P51 CLINICAL FEATURES OF ALS IN JAPAN FROM THE REGISTRATION SYSTEM OF INTRACTABLE DISEASES
Atsuta N1, Watanabe H1, Ito M1, Aoki M2, Nakano I3, Yuasa T4, Takano H5, Tsuji S6, Kuzuhara S7, Sobue G1
1Nagoya University Graduate School of Medicine, Nagoya, Japan, 2Tohoku University Graduate School of Medicine, Sendai, Japan, 3Jichi Medical University, Shimono, Japan, 4Kohnodai Hospital, National Center of Neurology and Psychiatry, Ichikawa, Japan, 5Brain Research Institute, Niigata University, Niigata, Japan, 6Graduate School of Medicine, University of Tokyo, Tokyo, Japan, 7Mie University Graduate School of Medicine, Tsu, Japan
E‐mail address for correspondence: [email protected]
Background: Nationwide registration of the 45 intractable diseases is conducted by the Ministry of Health, Labour and Welfare in Japan. ALS is one of these diseases. The registration system was started in 1972, and its principal mission has been public expenditure for the medical expenses of patients with the intractable diseases. In 2003, the format of the medical certificate for registration of each disease was revised substantially, and, in 2004, the guideline for research use of the data from the registration system was established.
Objectives: To describe the clinical features of the ALS patients in Japan using the data from the nationwide registration system of intractable diseases.
Methods: We analysed the data from the initial and renewal registration of 7463 ALS patients from 2003 to 2005. All of the patients provided written informed consent for the research use of the registration data, and the anonymity of the data was strictly secured. We implemented the ethics guideline for epidemiology studies endorsed by the Japanese government.
Results: The proportion of male and female patients was 60.4% and 39.6%, respectively. The mean age at onset in the patients of initial registration was 65.1 ± 11.0 years. The initial symptoms were weakness of upper extremities in 47.1%, dysarthria in 39.5%, weakness of lower extremities in 35.2%, dysphagia in 22.9% and dyspnea in 5.9%. Overlap among the groups existed. Of all the patients, 8.5% were at work or in school attendance, 62.7% were under home care and 28.8% were hospitalized. A gastrostomy tube was used by 33.1% of the patients, 8.6% used nasogastric feeding, 5.7% used non‐invasive positive pressure ventilation (NIPPV) and 34.3% continued tracheostomy positive pressure ventilation (TPPV). The mean duration from introduction of TPPV was 3.78±3.61 years. Ophthalmoplegia, vesicorectal disturbance and dyshidrosis were seen in 2.5%, 7.9% and 3.3% of the patients without TPPV, respectively. However, ophthalmoplegia, vesicorectal disturbance, and dyshidrosis were observed in 21.4%, 21.2%, and 8.4% of the patients, respectively, with duration from introduction of TPPV of greater than three years.
Discussion and conclusions: A large portion of the ALS patients in Japan are in advanced stages. The ratio of the patients on TPPV is much higher than those of the USA and EU. The data from the Japanese registration system of intractable diseases may provide beneficial information on the nature of ALS patients in Japan and may describe the clinical state of patients on TPPV in a large number of cases.
P52 PROGNOSIS OF AMYOTROPHIC LATERAL SCLEROSIS IN SOUTHERN ITALY: RESULTS FROM A POPULATION‐BASED REGISTRY, SLAP (SCLEROSI LATERALE AMIOTROFICA‐PUGLIA).
Zoccolella S1, Beghi E2, Guerra V3, Palagano G4, FraddosioA A4, Lepore V4, Simone I4, Lamberti P4, Serlenga L1, Logroscino G5
1Operative Unit of Neurology, L. Bonomo Hospital, Andria, Bari, Italy, 2Istituto Ricerche Farmacologiche Mario Negri, Milano, Italy, 3Laboratory of Epidemiology, IRCCS S. De Bellis, Castellana, Bari, Italy, 4Department of Neurological Sciences, University of Bari, Italy, 5Department of Epidemiology HSPH, Harvard University, Boston, MA, USA
E‐mail address for correspondence: [email protected]
Objective: To evaluate survivorship and the prognostic value of clinical factors in a population‐based cohort of amyotrophic lateral sclerosis (ALS) incident cases.
Background: Most of the data on ALS natural history have been obtained by retrospective studies based on clinical series enrolled by ALS referral centres. Recently, population‐based studies have provided prospective prognostic data but it is still not clear if El Escorial (EEC) diagnostic categories have prognostic value and whether advances in ALS therapy such as riluzole and non‐invasive ventilation have improved survivorship.
Methods: The source of cases for the study was a prospective population‐based registry established in Puglia, southern Italy. The diagnosis and the classification of cases were based on EEC criteria. Cases diagnosed as having ALS during 1998–99 were enrolled and followed up until death or 30 June 2004.
Results: We identified 130 ALS incident cases; four patients were lost to follow‐up. Median survival time from first symptom and from diagnosis was 28 and 18 months, respectively; survival rates at five years from first symptom onset and at four years from diagnosis were approximately 30%. Clinical course of suspected ALS was similar to that of definite ALS. Cases with predominant upper motor neuron (UMN) involvement, particularly among spinal onset ALS, presented a longer median survival time from onset and from diagnosis (45.2 and 23.8 months, respectively), associated with lower mortality rates (four years from diagnosis, 57%). Multivariate analysis revealed that advanced age and bulbar or generalized onset were independent predictors of adverse survival. Multivariate models after stratifying patients according to site of first symptoms (bulbar vs spinal) showed that age and site of onset were independently related to outcome, as no effect of age on survival was observed among bulbar ALS cases (HR:1.0.2; 95% CI 0.97–1.06; p = 0.4).
Conclusions: In this incident case series, survival times are consistent with other population‐based studies on natural history of ALS. Advanced age and bulbar onset of symptoms are significant indicators of poor prognosis while EEC category at time of diagnosis does not predict survival.
P53 PROGNOSTIC FACTORS IN AMYOTROPHIC LATERAL SCLEROSIS WITHIN SOUTHWESTERN ONTARIO, CANADA
Shoesmith CL, Rowe A, Strong MJ, Findlater K
London Health Sciences Centre, London, ON, Canada
E‐mail address for correspondence: [email protected]
Background: Accurate prognostic information is important to provide to patients diagnosed with amyotrophic lateral sclerosis. Limb onset, young age and male sex have been cited as good prognostic factors for patients diagnosed with ALS. Most of the studies in the literature which have addressed prognosis are from the United States and Italy. There is little recent data available for the Canadian population.
Objectives: To determine important prognostic indicators in the population of southwestern Ontario, Canada.
Methods: Our ALS clinic database, which documents prospectively collected information on our ALS clinic patients, was evaluated for patients seen from 1991 to April 2006. Univariate survival modelling was performed using Kaplan Meier survival analysis. Multivariable Cox proportional hazard modelling was used to evaluate potential prognostic factors including sex, age, occupation, smoking and site of symptom onset. Hazard ratios were determined for each variable.
Results: The database consisted of 791 individuals with definite or probable ALS. The mean age of onset was 59.6±12.9 years, with a range of 17 to 89 years. Mean age of onset was similar for onset prior to 1996 and onset after 1996 (59.1 and 60.2 years, respectively). The median and mean survival time from symptom onset to death or permanent assisted ventilation was 33.5 months and 50 months, respectively. Thirteen individuals (4.8%) survived for more than 10 years. Univariate analysis demonstrated that the survival was worse for age >45 years (median 31.3 vs. 62.3 months) and bulbar onset (median 28.0 vs. 37.0 months). Female sex was not found to be a negative prognostic factor in univariate analysis. The best prognostic category was very young males with onset prior to age 30 (median survival, 89.9 months). Cox proportional hazard modelling found that older age, bulbar onset, smoking, and onset after 1996 were negative predictive factors when other factors are controlled for. Sex and occupation were not significant prognostic factors.
Discussion: This study will allow better prediction of prognosis in our patients. The findings of this study are generally comparable to previously published survival evaluations with the exception of the finding that sex was not found to be a significant prognostic indicator. The finding of worse prognosis with more recent onset, despite controlling for other variables, has also been suggested in an evaluation of a Scottish database. A plausible explanation for the appearance of decline in survivorship over time is that it is likely that a statistical artefact is created by a greater degree of censoring in the more recent diagnostic group.
P54 MOTOR NEURON DISEASE IN NORTHERN TAIWAN
Su JJ, Yang CC
National Taiwan University Hospital Neurology Department, Taipei, Taiwan
E‐mail address for correspondence: [email protected]
Introduction: Motor neuron disease is caused by degeneration of neurons in the motor cortex, cranial nerve nuclei, and anterior horn cells. Upper and lower motor neurons may be affected but there is no sensory loss or sphincter disturbance. The cause is unknown.
In Taiwan, motor neuron disease belongs to group of rare diseases. Although there is a Taiwan MND Association to help patients with motor neuron disease, the actual prevalence in Taiwan is unknown. We collected data on patients admitted to a medical center in northern Taiwan who were diagnosed with motor neuron disease and analysed the epidemiology of these patients.
Methods: We retrospectively recorded patients admitted to a medical center in northern Taiwan with a final diagnosis of motor neuron disease from January 1988 to November 2005. We analysed age, sex, and duration from onset of symptom to diagnosis, type of motor neuron disease, treatment, number of hospitals patients visited and prognosis.
Results: During the 18 years of the study, 230 patients were admitted to our hospital with a discharge diagnosis of motor neuron disease. There were 85 female patients and 145 males, a sex ratio of 1.7. The average age during admission was 56.6 years and there was no significant difference in age between females (52.8 years old) and males (58.8 years old). The youngest patient was one year old and the eldest was 88 years old. Most of patients were diagnosed with amyotrophic lateral sclerosis. Only patients diagnosed with amyotrophic lateral sclerosis can be prescribed riluzole under application from clinical doctors. Most patients were admitted to a neurology ward. There were still a few patients admitted to an internal medicine ward, pediatric ward or surgery ward under other causes and diagnosed under neurology consultation. Average admission time was around 7.8 to 44.1 days and the longest duration of admission was 227 days. In the past many patients had visited other hospitals for evaluation. There was a slight elevation in the number of patients admitted (the fewest, one patient in 1989 and the most, 28 patients in 2004).
Conclusions: Patients diagnosed with motor neuron disease in northern Taiwan had a similar sex ratio as reference. Although there were very young and old patients, the average age at diagnosis was 56.6 years. It is worth noting that many patients had visited other hospitals for a second opinion. There is an increasing frequency for a non‐neurologist to transfer patients to a neurologist under suspicion of motor neuron disease. We should continue to follow up patients diagnosed with motor neuron disease and consider how to improve their quality of life under an incurable disease.
P55 THE AGE AT ONSET OF AMYOTROPHIC LATERAL SCLEROSIS PATIENTS WITH BULBAR DYSFUNCTION OR FACIAL DIPLEGIA IS HIGHER THAN THAT OF ALS PATIENTS WITHOUT THESE ABNORMALITIES
Nakamura K, Kimura N, Horinouchi H, Arakawa R, Obayashi K, Kumamoto T
Oita University Faculty of Medicine, Oita, Japan
E‐mail address for correspondence: [email protected]
Background: In the study of autopsy cases of amyotrophic lateral sclerosis (ALS), the age at onset of the disease was significantly higher for the bulbar onset form than for the limb onset form.
Objctives: The aim of this study was to investigate the correlation between the neurological signs and the age at onset in patients with ALS.
Methods: We studied 29 consecutive patients (19 men and 10 women, mean age 62.8 years old; range 38–85 years) who were admitted to the Department of Neurology and Neuromuscular Disorders, Oita University Hospital, between January 1999 and December 2004. We evaluated the clinical manifestations and the mean age at onset of these patients with each neurological sign or symptom. According to the revised El Escorial criteria (Airlie House Conference, 1998), all patients were clinically definite for ALS. Differences between the variances were tested using the Mann‐Whitney U‐test as a non‐parametric method. The level of statistical significance was set at p<0.05.
Results: Despite no significant difference in the duration of illness, the mean (±SE) age at onset in ALS patients with bulbar dysfunction (dysphagea and/or dysarthria) was significantly higher than that of ALS patients without this sign (14 cases vs. 15 cases, 67.4±2.3 vs. 58.5±2.5; p<0.05). The mean (±SE) age at onset in ALS patients with facial diplegia was significantly higher than that of ALS patients without this sign (16 cases vs. 13 cases, 68.3±1.7 vs. 56.1±2.8; p<0.01).
Discussion and conclusion: The age at onset of ALS patients with bulbar dysfunction or facial diplegia is higher than that of ALS patients without these abnormalities.
P56 BLINK REFLEX HABITUATION IS REDUCED IN THE EARLY STAGE OF AMYOTROPHIC LATERAL SCLEROSIS
Gutierrez J, Lara G, Zaldivar T, Lestavo Z, Mistelier R, Hardiman O
1Institute of Neurology, Havana, Cuba, 2Beaumont Hospital & RCSI, Dublin, Ireland
E‐mail address for correspondence: [email protected]
Background: The assessment of Blink Reflex Habituation (BRH) is a sensitive method to evaluate the influence of suprasegmental structures on brainstem interneurons. BRH could be used as a marker of non‐compressive upper motor neuron (UMN) dysfunction. Previous studies of BRH in patients with amyotrophic lateral sclerosis (ALS) are scarce and contradictory.
Objective: The aim of the present study was to assess the BRH by using paired electrical stimuli in patients with early stages of ALS.
Methods: We studied 21 patients with definitive diagnosis of ALS (12, bulbar onset; 9, limb onset), with less than one year from symptom onset, and 18 age‐matched healthy controls. A typical evoked potential study of the BR was employed. The effects of paired stimulation on R1 and R2 components, with interstimulus intervals (ISI) of 100, 250, 500 and 1000 milliseconds (ms) were compared in both groups. BRH was defined as the percentage of change of the amplitude of the test response compared to the conditioning response ((+) increased; (−) decreased).
Results: R1and R2 latencies and R1 amplitude elicited by single stimulation were similar in patients and controls; however, ALS patients showed significantly reduced R2 amplitudes compared to healthy subjects (280 (140) uv vs. 400 (81) uv). The most significant differences in BRH between groups were detected with an ISI of 250 ms. The amplitude of test R1 was facilitated to a significantly greater extent in the patients (+35.5% (15.4)) than in the controls (+10.2% (5.2)), p<0.05. Conversely, the change in amplitude of test R2 was significantly less in ALS patients (−15.5% (14.8)) compared to healthy volunteers (−71% (24.2)), p<0.01.
Conclusions: These findings demonstrate that patients with ALS, even at early stages of the disease, have a reduced habituation of the electrically induced blink reflex. These changes may relate to increased suprasegmental facilitatory influences on brainstem interneurons. The evaluation of BRH could provide evidence of subclinical UMN involvement, which might help to establish an earlier diagnosis of ALS, particularly in those with predominantly LMN dysfunction.
P57 ELECTROPHYSIOLOGICAL ABNORMALITIES IN ALS ACCORDING TO THE EL ESCORIAL CRITERIA
De Jong SW, Franssen H, Wokke JHJ, van den Berg LH
University Medical Centre Utrecht, Utrecht, Netherlands
E‐mail address for correspondence: [email protected]
Background: A wide variety of clinical features may be present early in the disease course of ALS and this makes diagnosis difficult. Since there is no reference test for diagnosing ALS, in 1990 a set of diagnostic criteria, the El Escorial criteria, was put forward by the World Federation of Neurology. In 1998 the El Escorial criteria were revised. This diagnostic set consists of a combination of clinical and electrophysiological abnormalities. The added value of electrophysiological studies in the El Escorial criteria has, however, not yet been validated.
Objective: To describe the contribution of electrophysiological signs in diagnosing ALS in clinical practice.
Methods: All patients who visited our outpatient clinic were included in our study and classified according to the revised El Escorial criteria. Electrophysiological studies were performed in patients who fulfilled the criteria for possible, probable or definite ALS, based on clinical signs of motor neuron dysfunction.
Results: In 2003, 147 patients visited our outpatient clinic. Of these, 84 patients were diagnosed as having ALS. According to the El Escorial criteria, one (1%) patient had definite ALS, 24 (29%) patients had probable ALS and 59 (70%) patients had possible ALS. After performance of electrophysiological studies, nine (15%) of the patients who were clinically diagnosed as having possible ALS moved up a diagnostic category to probable laboratory‐supported ALS. Discrepancies were found between clinical signs of LMN dysfunction and electrophysiological features in bulbar and thoracic regions.
Conclusion: Our study shows that electrophysiological studies may have a limited contribution to the El Escorial criteria. The true added value of electrophysiological studies should be investigated in well designed diagnostic research.
P58 APPLICATION OF THE NEUROPHYSIOLOGICAL INDEX IN ALS PATIENTS
Kim H, Koh S, Nam Y, Kim Y, Noh M, Yoo A, Cho K, Kim H, Kim J, Kim S
Department of Neurology, College of Medicine, Hanyang University, Seoul, South Korea
E‐mail address for correspondence: [email protected]
Background: Neurophysiological Index (NI) is a neurophysiological measure made up from the M wave amplitude, the distal motor latency and the F‐wave frequency in ulnar nerves. Several studies have suggested that NI could be used as a sensitive measure of changes during the course of ALS. However, NI has several limitations, in that it was only derived from the ulnar nerve in previous studies and is less valuable when the patient is in the terminal or very early stages of the disease. This study evaluated the validity of NI, obtained from the median and posterior tibial nerves.
Methods: Twenty‐nine consecutively recruited patients with ALS were studied prospectively. Patients with other medical conditions (e.g. diabetes mellitus, polyneuropathy, and nerve entrapment) were excluded. NI obtained from ulnar, median and posterior tibial nerves were recorded and ALS‐FRS, Norris scale, and Appel scores were also recorded serially in some patients. NI data were compared with ALS‐FRS, Norris scale and Appel scores.
Results: The mean age of the patients was 48.9 years; 19 patients were male and 10 patients were female. Eighteen patients were probable ALS and 11 patients were definite ALS. Eight patients were bulbar onset type and the others were limb onset type. NI, obtained from each nerve, showed a significant correlation with other data from various scales in ALS patients.
Conclusion: In our study, we proposed that NI obtained from median and posterior tibial nerves should also be available to measure the changes during the course of ALS and its treatment.
P59 NEEDLE ELECTROMYOGRAPHY OF THE RECTUS ABDOMINIS MUSCLE IN PATIENTS WITH AMYOTROPHIC LATERAL SCLEROSIS
Xu Y, Zheng J, Zhang S, Kang D, Zhang J, Fan D
Peking University Third Hospital, Beijing, China
E‐mail address for correspondence: [email protected]
Background and objective: Needle electromyography (EMG) of the rectus abdominis muscle (RA) was performed to assess thoracic involvement in the diagnosis of amyotrophic lateral sclerosis (ALS).
Methods: EMG of the RA was performed in 67 patients with sporadic ALS and 110 healthy controls. EMG parameters included the presence of spontaneous activity, configuration of motor unit action potentials (MUAP), and recruitment pattern of motor unit potential.
Results: MUAP RA parameters in controls were: duration (9.95±1.13) ms, amplitude (373.78±56.46) µV, and polyphasic waves 11.75±3.26%. In comparison, ALS patients displayed: duration (13.02±1.30) ms, amplitude (537.19±159.04) µV, and polyphasic waves 31.19±8.84%. Significant differences in MUAP parameters, spontaneous potentials and reduced interference patterns were noted between ALS patients and healthy controls. Additionally, we found that active denervation was more frequent in RA in ALS patients with dyspnoea than those without dyspnoea.
Discussion: Our data suggested that conventional needle EMG of RA was a valuable electrophysiological method to assess the clinical and subclinical involvement of the lower motor neuron, in the thoracic region, in ALS patients.
P60 PROSPECTIVE STUDY OF MOTOR FUNCTION AND MOTOR UNIT NUMBER ESTIMATION IN SPINAL MUSCULAR ATROPHY
Kaufmann P1, Gooch CL1, Darras B2, Kang P2, Finkel R3, Garcia J1, Rascoll J1, Oskoui M1, Ryan P1, Riley S2, Quigley J2, Glanzman A3, Flickinger J3, Sanborn E2, Murphy L3, Annis C4, McDermott M4, de Vivo DC1
1Columbia University, New York, NY, 2Harvard University, Boston, MA, 3University of Pennsylvania, Philadelphia,PA, 4Univeristy of Rochester, Rochester, NY, USA
E‐mail address for correspondence: [email protected]
Background: Motor unit number estimation (MUNE) has been used to measure the number of functional motor units in spinal muscular atrophy (SMA). In previous studies, MUNE did not correlate with strength in proximal muscles (1), but correlated with clinical phenotype (SMA types I, II, or III) and with a five‐step functional scale (2).
Objective: To study the relationship between MUNE and clinical phenotype using two more detailed motor function measures that have been independently validated in the SMA population (3,4).
Methods: Forty‐one subjects with SMA types I (n = 5), II (n = 20) and III (n = 16), aged seven months to 45 years, were prospectively evaluated as part of a comprehensive, longitudinal study. Using the multiple point stimulation technique, MUNE was measured in the hypothenar muscle group at baseline (in all subjects) and at six months (in 19 subjects to date). In subjects older than two years, motor function was assessed using the Gross Motor Function Measure (GMFM) (4) and/or the Hammersmith Functional Motor Scale (HFMS) (3).
Results: MUNE values differed between the three clinical phenotypes, but showed some overlap. The lowest values were seen in SMA type I (mean = 6.1, interquartile range, IQR = 0.8), intermediate levels in type II (mean = 20.0, IQR = 10.1), and highest levels in type III (mean = 96.5, IQR = 97.8). There was a significant correlation between MUNE and gross motor function score for both the GMFM (r = 0.71), and the HFMS (r = 0.79). In the 19 subjects with follow‐up MUNE, there was no significant change over six months (mean change 1.5, median change 0.7, SD 7.0).
Discussion and conclusions: MUNE correlates with two independent gross motor function scales. This suggests that MUNE is a potentially valid biomarker reflecting disease severity. Further research is needed to study its utility as secondary outcome measure for SMA clinical trials.
References
- Galea V, Fehlings D, Kirsch S, et al. Depletion and sizes of motor units in spinal muscular atrophy. Muscle Nerve 2001;24:1168–72.
- Swoboda KJ, Prior TW, Scott CB, et al. Natural history of denervation in SMA: relation to age, SMN2 Copy number, and function. Ann Neurol. 2005;57:704–12.
- Mercuri E, Messina S, Battini R, et al. Reliability of the Hammersmith Functional Motor Scale for spinal muscular atrophy in a multicentric study. Neuromusc Dis. 2006; 16:93–8.
- Iannaccone ST, Hynan LS, AmSMART Group. Reliability of four outcome measures in paediatric spinal muscular atrophy. Arch Neurol. 2003;60:1130–6.
P61 PREDICTIVE USE OF I‐123‐MIBG SPECT IN PATIENTS WITH AMYOTROPHIC LATERAL SCLEROSIS
Tanaka Y, Kimura A, Hozumi I, Inuzuka T
Gifu University, Gifu, Japan
E‐mail address for correspondence: [email protected]
Background: Autonomic dysfunction is generally not considered to be a typical clinical feature of amyotrophic lateral sclerosis (ALS). However, previous studies revealed subclinical abnormalities of the autonomic system in patients with ALS. Sympathetic innervation of the heart was shown by I‐123‐metaiodobenzylguanidine‐single photon emission computed tomography (MIBG‐SPECT), which has been used for evaluation of cardiac autonomic function of neurodegenerative diseases such as PD, DLB.
Objectives: To investigate the autonomic nervous function of patients with ALS using MIBG‐SPECT and to elucidate the relation between MIBG‐SPECT and other autonomic examination.
Methods: Twenty‐six consecutive patients diagnosed with definite or probable ALS were examined by MIBG‐SPECT and ECG (CVR‐R), and serum catecholamine levels were determined.
Results: 1) Washout rate (WR) of cardiac MIBG‐SPECT was significantly increased in all ALS patients compared with controls (p<0.05). The heart/mediastinum ratio of the early phase and the delayed phase in all ALS patients is not significantly different in comparison with controls. 2) WR of cardiac MIBG‐SPECT was significantly increased in patients with ALS where the period from onset to first medication was within one year compared with those where the period was over one year (p<0.05). 3) WR of cardiac MIBG‐SPECT was significantly increased in patients with ALS whose progression rate (the delta FS) was over 1, compared with patients with ALS where the delta FS was under 1 (p<0.05). The relation between MIBG‐SPECT and other autonomic examination is not significant.
Discussion and Conclusions: Increased WR of cardiac MIBG‐SPECT suggested sympathetic nervous hyperfunction. This finding supports the previous study that autonomic dysfunction of patients with ALS is due to sympathetic nervous hyperfunction. WR of cardiac MIBG‐SPECT was significantly increased in the rapidly progressing ALS patients at the time of diagnosis. It is reported that progression rate at time of diagnosis in each patient is associated with prognosis in Japan. WR of cardiac MIBG‐SPECT could be used in the follow‐up of individuals with ALS in therapeutic trials. In future, it is necessary that the prognosis of these patients with ALS is evaluated.
P62 [11C]‐FLUMAZENIL PET IN PLS: COMPARISON WITH SPORADIC AND HOMOZYGOUS ‘D90A’ SOD1 ALS
Turner MR1, Hammers A2, Al‐Chalabi A3, Shaw CE3, Andersen PM4, Brooks DJ2, Leigh PN3
1The Radcliffe Infirmary, Oxford, UK, 2MRC Clinical Sciences Centre and Division of Neuroscience, Imperial College, London, UK, 3MRC Centre for Neurodegeneration Research, King's College, London, UK, 4Department of Neurology, Umeå University Hospital, Umeå, Sweden
E‐mail address for correspondence: [email protected]
Background: Primary lateral sclerosis (PLS), despite its consistently slower progression and sine qua non of clinically pure upper motor neuron involvement, is generally accepted as a rare extreme of the clinicopathological spectrum of ALS/MND. Patients homozygous for the 'D90A' SOD1 gene mutation (homD90A) also have a consistent phenotype that is associated with slower disease progression (mean 14 years). [11C]‐flumazenil PET has been used to demonstrate a different pattern of cerebral pyramidal neuronal loss/dysfunction in sporadic (SALS) and homD90A ALS patients when both were compared with healthy controls (1).
Objectives: To compare the pattern of reduction in the cerebral binding of [11C]‐flumazenil in PLS patients with that seen in SALS and homD90A patients; first, when all patient groups are compared separately with healthy controls, and secondly when comparing the PLS patients directly with the SALS and homD90A groups.
Methods: Four PLS, 24 SALS and 10 homD90A patients underwent [11C]‐flumazenil PET of the brain, and results for each group were compared separately with a group of 24 healthy controls. The PLS patients were then compared directly with the SALS and homD90A groups in turn.
Results: The pattern of reduction in the cerebral binding of [11C]‐flumazenil in PLS patients compared with controls was similar to that seen in SALS patients, involving predominantly the motor cortex bilaterally and extending to the right parietal cortex. Additional reductions were seen in the margin of the left superior temporal lobe and anterior cingulate gyrus in the PLS group. When the SALS and homD90A groups were directly compared with the PLS patients, relative decreases were found bilaterally in the anterior frontal and orbito‐frontal regions of the non‐PLS groups, and these were most marked in the homD90A patients.
Conclusions: These [11C]‐flumazenil PET brain findings support the concept that PLS is part of the clinicopathological spectrum of sporadic ALS. They also provide evidence that PLS patients may have a relative preservation of frontal lobe neuronal pathways (or delayed progression of disease in these areas) compared to other ALS patient groups. Detailed comparative cognitive studies, focusing on frontal lobe tasks, may support these observations.
References
- Turner MR, Hammers A, Al-Chalabi A, et al. Distinct cerebral lesions in sporadic and ‘D90A’ SOD1 ALS: Studies with [11C]-flumazenil PET. Brain 2005;128:1323–9.
P63 WHITE MATTER BRAIN INJURY AS MEASURED BY MAGNETIZATION TRANSFER MAY CORRELATE WITH DISEASE DURATION
Tartaglia MC, Findlater K, Rowe A, Kennedy K, Lee D, Strong MJ
London Health Sciences Centre, London, Ontario, Canada
E‐mail address for correspondence: [email protected]
Background: Primary lateral sclerosis is an idiopathic, non‐familial neurodegenerative disorder of the upper motor neurons whose pathophysiology is still unknown. Although a few studies have revealed brain atrophy most notable in the cortical and subcortical portions of the precentral area, there is very little information on the integrity of the remaining brain. Magnetization transfer (MT) imaging is a novel MRI technique that facilitates the quantitative evaluation of the integrity of the brain parenchyma. The MT ratio (MTR) images have advantages over conventional T2‐ and T1‐weighted images in that they have greater pathological specificity and are intrinsically semi‐quantitative. A low MTR reflects a reduced exchange of magnetization between macromolecules and surrounding water molecules. MTR has revealed abnormalities in a number of conditions, including Alzheimer's disease, multiple sclerosis, Parkinson's disease, and stroke (1). In addition, a reduced MTR has been reported in the corticospinal tract of patients with amyotrophic lateral sclerosis (2).
Objectives: The aim of this study was to assess whether MTR in the centrum semiovale or precentral gyrus was related to disease severity and/or disease duration.
Methods: Patients with a clinically definite diagnosis of PLS were recruited from the neuromuscular clinic. They underwent a routine MR examination on a 1.5 T MR scanner using a phased‐array head coil. The MRI protocol included an MT on‐and‐off sequence so as to be able to calculate MTR. The MT images were acquired with a pair of 3D spoiled gradient echo sequences with a TR of 33, a TE of 9 ms, an excitation angle of 15°, a FOV of 250 mm, and a 256×256 matrix. Three mm‐thick slices through the whole brain were acquired with (Sat) and without (NoSat) saturation. A percent difference image, hereafter called the MTR image, was calculated on a voxel‐by‐voxel basis according to the equation: MTR = (1 – Sat/NoSat) ×100, for those voxels that exceeded a background noise threshold. Mean MTR values were obtained from regions of interest (ROI) manually drawn. Spearman's rho correlations were calculated.
Results: Six patients have been scanned to date. There was a trend for MTR median in the centrum semiovale to decrease with disease duration, r = −0.543, p = 0.13. The trend was less evident in the precentral cortex, r = −0.429, p = 0.2. There was no correlation with age or severity of disease.
Conclusions: Our preliminary results suggest that MTR could be useful for assessing brain integrity and that there is ongoing damage that is more evident in the white matter.
References
- Filippi M, Rocca MA. J Neuroimaging 2004;14:303–13.
- Tanabe JL, et al. Magn Reson Imaging 1998;16:1163–9.
P64 REDUCED ANISOTROPY OF THE CORTICOSPINAL TRACT DETECTED BY CONVENTIONAL DIFFUSION WEIGHTED MR‐IMAGES (DWI) IN ALS
Hecht MJ1, Heuss D1, Neundörfer B1, Schwab S1, Schmid A2
1Department of Neurology, University of Erlangen, 2Institute of Diagnostic Radiology, Erlangen, Germany
E‐mail address for correspondence: [email protected]
Background: Diffusion tensor imaging (DTI) is able to reveal reduced anisotropy along the corticospinal tract (CST) in ALS patients. However, DTI requires specialized equipment not available in most clinics. Therefore, only a small number of patients in a few centres have been studied until now.
Objectives: We investigated whether common diffusion weighted images (DWI) are also suitable to detect abnormalities of CST anisotropy in ALS patients.
Methods: We examined 35 ALS patients (18 males, 17 females; mean age 61.6±9.9 years, median duration of disease 10 months) and 19 controls (10 males, 9 females; 57.7±12.2 years). MRI scans were recorded with a 1.5T MR device (Sonata, Siemens) with standard commercial diffusion weighted sequences. We quantified CST signal intensity in five levels along the CST. Signal values in right to left, and anterior to posterior direction, were averaged. We calculated the ratio of this mean value to the signal value of the cranio‐caudal direction and named it the anisotropy ratio (AR). Due to the direction of the CST in cranio‐caudal direction, AR should be high in the case of intact CST (high anisotropy) and low in the case of degenerated CST (low anisotropy).
Results: At two levels of the internal capsule (upper and lower IC, posterior limb), AR was significantly reduced in ALS patients compared to controls (upper IC right: ALS 2.04, control 2.16, p = 0.088; upper IC left: ALS 2.07, control 2.23, p = 0.03; lower IC right: ALS 1.67, control 2.23, p<0.005; lower IC left: ALS 1.75, control 2.16, p<0.005). AR values at the level of the crus cerebri and pons were lower in ALS patients, but the difference was not significant. At the level of the precentral white matter, AR was significantly lower for the right medial ROI (ALS 1.41, controls 1.60; p = 0.032), but not for the left medial and left and right lateral ROI.
Conclusion: At the level of the internal capsule reduced anisotropy is detectable with common commercial DWI in ALS. This pilot study has to be completed by a follow‐up study. Possibly, calculation of the AR at the level of the interne capsule might be used as a simple marker of CST degeneration.
P65 IS CORTICAL EXCITABILITY ABNORMAL IN MND? A STUDY USING PHARMACOLOGICAL FMRI
Azam S, Leigh PN, Williams SCR, Koritnik B
Institute of Psychiatry, King's College, London, UK
E‐mail address for correspondence: [email protected]
Background: Motor neuron disease (MND), also known as amyotrophic lateral sclerosis (ALS), is a progressive and ultimately fatal disease characterized by degeneration of corticospinal tract and spinal motor neurons. There is evidence that excitotoxity contributes to neuronal damage and death in MND. Excess glutamate induced corticomotor neuronal excitotoxicity, and subsequent loss of recurrent collaterals of corticospinal tract pyramidal neurons that are known to activate intrinsic GABAergic interneurons or a primary loss of these GABAergic interneurons are possible mechanisms responsible for the altered intracortical balance between excitation and inhibition, observed during electropysiological and neuroimaging studies.
Objective: To investigate, at a synaptic level, the possible role of altered excitatory and inhibitory mechanisms in the pathophysiology of ALS using fMRI and intravenous challenge of a GABA‐A receptor agonist midazolam.
Methods: Using functional imaging (fMRI) we studied seven patients with typical ALS and seven healthy controls matched for age and sex, while they performed a visually paced motor task. All the subjects were scanned while they received an intravenous challenge of normal saline and on a separate visit an infusion of midazolam.
Results: Task related functional changes were identified in motor cortical and subcortical regions. Following intravenous midazolam, direct group comparisons revealed a decreased BOLD response in the contralateral sensorimotor cortex, contralateral premotor area and supplementary motor areas in healthy controls. Furthermore, the BOLD response was increased in subcortical areas bilaterally and the cerebellum of healthy controls. In the ALS group, post midazolam, the BOLD response was increased in subcortical and cortical motor areas.
Conclusions: The suppression of BOLD signal seen in the cortical areas of healthy volunteers following midazolam challenge may be a result of direct GABA‐A receptor mediated inhibition but may also be due to dampening down of glutamatergic output from the motor cortex. One of the consequences of this ‘cortical suppression’ might be an increased input from a parallel motor loop to the subcortical area reflected in a BOLD signal in this area. The lack of suppression of the BOLD signal in the ALS group following a midazolam challenge may be a consequence of loss of inhibitory GABAergic neurons in the motor cortex.
P66 DIFFUSION TENSOR IMAGING (DTI) AND MAGNETIC RESONANCE SPECTROSCOPY (MRS) IN AMYOTROPHIC LATERAL SCLEROSIS (ALS): A LONGITUDINAL STUDY
Bongioanni P1, Lombardo F2, Frijia F2, Minichilli F2, Bianchi F2, Tuccio MC1, Canapicchi R2, Rossi B1, Montanaro D2
1Azienda Ospedaliero‐Universitaria Pisana, Pisa, Italy, 2Fisiologia Clinica ‐ CNR, Pisa, Italy
E‐mail address for correspondence: [email protected]
Background: Looking for an objective marker for upper motor neuron involvement in amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND) patients, non‐conventional magnetic resonance imaging (MRI) techniques, such as diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (H‐MRS), have been recently employed.
Objectives: The aim of our work was to discover neuroimaging markers for progressive clinical impairment of ALS/MND patients.
Methods: We studied 32 ALS/MND patients, 13 with definite/probable (D/P) and 19 with possible (P) ALS, according to the El Escorial criteria. All subjects underwent brain MRI scans every four months by 1.5‐T device (GE Signa ExciteTM HD, Milwaukee, USA). H‐MRS was carried out by sampling rolandic regions by the single voxel technique. Diffusion fractional anisotropy (FA) and average apparent diffusion coefficient (avADC) were analysed along the cortico‐spinal tract from grey and white prerolandic matter down to the bulbar pyramids. Patients' data were compared among each other according to progressive clinical impairment.
Results: Taking into account that our data are preliminary, we found a significant relationship between decreased FA values and increased clinical impairment over time in both all patients as a whole and the D/P ALS group only, for right prerolandic white matter, left brain peduncle and bilateral pons. Moreover, a significant correlation between enhanced avADC values and increased clinical impairment was observed only in D/P ALS patients for right prerolandic white matter and right posterior limb of the internal capsule. An inverse relationship between NAA/Cr ratio and clinical impairment was observed in H‐MRS scans of both rolandic regions in all subjects (but only at right side in D/P ALS patients).
Discussion: Altered diffusion indices can be explained by a progressive cortico‐spinal tract derangement due to motor fibre degeneration. Spectroscopic data, according to ALS pathophysiology, might be regarded as a marker for neuronal loss or dysfunction over time.
Conclusions: Our findings, although incomplete and preliminary, are encouraging and allow us to hope that H‐MRS, but especially DTI, are useful tools in disease monitoring of patient groups, and therefore during clinical trials.
P67 DISCOVERY OF NEW CEREBROSPINAL FLUID PROTEIN BIOMARKERS FOR AMYOTROPHIC LATERAL SCLEROSIS
Lukas TJ, Ajroud‐Driss S, Luo W‐W, Siddique N, Casey P, Heller S, Siddique T
Northwestern University, Chicago, IL, USA
E‐mail address for correspondence: [email protected]
Background: Confirming diagnosis of ALS or other motor neuron disease currently entails several months. Accomplishing this task rapidly would benefit patients so that they may begin appropriate therapy. Determing the nature and status of motor neuron disease may be realized by detecting biomarker proteins in patient cerebrospinal fluid (CSF). Using a systems biology approach we have analysed changes in gene and protein expression in the spinal cord tissue of a mouse model of amyotrophic lateral sclerosis (ALS) using gene ontology mapping (1). The results indicated that cellular communication was the largest category containing expression differences. One subcategory within this group includes proteins involved in cell adhesion. These are proteins associated with the extracellular matrix and establishment of cell‐cell contacts. We hypothesized that changes in the expression of these proteins may be reflected in the CSF and serve as disease‐related biomarkers.
Objectives: 1. Obtain profiles of CSF proteins from control and ALS patient groups. 2. Identify a panel of biomarkers that distinguish ALS from controls.
Methods: Patient and control CSF samples were analysed using proteomics methods. Albumin and immunoglobulins were removed using an Agilent immunodepletion column. The eluant was fractionated using single dimension sodium dodecyl sulphate‐polyacrylamide gel electrophoresis (1D‐SDS PAGE). Twelve gel slices were digested with trypsin and peptides extracted. Peptides were analysed by nanoscale liquid chromatography coupled to an ion trap mass spectrometer. Mass spectral data accumulated from multiple runs were then processed and searched against the human International Protein Index database to directly identify the proteins represented by the individual peptides.
Results: Relative protein abundance data from ALS compared to control samples was analysed using BRB‐array tools. Class prediction algorithms were employed to discover biomarkers associated with ALS. Three of the seven identified proteins belong to the extracellular‐matrix protein category supporting our hypothesis of detecting changes in these proteins in the CSF of ALS patients compared to controls.
Conclusion: Ongoing analysis of additional samples and validation of newly identified protein candidates using immunoassays will ultimately allow a panel of disease relevant biomarkers to be used in the diagnosis of motor neuron disease from patient CSF.
Acknowledgements: This study was supported in part by the National Institutes of Health, Les Turner ALS Foundation, Playing to Win4Life Foundation, V. E. Schaff ALS Research Fund, H. Post Research Professorship, Falk Medical Research Trust, Les Turner/ Herbert H. Wenske Foundation Professorship and The David C. Asselin MD Memorial Fund.
References
- Lukas TJ, Luo W-W, Mao H, Cole N, SiddiqueT. Informatics assisted protein profiling in a transgenic mouse model of amyotrophic lateral sclerosis. Mol Cell Proteomics (2006), in press.
P68 PROTEIN BIOMARKERS FOR DISEASE PROGRESSION DURING AMYOTROPHIC LATERAL SCLEROSIS
Bowser R, An J, Darko S, Ryberg H, Lacomis D
University of Pittsburgh, Pittsburgh, PA, USA
E‐mail address for correspondence: [email protected]
Background: Biomarkers specific to motor neuron disease will aid in the diagnosis of disease and identify new therapeutic targets. Recent studies have identified individual or panels of protein biomarkers that represent putative ALS biomarkers. Beyond the use of biomarkers in disease diagnosis, protein biomarkers that can monitor disease progression would be quite useful as surrogate markers in clinical trials to test drug efficacy and to identify drug combinations that may provide the best treatment strategy.
Objectives: To perform mass spectrometry based proteomics on cerebrospinal fluid (CSF) collected over time from individual ALS subjects. By comparing the CSF protein profile during the course of disease we will attempt to uncover protein alterations that correlate to clinical signs of ALS disease progression.
Methods: CSF was collected every four to six months from a cohort of ALS subjects enrolled at the University of Pittsburgh School of Medicine ALS/MND clinic. Clinical measurements were performed at each clinic visit to evaluate disease progression. CSF was collected over a two‐year time frame from each subject and analysed by mass spectrometry. Results were compared to the CSF profile of healthy control subjects.
Results: By comparing the CSF protein profile over time, we identified a group of protein peaks that exhibit alterations (increased or decreased levels) that correlate to disease progression within individual patients. While a few protein peaks were unique to specific patients, all contained a common set of proteins that changed during disease progression. However, each patient exhibited an individual rate of protein alterations over time that correlated with their individual rate of clinical disease progression. Finally, protein biomarkers identified for disease progression were largely distinct from diagnostic protein biomarkers.
Discussion and conclusions: Our results suggest that protein biomarkers for ALS disease progression can be identified in the CSF. Biomarkers for disease progression will aid in the development of effective drug treatments for ALS and other motor neuron diseases.
P69 ABSTRACT WITHDRAWN
P70 TOWARDS IDENTIFYING A MEANINGFUL BIOMARKER FOR ALS: A RETROSPECTIVE CLINICAL STUDY
Lange DJ, Zhou R, Wang J, Ho L, Salton S, Passinetti GM
Mt. Sinai School of Medicine, New York, USA
E‐mail address for correspondence: [email protected]
Background: There is no universally accepted biomarker that uniquely identifies patients with amyotrophic lateral sclerosis (ALS) though many have been proposed. Using SELDI proteomics, we previously identified down‐regulation of a three‐protein profile in patients with ALS (VGF fragment, cystatin C, and a 6.7kD protein yet to be identified) that is 95% accurate, 91% sensitive and 97% specific. One of these proteins is VGF (non‐acronymic name given to a nerve growth factor inducible protein instrumental in maintaining metabolic homeostasis). VGF is a member of the granin family of proteins (chromogranin A and B) that form neurosecretory granules. We have created an ELISA that quantifies VGF (entire molecule) and chromogranin A to begin validation that these proteins may indeed be true biomarkers for ALS. One requirement for a biologically meaningful marker of disease is that it varies with disease severity.
Objective: To determine if levels of VGF and chromogranin A (CgA) vary with disease severity in patients with ALS.
Methods: A retrospective survey was performed for all patients who participated in our ALS and motor neuropathy biomarker study between November 2004 and May 2006 (n = 43). Selection criteria consisted of the following: El Escorial defined probable or definite ALS, cerebrospinal fluid (CSF) available for ELISA analysis, clinical examination with quantitative muscle strength measurements within four weeks of CSF acquisition. Patients were classified according to number of segments with clinical weakness from a total of three segments of the central nervous system (cranial, cervical and lumbar). Quantitative muscle testing was based on the MRC grading system out of a total of 200 possible points. Concentration of total VGF and CgA was calculated for each patient. Statistical analysis of muscle scores and concentration of VGF and CgA was performed using independent‐measures t‐tests.
Results: Out of 43 patients identified, 17 had ALS. The remaining 26 patients did not satisfy criteria for the following reasons: three had frontotemporal dementia, three had primary lateral sclerosis, and 20 had diseases other than ALS or did not have clinical measures available for review. Clinical weakness identified only in one segment occurred in 10 patients; weakness in two segments was identified in seven patients. Patients with two affected segments were significantly weaker (muscle testing score 149.8 vs. 183.3, p = 0.018) and have significantly lower concentrations of VGF (4.47 vs. 5.48, p = 0.038) and CgA (39.25 vs. 70.69, p = 0.038) than those with only one segment affected.
Discussion and conclusion: In a retrospective study, we have demonstrated that potential biomarkers for ALS which we previously identified using SELDI proteomics are able to be quantitatively measured using ELISA. We further showed that there is a statistically significant reduction in concentrations of VGF and CgA in more severely affected patients suggesting that such markers may correlate with disease severity. These studies further support our findings that VGF and possibly CgA may be biologically significant biomarkers for ALS. Prospective studies are needed.