THE SPG4 locus is frequently

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1 ORIGINAL CONTRIBUTION Subtle Cognitive Impairment but No Dementia in Patients With Spastin Mutations Chantal M. E. Tallaksen, MD, PhD; Elodie Guichart-Gomez; Patrice Verpillat, MD, PhD; Valérie Hahn-Barma; Merle Ruberg, PhD; Bertrand Fontaine, MD, PhD; Alexis Brice, MD; Bruno Dubois, MD, PhD; Alexandra Dürr, MD, PhD Background: The most frequent form of autosomal dominant hereditary spastic paraparesis is associated with the SPG4 locus, described originally as a pure form of the disease. Mutations of the SPG4 gene have been increasingly associated with reports of cognitive impairment. Objective: To investigate cognitive function in 10 families with hereditary spastic paraparesis due to mutations in the SPG4 gene, using intrafamilial control subjects. Patients and Methods: Neuropsychological examinations, including the Cambridge Cognitive Evaluation, were conducted in 9 carriers with identified SPG4 mutations and 9 intrafamilial controls. Results: were not demented but had a subclinical cognitive impairment primarily affecting executive functions. The dysfunction was more severe in those carriers older than 50 years, but was correlated with the progression of the disease, not with age. Disease progression and cognitive impairment appeared to be more severe in the carriers of missense mutations than in those with truncating mutations. Conclusion: Asymptomatic cognitive impairment mostly affecting executive functions is present in SPG4 mutation carriers and is more frequent in those with missense mutations. Arch Neurol. 003;60: From the Institut National de la Santé et de la Recherche Médicale Unit 89 (Drs Tallaksen, Ruberg, Verpillat, Brice and Dürr), Fédération de Neurologie (Drs Tallaksen, Fontaine, and Dubois and Mss Guichart-Gomez and Hahn-Barma), Département de Génétique, Cytogénétique et Embryologie (Drs Brice and Dürr), Hôpital de la Salpêtrière; and Département d Epidémiologie, de Biostatistique et de Recherche Clinique, Hôpital Bichat-Claude Bernard (Dr Verpillat), Paris, France. Dr Verpillat is now with the Département de Santé Publique, Hôpital Louis-Mourier, Assistance Publique Hôpitaux de Paris, Colombes, France. THE SPG4 locus is frequently involved in pure autosomal dominant hereditary spastic paraparesis (HSP), at least in Europe, 1, and more than 60 different mutations in the SPG4 gene have been described to date The SPG4 phenotype is variable within and among families in terms of severity and age at onset. 4 The core symptoms consist of isolated spasticity of the lower limbs, but decreased vibration sense and sphincter disturbances are frequently observed. 14 The SPG4 gene encodes the protein spastin, 3 a member of the AAA family of adenosine diphosphatase, and may be involved in microtubule dynamics. 15 Whereas truncating mutations have been found throughout the coding region of the gene, missense mutations are clustered in the AAA cassette, a highly conserved domain of the gene predicted to encode the peptide sequence responsible for the adenosine diphosphatase activity of the protein In addition to the molecular analyses, several studies have tried to deduce the function of SPG4 from the clinical characteristics of the patients. The few reported autopsies of patients with HSP, 19-1 and the even fewer neuropathological studies 8,1 of patients with identified spastin mutations, suggest that spastin mutations may cause damage to brain structures involved in cognition, in addition to the well-known corticospinal tract lesion that is responsible for spastic paraparesis. In addition, several recent neuropsychological studies -5 reported various degrees of cognitive impairment in a few Irish, Welsh, and French families with pure spastic paraparesis, some of which are linked to p1-p, 3-5 and dementia has been reported in an English family. However, these cognitive deficits appeared late in the course of the disease and were not present in all the families or in all affected members of a given family. Their relationship to SPG4 mutations in the patients remains, therefore, a matter of speculation. More recently, advances in our understanding of the molecular basis of spastin function have suggested that missense mutations may have a dominant negative effect. 3 This might account, at least in part, for the intrafamilial and interfamilial variability of the disease. The present study was therefore designed to in Downloaded From: on 1/04/ American Medical Association. All rights reserved.

2 Table 1. Clinical Characteristics of Patients From 10 Families With SPG4 Mutations Family No. Mean Disease Severity* (Individual Severities) Age at Onset, y Spasticity Motor Deficit Decreased Vibration Sense at Ankles Sphincter Disturbances (3,,, 1, 1, 0) 30, 45, 5, 3, 74, 57 Gait Mild Mild Mild (, 3, 0) 30, 5, 41 Gait rest No Mild Mild (4, 3, 0, 0) 33, 47, 51, 55 Gait = rest Mild to moderate Moderate Moderate to severe () 10 Gait No Normal No (3, 3, 3), 8, 17 Gait rest Mild Mild Mild (3) 40 Gait No No Mild (1, 4, 5, 3) 36, 36, 13, 36 Gait rest Severe Moderate to severe Mild (5, ) 1, 48 Gait rest Mild Moderate Mild (5, 4) 5, 5 Gait rest Mild Severe Mild (5, 5, 4) 1, 0, 35 Gait = rest Moderate Severe Moderate to severe *Mean disease severity is the sum of the individual severities divided by the number of individuals. Stage 0, asymptomatic; 1, no functional handicap but signs at examination (slight gait stiffness);, mild gait stiffness, walking unlimited, and limited running still possible; 3, moderate gait stiffness, limited walking without aid, and running impossible; 4, moderate to severe gait stiffness, walking possible with aid; and 5, walking impossible, wheelchair bound. Italics indicate ages for asymptomatic carriers. Exhibited pes cavus. Table. Types of SPG4 Mutations in the 10 Families Family Location of the Mutation Mutation Amino Acid Change Consequence Missense 67 Exon C T A556V Missense 618 Exon C T R499C Missense 19 Exon C G L46V Missense Truncation 616 Exon C T R431STOP Nonsense 645 Exon del 4 PTC + 7aa Frameshift 18 Exon del 5 PTC + 35aa Frameshift 166 Intron g a Unknown Splicing mutation 160 Intron g a PTC + 6aa Exon 11 skipping + frameshift 65 Exon del 5 PTC + 35aa Frameshift 16 Intron t g Unknown Splicing mutation vestigate the cognitive status of carriers with different types of SPG4 mutations, using proven noncarriers as intrafamilial control subjects. The aims of the study were to confirm the presence of and to quantify cognitive impairment in SPG4 mutation carriers, using the Cambridge Cognitive Evaluation (CAMCOG) battery and other neuropsychological tests, and to determine whether it is correlated with age, disease severity, or type of mutation. METHODS PATIENTS AND CONTROLS Ten of 9 French families with identified SPG4 mutations 4 agreed to participate in the study. Twenty-nine mutation carriers were included, 5 of whom had definite symptoms of spastic paraparesis. The other 4 were asymptomatic at the time of the study. The severity of the disease in the patients was scored from 0 to 5, according to the previous classification used by Dürretal. 14 Details are given in Table 1. To minimize the bias introduced by cultural and environmental differences between carriers and controls, 9 siblings who were proven noncarriers of the mutation in their family were included as paired controls. The siblings were matched for educational level and age. The study was approved by the ethics committee of the Pitié-Salpêtrière University Hospital. All 58 participants, 39 women and 19 men, gave their written and fully informed consent. MUTATIONS Nine different mutations, previously reported by Fonknechten and collaborators, 4 were found in 10 families (Table ). The mutations were divided into groups according to their predicted effect: missense (3 families) and truncation (7 families). COGNITIVE ASSESSMENT All 58 individuals were assessed with the CAMCOG, the cognitive portion of the Cambridge Mental Disorders of the Elderly Examination, 6 which had previously proved to be sensitive to cognitive dysfunction in HSP. 7,8 The CAMCOG is an extension of the Mini-Mental State Examination, 9 incorporating 14 of its 19 items, with an additional 43 items evaluating functional calculation, perception, abstract thinking, attentionconcentration, praxis, memory, language, and orientation. We used the latest version of the CAMCOG battery, in which the total score is 105 instead of 107, due to the absence of a tactile recognition subscore. 8 STATISTICAL ANALYSIS Statistical analysis was performed using StatView software (SAS Institute Inc, Cary, NC). Results are expressed as mean (±SD) Downloaded From: on 1/04/ American Medical Association. All rights reserved.

3 The Wilcoxon signed rank test was used for paired data (comparing carriers vs noncarriers) and the Mann-Whitney test for unpaired data. The nonparametric Spearman correlation coefficient was calculated to detect correlations between quantitative variables. Multiple linear regression was performed to detect potential factors that would bias the CAMCOG scores. For the primary objectives, differences in total CAMCOG scores were considered to be statistically significant at P.05. For the subscores of the CAMCOG, values of P.01 were required to take into account multiple testing. For all other comparisons and correlations, the level of significance was set at P=.05. RESULTS The mean age at examination of the 0 women and 9 men with SPG4 mutations and their noncarrier siblings (19 women and 10 men) was similar (51.5 [.7] and 53. [14.4] years, respectively). Ten subjects (5 carriers and 5 noncarriers) were younger than 40 years, 13 (7 carriers and 6 noncarriers) were between 40 and 50 years, 15 (9 carriers and 6 noncarriers) were between 50 and 60 years, and 0 (8 carriers and 1 noncarriers) were older than 60. The educational level was low overall (mean, 7.4 [3.] years [range, 5-17 years]) but similar in carriers and noncarriers (7.0 [.5] and 7.8 [3.8] years, respectively). The mean disease duration was 19.9 (16.6) years. CLINICAL SIGNS The clinical characteristics of the families are summarized in Table 1. Symptoms included progressive spasticity in the lower limbs that was usually predominant while walking (n=5), hyperreflexia in the lower (n=5) and upper (n=0) limbs, extensor plantar reflexes (n=5), impaired vibration sense in the lower limbs (n=16), and sphincter disturbances (n=16). There were no other remarkable neurological signs in these patients. No evident cognitive impairment or dementia was reported by the examiners in any of the participants. CAMCOG SCORES The total CAMCOG scores were normal in of 9 carriers and in 4 of 9 noncarriers. Variations between families were notable, and intrafamilial differences were such that some noncarriers had abnormal scores (Figure). Forty-six subjects (78%) had normal CAMCOG scores (score, 81.), and 9 (16%) had questionable dementia scores ( 68. to 81.). Only 3 subjects (7%) had mild dementia scores ( 63.8 to 68.). The latter were members of families, family 19 with a missense mutation and family 160 with a truncating mutation (Table 1). All had symptomatic HSP and were wheelchair bound. Of the 9 subjects with minimal dementia, 5 were noncarriers (3 of them from family 16) and 4 were carriers from different families (families 645, 65, 618, and 19). The total CAMCOG scores were significantly correlated with the severity of the disease (r =0.4, P.01), but not with age or disease duration. CARRIERS COMPARED WITH NONCARRIERS The total CAMCOG scores tended to be lower in carriers compared with their matched controls, although the CAMCOG Score Disease Severity Family Number difference did not reach statistical significance (P=.051). Only the CAMCOG subset scores, attention-concentration and calculation, were significantly lower (P=.003) in the carriers (Table 3). There was a trend, however, toward impairment in some instrumental functions (Rey figure copy, language expression, and word definitions), the implications of which remain to be determined. The cognitive deficits remained within the limits of mild dementia, however, and were limited to abstract word definitions and calculation. When stratified according to age ( 50 vs 50 years), there were no significant differences in the total CAMCOG scores or any of the subset scores of carriers compared with noncarriers or among noncarriers. Significantly lower scores were obtained, however, by patients older than 70 with those younger than 70 on tests of executive functions (1.9±5.1 vs 18.3±3.6, P.01), as is usual for subjects of this age. CARRIERS OF MISSENSE VS TRUNCATING MUTATIONS Individual Cambridge Cognitive Evaluation (CAMCOG) scores assessing dementia in 10 families with hereditary spastic paraplegia associated with SPG4 mutations. Each family is indicated by its number on the x-axis. Scores higher than 81. are normal; scores of 68.3 or lower indicate mild dementia. Scores in between indicate questionable or minimal dementia. The bold numbers indicate families with missense mutations; the numbers alongside the symbols, the number of subjects. There were 9 subjects with missense mutations (3 families) and 0 patients with truncating mutations (7 families). Patients with missense and truncating mutations were similar with respect to age at onset, age at examination, duration of symptoms, disability stage, and educational level (Table 4). The total CAMCOG scores and subset scores did not differ significantly between patients with missense and truncating mutations, but reached significance when carriers of missense mutations were compared with their matched controls (P=.05). There was also a tendency toward an attention deficit in carriers compared with noncarriers of missense mutations (P=.04), but not in carriers of truncating mutations compared with their controls. After stratification according to the type of mutation, age at onset and total CAMCOG score were Downloaded From: on 1/04/ American Medical Association. All rights reserved.

4 Table 3. Cambridge Cognitive Evaluation (CAMCOG) and Subset Scores in the and * Score (n = 9) (n = 9) P Value Total CAMCOG 84.6 (10.4) 90.0 (8.4).051 Orientation 9.6 (0.7) 9.4 (0.8).45 Language 4.7 (3.) 6.0 (.7).07 Language comprehension 8 (0.8) 8.5 (0.7).73 Language expression 16.1 (.9) 17.6 (.4).04 Word definitions 4. (1.) 4.9 (1.0).0 Memory 19.4 (4.0) 0.8 (3.).11 Ancient memory.9 (1.6) 3.3 (1.5).8 Recent memory 3.0 (1.) 3.4 (1.0). Grober et al 30 Cued recall, maximum (.4) 14.7 (.1).93 Free recall, maximum 48. (7.6) 6.9 (6.1).055 Total recall, cued free 4.7 (6.5) 45.1 (3.8).38 Delayed total recall 15.1 (1.4) 15.3 (1.8).67 Attention-concentration 7.6 (1.9) 8.6 (0.6).003 Calculation 5.8 (1.53) 6.6 (0.6).003 Praxis 11.0 (1.1) 10.9 (1.).99 Perception 7.9 (1.1) 8.4 (0.8).08 Rey figure copy 3.9 (3.7) 34.5 (1.0).047 Rey figure memory 11.9 (8.0) 17.9 (6.1).11 Executive functions 15.5 (5.4) 18.0 (4.5).11 Abstract thinking 4.3 (.30) 5.5 (.4).07 Frontal 48. (8.8) 50.9 (8.3).38 Mini-Mental State Examination 6.6 (.6) 7.5 (1.9).10 *Values are given as mean (SD). P values were considered significant at P.05 for the total CAMCOG score and at P.01 for subscores to take into account multiple testing. Performed in 19 patients and 15 controls. Table 4. Comparison Between of Missense and Truncating Mutations and Their Matched Controls* Missense Mutations Truncating Mutations Variable (n=9) (n=9) P Value (n = 0) (n = 0) P Value Age at onset 0.4 (9.7) 31.5 (17.4) Age at examination 46.0 (5.9) 43.7 (9.7) NS 57.6 (14.3) 54.0 (14.) NS Severity 3.1 (1.5).5 (1.7) CAMCOG score 81.4 (1.1) 93.1 (6.1) (9.6) 88.5 (9.1) NS Total subset score Orientation 9.8 (0.4) 9.8 (0.4) NS 9.5 (0.8) 9.3 (0.9) NS Language 4. (.6) 6.7 (1.9) (3.5) 5.8 (3.0) NS Language comprehension 8.7 (0.5) 8.9 (0.3) NS 8.5 (0.9) 8.4 (0.8) NS Language expression 15.6 (.6) 17.8 (1.8) (3.1) 17.5 (.7) NS Memory 18.1 (3.4) 1.4 (.1) NS 0.0 (4.1) 0.4 (3.6) NS Recent memory.6 (1.) 3.7 (1.0) NS 3. (1.1) 3. (1.0) NS Learning memory 13.4 (1.5) 15.1 (0.9) (1.7) 13.4 (.) NS Attention-concentration 6.8 (.8) 8.9 (0.3) (1.3) 8.5 (0.7) NS Praxis 10.9 (1.1) 11. (1.1) NS 11.0 (1.1) 10.8 (1.3) NS Perception 7.9 (1.4) 8.6 (0.7) NS 7.9 (0.9) 8.4 (0.8) NS Executive functions 13.7 (6.) 0.7 (3.6) NS 16.3 (4.9) 16.7 (4.4) NS Abstract thinking 3.8 (3.1) 6.6 (1.9) NS 4.5 (1.9) 5.0 (.4) NS Abbreviations: CAMCOG, Cambridge Cognitive Evaluation; NS, not significant. *Values are given as mean (SD). significantly correlated in patients with missense but not in those with truncating mutations (r =0.50, P.05 vs r =0.07, P=.5). After adjustment for age at onset and disease duration, disability was the only factor that remained significantly correlated with total CAMCOG score (P.05), with a lower score being associated with more severe manifestations of disease. COMMENT This study of patients with missense and truncating mutations in the spastin gene compared with their noncarrier sibs, using the CAMCOG battery of neuropsychological tests, did not provide evidence of definite cognitive impairment in patients with HSP associated with SPG Downloaded From: on 1/04/ American Medical Association. All rights reserved.

5 mutations. Items defining a functional pattern characteristic of a dysexecutive syndrome abstract word definitions, similarities in the abstract thinking subset, ideational fluencies in the executive functions subset, and serial sevens in the attention-concentration subset were impaired in carriers compared with noncarriers, but the differences did not reach the significance level of P=.01 required for multiple testing among subscores of the CAMCOG battery. 31 Overall, the deficits shown in subgroups of carriers were correlated with the degree of disability but not with age, as in previous studies, 3-5 and thus do not confirm earlier reports of an age-dependent association between HSP and cognitive impairment. 3,3-35 Mild cognitive impairment has been reported in the index cases in several studies of HSP, 0,,3,34,36,37 but the nature of the deficits was not described. Byrne et al 5 described 10 (4%) of 41 haplotype carriers with mild cognitive impairment (CAMCOG scores, 60-80), which was comparable to the findings in our study (8/9 [8%]), with similar deficits in memory and language comprehension and expression. In the extensive neuropsychological study of families with HSP by Webb and Hutchinson, all affected members presented similar patterns of impairment, characterized by slowness of information processing, forgetfulness, and difficulty in shifting mental set, but maintained verbal fluency, which is typical of a dysexecutive syndrome or subcortical dementia, as these authors called it. As in our study, they observed a minimal effect of this syndrome on the patients autonomy in daily life, referring to it as asymptomatic dementia. It should be noted that the subtle cognitive deficits in the patients with identified mutations in the spastin gene studied herein remained subclinical. Three of the 9 individuals with minimal dementia came from the same family with a truncating mutation (family 16), but were noncarriers. Their matched carriers had CAMCOG scores in the normal range. This confirms the lack of association of their dementia with HSP caused by SPG4 mutations. One control with minimal dementia in our study was a 45-year-old man who had experienced a short episode of coma ( days) following an accident 3 years earlier and, more recently, depression that was successfully treated. He was included in the study, although his impaired memory was probably a consequence of the coma. Another control with minimal dementia was a 63-year-old retired accountant, with no particular history or clinical symptoms that could explain his cognitive status. In a previous study, 5 5patients considered to have minimal dementia came from the same family, suggesting that they might have inherited cognitive deficits that were independent of their spastic paraparesis. This could not be assessed in our study, however, because the controls were not from the same family. The dysexecutive syndrome in our patients also differs from the recently described dementia associated with spastic paraplegia transmitted as an autosomal dominant trait in several families that is a variant of Alzheimer disease caused by mutations in the presenilin gene Our results suggest that, in addition to damage to the corticospinal tracts responsible for spastic paraparesis, mutations in the SPG4 gene could cause at least in a subset of patients lesions in cortical or subcortical structures that would result in a dysexecutive syndrome. Magnetic resonance imaging studies that have been performed in patients with HSP have shown abnormalities in white matter in the corpus callosum 41 and cerebral hemispheres, 18 as well as cortical atrophy, 18 but further investigations using functional magnetic resonance imaging and positron emission tomographic techniques should be done. The observation of more severe manifestations of disease in our patients with SPG4 missense mutations, in terms of their motor disability and cognitive impairment, suggests that this type of mutation may be more deleterious than others. The lack of significant differences between the scores of carriers of missense and truncating mutations may be due to the small size of the samples, as the scores were lower in patients with missense mutations and memory impairment was found only in such patients. The 3 members of family 19, with an L46V mutation, had more severe manifestations of disease. However, the lower scores of the controls of subjects with truncating mutations compared with the controls of those with missense mutations (significantly so on critical subtests) may account for the overall findings in the groups. Indeed, Fonknechten et al 4 found no genotype-phenotype correlations in their clinical study, which included another 8 missense mutations and 16 truncating mutations, in addition to the families in the present study. This may be explained by the subclinical nature of the cognitive deficits detected herein. These observations must be confirmed in larger series of mutation carriers and noncarrier sibling controls. Cognitive impairment was not mentioned in most of the molecular studies that have been performed. Lindsey et al, however, described late progressive dementia starting at age 8 in an affected patient with a mutation in exon 17, and dementia in a member of another pedigree with a 1395A G, R44G mutation in exon The neuropathological findings in the latter patient 1 showed neuronal loss, and tau-immunoreactive neurofibrillary tangles in the hippocampus that differed from previously described tau-related cortical changes. However, the patient had severe dementia, unlike the subclinical impairment described in our patients. Lindsey and colleagues 8 also described carriers of splicing mutations in different pedigrees with late-onset dementia. All of these cases of dementia, however, may be coincidental. Nevertheless, all missense mutations described so far -13 are located within the functional domain of the spastin protein, except for 1 mutation present homozygously in exon 1. 8 This mutation may be more deleterious than others, perhaps because of a dominant negative effect on spastin function, as already mentioned. 3 In conclusion, our study showed that there is no dementia associated with SPG4 gene mutations but, at most, a subtle cognitive impairment characterized as subcortical that correlates with the severity of the motor dysfunction. Accepted for publication January 14, 003. This study was performed with the collaboration of the other members of the European Network for Spastic Paraparesis and Cerebellar Ataxias (SPATAX), funded by Institut National de la Santé et de la Recherche Médicale (Project 4MR1F/AOO044DS) Downloaded From: on 1/04/ American Medical Association. All rights reserved.

6 This study was funded by the French Spastic Paraplegia Association, Besançon, the Association Française contre les Myopathies, Evry, and Institut National de la Santé et de la Recherche Médicale (Project 4MR1F). We thank Sylvia Cogilnicean, Myriem Abada, MD, PhD, M. Gateau, M. Durant, P. E. Le Biez, and Imed Feki, MD, who referred the patients, and Jamilé Hazan, PhD, for her collaboration. Author contributions: Study concept and design (Drs Tallaksen, Brice, Dubois, and Dürr and Ms Hahn- Barma); acquisition of data (Drs Tallaksen and Dürr and Ms Guichart-Gomez); analysis and interpretation of data (Drs Tallaksen, Verpillat, Ruberg, Fontaine, Brice, and Dürr and Ms Guichart-Gomez); drafting of the manuscript (Drs Tallaksen and Dürr and Ms Hahn-Barma); critical revision of the manuscript for important intellectual content (Drs Tallaksen, Ruberg, Brice, Dubois, and Dürr and Ms Hahn-Barma); statistical expertise (Dr Verpillat); obtained funding (Drs Tallaksen and Dürr); study supervision (Drs Ruberg, Brice, Dubois, and Dürr). Corresponding author: Alexandra Dürr, MD, PhD, Institut National de la Santé et de la Recherche Médicale Unit 89, Hôpital de la Salpêtrière, 47 boulevard de l Hôpital, Paris, France ( durr@ccr.jussieu.fr). REFERENCES 1. Tallaksen CM, Dürr A, Brice A. Recent advances in hereditary spastic paraplegia. 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