Juhani Wikström

Genomewide Scan of Multiple Sclerosis in Finnish Multiplex Families

Multiple sclerosis (MS) is a neurological, demyelinating disorder with a putative autoimmune etiology. It is thought to be a multifactorial disease with a complex mode of inheritance. Here we report the results of a two-stage genomewide scan for loci predisposing to MS. The first stage of the screen, with a low-resolution map, was performed in a selection of 16 pedigrees collected from an isolated Finnish population. Multipoint, non-parametric linkage analysis of the 328 markers did not reveal statistically significant results. However, 10 slightly interesting regions (P = .1-.15) emerged, including our previous findings of the HLA complex on 6p21 and a putative locus on 5p14-p12. Eight of these novel regions were further analyzed by use of denser marker maps, in the second stage of the scan. For the chromosomal regions 4cen, 11tel, and 17q, the statistical significance increased, but not conclusively; for 2q32 and 10q21, the statistical significance did not change. Accordingly, genotyping of the high-density markers in these regions was performed, and the data were analyzed by use of two-point, parametric linkage analysis using the complete pedigree information of the 21 Finnish multiplex families. We detected suggestive evidence for a predisposing locus on chromosomal region 17q22-q24. Several markers on 17q22-q24 yielded positive LOD scores, with the maximum LOD score (Zmax) occurring with D17S807 (Zmax = 2.8, theta = .04; dominant model). Interestingly, a suggestive linkage between MS and the markers on 17q22-q24 was also revealed by a recent genomewide scan in MS families from the United Kingdom.

Prevalence of severe dementia in Finland

A sample of 8,000 subjects to represent the population of Finland aged 30 years and over was used to identify patients with severe dementia; 141 cases were found. The prevalence of all types of severe dementia was 1.8% in the whole study population and 6.7% in the population aged 65 years and over. The prevalence increased with advancing age to 17.3% in the age group 85 years and over. Primary degenerative dementia constituted 50% of all cases; multi-infarct and combined dementia, 39%; and secondary dementia, 11%. Fifty-seven percent of the patients lived in institutions.

Short Portable Mental Status Questionnaire as a Screening Test for Dementia and Delirium Among the Elderly

Pfeiffers Short Portable Mental Status Questionnaire (SPMSQ) is a brief screening test for organic brain syndromes. The validity of the SPMSQ was evaluated in a random sample of 119 community residents and 282 consecutively admitted medical inpatients. The SPMSQ proved to be a sensitive and specific screening test for moderate to severe dementia both in the community and hospital. Using the cut‐off point (number of errors accepted) of three errors, the sensitivity of the test was 86.2% and the specificity 99.0% among medical inpatients. The percentages in the community sample were 66.7% and 100%, respectively. The validity of the SPMSQ was not as good for delirium because of its variable clinical picture. For screening purposes lower cut‐off points than previously recommended should be used: three errors for dementia and two errors for delirium. Among Finnish elderly people it was not necessary to use correction for education in the SPMSQ.

Increasing prevalence of multiple sclerosis in Finland

Objectives – To follow‐up the prevalence trends of MS from 1983 to 1993 in western and southern Finland. MS epidemiology has been previously followed from 1964 to 1978 in these regions. The updated prevalences were correlated with incidence trends in the same period. Methods– Age‐adjusted and age‐specific MS prevalence rates were calculated for cases classified by Posers criteria. Results– In the western health‐care districts, Seinäjoki and Vaasa, prevalences in 1993 were 202/105 and 111/105. In the southern district Uusimaa the respective figure was 108/105. In Seinäjoki a significant 1.7‐fold increase was found in 1993 as compared to 1983, mainly due to increased incidence. In Uusimaa a significant 1.2‐fold increase in prevalence was found in the presence of stable incidence. In Vaasa prevalence was stable, although incidence was declining. Conclusion– The prevalence of MS is increasing in Seinäjoki and Uusimaa but not in Vaasa. Both the prevalence and incidence in Seinäjoki are now among the highest reported.

HLA class II associated risk and protection against multiple sclerosis—a Finnish family study

We analyzed the HLA class II haplotypes in 249 Finnish nuclear families and compared the frequencies of parental haplotypes transmitted or non-transmitted to multiple sclerosis (MS) patients. The most important predisposing haplotype was DRB1*15-DQB1*0602 (P<10(-6)) as expected and a weak predisposing effect of DRB1*04-DQB1*0302 was revealed after the elimination of DRB1*15-DQB1*0602. HLA-DRB1*01-DQB1*0501 and DRB1*13-DQB1*0603 were negatively associated with MS in transmission disequilibrium test, but only the DRB1*13-DQB1*0603 association remained significant (P=0.008) after the elimination of DRB1*15-DQB1*0602 haplotypes. Based on this study HLA class II haplotypes exhibit both predisposing and protective effects in MS.

Measuring Deterioration in International Classification of Functioning Domains of People With Multiple Sclerosis Who Are Ambulatory

Background and Purpose: Measures to detect important effects related to physical therapy interventions must be able to detect an important change. The purpose of this study was to select the most responsive physical functioning measures for multiple sclerosis (MS) using the International Classification of Functioning, Disability and Health (ICF) as a framework. Subjects: The participants were 120 people with MS who were ambulatory from a population-based sample. Methods: Physical functioning was assessed by quantitative clinical measures of activities (n=5) and body functions (n=7) and by self-reported performance in self-care, mobility, and domestic life domains in the activities and participation component of the ICF at baseline and 2 years later. A participants perception of change and a change in Expanded Disability Status Scale (EDSS) scores were used as external criteria in the analysis of the receiver operating characteristic curve and the minimally important change score. The minimal detectable change was calculated as distribution-based responsiveness. Results: According to the external criteria, 51% of the participants showed deterioration as measured by their own perceptions compared with the 26% of the participants who showed deterioration as rated by the clinician. Regardless of the external criterion applied, the measures most responsive to deterioration were self-reported scores in self-care, mobility, and domestic life; distance walked and change in heart rate during a 6-minute walk test; 10-m walk test speeds, stride length, and cadence; repetitive squatting; and Box and Block Test scores. Discussion and Conclusion: The results show the relative responsiveness of different measures in the subsample who deteriorated and provide data that can facilitate the interpretation of score changes in people with MS who are ambulatory for future studies and in clinical practice.

Regional and Temporal Variation in the Incidence of Multiple Sclerosis in Finland 1979–1993

Previous surveys in Finland from the 1960s have documented an uneven geographic distribution of multiple sclerosis (MS). In the present study, the incidence of MS was studied during 1979–1993 in the western Vaasa and Seinäjoki regions and in southern Uusimaa. The overall difference between the western and southern regions persisted; 8.7 per 100,000 in the western, and 5.1 per 100,000 in the southern region. The incidence of 11.6 per 100,000 in Seinäjoki was more than twofold greater than the 5.2 per 100,000 incidence found in neighboring Vaasa. An increasing incidence trend was observed for men in Seinäjoki, and a decrease for both sexes in Vaasa, while in Uusimaa the incidence remained stable for both sexes. The different incidence trends could not be readily explained by differences in case ascertainment but suggest the effect of environmental factors that have modulated the incidence of MS during the 15-year study period.

Occurrence of multiple sclerosis in central Finland: a regional and temporal comparison during 30 years

Objective – We estimated the prevalence and incidence of multiple sclerosis (MS) in central Finland up to 2000. Rates were compared with those in other areas in Finland.

Intercellular Adhesion Molecule-1 K469E Polymorphism: Study of Association With Multiple Sclerosis

Intercellular adhesion molecule-1 (ICAM-1) is involved in the pathogenesis of multiple sclerosis (MS), whereas sequence variations in the ICAM-1 gene could potentially be responsible for the genetic susceptibility to MS. We studied an association of MS with the 13,848A>G (K469E) polymorphism of the ICAM-1 gene in Finnish and Spanish cases and controls and affected families. An increased risk for the AA (Lys(469)/Lys(469)) genotype was found in both populations. The effect observed was found to be strongest among the HLA-DQB1*0602-positive subjects, which implies genetic heterogeneity of MS. Meta-analysis of all published datasets supports increased risk of MS for the ICAM-1 Lys(469) homozygotes (relative risk = 1.3, p = 0.002).

STUDIES ON THE CLUSTERING OF MULTIPLE SCLEROSIS IN FINLAND II: MICROEPIDEMIOLOGY IN ONE HIGH‐RISK COUNTY WITH SPECIAL REFERENCE TO FAMILIAL CASES

The epidemiology of multiple sclerosis (MS) was investigated in a small selected area within the western high‐risk county of Finland. The investigation was extended to the level of single communes, villages and even houses, together with the search for all familial cases born in this district. The results were compared to those obtained for Helsinki, a city of medium‐risk for MS. Prevalences by present domicile that exceeded 100 per 100,000 inhabitants were recorded in several communes of the western high‐risk county. The highest prevalence was 174.2. Seventy patients were born in the small high‐risk area. This was 25% of the MS patients born in the whole county and much higher than expected (16%). A positive familial history of another MS patient was recorded in 8 cases (11%). They were all living, first‐degree relatives. A similar history was found in only 2 cases (2%) among the 99 MS patients born in Helsinki. The birthplaces of the 123 parents of these 70 MS cases could be confirmed. All villages with high MS frequencies were located along the rivers running through the area. The birthplaces of the patients showed a similar accumulation to the valleys. No conjugal cases were found. If the preponderance of familial cases in the small high‐risk area reflects the role of genetic factors in the aetiology of MS, it is only of polygenic nature. The pronounced clustering of the birthplaces in the small high‐risk area and, especially, along the rivers also suggests the importance of environmental influences in early childhood.