PLATFORM PRESENTATION

FACILITATION OF THE JAW-JERK REFLEX IN BULBAR ONSET ALS PATIENTS

GUTIERREZ J1, ALVARAZ I1, MUSTELIER R1,LESTAYO Z1, LARA G1, ZALDIVAR T1,

HARDIMAN O2

1Cuban Institute of Neurology and Neurosurgery,, Havana, Cuba,

2Beaumont Hospital &Trinity College, Dublin, Ireland

E-mail address for correspondence: orla@hardiman.net

Keywords: ALS, jaw-jerk reflex

Background: The jaw-jerk Reflex (JJR) is the trigeminal equivalent of monosynaptic myotatic reflexes in limb muscles. JJR excitability is determined by suprasegmental influences on

brainstem motor circuits, and could be used as an indirect assessment of upper motor neuron tone. There are no previous studies of JJR in patients with amyotrophic lateral

sclerosis (ALS).

Objective: To describe the electrophysiological features of the JJR in patients with early-stage ALS.

Methods: We studied 17 patients with a definitive diagnosis of bulbar onset ALS (B1 year of evolution) and 15 agematched healthy controls. The reflex was evoked by tapping the subject’s chin at rest with a modified neurologist’s reflex hammer that also triggered the oscilloscope recordings. The responses were recorded with surface electrodes placed over the masseter muscle. All subjects were stimulated 20 times, at intervals of 30 seconds. Average onset latency and peak to peak amplitude, as well as the percentage of occurrence of the responses, were measured in all subjects.

Results: ALS patients showed significantly increased JJR amplitudes compared to controls (370965 uv. vs. 2509110 uv.), pB0.05). The percentage of occurrence was also significantly higher in patients than in normal subjects (75.5917.3% vs. 55.5918.2%, pB0.05) and ALS patients showed a poor habituation of the responses over repeated tapings. Average onset latency was reduced in the ALS group, as compared to controls, but this difference was not statistically

significant (6.791.5 ms. vs. 7.391.3 ms, p_0.05).

Conclusion: These findings demonstrate that patients with early stage ALS have a facilitated JJR. These enhancement could be explained by two reasons:

1- Increased suprasegmental excitatory influences on brainstem motor circuits.

2- Decreased cortico-bulbar inhibitory influences on brainstem motor neurons, as happen     with the other myotatic reflexes. The study of JJR could provide evidence of UMN involvement, independent of cervical spinal cord compression, which could be helpful to support an earlier ALS diagnosis.

POSTER PRESENTATIONS

GENOME-WIDE STUDY OF COPY NUMBER VARIATION IN THE IRISH AND DUTCH ALS POPULATIONS

CRONIN S1, BLAUW HM2, VELDINK JH2, VAN ES MA2,

OPHOFF RA2, BRADLEY DG3, VAN DEN BERG LH2,

HARDIMAN O3

1Beaumont Hospital, Dublin, Ireland, 2Rudolf Magnus Institute of

Neuroscience, University Medical Center Utrecht, Netherlands,

3Trinity College Dublin, Ireland

E-mail address for correspondence: scronin@rcsi.ie

Keywords: CNV,genome wide study,genetics

Background: Sporadic ALS is an unrelenting neurodegenerative condition characterized by progressive limb and bulbar weakness. Genetic risk factors have been implicated in its

pathogenesis. Copy number variations (CNVs) have the capacity to alter gene dosage and CNVs in SMN are a precedent for a biological role for CNVs in ALS. 

Objective: To investigate the contribution of CNVs to ALS in the Irish and Dutch populations.

Methods:   We did a genome-wide analysis of CNVs by comparison of Illumina 550K SNP array data on 206 Irish patients with ALS and 202 Irish controls with Illumina 317K

SNP array data on 445 Dutch patients with ALS and 423 Dutch controls. The total number and length of CNVs, association of common CNVs with ALS and the co-occurrence of novel ALS-specific CNVs was examined using the QuantiSNP algorithm and data from the Database of Genomic Variants build 36.

Results: We detected 4,987 CNVs using 550K data in 408 Irish individuals and 4,103 CNVs using 317K data in 868Dutch individuals. Using pooled data, no SNP showed a

significant copy number difference between ALS patients andcontrols after correction for multiple testing. We identified 16 genes bearing loss or gain of copy number exclusively among ALS patients replicating in both the Irish and Dutch analyses.  Among these, there were three genes where the same copy number alteration was observed in 6 individual patients.  These variants did not occur in controls and have not been reported in previous studies of CNVs.  Discussion: Common CNVs in the regions of the genome included on the current SNP arrays do not alter susceptibility to ALS. However, rare CNVs observed uniquely in ALS patients may contribute to ALS pathogenesis. Future work should seek to profile the contribution of CNVs located in regions not covered on the present SNP platforms.

A POPULATION BASED SURVEY OF COGNITIVE DECLINE IN ALS

PHUKAN J, GALLAGHER L, CORR B, PENDER N,HARDIMAN O

Beaumont Hospital, Dublin, Ireland

E-mail address for correspondence: juliephukan@yahoo.co.uk

Keywords: cognitive, FTLD, population

Background: Up to 60% of the ALS patients attending specialist clinics are reported to have mild cognitive decline and a proportion of these may progress to develop frontotemporal dementia. However, the population-based frequency and natural history of cognitive decline in ALS remains to be established.

Objective: To determine the frequency and natural history of cognitive decline in ALS in a defined population-based cohort.  Design and Methods: All Incident patients in the Republic of Ireland are identified through the Irish ALS Register. Each patient is assessed in their own home, provides a detailed family history and undergoes a full neurological examination and validated neuropsychological evaluation, modified to control for slower motor speed and speech difficulties.  Progression is determined by three separate evaluations at 6-month intervals.

Results: 70 incident patients have been identified over an 18 month period. 51 patients  and matched controls have participated in a detailed neuropsychological assessment to date. 13 patients have bulbar-onset disease and 17 have a family history of neurodegenerative disease. Cluster analysis based on executive function was performed to generate 2groups: impairment (n_23) and no impairment (n_28).  ALS patients demonstrated performance below control means on several measures of executive function and memory.  Patient mean z-scores indicate verbal memory and behaviour change were more prominent in those with evidence of executive impairment. Those with executive impairment had significantly greater change in executive dysfunction and apathy (as per Frontal Systems Behaviour Scale). Apathy was the most marked behavioural change in both groups.  Other cognitive processes such as naming were intact.  6 patients met consensus criteria for frontotemporal lobar dementia: 3 for behavioural variant FTD, 1 for non-fluent progressive aphasia, and another for semantic dementia.  Cognitive impairment did not correlate with ALS severity.  Kindreds of ALS patients with cognitive impairment had a higher frequency of other neurodegenerative disease.

Conclusion and Relevance: There is a high prevalence of cognitive impairment (primarily affecting executive function and memory) and behavioural change in ALS. However preliminary data suggests that the population based frequency of cognitive impairment is lower than that reported from clinic based studies. This study supports the conjecture that ALS is part of a continuum of neurodegenerative disease.

TO ASCERTAIN THE ACCURACY OF DEATH CERTIFICATES FOR ALS IN CUBA AND TO DETERMINE THE CAUSE AND PLACE OF DEATH OF ALS PATIENTS OVER A 5 YEAR PERIOD (2001-2006)

ZALDIVAR T1, GUTIERREZ J1, LARA G1, HARDIMAN O2

1Institute of Neurology, Havana, Cuba, 2Beaumont Hospital & Trinity College Dublin, Ireland

E-mail address for correspondence:orla@hardiman.net

Keywords: Mortality study, epidemiology, cause of death

Background: Death certification is a recognized means to ascertain ALS although this method has been shown to be less complete compared to incidence based studies.

We have recently completed a mortality study of ALS in Cuba, and shown that age adjusted mortality is 0.8/100,000.

Objectives: To correlate the mortality study with ongoing incidence-based study in Havana City and Province.

Results: We will determine the completeness of population-based ascertainment of ALS in the region; ascertain immediate cause of death as documented on all death certificates; ascertain place of death (home / hospital); and determine the accuracy of death certification by comparison with datasets generated as part of the ongoing incidence based study of ALS in the Havana region.

Conclusions: This study will test the accuracy of death certification of ALS in Cuba and will provide information about management of the terminal stages of the disease.