Purkinje this can help with risk stratification and screening and offering cells, Cornu Ammonis (CA) region of the hippocampus, retina specific neuropsychological rehabilitation. Future studies and the peripheral nerve. These might be responsible for some could include acquisition of longitudinal data in order to of the neuropsychological deficits. examine which cognitive and neuropsychological functions It is important to note that myelination is critical in DMD are non-progressive or progressive. This is impor- in the central nervous system (CNS) for complex brain tant in counselling and future planning. Previous studies processing and therefore the disorders affecting the neuronal suggested that more research is needed about characterizing myelination, by a process regulated by oligodendrocytes in 12 the features of neuropsychological profile in determining the the CNS, may produce neurological deficits. In a recent use and effectiveness of cognitive rehabilitation and retraining study, researchers have found that for proper maturation of for children with DMD. In-depth review of the literature has oligodendrocytes and effective myelination during postnatal revealed that there are no longitudinal studies that have inves- brain development, normal expression of dystrophin isoforms tigated whether the cognitive and neuropsychological impair- is required. Oligodendrocytes express three different ment in DMD is progressive. To the best of our knowledge, forms of dystrophin, Dp427, Dp140 and Dp71, and loss of this is the global first longitudinal study which has described oligodendroglial dystrophin, particularly Dp427, was found the neuropsychological function in DMD patients. The aim to be contributory to neurodevelopmental deficits in their of this longitudinal study was to use a battery of intelligence, experimental mdx mouse model of DMD. In this study, in learning and memory tests to characterize the neuropsycho- mice without functional Dp427 dystrophin protein had late logical profile in boys with DMD by following them up for development of myelination with significantly affecting the long-term changes in various domains. cerebral cortex. A past review identified lack of Dp427 to be associated with progressive muscle weakness in all DMD patients, likely responsible for both muscle degeneration and Methods brain dysfunction. Despite involvement of common gene isoforms, Subjects: A total of 30 DMD subjects were recruited according Wingeier et al. in their study found no correlation of declining to the guidelines of Institutional Ethics Committee (IEC) of cognitive function with the progression of muscular deteri- Postgraduate Institute of Medical Education and Research, oration. Another study reported that cognitive impairment Chandigarh, India. Informed assent and written informed in DMD is non-progressive and unrelated to the severity of consent was obtained from the participants before enrolment. muscle disease. Additionally, varying phenotypic expressions The study was approved by IEC vide no. INT/IEC/2015/732 of specific neuropsychological impairments is also notable in dated 19 November 2015. The recruitment guidelines adhered DMD patients. The reason for this divergence is inconclu- to the Helsinki Declaration. The DMD patients were enrolled sive, but this might be associated with the timing and locali- with the help of Indian Association of Muscular Dystrophy zation of human dystrophin isoforms expression. In contrast, (IAMD). Cases were also recruited retrospectively with previous studies reported that intellectual functioning in DMD the help of patient support groups. The prevalence-based patients deteriorates as the disease progresses with progres- sample size was derived, that is, 1/3500 males for DMD. sive reduction in all IQ scores. As previously noted, varying For inclusion in the study, cases with characteristic clinical neuropsychological deficits affect overall cognitive perfor - features of the Duchenne phenotype were identified. The cases mance of the boys with DMD. For example, boys with DMD with BMD or intermediate phenotypes and other myopathies 44 Annals of Neurosciences 26(3–4) were not considered for inclusion. The entire study was Statistical Analysis conducted according to the quality assurance protocols of the Neuroscience Research Lab. Genetic diagnosis was carried We used SPSS version 21 to analyse the neuropsychological out by Multiplex Ligation Dependent Probe Amplification data. Normal distribution was analysed by Kolmogorov– 19,20 (MLPA) as described previously. Smirnoff statistics. Normally distributed data was further IQ: Malin’s intelligence scale for Indian Children analysed by paired t test. Level of significance was analysed (MISIC), an adaptation to Wechsler intelligence scale for chil- at p < 0.05. dren (WISC), was employed to assess the IQ. Briefly, verbal- and performance-based IQs (VIQ and PIQ) were derived to Results finally form the IQ. VIQ was derived by six subtests, that is, information, comprehension, arithmetic, digit span, vocabu- Participants: A total of 30 cases diagnosed with DMD were lary and similarity. PIQ was derived from four subtests, that enrolled. Participant demographic details have been provided is, picture completion, block designing (BD), coding and in Table 1. Genetic investigations were carried out in all DMD maze. The detailed description is provided in the supplemen- cases. Representative electropherogram is provided in Figure 1. tary material. Neuropsychological Assessments: Neuropsychological Table 1. Details of Participants assessments were carried out in 30 DMD cases. Memory (visual and verbal), attention (selective and sustained), Variables Mean (SD) executive functioning (cognitive flexibility, cognitive control, Cases n = 30 response inhibition, interference), verbal fluency (semantic and Gender All males category) and visuo-constructive ability were assessed using standard test batteries including Rey Auditory Verbal Learning Age 11.54 (2.71) Test (RAVLT), Rey–Osterrieth Complex Figure Test (RCFT), Education 4.93 (2.87) Stroop Colour and Word Test (SCWT), Colour Cancellation Age of onset 3.54 (1.41) Test (CCT), Children’s Colour Trail Test (CCTT), Visual Disease duration 8.31 (3.17) Recognition test (VRT), Controlled Oral Word Association Follow-up duration 10 months (COWA), Animal Naming Test (ANT). Follow-up assessments were carried out at single time point. The detailed description Dp140 isoform alteration n = 20 is provided in the supplementary material. Source: Authors’ own data. Figure 1. Electropherogram Obtained after Multiplex Ligation Dependent Probe Amplification (MLPA) PCR Followed by Capillary Electro- phoresis of the Amplified Products. (A & B) Electropherogram and Ratio Chart Representing Profile of a Normal Control Sample. (C & D) Electropherogram and Ratio Chart Representing Deletions Between Exon 45–50 (see arrow) in the Patients Clinically Diagnosed for DMD. Ratio Between 0.70 and 1.30 is Considered in the Normal Range While a Ratio of 0.00 is Considered as Deletion (Depicted in Red Dots). Source: Authors’ own. Tyagi et al. 45 achieved in the block designing task was improved to two Longitudinal Analysis of Cognitive levels with significant improvement in the block designing and Neuropsychological Profile in efficiency (t = –2.706, p = 0.014). However, the mean time DMD Subjects in completing the block designing task was significantly increased in the follow-up (t = –2.741, p = 0.013). An Follow up of 30 DMD subjects was carried out to assess improved serial positioning effect of primacy component the progression of impairment in the general and specific in trial 1 showed a statistically significant improvement (t = cognitive domains. The mean follow-up duration was 10 –3.422, p = 0.002). DMD subjects also performed better and months. Among the MISIC subsets, the DMD group showed took less time in the colour cancellation task in the follow-up (t = 3.929, p = 0.001). Remaining variables were comparable marginally significant improvement in the block designing to the pre-follow-up status (Tables 2–5). task (t = –2.074, p = 0.050). Moreover, the mean levels Table 2. Comparison of General Intelligence on Pre and Post Follow-Up in DMD Subjects (n = 30) Using Paired t Test Cognitive Domain Neuropsychological Battery DMD-Pre DMD-F and Neuropsychological Battery Variables Mean ± SD Mean ± SD t Value P Value Information 93 ± 14.63 94 ± 11.99 –0.576 0.570 • Verbal intelligence Comprehension 84 ± 21.71 88 ± 12.43 –1.192 0.245 • Performance intelligence Arithmetic 85 ± 14.28 86 ± 11.60 –0.438 0.665 • General intelligence Digit span 88 ± 14.43 86 ± 14.97 0.974 0.340 Vocabulary 78 ± 11.57 75 ± 14.17 1.022 0.334 Similarity 94 ± 35.14 102 ± 33.26 –1.063 0.303 VIQ 89 ± 11.87 92 ± 13.36 –1.464 0.154 Picture completion 79 ± 21.14 83 ± 12.62 –1.078 0.293 Block designing 93 ± 30.23 103 ± 19.97 –2.074 0.050 Coding 84 ± 35.94 95 ± 23.60 –1.569 0.132 Maze 107 ± 39.00 110 ± 12.53 –0.414 0.683 PIQ 66 ± 10.80 63 ± 6.78 0.559 0.591 IQ 97 ± 14.00 100 ± 15.62 –1.419 0.167 Source: Authors’ own data. Note: Bold values represent significant p values. Table 3. Comparison of Neuropsychological Variables in DMD Subjects on Follow-Up (n = 30) Using Paired t Test for RAVLT Variables Cognitive Domain Neuropsychological Battery DMD-Pre DMD-F and Neuropsychological Battery Variables Mean (SD) Mean (SD) t Value P Value RAVLT RAVLT-trial 1 6.68 (2.58) 7.50 (3.27) –1.856 0.074 • Verbal learning RAVLT-trial 5 12.00 (3.09) 12.61 (2.45) –1.030 0.312 • Working memory RAVLT-learning capacity 50.11 (12.44) 52.39 (12.86) –1.156 0.258 • Short-term verbal memory • Long-term verbal memory RAVLT-IR 11.04 (3.12) 11.71 (3.02) –1.565 0.129 RAVLT-DR 10.61 (3.00) 11.36 (3.65) –1.446 0.160 LTPR 90.02 (23.39) 90.50 (30.53) –0.066 0.948 RAVLT Primacy T1 2.53 (1.23) 3.39 (1.34) –3.422 0.002 • Serial positioning effect Middle-T1 1.96 (1.07) 2.17 (1.33) –0.691 0.495 • Working memory Recency-T1 1.86 (1.09) 1.93 (1.65) –0.232 0.818 Primacy-total 18.60 (4.05) 19.92 (4.31) –1.655 0.110 Middle-total 15.53 (4.24) 16.35 (4.89) –1.107 0.278 Recency-total 15.10 (4.66) 16.60 (5.3) –1.499 0.145 RAVLT Proactive interference 0.93 (0.34) 0.94 (0.68) –0.113 0.911 • Susceptibility to interferences Retroactive interference 0.93 (0.19) 0.94 (0.26) –0.258 0.799 Forgetting speed 0.97 (0.18) 0.90 (0.29) 1.164 0.254 RAVLT efficiency 1.96 (0.28) 2.03 (0.34) –1.287 0.209 Source: Authors’ own data. Note: Bold values represent significant p values. 46 Annals of Neurosciences 26(3–4) Table 4. Comparison of Neuropsychological Variables in DMD Subjects on Follow-Up (n = 30) Using Paired t Test Cognitive Domain Neuropsychological Battery DMD-Pre DMD-F and Neuropsychological Battery Variables Mean (SD) Mean (SD) t Value P Value COWA and ANT COWA-K 6.04 (3.65) 6.07 (3.31) –0.082 0.935 • Executive Functioning Semantic COWA-M 5.18 (3.76) 5.57 (3.26) –0.763 0.452 Fluency COWA-P 4.57 (3.61) 5.03 (3.15) –1.045 0.305 • Category Fluency COWA-Avg 5.18 (3.48) 5.45 (3.03) –0.813 0.423 ANT 9.60 (3.67) 8.80 (3.26) 1.046 0.304 • Executive Functioning Cognitive Stroop-w 52.14 (20.11) 60.91 (20.70) –2.523 0.020 Flexibility Stroop-C 38.05 (13.78) 47.50 (15.87) –3.059 0.006 • Cognitive Control Stroop-CW 23.79 (9.14) 26.58 (14.98) –1.138 0.267 • Response Inhibition • Interference Stroop effect 1 14.18 (9.70) 18.50 (11.20) –1.617 0.121 Stroop effect 2 0.48 (0.16) 0.51 (0.26) –0.650 0.522 Stroop effect 3 0.65 (0.20) 0.61 (0.18) 0.876 0.391 RCFT RCFT-Copy 31.05 (6.70) 32.52 (3.53) –1.068 0.298 • Visuo-constructive ability RCFT-IR 21.39 (8.87) 23.98 (8.84) –1.661 0.111 • Visual short and long-term RCFT-DR 21.05 (8.25) 25.09 (6.11) –3.417 0.003 memory Source: Authors’ own data. Note: Bold values represent significant p values. Table 5. Comparison of Neuropsychological Variables in DMD Subjects on Follow-Up (n = 30) Using Paired t Test Cognitive Domain Neuropsychological Battery DMD-Pre DMD-F and Neuropsychological Battery Variables Mean ± SD Mean± SD t Value P Value DIGIT span test 5.17 (1.03) 5.30 (1.06) –0.680 0.503 DSF • Short term memory 3.17 (1.70) 3.04 (1.55) 0.680 0.503 • Working memory DSB Maze MAZE-TT 158.87 (93.58) 165.73 (81.84) –0.272 0.790 • Visuo-spatial planning MAZE-E 6.69 (8.31) 6.13 (8.66) 0.872 0.397 Block design test BD-TT 147.19 (104.72) 215.86 (105.21) –2.741 0.013 BD-levels 4.95 (2.73) 6.33 (2.73) –3.512 0.002 BD-EFFIC 0.22 (0.24) 0.35 (0.26) –2.706 0.014 CCTT and CCT CCTT1 46.06 (21.76) 47.17 (24.67) –0.190 0.851 attention CCTT2 83.00 (39.65) 75.17 (34.82) 1.677 0.112 • Divided attention CCT 137.15 (60.20) 93.45 (40.47) 3.929 0.001 • Focused attention • Interference CCTT interference 0.89 (0.53) 0.79 (0.80) 0.466 0.647 CCT error 1.22 (2.02) 2.28 (2.08) –1.679 0.111 VRT VRT 8.05 (1.50) 8.48 (1.36) –1.441 0.165 • Visual agnosia Source: Authors’ own data. Note: Bold values represent significant p values. Table 6. Representing Temporal Changes in Neuropychological Functioning Due to DMD Gene Mutation Affecting Dp140 Isoform Scale Variable Pre (SD) Post (SD) t Value P Value RAVLT Primacy effect 2.50 (1.46) 3.22 (1.43) –2.060 0.050 SCWT SCWT-colour 37.46 (13.96) 46.00 (17.43) –2.504 0.028 RCFT RCFT-delayed recall 20.17 (9.21) 25.32 (6.15) –3.457 0.004 CCT Colour cancellation 155.86 (60.01) 105.21 (42.38) 3.317 0.006 Source: Authors’ own data. Tyagi et al. 47 boys with DMD found their inability to sustain attention to Effect of Mutation Location on Temporal the task; however, temporal changes were not investigated. Change in Neuropsychological Functioning Furthermore, executive function and information processing speed were assessed with Stroop Colour Test We analysed the trends of neuropsychological functioning in (SCT), Stroop Colour and Word Test (SCWT), COWA cases with distal mutation location affecting Dp140 isoform. test. Stroop test is used to measure cognitive flexibility and Among 30 DMD subjects, 20 had mutations in the DMD gene selective attention. Examination was performed at base- affecting Dp140 isoform, that is, exon 44 or upstream. No line and during follow-up rounds. Our study found signifi- changes in the cognitive and neuropsychological functioning cant improvement in the SCT during follow-up, suggesting were observed over time in majority of parameters except improvement in the executive function of this population. primacy, Stroop colour and word task-colour component, The improved performance on tests assessing executive func- and RCFT-delayed recall, which showed improvement from tions such as cognitive flexibility is in contrast to a past study baseline assessment as shown in Table 6. which showed poor performance on tests for executive func- tion among DMD patients. Chamova et al. reported poor Discussion performance on all neuropsychological tests (general cogni- tive abilities, verbal memory, attention and executive func- We provide a comprehensive longitudinal analysis of cog- 9 tions) in patients with non-functional Dp140 isoforms. nitive and neuropsychological profile in DMD subjects. The Remmelink et al. examined the effect of an absent full-length detailed analysis of neuropsychological domains and their dystrophins (Dp427) on behavioural consequences in DMD progressive nature in boys with DMD provide better under- 26 patients and found a deficit in cognitive flexibility. standing of the use and effectiveness of specific rehabilitation In our study, all other neuropsychological functions regime required for retraining these patients. Additionally, remained unchanged over the period. However, improvement this will enable future interventional studies targeting specifi- in colour cancellation task, block design task, visual long- cally impaired neuropsychological function. term memory and primacy effect indicate possibilities When investigating cognitive process, analysing different of improvement in cognitive domains. The domains that aspects of the function is critical. In the present study, 30 boys remained unchanged can be further analysed in future studies, with DMD were assessed for the progression of impairment by profiling the expression of dystrophin isoforms in post- in the general and specific cognitive domains over a mean mortem brain samples of the DMD patients. This will help follow-up duration of 10 months. The findings of this study elucidate underlying genetic basis for the observed variable showed that after a mean follow-up of 10 months, boys with phenotypic changes in the specific neuropsychological DMD had no change in their general, verbal and performance function. Additionally, interventional studies can enhance intelligence. Data regarding non-progressive nature of intel- characterization of clinical and genetic variability and ligence was consistent with previous findings. DMDs have develop newer interventions specific to neuropsychological lower verbal IQ score than performance IQ score, and all IQ deficits. This may also serve to explore genotype-phenotype 15, 21 scores progressively reduce as the disease progresses. The relationship in subsets of DMD patients with other coexisting risk of cognitive deficit is determined by the location of muta - neurodevelopmental disorders such as ADHD and ASD. tion in the DMD gene that ensues specific functional dystro- The significant improvement of executive functions in phin isoforms as described earlier. For example, patients who our study suggests that genetic prediction models can be get lower IQ score were found to have a mutation in the distal developed to facilitate risk assessment, early detection and region of the gene, whereas those with full-length mutation targeted treatment in such patient populations. Bailey et al. had highest scores. However, our study confirmed supe- have recently developed a bioinformatics tool, called DMD rior cognitive performance on block design task, designed to Open access Variant Explorer (DOVE), to facilitate effective assess visuospatial ability, with significant improvement in analysis of pathologic DMD gene variants, resulting in scope the designing efficiency. 27 of precision medicine treatment for DMD. The study also undertook the neuropsychological assess- The functional improvement observed during the ment of boys with DMD for the RAVLT. We found a significant follow-up period shows that boys with DMD may be more improvement in serial positioning effect of primacy compo- amenable to neurocognitive rehabilitation. The substantial nent. In this effect, the person is assessed for the tendency to economic burden of physical and neuro-developmental better recall the first items in a list than those in the middle disability makes DMD patients vulnerable. Several studies or last. The finding that DMD patients had improvement in have shown such economic burden of DMD on patients primacy component reflects their ability to improve the long- 28, 29 and their family. Since the advent and progress in term memory after repeated exposures. However, there is a multidisciplinary management for DMD, the functional paucity of evidence that showed this effect in DMD patients. outcome, quality of life and longevity of the patients have A previous study investigating serial positioning memory of significantly been improved. 48 Annals of Neurosciences 26(3–4) Supplemental Material Conclusion Supplemental material for this article is available online. The neuropsychological profiling of DMD patients provides a well-recognized pattern of cognitive strengths and weaknesses References among DMD patients. This opens new vistas to explore other comorbid neurodevelopmental and neuropsychiatric disorders. 1. Doorenweerd N, Mahfouz A, van Putten M, et al. 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Annals of Neurosciences – SAGE
Published: Jul 1, 2019