International 2018; volume 10:7473

Cognitive impairment in neuromuscular : Introduction Correspondence: Francisco Victor Costa Marinho, Federal University of Piauí, Brazil. A systematic review Neuromuscular diseases present a wide Mapping and Plasticity Laboratory- Av. variety of clinical manifestations, but their São Sebastião nº2819 – Nossa Sra. de Fátima effects on the cognitive function spectrum Marco Orsini,1,2 Ana Carolina – Parnaíba, PI, CEP: 64202-020, Brazil. are still poorly understood.1 In contrast to the Tel.: +55.86.994178117. Andorinho de F. Ferreira,3 studies on how altered executive functions in E-mail: [email protected] 3,4 Anna Carolina Damm de Assis, mental disorders such as anxiety, depression 3 2 Thais Magalhães, Silmar Teixeira, and bipolar disorder can affect motor perfor- Key words: Cognitive Impairment; Victor Hugo Bastos,2 Victor Marinho,2 mance,2-4 the mechanisms by which essen- Neuromuscular Diseases; Motor Neuron Thomaz Oliveira,2 Rossano Fiorelli,1 tially motor dysfunctions can affect cogni- Diseases; Dystrophinopathies; Mitochondrial Acary Bulle Oliveira,4 tive performance still remain poorly under- Disorders. 5 stood and studied.5-8 Although it is known Marcos R.G. de Freitas Contributions: the authors contributed equally. that neuromuscular diseases mainly affect 1Master’s Program in Health Applied the motor functioning of the patient, the cog- Sciences, Severino Sombra University, Conflict of interest: the authors declare no nitive effects of these conditions can be sig- Vasssouras, Rio de Janeiro; 2Brain potential conflict of interest. nificant.5 This can occur from molecular Mapping and Plasticity Laboratory, defects that significantly affect neuromotor Funding: none. Federal University of Piauí, Parnaíba; functioning but also participate in the func- 3Department of Neurology, Federal tioning of neural networks involved in cogni- Received for publication: 31 October 2017. Fluminense University, Rio de Janeiro; tive processes, leading to dysfunctions of Revision received: 4 December 2017. 4Department of Neurology, Federal executive, behavioral and psychosocial func- Accepted for publication: 12 December 2017. University of São Paulo; 5Department of tions.6-8 For example, in the dys- This work is licensed under a Creative Neurology, Federal University of Rio de trophin protein , responsible for the Commons Attribution NonCommercial 4.0 Janeiro, Brazil Duchenne (DMD) phe- onlyLicense (CC BY-NC 4.0). notype, concurrently affect the stability and function of muscle fibers and central nervous ©Copyright M. Orsini et al., 2018 system (CNS) function. However, the com- Licensee PAGEPress, Italy Neurology International 2018; 10:7473 Abstract plex nature of neuromuscular diseasesuse and the different effects on cognition make it dif- doi:10.4081/ni.2018.7473 Neuromuscular diseases are multifactorial ficult to understand the neuropathological pathologies characterized by extensive muscle process.7,8 puter-based literature search was conducted fiber damage that leads to the activation of Three large, heterogeneous groups of in two main databases: ISI Web of Science satellite cells and to the exhaustion of their neuromuscular diseases have been implicat- and PubMed (2003-present) were initially pool, with consequent impairment of neurobi- ed in cognitive alterations. i) Motor Neuron performed in October 2017 using relevant ological aspects, such as cognition and motor Diseases, neurological disorders that affect search terms: (e.g. [Cognitive Impairment control. To review the knowledge and obtain a the neurons that control voluntary motor and Neuromuscular Diseases] [Motor broad view of the cognitive impairment on activity;9,10 ii) Muscular dystrophies, repre- Neuron Diseases and Cognitive Neuromuscular Diseases. Cognitive impair- sented mainly by dystrophinopathies, dis- Impairment] [Cognitive Impairment and ment in neuromuscular was explored; eases caused by hereditary defects in the Dystrophinopathies] [Cognitive a literature search up to October 2017 was protein gene;11 iii) Impairment and Mitochondrial Disorders]. conducted, including experimental studies, Mitochondrial disorders, which are caused Abstracts were examined for references to case reports and reviews written in English. by mutations in cytoplasmic or nuclear the research question and if the study Keywords included Cognitive Impairment, mitochondrial DNA, which alter the struc- appeared relevant, then the full text was 10,12 Neuromuscular Diseases, MotorNon-commercial Neuron ture and mitochondria function. Often retrieved. As selection criteria: (a) Diseases, Dystrophinopathies and comes from an Experimental studies, case reports and Mitochondrial Disorders. Several cognitive already known molecular disorder that is reviews written in English; (b) Without evaluation scales, neuroimaging scans, genet- also associated with changes in brain func- restriction of publication dates of the paper ic analysis and laboratory applications in neu- tion and cognition, such as mitochondrial (c) Magnetic Resonance Imaging (MRI) romuscular diseases, especially when it comes . In other cases, neuromuscular scans, assessments with cognitive and func- to the Motor Neuron Diseases, disorders also have cognitive deficits, but tional scales applied to neuromuscular dis- Dystrophinopathies and Mitochondrial without a well-defined molecular alteration eases, and cognitive tasks healthy individu- Disorders. In addition, organisms model using such as Amyotrophic Lateral Sclerosis als and/or individuals with neuromuscular 8,13 rats in the genetic analysis and laboratory (ALS). In this context, the present diseases (e.g. children, young adults, mid- review aims to highlight the neurofunction- applications to verify the cognitive and neuro- dle-aged and elderly). In addition, experi- al and cognitive alterations in the main con- muscular impacts. Several studies indicate mental studies using rats were considered. genital neuromuscular disorders. that congenital molecular alterations in neuro- Criteria for exclusion were: (a) disserta- muscular diseases promote cognitive dysfunc- tions, book reviews, conference proceed- tions. Understanding these mechanisms may ings, or editorials. Data were extracted in the future guide the proper management of Materials and Methods based on study design and setting. The dis- the patient, evaluation, establishment of prog- cussion was written after observing com- nosis, choice of treatment and development of The systematic review was conducted mon points among the articles selected. innovative interventions such as gene . in line with the PRISMA statement. A com- This observation was conducted in order to

[Neurology International 2018; 10:7473] [page 3] Review analyze the papers results and answer the Examination (MMSE), Addenbrooke’s muscular diseases is greatly variable, and hypothesis of the present research. Cognitive Examination-Revised (ACE-R), significant cognitive impairment is California Verbal Learning Test (CVLT), observed only in some patients. Symptoms Study selection and data extraction Stroop Color and Word Test (SCWT). such as depression and anxiety as well as Three reviewers (M.O, S.T and V.M) Outcome: The primary outcome mea- deficits of visuospatial abilities, executive independently read the titles and/or sure was the potential ability to accurately functions, and naming have been frequently abstracts of the identified papers and elimi- assess neuromuscular diseases and their reported. Several MRI studies have shown nated irrelevant studies. Studies considered implications for cognitive impairment that neuromuscular diseases patients have eligible for inclusion were read in full and through screening: Genetic analysis, MRI generally more deficiencies of neural con- their suitability for inclusion was deter- scans, mobile transcutaneous sensor for tis- nections in the frontal, parietal and temporal mined independently by three reviewers sue gas tensions and cognitive Scales. regions and; these dysfunctions increase (M.O, S.T and V.M) Disagreements were Papers were assessed for eligibility with the progression of the disease. managed by consensus. However, if this based on title and abstract; 80 were classi- was not successful, consensus was sought fied as meeting eligibility criteria. The next by a fourth reviewer (M.R.G.F.). Data were stage of the winnowing process involved extracted based on study design and setting. full-text screening of the potentially rele- Discussion Some authors were contacted to provide vant papers; Eventually, 63 studies were supplementary information when insuffi- included in the review. Motor neuron diseases and cognitive cient data were provided in the study. The impairment authors of three studies were contacted for Motor Neuron Disease (MND) is a further information having read their titles degenerative disease caused by motor neu- and abstracts. Two replied; since it bases the Results ron degeneration, whether inferior or supe- review of literature fulfilled the inclusion rior. Amyotrophic Lateral Sclerosis (ALS), Seventeen experimental studies and 30 criteria. the most well-known form of MND, is a case reports with cognitive scales and neu- devastating severe disease that simultane- romuscular assessment using scales, as well only Study selection ously affects the lower motor neuron as genetic studies and neuroimaging studies 9,10 Studies were included if they met the (LMN) and upper motor neuron (UMN). with MRI, 16 review papers about neuro- following inclusion criteria. Initially, Descriptions in the literature have been muscular diseases. This study demonstrated retrieved papers from each database were linking, for more than a century, emotional that the neuromuscular diseases are multi-use compared to remove duplicate records. liability with bulbar-onset ALS. After factorial pathologies characterized by Papers were then screened for eligibility pathological and genetic discoveries, over extensive muscle fiber damage that leads to based on their title and abstract and, once the years, the overlap of frontotemporal the activation of satellite cells and to the they were elicited, the full text publication (FTD) and MND was strength- exhaustion of their pool, with consequent 9,10 was reviewed. ened. Data from recent studies show that impairment of the regenerative process. In summary: Study design: Case more than 50% of ALS patients at some reports, original papers and reviews designs point in the disease course, will develop were included. The prospective population-based phenotypic picture of cognitive or Population: Study population com- study of cognitive impairment in behavioural impairment, and about 13% posed of healthy individuals and/or individ- neuromuscular diseases will exhibit concomitant behavioural-vari- uals with neuromuscular diseases (e.g., chil- The majority of neuromuscular diseases ant frontotemporal dementia (b-FTD).10-16 dren, young adults, middle-aged and elder- patients presented with features consistent Patients who present cognitive or ly). In addition, experimental studies with with executive dysfunction, and have short- behavioural changes, that do not fulfil all rats were included. er survival time. This last finding, in turn, the formal criteria for FTD, can be grouped Intervention: Neurobiological interven- suggests that studies reliant on prevalent into three different categories: ALS with tions were defined as any intervention cases are likely to underestimate the inci- behavioural impairment; ALS with execu- aimed at evaluating the neuromuscularNon-commercial dis- dence of these frontotemporal syndromes. tive dysfunction; and ALS non-executive eases - Motor Neuron Diseases, In patients without dementia, we observed dysfunction.10,17,18 Dystrophinopathies and Mitochondrial. an overrepresentation of executive dysfunc- Frontotemporal dysfunction, when pre- Disorders. tion. The incidence of executive impairment sent, is strongly linked to lower survival in Screening: Genetic analysis in vivo and in this cohort was higher using the screen- patients with ALS. In addition, regardless of post-mortem, MRI scans, mobile transcuta- ing criteria. The cognitive evaluation and the age of onset, delayed diagnosis, baseline neous sensor for tissue blood gas tensions, cognitive tasks demand heavily on multiple severity, education and respiratory status, ALS Functional Rating Scale, Reye frontostriatal circuits leading to sensitivity the presence of executive dysfunction is a Osterrieth Complex Figure Test, Premorbid in detecting any disturbance of neural cir- factor and risk for a worse prognosis.10,16 Full-Scale IQ, Wechsler Test of Adult cuits established for cognitive and motor Unless FTD is advanced enough to cause Reading, Pyramid and Palm Trees Test, demands. significant frontal and temporal lobe atro- Boston Naming Test, Rey-Osterrieth In this present study, neuromuscular phy, neuroimaging is rarely useful in diag- Complex Figure, Reverse Digit Span sub- diseases patients showed generally a mod- nosing cognitive and behavioural deficits in test, Oral Trail Making Test, Edinburgh erate muscular impairment, impaired cogni- ALS. Studies of neural networks have been Cognitive, Behavioural ALS Screen tive performance over a broad range of increasingly used for the analysis of fron- (ECAS),Griffiths scale, Behavior functions, including frontal, visuospatial, totemporal dysfunction in ALS. In studies Check List (CBCL), Youth Self Report naming and abilities and working with resting state functional MRI, it has (YSR),Strength and Difficulties memory abnormalities. The degree of cog- been observed three main dysfunctional Questionnaire (SDQ), Mini Mental State nitive impairment in patients with neuro- networks in ALS: the salience network, the

[page 4] [Neurology International 2018; 10:7473] Review default mode network, and the central exec- utive network.16,19 Several screening tools specifically created for rapid neuropsycho- logical assessment of patients with ALS. Some of these tools, currently available, include the ALS-Brief Cognitive Assessment (ALS-BCA), the ALS- Cognitive Behavioural Screen (ALS-CBS), the ALS-FTD-Q, Edinburgh Cognitive and Behavioural ALS Screen (ECAS). Patients who are in compliance with the cut-off score of these tests have formal indication of complete neuropsychological assess- ment.10,20-22 In addition, the GGGGCC hexanu- cleotide repeat expansion in the chromo- some 9 open reading frame 72 (C9orf72) is a frequent cause of familial MND, FTD and especially frontotemporal dementia-motor Results neuron disease. The repeat expansion of C9orf72 results in dipeptide repeat proteins (DPRs), which form inclusions in central (CNS). Finally, it induces the mislocalization and aggregation of TAR DNA-binding protein 43 (TDP-43). It is only estimated that in the European population, 50 to 70% of patients with familial fron- totemporal dementia-motor neuron disease and 15 to 20% with apparent sporadic familial frontotemporal dementia-motor use neuron disease, exhibit the expansion of the C9orf72 gene. The penetrance of C9orf72 gene expansion has not yet been deter- mined, but it seems unlikely to be a com- plete penetrance.18,23,24 TAR DNA-binding protein of 43 kDa (TDP-43), was proved to be present in neuronal cytoplasmic inclu- sions and dystrophic neurites in the hip- pocampal region and temporal cortex of patients with frontotemporal dementia- motor neuron disease. Although C9orf72 is the most frequent genetic cause of frontotemporal dementia- motor neuron disease, other gene mutations (VCP, SQSTM1, OPTN and UBQLN2) have already been linked to this pathology,Non-commercial but they are rare causes.23 Another MND with cognitive impair- Protocol ment is the bulbospinal muscular or Kennedy’s Disease (KD). KD is an X- linked recessive pathology that affects men and is caused by the repetition of the CAG trinucleotide in exon 1 of the androgen receptor gene, slowly progressive, with adult-onset. It is characterized by degenera- tion of LMN that leads to atrophy, weak- ness, and fasciculation of limbs and bulbar musculature. A striking feature in KD is the presence of minipolymyoclonus.25 It is , 2017 Group: 133 boys with DMD (aged from 2,8 to 32 years). Evaluation: The mean FSIQ in DMD patients was more than one SD below the mean (80.38), with a greater impairment of impairment a greater with (80.38), mean the below SD one than more was patients DMD in FSIQ mean The Evaluation: years). 32 to 2,8 from , 2017 (aged DMD with boys 133 Group: , 1999 Group: Twenty-two children with merosin-positive or merosin-deficient congenital Twelve were merosin-positive and ten merosin-deficient. The full scale IQ in the remaining 21 ranged from 51 from ranged 21 remaining the in IQ scale full The merosin-deficient. ten and merosin-positive were Twelve congenital merosin-deficient or merosin-positive with children , 1999Twenty-two Group: required more than 38 repeats to consider impaired impairment, muscular a moderate showed patients DM1 in tasks cognitive and MRI of Results expansions repeat triplet CTG for analysis Genetic Evaluation: patients. DM1 13 Group: , 2016 , 2017 Group: 416 patients witn DMD. Evaluation: Muscular Impairment Rating Scale, A significant worsening over time was observed for verbal memory, visual attention, and processing speed. processing and attention, visual memory, verbal for observed was time over worsening A significant Scale, Rating Impairment Muscular Evaluation: DMD. witn patients 416 Group: , 2017 , 2017 Case report: Mutations in GMPPB gene in patients with early-onset disease ranging The results of the two cases with LGMD that underwent clinical, histopathological and genetic studies. genetic and histopathological clinical, underwent that LGMD with cases two the of ranging results The disease early-onset with patients in gene GMPPB in Mutations report: Case , 2017 , 2016. Group: Fifteen patients with DMD (mean age = 30.4 years, Evaluation total cognitive were significantly deficient in adults with DMD in comparison to the normal the to comparison in DMD with adults in deficient significantly were cognitive total Evaluation years, = 30.4 age (mean DMD with patients , 2016. Fifteen Group: , 2016 Group: 101 DM1 and 46 DM2adult patients. Evaluation: Patients underwent analysis of five cognitive domains (visuospatial, executive, attention, memory and memory attention, executive, (visuospatial, domains cognitive five of analysis underwent Patients Evaluation: patients. DM2adult 46 and DM1 101 Group: , 2016 the CAG trinucleotide expansion as al. et et al. et et al. et , 2016 Group: 12 patients [age 9.14±2.52 years] with a diagnosis of DMD, Compared with the 14 subjects in the normal control group, no gross structural abnormalities had detected in detected had abnormalities structural gross no group, control normal the in subjects 14 the with Compared DMD, of a diagnosis with years] 9.14±2.52 [age patients 12 , 2016Group: et al. et et al. et et al. et pathogenic. The CAG repeat size correlates al. et inversely with disease onset, but not with al. et of CC and the full intelligence quotient (FIQ). quotient intelligence full the and CC of was 30-40 years and the progression rate mild to moderate. No cognitive or behavioral symptoms were noted. were symptoms behavioral or cognitive No moderate. to mild rate progression the and years 30-40 was normal merosin one had a mild delay (IQ<75) and two were borderline (IQ 75-95). While the children with children the While 75-95). (IQ borderline were two and (IQ<75) delay a mild had one merosin normal scores. normal had MRI on changes matter white diffuse typical the with deficiency merosin affected. were domains 1–2 approximately two-thirds other mostly been have findings MRI patients DM1 abnormalities.In WM and abilities size. expansion repeat CTG relatedto Wechsler Intelligence Scale (WISC-III or WIPPSI) or Griffiths scale, Child Behavior verbal components (VIQ: 82.88) than of performance components (PIQ: 85.83); difference in FSIQ between FSIQ in difference 85.83); (PIQ: Behavior components Child scale, performance of than Griffiths or 82.88) (VIQ: WIPPSI) or components (WISC-III Scale verbal Intelligence Wechsler sample. total the of 36.2% in found was mutations of types two the Strength and (YSR), Report Self Youth (CBCL), 6-18 List Check (SDQ). Questionnaire Difficulties and muscular nCTG, with not but duration, disease and age with correlated scores cognitive in progression The Stroop and (RCFT) Tests Figure Complex Rey (CVLT), Test Learning Verbal California baseline. at education nor impairment (SCWT). Test Word and Color and 14 healthy volunteers [age 9.39±2.99 years].Evaluation: Wechsler intelligence conventional MRI examination. In the DMD group,there was a significant correlation between FA of the of FA between correlation a significant was group,there DMD the In examination. MRI conventional intelligence splenium the of FA Wechsler between not but P=0.044) years].Evaluation: t=0.588, 9.39±2.99 (VIQ; [age quotient volunteers healthy 14 intelligence and verbal and CC of splenium examination. MRI and scale from severe congenital muscular dystrophies to limb-girdle muscular dystrophy In both cases, we found identical compound heterozygous GMPPB mutations c.79G>C p.D27H and and p.D27H c.79G>C mutations GMPPB heterozygous compound identical found we cases, both In weakness dystrophy muscle of muscular onset The limb-girdle to dystrophies alpha-dystroglycan. of defect muscular congenital a to glycosylation severe from leading p.R287W, c.859C>T retardation. mental with (LGMD) muscular dystrophy. Evaluation: FMRI and Wechsler Intelligence Scale. to 134, the verbal IQ ranged from 78 to 136 and the performance from 51 to 136. Of the twelve children with children twelve the Of 136. to 51 from performance the and 136 to 78 from ranged IQ verbal the 134, to Scale. Intelligence Wechsler and FMRI Evaluation: dystrophy. muscular (WAIS-III), III Scale (P<0.05). population Intelligence WechslerAdult Evaluation: years). = 19–44 range age (CAT) Attention for ClinicalAssessment the affected. domains cognitive 2–3 approximately with defect cognitive had patients DM1 all Virtually (MMSE) language). Examination State Mental Mini in and (MIRS), Scale findings, Rating Impairment neuropsychological Muscular normal completely had patients DM2 of one-third hand, other the On (ACE-R). Examination-Revised Cognitive Addenbrooke’s and memory and naming visuospatial, frontal, including functions, of range a broad over performance cognitive scans MRI examination, EMG (PCR), reaction chain polymerase small-pool including Colombo Colombo Gallais Fu Fu Balcin Balcin Author Author Mercuri Ueda Peric Bajrami disease progression or severity.25 Systemic 1. Summary of studies Table the investigating impact of deficit cognitive in dystrophinopathies.

[Neurology International 2018; 10:7473] [page 5] Review symptoms are also found in KD. The most course of the disease seem to be related to a Dp71 the main product expressed in the common non-neurological manifestation is less severe and remaining glycosylation of brain. Dp71 is found around perivascular gynecomastia. In addition, reduced fertility α-DG.30 In the more severe end of the clin- astrocyte end feet, which suggests its role in due to testicular atrophy, oligo/azoosper- ical spectrum, there are brain and eye- BBB function and possible in the possible mia, erectile dysfunction and reduced libido abnormalities, as illustrated by: Fukuyama access of peripheral inflammatory may be present.25,26 Cognitive impairment congenital muscular dystrophy (FCMD), molecules into the brain. In the CNS, may be found in KD. Guidetti et al.26 have muscle-eye-brain (MEB) disease and Dp427 is only found in neurons, and only observed in their patients a predominant WWS, examples of a continuum in increas- within specific regions of the brain such as impairment in long-term memory and selec- ing of severity.30,31 The typical CNS the hippocampus, amygdala, cerebellar tive attention. Kessler et al.27 observed clin- involvement among dystroglicanopathies Purkinje cells, and neocortex. The interac- ical characteristics of frontal lobe dysfunc- includes various degrees of lissencephaly tion of Dp47 with DGC would be important tion with disinhibition, impaired executive type II (also known as cobblestone com- for the formation and maintenance of new functions and reduced affective plex), pachygyria, neuronalheterotopias, synaptic connections.36 modulation.27 ponto cerebellar hypoplasia, and cerebellar The lack of dystrophin in mdx mice) cysts.28 seems to alter neuron proliferation, survival Cognitive impairment of muscular Merosin-deficient congenital muscular and/or differentiation and perturb neuronal dystrophies: dystrophinopathies dystrophy also referred to as MDC1A, is migration (The density of CA1 pyramidal Congenital muscular dystrophies caused by mutations in the LAMA2 gene, neurons was reduced by ~34% in the (CMDs) are clinically and genetically het- which encodes the α2 subunit of laminin anterodorsal hippocampus, although quanti- erogeneous inherited disorders that com- (merosin).29 Patients manifest severe mus- tative reductions varied along the hip- pass muscle weakness typically manifested cular weakness and atrophy, diffuse con- pocampal antero-posterior axis.35 In their at birth or in infancy.11 The spectrum ranges tractures, inability to walk and facial dys- hippocampus were identified cytokines, from severe floppy infant syndrome to mod- morphism.31 Ventilatory is needed within which are also chronically elevated in erate motor delay and mild or moderate the first 10 years for most patients.28 Since peripheral tissue and plasma of patients limb-girdle involvement during childhood, laminin-α2 chain is localized to the basal with onlyDMD. Key proinflammatory cytokines compatible with survival into adult life and lamina of all cerebral blood vessels, the lack such as IL-1, TNF-α, and IL-6 exert neuro- relatively good quality of life.6 Besides of α2 may lead to a disruption of the blood- modulatory effects on the hippocampus and muscle compromise, white matter and brain barrier (BBB), increased water con- have been linked to altered capacities for structural abnormalities of the brain, tent, and a resulting abnormal white matteruselearning and the formation of . , cognitive impairment, and eye signal intensity (WM).31 The typical abnor- Hence, there may be a neuroimmune contri- abnormalities may occur depending on the mal signal in WM seem in T2-wheited MRI bution in the CNS disturb of dystrophin- genetic cause. Mutations occur in (T2 MRI) spares the compacted fibre tracts deficient patients.36 encoding structural proteins of the extracel- such as the corpus callosum (CC). The cog- In mice, the loss of DYS leaded to lular matrix, glycosylation enzymes, and nitive functions are not impaired if the WM enhanced unconditioned fears, anxiety and proteins of the endoplasmic reticulum (ER) changes are isolated.28 Nevertheless, it has deficits in fear conditioning and memories, and nuclear envelope. However, just in 25- been reported a child with cortical dysplasia suggesting the role of the protein in the 50% of CMD-affected subjects, mutations and severe mental retardation, and a series functioning of the neuronal circuit of fear.7 can be identified, suggesting that there are of children who in addition to the typical The absence of dystrophin resulted in a sig- additional genes to be acknowledged.11 On findings had cerebellar hypoplasia and a nificant elevation of [Ca2+]i and [Na+]i in the other hand, it is frequently unfeasible to lower performance IQ.32 intact adult cortical and especially hip- establish a one-to-one relationship between Duchene muscular dystrophy (DMD) is pocampus pyramidal neurons of mice, as a given gene and a defined . For one of the most common genetic disorders, well as an increase in ROS production, and example, mutations in the FKRP (Fukutin- affecting about 1:3000 boys.33,34 It is an X- death. This ion dyshomeostasis was related protein) gene may lead to manifesta- linked dystrophy caused by genetic muta- related to a spatial learning deficit.34 tions extended from the severe Walker- tions disrupting the protein dystrophin In humans, the lack of this protein Warburg (WW) syndrome to the lateNon-commercial adult- (DYS), another core protein of dystrophin- might also lead to neurobehavioral disor- onset limb-girdle muscular dystrophy glycoprotein Complex (DGC), as ders, including attention-deficit/hyperactiv- (LGMD).28 The genetic defects might not DG.29,33,34 DMD is characterized by pro- ity disorder (ADHD), autism spectrum dis- only interfere with the translated sequence, gressive muscle degeneration and non-pro- orders, and obsessive-compulsive disorder. but also with the posttranslational process- gressive cognitive deficits.33-35 DYS also In the context, Colombo et al.33 reported a ing, as described with α-dystroglycan, a plays an important role in the architectural non-progressive lower IQ in DMD boys major extracellular matrix receptor on mus- organization of the CNS.33 It is involved in compared to controls. Boys may present cle.28 the organization of GABAA receptors, once specific learning disabilities such as dyslex- The term dystroglycanopathies encom- is normally expressed at the postsynaptic ia and impaired executive functions, namely pass the in the dystroglycan gene membrane in inhibitory synapses of struc- problem solving, inhibition and working (DAG1) itself or mutations in genes encod- tures related to cognition and emotional memory.33 In addition, Astrea et al.37 ing glycosyltransferases of alpha-dystrogly- behaviour, such as hippocampus, amygdala, demonstrated that 15 patients with DMD can (α-DG), which are necessary to allow α- cerebellum and sensory cortices.7,8 (age range = 19-44 years) demonstrated DG binding to laminin.29,30 In brain, dystro- Although dystrophin expression in impairment in the ability to sequentially glycan is expressed in astrocytic end feet brain is only one-tenth of that found in mus- process auditory and visual information and abutting the glia limitans and the intracere- cle, brain tissue exhibits much greater vari- attention.6 A controlled study of diffusion bral vasculature, in photoreceptor cells of ability in the protein products from the dys- tensor imaging (DTI) involving 15 boys the retina, and in major neurons and glia in trophin gene. It includes the full-length pro- with DMD showed significantly lower frac- the developing CNS.29 Cases of milder tein, Dp427, and shorter proteins being tional anisotropy (FA) values in the spleni-

[page 6] [Neurology International 2018; 10:7473] Review um of CC and these values were positively severe neuromuscular impairment.6 entorhinal, anterior corona radiate, correlated with verbal IQ.37 Neuropsychological analysis of 101 DM1 orbitofrontal, and lateral occipital areas. A recent study assessing 47 Italian boys patients (childhood, juvenile, adult, and This study revealed higher occurrence of with DMD found that 14.89% of the boys late-onset) registered normal general intel- WM than cortical abnormalities. This find- had a diagnosis of ASD. Full Scale lectual level. Visuospatial impairment was ing together with the correlation between Intelligence Quotient (FSIQ) <70 were reg- the main cognitive defect with prevalence WM lesion severity and disease duration istered in 36.2% of them, with a greater of 75-86% among different . suggests that DM1 represents a slow impairment of verbal than other perfor- Executive dysfunction was the second most demyelinating process, which eventually mance components.33 Distal DMD muta- common cognitive impairment, affecting progresses to axonopathy. Moreover, the tions were implicated to more severe cogni- 60-79% of the sample. Adult DM1 subjects decreased integrity of connectivity, as well tive deficit, as reported by previous with older age and longer duration of dis- as cortical pathology, was located mostly in studies.6,33 Similar results were found in a ease were more susceptible to memory and the ventral side connecting the fronto-tem- longitudinal study following 41 preschool language defects. Late onset was associated poral cortex. These findings may be rele- DMD boys until school age. It was con- with the affection of multiple cognitive vant to the behavioural symptoms, includ- firmed a correlation between neurodevelop- domains including the highest prevalence of ing dysexecutive syndrome, apathy, and mental assessments and later cognitive memory impairment (more than 80%). depression. In that study, diffusion metrics scales and on both evaluation the overall Among 46 DM2 patients, it was showed were also affected in the external capsule, results were better when the mutation was that even one-third of them had completely which might be related to decrease verbal upstream or in the exon 44 without affecting normal neuropsychological findings. fluency resulting from impairment in Dp140 expression.38 Distal mutations are Visuospatial and executive dysfunctions semantic processing.42 Bajrami et al.43 sug- associated with loss of cerebral dystrophin were also the most prevalent in DM2, but gest that the WM hyperintense lesions isoforms, which are more expressed in the less common than in DM1.40 (WMHLs) located at the temporal poles cerebellum and limbic system. It is worth to A longitudinal neuropsychological seem to be characteristics of the disease, remember that literature supports the cere- assessment among 115 DM1 – only adult while others, small and diffuse WMHLs bellar contribution even to aspects of social phenotypes disclosed that executive func- wouldonly be similar to the age-related alter- emotional and regulatory behaviour.33 tions (Stroop color-word, fluency tests and ations.43 Mutations in the DYS gene are also WAIS-R for digit symbol coding and block responsible for causing Becker muscular design), language (fluency and Boston Mitochondrial disorders and cogni- dystrophy (BMD). However, in BMD there Naming Test), and visual memoryuse (Rey tive impairment is a production of partially functional dys- Complex Figure Test) were the most Mitochondrial diseases (mtD) are those trophin. Patients typically remain ambulato- impaired cognitive functions at baseline. caused by mutations in mitochondrial DNA ry at least until age 15 and commonly well However, they did not significantly decline (mtDNA) and/or nuclear DNA (nDNA) into adult life. Cognitive impairment and through the time, in opposition to verbal genes due the dual genetic control (nDNA neurobehavioral comorbidities are also not memory, processing speed, and visual atten- and mtDNA) of the respiratory chain (RC), as common or severe in BMD compared tion, which, actually, also imply the require- the complexity of intergenomic signalling with DMD.39 ment of some specific executive functions and its functional consequences.44,45 The Myotonic dystrophies (DM) are autoso- (i.e. processing speed itself, mental flexibil- mutation rate for mtDNA is much higher mal dominant multisystemic disorders that ity, and selection and maintaining of accu- than that for nuclear DNA, especially for affect also the brain.40 rate strategies). The FSIQ and the visual deletions.46 The diagnosis of mtD is chal- type 1 (DM1) is caused by a CTG trinu- construction also remained stable. The adult lenging since the clinical picture is varied cleotide repeat expansion in the non-coding phenotype performed more poorly than the and can occur at almost any stage of life, region of the dystrophiamyotonica-protein late-onset phenotype on most of the tests, often with involvement of unusual combi- kinase (DMPK) gene, resulting in alterna- both at baseline and follow-up. nation of organs.45,47 Systems/organs most tive splicing of pre-messenger RNAs for Nevertheless, the rate of decline was higher frequently clinically or subclinically affect- various proteins, including the TAU and in the late-onset than in the adult phenotype. ed in mtD are the peripheral nervous system NMDA.6,40 Cognitive deficits Non-commercial have been The level of progression in most of the cog- (PNS), the central nervous system (CNS), observed in 24-75% of DM1 patients and it nitive performances correlated with age and endocrine glands, , ears, eyes, gas- depends on the age at onset of the dis- disease duration but not with the CTG trointestinal tract, liver, kidneys, bone mar- ease.6,31,40 Congenital patients tend to have repeats, educational level nor muscular row, and dermi. The second most frequently mental retardation, while those with onset impairment. These findings are consistent affected system is the CNS.48 Common in the childhood have learning disabilities with the hypothesis that DM1 could be con- CNS findings are fluctuating encephalopa- due to lower IQ, the ADHD, autistic sidered as a progeroid disease (an accelerat- thy, seizures, migraine, stroke-like behaviour, visuospatial impairment, lack of ed and increased ageing process).41 episodes, , and cognitive interest and inhibition. Adult onset is related A comparative study involving nine decline through dementia.49 The cognitive to the dysexecutive syndrome and visuospa- DM1 patients and age matched healthy con- decline among manifestations of CNS is tial deficit, while verbal functions and trols using T1-weighted and DTI disclosed increasingly recognized and diagnosed, it is memory seem to be age dependent. Late- changes in cortical thickness and WM in the essential to guide the optimal management onset DM1 patients were reported to have widely distributed network of the frontal, of these patients. predominantly age-dependent memory temporo-occipital, medial parietal, and sen- Mitochondrial syndromes associated deficit.40 sorimotor areas. CTG repeats were nega- with cognitive impairment due to mtDNA Lower IQs seems to be correlated with tively correlated to thickness in the right mutations include mitochondrial longer expansions, mainly related to mater- medial orbitofrontal cortex, left middle tem- encephalopathy, lactic acidosis and stroke- nal inheritance and age of onset of symp- poral, supramarginal, and the lateral occipi- like episodes (MELAS) syndrome, toms although it does not represent a more tal cortex and to the WM integrity in the left with ragged-red fibres

[Neurology International 2018; 10:7473] [page 7] Review

(MERRF) syndrome, maternally inherited patients were divided into groups (asymp- and deafness (MIDD), mitochon- tomatic, oligosymptomatic and symptomat- drial chronic progressive external ophthal- ic), and submitted to neurologic examina- moplegia (CPEO), Kearns-Sayre syndrome tion, neuropsychological testing and spec- (KSS) and neuropathy, ataxia and retinitis tral resonances. The study showed that the pigments (NARP) syndrome.50 The assess- MELAS probands had higher ventricular ment of cognitive functions in these patients lactate estimates on spectral resonances is made through a neuropsychological test, than the MEERF probands, and the MELAS and the domains impaired were abstract rea- probands had lower scores on formal neu- soning, verbal memory, visual memory, lan- ropsychological testing than MEERF guage, executive or constructive functions, probands. In this way the authors correlated calculation, attention or visuospacial func- high levels of ventricular lactate, the brain tions. Cognitive functions and intellectual spectroscopic signature of MELAS are abilities may decline from initially focal associated with more severe neurologic cognitive impairment to lastly dementia.51 impairment. The study also evidenced that In addition, the investigation proposed to the 15 patients with MEERF had score for

detect mitochondrial dementia is based on degree of impairment on neurologic exami- Results imaging studies, including MRI, PET, nation lower than MELAS patients and that SPECT or MR-spectroscopy, cerebrospinal worsening of neuropsychological functions fluid (CSF) investigations or electroen- was independent of the severity of clinical cephalography.52 manifestations.56 The mitochondrial disorders are a Kearns-Sayre syndrome (KSS) presents genetically heterogeneous group and vari- that classic triad: pigmentary retinopathy, able phenotype, therefore we select the chronic progressive external ophthalmople- most frequent mitochondrial diseases with gia and heart block, beyond features like only cognitive impairment to approach: .57 Chronic Progressive MELAS - mitochondrial encephalopa- External Ophthalmoplegia (CPEO) is a thy, lactic acidosis and stroke-like syn- mitochondrial with slowly pro- drome is typified by characteristic neuro- gressive, often symmetric blepharoptosisuse logical manifestations including seizures, and limitation of ocular motility in all direc- encephalopathy, and stroke-like episodes, tions of gaze.58 Bosbach et al.59 performed and other secondary manifestations just like a study with 22 patients with CPEO or KSS short stature, cognitive impairment, included screening for mitochondrial DNA migraines, depression, , (mtDNA) point mutations (3243/8344) and cardiac conduction defects and diabetes mtDNA deletions. All patients underwent a mellitus.53 The patients suffer from cogni- neuropsychological test battery. The neu- tive dysfunction of nuclear pathogenesis. ropsychological testing did not reveal signs Emmanuele et al.54 present a study explor- that would suggest general intellectual ing a possible link between cognitive dys- decline or dementia, but provided evidence function and hippocampal expression of of specific focal neuropsychological calbindin D 28KD (CB), a high-affinity cal- deficits, suggesting particular impairment cium-binding protein, in four MELAS of visuospatial perception associated to patients, using post mortem hippocampal parieto-occipital lobes and executive tissues. Reduction in CB expression is asso- deficits associated to the prefrontal cortex.59 ciated with aging and with neurodegenera- Autosomal CPEO presents with similar Protocol tive disorders. They found a reductionNon-commercial in manifestations as mitochondrial CPEO but CB expression in these patients and postu- is due to mutations in the twinkle, POLG1 lated that the reduced CB expression may or ANT1 genes.50 Simoncini et al.60 report- play a role in the cognitive abnormalities in ed a case of a woman with ANT1- related MELAS.54 adPEO and dementia. The patient started to MERRF – Myoclonus Epilepsy associ- report disorders of short-term memory, and ated with Ragged-Red Fibers had as diag- the neuropsychological evaluation showed nostic criteria typical manifestations of the a mild impairment of verbal memory and disease such as myoclonus, generalized the attentive functions, magnetic resonance epilepsy, cerebellar ataxia and ragged-red of brain revealed widespread moderate cor- fibres on muscle biopsy. Other multisys- tical atrophy, and magnetic resonance spec- temic alterations can be found as: deafness, troscopy of brain disclosed mild elevation exercise intolerance, , of lactate in the posterior interhemispheric 2012 Evaluation: human postmortem brain specimens from 4 MELAS The results showed reduced CB levels in all patients by immunohistochemistry, Western blot, and blot, Western immunohistochemistry, by patients all in levels CB reduced showed results The 4 MELAS from specimens brain postmortem human 2012Evaluation:

abnormal cardiac conduction, dementia, region and in ventricular region. However, groups. other the than lactate ventricular higher significantly had MELAS with subjects The mutation point A3243G the and MELAS with families 34 from individuals 91 Group: 2004

55 56 patients 22 of out 15 in deletions large-scale single revealed mtDNA of analysis genetic Molecular (CPEO) ophthalmoplegia external progressive withchronic patients 22 Group: , 2003

among others. Kaufmann et al. studied studies are needed to assess the prevalence al., et et al., et

91 individuals from 34 families with of central neurological manifestations in al. et MELAS and the A3242G ANT1 .60 and 15 individuals from two families with also referred to as sub- patientsharboring the m.3423A>G mutation.The diagnosis:Muscle biopsy, quantitative real-time PCR. Reduction in CB expression has been associated with aging and with with and aging with associated been has expression CB in Reduction PCR. real-time quantitative biopsy, diagnosis:Muscle mutation.The m.3423A>G the patientsharboring play may expression CB reduced the that postulated hypothesis The disorders. neurodegenerative genetic molecular and brain, and muscle in activities enzyme chain MELAS. with respiratory associated abnormalities cognitive the in a role mutation. m.3243A>G the revealing studies (GNP). score neuropsychological global function: Cognitive or Kearns-Sayre syndrome (KSS), and healthy control subjects.Evaluation: and the tRNA (Leu) A3243G point mutation in two out of 22 patients.Neuropsychological testing did did testing patients.Neuropsychological 22 of out two in mutation point A3243G (Leu) tRNA the and subjects.Evaluation: control healthy and (KSS), syndrome visual in Kearns-Sayre or particularly deficits, cognitive specific but deterioration, intellectual general reveal not battery. test neuropsychological and tissue, muscle skeletal of analysis Genetic and 15 individuals from two families with myoclonus epilepsy and ragged red fibers There was a significant correlation between degree of neuropsychological and neurologic neurologic and neuropsychological of degree between correlation fibers red a significant was ragged There and epilepsy myoclonus with families two from individuals 15 and acidosis. lactic cerebral and impairment battery, test Neuropsychological Evaluation: mutation. A8344G the and (MERRF) MRS. by lactate ventricular and brain of estimation and construction, attention and abstraction/flexibility. and attention construction, Bosbach Bosbach Emmanuele Emmanuele Author Author Kaufmann MEERF and the A8344G mutation. The acute necrotizing encephalomyelopathy is a 2. Summary of studies Table the investigating impact of deficit cognitive in mitochondrial diseases.

[page 8] [Neurology International 2018; 10:7473] Review Results

only use

Protocol Protocol Non-commercial , 2012. Total of 103 patients with ALS divided into five Groups. Evaluation: ALS-FTD-Q and The ALSFTD-Q showed construct validity because it correlated highly with other behavioral behavioral other with highly correlated it because validity construct showed ALSFTD-Q The and ALS-FTD-Q Evaluation: Groups. five into divided ALS with patients 103 of , 2012.Total , 2014. Group: Healthy controls (18 males, 22 females) and ALS patients (33 males, 15 females). Data from healthy controls produced abnormality cut-offs of 77/100 ALS-Specific score; score; ALS-Specific 77/100 of cut-offs abnormality produced controls healthy from Data females). 15 males, (33 patients ALS and females) 22 males, (18 controls Healthy Group: , 2014. , 1996 Group: Familiar molecular study in 28 family members. Evaluation: ALS Functional Rating Scale. The results showed an increase in the number of CAG repeats in 6 affected males males 6 in affected repeats CAG of number the in increase an showed results Scale.The Rating Functional ALS Evaluation: members. family 28 in study molecular Familiar Group: , 1996 , 2010 Group: 112 ALS patients. Evaluation:ALS Cognitive Behavioral Screen. The results demonstrated that mean cognitive scores differed between ALS and normal normal and ALS between differed scores cognitive mean that demonstrated results The Screen. Behavioral Cognitive Evaluation:ALS patients. ALS 112 Group: , 2010 , 2012 Group: 160 ALS patients and 110 controls. Interviews: Collect the demographic and clinical data. 13.8% of patients fulfilled the Neary criteria for frontotemporal dementia. In addition, 34.1% 34.1% addition, In dementia. frontotemporal for criteria Neary the fulfilled data. patients of clinical 13.8% and demographic the Collect Interviews: controls. 110 and patients ALS 160 Group: , 2012 , 2016 Group: 435 samples, 191 belonged to population-based incident patients diagnosed with ALS. 20 (41%) cases of familial ALS and 19 (5%) cases of apparently sporadic ALS had the the had ALS sporadic apparently of cases (5%) 19 and ALS familial of cases (41%) 20 ALS. with diagnosed patients incident population-based to belonged 191 samples, 435 Group: , 2016 , 2013 Case-control study: Population of the Republic of Ireland.Evaluation: Executive impairment was associated with higher rates of disability or death and faster faster and death or disability of rates higher with associated was impairment Executive Ireland.Evaluation: of Republic the of Population study: , 2013Case-control , 2015 Group: Thirty right-handed ALS patients. Evaluation: Magnetic resonance imaging, No difference between patients and control group for demographic variables. variables. demographic for group control and patients between difference No imaging, resonance Magnetic Evaluation: patients. ALS right-handed Thirty Group: , 2015 et al. et et al. et et al. et et al. et , 2013 Group: 37 ALS patients and 43 controls.Evaluation: ALS Functional Rating Scale, The ALS-BCA was highly sensitive (90%) and specific (85%) for ALS-dementia (ALS-D) ALS-dementia for (85%) specific and (90%) sensitive highly was ALS-BCA The Scale, Rating Functional ALS controls.Evaluation: 43 and patients ALS 37 Group: , 2013 et al. et et al. et et al. et et al. et et al. et ALS-FTD with 80% sensitivity and 88% specificity. 88% and sensitivity 80% with ALS-FTD was significantly lower in the ALS cohort compared to controls (p < 0.0001) and predicted and < (p 0.0001) controls to compared cohort ALS the in lower significantly was any cognitive deficit with 71% specificity and 85% sensitivity. A separate behavioral score behavioral A separate sensitivity. 85% and specificity 71% with deficit cognitive any functions and fluency (23%each). fluency and functions findings abnormal and involvement, nerve sensory of signs neurophysiological with 100% accuracy. Cognitively normal ALS patients could be distinguished from those with those from distinguished be could patients ALS normal Cognitively accuracy. 100% with The most prevalent deficit occurred in language functions (35%) followed by executive by followed (35%) functions language in occurred deficit prevalent most The X-BSMA, of manifestation typical the besides showed, patients symptomatic All abnormal ALS-Specific scores, and 6% also showed abnormal ALS Non-specific scores. scores. Non-specific ALS abnormal showed also 6% and scores, ALS-Specific abnormal carriers. obligate 5 were whom of females, 10 in and patients), 2 presymptomatic (including at baseline. Normal cognition at baseline was associated with tendency to remain remain to tendency with associated was baseline at cognition Normal baseline. at progression. cognitive and motor slower with and intact, cognitively adjusting after behaviors apathetic or disinhibited with patients ALS-D among (P<0.05). demographic for motor and anxiety/depression with poorly and r=0.32), (r=0.37; functioning cognitive ALS with patients between discriminated ALS-FTD-Q The both). for (r=0.18 impairment subjects. control and ALS, with patients bvFTD, expansion. repeat the with those of (86%) 18 in present was FTD or ALS of history family cortex non-motor of pattern a distinct demonstrated expansion repeat the with Patients structural. resonance 3 T magnetic high-resolution on changes tests. neuropsychological in patients showed a mild stage of disease disability: mean score of ALSFRS-R was >22, while >22, was ALSFRS-R of score mean disability: disease of stage a mild showed patients 13 of bv FTD patients show a mild grade of disability and 2 a moderate grade of disability of grade 2 a moderate and disability of grade a mild show patients FTD bv of 13 almost half the cohort (46.9%). Blood gases were documented and None of the patients the of None and documented were gases Blood (46.9%). cohort the half almost according to Frontotemporal Dementia Rating Scale Stage. Scale Rating Dementia Frontotemporal to according had evidence of hypoxaemia (oxygen saturation <92 mm Hg). mm <92 saturation (oxygen hypoxaemia of evidence had Screen results were validated by determining the accuracy against the full battery. controls (P<0.0001). The cognitive section differentiated ALS-FTD from other ALS patients ALS other from ALS-FTD differentiated section cognitive The (P<0.0001). controls battery. full the against accuracy the determining by validated were results Screen Evaluation: Edinburgh Cognitive and Behavioural ALS Screen (ECAS), developed for ALS patients. 24/36 ALS Non-specific score; 105/136 ECAS Total. Twenty-nine percent of patients showed patients of percent Twenty-nine Total. ECAS 105/136 score; Non-specific ALS patients.24/36 ALS for developed (ECAS), Screen ALS Behavioural and Cognitive Edinburgh Evaluation: ALS Functional Rating Scale (ALSFRS-R), Boston Naming Test, Rey-Osterrieth Complex Figure, rates of motor functional decline, particularly decline in bulbar function. function. bulbar in decline particularly decline, functional motor of rates Figure, Complex Rey-Osterrieth Test, Naming Boston (ALSFRS-R), Scale Rating impaired Functional ALS cognitively were who patients in faster was function cognitive in Decline tensions. gas blood tissue for sensor transcutaneous a mobile and survival poor the to due primarily survival, overall shorter had patients ALS-D (P<0.05). Test Making Trail subtest,Oral Span Digit Reverse global and functions frontal of measures with moderately r=0.79), and (r=0.80 measures (FrSBe). Scale Behavior Systems Frontal The the had (11%) 21 data: phenotype whom for patients 191 the Of expansion. repeat C9orf72 survival and MRI, structural data, behavioural and neurocognitive, clinical, longitudinal Detailed A expansion. repeat the with patients in lower was onset disease at Age expansion. repeat analysis. genomic for banked been has DNA and cohort, this on gathered been have data Screening: ALS Functional Rating Scale, ReyeOsterrieth Complex Figure Test, of ALS patients without evidence of dementia fulfilled the recently published consensus published recently the fulfilled dementia of evidence without patients ALS of Test, Figure Complex ReyeOsterrieth Scale, Rating Functional ALS Screening: ALS functional rating scalerevised (ALSFRS-R) score. Disease duration did not differ between the ALS and bvFTD groups. Both cohorts of cohorts Both groups. bvFTD and ALS the between differ not did duration Disease score. (ALSFRS-R) scalerevised rating functional ALS Premorbid Full-Scale IQ, Wechsler Test of Adult Reading, and Pyramid and Palm Trees Test. criteria for cognitive impairment (P<0.05). 14% of ALS patients had evidence of cognitive of evidence had patients ALS of 14% (P<0.05). impairment cognitive for criteria Test. Trees Palm and Pyramid and Reading, Adult of Test Wechsler IQ, Full-Scale Premorbid Mobile transcutaneous sensor for arterialized capillary blood gas tensions. impairment without executive dysfunctioxn, and no cognitive abnormality was detected in detected was abnormality cognitive no and dysfunctioxn, executive without impairment tensions. gas blood capillary arterialized for sensor transcutaneous Mobile Woolley Woolley Abrahams Guidetti Author Author Elamin Hu Raaphorst Burrell Phukan Phukan Trojsi Trojsi Table 3. Summary of studies Table the investigating impact of deficit cognitive in Diseases. Motor Neuron

[Neurology International 2018; 10:7473] [page 9] Review disease that results in the regression of both potential limitation is the possible con- Neurosurg 2006;108:465-9. mental and motor skills, leading to disabili- founding variables in case reports and the 3. Nieuwenhuys A, Oudejans RRD. ty and rapid progression to death.61 The low sample size. Anxiety and perceptual-motor perfor- patients also present refractory seizures, The majority of the findings are based mance: toward an integrated model of optic atrophy, ophthalmoparesis. Mental cross-sectional methods; further longitudi- concepts, mechanisms, and processes. development is typically delayed at early nal studies are needed in order to model Psychol Res 2012;76:747–59. age. Imaging studies show focal, bilaterally within-person change and avoid cohort 4. Krane-Gartiser K, Steinan MK, symmetric lesions of the basal ganglia, the effects, have been conducted. There are also Langsrud K, et al. Mood and motor thalamus and/or the brainstem. Moreover, other sources of variability within the liter- activity in euthymic bipolar disorder there is raised lactate levels in blood and/or ature that may have limited the conclusions with sleep disturbance. J Affect Disord cerebrospinal fluid.50,61 drawn from this review, such as the lack of 2016;202:23-31. Mitochondrial neurogastroinstestinal standardization in the cognitive and neuro- 5. Argento AG, Kaufman J. Cognition in encephalomyopathy (MNGIE) is a rare muscular evaluation. This plethora of neuromuscular disease. J Pediatr autosomal recessive disorder in which the effects poses a serious challenge to Rehabil Med 2008;1:199-210. patients suffer from gastrointestinal dys- researchers seeking neuromuscular diseases 6. Astrea G, Battini R, Lenzi S, et al. motility, cachexia, , external ophthal- unifying principles. Limitations were also Learning disabilities in neuromuscular moparesis, myopathy, and polyneuropathy. secondary to population size and pheno- disorders: a springboard for adult life. MRI shows leukoencephalopathy.62 Carod- types in relation to sample size in genetic Acta Myol myopathies cardiomy- Artal et al.63 reported a case of a Brazilian research. In addition, the studies differ in opathies Off J Mediterr Soc Myol man with MNGIE who had poor weight terms of neuroimaging analysis. 2016;35:90-5. gain, muscular atrophy, and chronic diar- 7.Vaillend C, Chaussenot R. rhoea since childhood. He presents episodic Relationships linking emotional, motor, gastric pain, recurrent nausea and vomiting, cognitive and GABAergic dysfunctions muscle aching and cramps, and had signs of Conclusions in dystrophin-deficient mdx mice. Hum memory impairment. On neuropsychologi- Mol Genet 2017;26:1041-55. The literature about cognition in neuro only cal examination, patient scored 28/30 on 8. Ueda Y, Suwazono S, Maedo S, muscular diseases is still scarce, but studies MMSE. Working memory scores were Higuchi I. Profile of cognitive function converge on the influence of these disorders 14/25 and 7/25 on immediate recall, and in adults with duchenne muscular dys- on mental processes (see Tables 1-3 for a 6/25 and 1/25 on long-term recall. The trophy. Brain Dev 2016;1-6. summary on previous studies). Congenital patient could repeat seven digits in direct use9. Mitchell JD, Borasio GD. Amyotrophic disorders are common to neuromuscular order and only four digits in reverse lateral sclerosis. Lancet. 2007;36:2031- function and brain function impaired. sequence. Verbal learning was involved 41. Considering that severe neuromuscular con- (7/15 words).63 10. van Es MA, Hardiman O, Chio A, et al. ditions such as DMD and ALS have shown The treatment of mitochondrial demen- Amyotrophic lateral sclerosis. Lancet a marked improvement in prognosis in the tia includes general measures and specific 2017;6736:1-15. last decades, the search for the improve- therapy, which encompass: physiotherapy 11. Wiessner M, Roos A, Munn CJ, et al. ment of patients’ quality of life has become and physical exercise below the maximal Mutations in INPP5K, Encoding a increasingly important, which can be com- individual limit; dietary measures; avoid- Phosphoinositide 5-Phosphatase, Cause promised by the primary and secondary ance of mental and physical stress, alcohol, Congenital Muscular Dystrophy with cognitive effects the evolution of the dis- nicotine and infections; supplementation of Cataracts and Mild Cognitive ease. More work should be done to better respiratory chain components such as coen- Impairment. Am J Hum Genet 2017; evaluate cognitive deficits in patients with zyme Q., Various studies have reported a 100:523-36. neuromuscular disorders, in order to positive effect of coenzyme Q in mitochon- 12 Phukan J, Elamin M, Bede P, et al. The improve the patient’s relationship with the drial dementia; administration of artificial syndrome of cognitive impairment in medical staff, the family, and society and electron acceptors, such as vitamin C or K; amyotrophic lateral sclerosis: a popula- improve the patient’s quality of life. In addi- administration of metabolites or cofactors tion-based study. J Neurol Neurosurg Non-commercialtion, knowing the evolution of the cognitive like . Overall, cognitive decline in Psychiatry 2012;83:102-8. symptoms of each disease is important for mitochondrial dementia needs to be includ- 13. D’Angelo MG, Bresolin N. Cognitive proper management of the patient, evalua- ed in the differentials of dementia.52 impairment in neuromuscular disorders. tion of survival, establishment of prognosis Muscle Nerve 2006;34:16-33. and choice of appropriate therapeutic inter- Limitations of existing research 14. Moher D, Liberati A, PRISMA Group. vention. There are limitations to our study. In Preferred Reporting Items for terms of research strategy and data collec- Systematic Reviews and Meta- tion, we opted to evaluate only studies that Analyses: The PRISMA Statement. Ann we found through the ISI Web of Science References Intern Med 2009;151:264-9. and PubMed database, which may have lim- 15. Elamin M, Bede P, Byrne S, et al. ited the number of included studies. 1. Katz JA, Murphy GS. Anesthetic Cognitive changes predict functional Furthermore, we only looked at studies consideration for neuromuscular dis- decline in ALS: A population-based lon- written in English. Concerns about the reli- eases. Curr Opin Anaesthesiol gitudinal study. Neurology ability and validity of the applicability con- 2017;30:1. 2013;80:1590-7. ditions of the questionnaires, as well as their 2. Papapetropoulos S, Ellul J, Argyriou 16. Woolley SC, Strong MJ. potential subjectivity of neurofunctional AA, et al. The effect of depression on Frontotemporal Dysfunction and and cognitive evaluation, to biased esti- motor function and disease severity of Dementia in Amyotrophic Lateral mates of intervention effectiveness. Another Parkinson’s disease. Clin Neurol Sclerosis. Neurol Clin 2015;33:787-

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