Jorma Palo

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.

CT in the differential diagnosis between Alzheimer's disease and vascular dementia

ABSTRACT— A prospective series of consecutively admitted patients with Alzheimers disease (AD) (n = 68), multi‐infarct dementia (MID) (n = 79) and probable vascular dementia (PVD) (n = 46) were studied by CT of the head. In MID 88.6% and in PVD 41.3% of the patients had at least one brain infarct on CT, but only one patient (1.5%) with AD. White matter low attenuation (WMLA) also differentiated MID and PVD from AD, especially among patients aged 75 years or less, and with mild or moderate dementia. In all types, brain atrophy on CT had a positive correlation with the degree of dementia. Infarcts and WMLA on CT, but not brain atrophy seem to be of differential diagnostic value between vascular and degenerative dementia.

Amyloid protein in familial amyloidosis (Finnish type) is homologous to gelsolin, an actin-binding protein

Familial amyloidosis, Finnish type, is clinically characterized by cranial neuropathy and lattice corneal dystrophy. It is an autosomal dominant form of systemic amyloidosis with small deposits of congophilic material occurring in most tissues, particularly in association with blood vessel walls and basement membranes. Amyloid fibrils were extracted from the kidney of patient VUO, and rabbit antiserum raised against the 12 kDa purified amyloid subunit displayed strong immunohistochemical reactivity with the amyloid deposits. The amino terminal sequence of this 12 kDa amyloid protein (ATEVPVSWESFNNGD) showed homology with gelsolin (or actin depolymerizing factor), a 93 kDa plasma protein. The amyloid peptide is a degradation product, starting at position 173, of the gelsolin molecule.

A post-mortem comparison of the cortical cholinergic system in Alzheimer's disease and Pick's disease

Assessment of neurochemical markers in the frontal cortex indicates that choline acetyltransferase is significantly decreased in Alzheimers and Gerstmann-Straussler dementias but not in Picks dementia. It therefore appears that the cholinergic innervation of the cortex from the basal forebrain is intact in Picks disease. Cortical somatostatin was decreased only in Alzheimers disease (AD), indicating that loss of somatostatin is not a constant feature in different forms of dementia. Muscarinic binding sites were unaltered in Picks disease and Gerstmann-Straussler syndrome but were decreased in a subpopulation of AD patients. These data suggest that in some cases of AD a significant loss of cholinoceptive neurones in the cortex is evident.

CSF in Alzheimer's disease. Studies on blood-brain barrier function and intrathecal protein synthesis

Serum and cerebrospinal fluid (CSF) from 22 ambulatory and 10 institutionalised patients with Alzheimers disease (AD) and 22 age-matched controls were assayed nephelometrically for concentrations of IgG, IgA, IgM, haptoglobin, transferrin, prealbumin and albumin. The CSF/serum ratio and index were calculated for each protein. In the CSF of ambulatory patients IgG, transferrin and albumin were elevated while the institutionalised patients had higher IgG and IgA levels compared to the controls. The CSF haptoglobin was elevated in institutionalised AD patients compared to those who were ambulatory. The CSF/serum ratio for albumin was elevated in both groups. An increase in the IgG ratio was also found in both groups. The ratios for haptoglobin and prealbumin were markedly increased in the institutionalised patients. CSF indices gave no evidence for increased intrathecal synthesis of any of the proteins investigated. The increased CSF/serum ratios for IgG and albumin and also the higher CSF albumin in patients with AD suggest an increased blood-brain barrier permeability in this disease. The high prealbumin ratio may be related to amyloidogenesis often present in AD.

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.

Studies on the Pathogenesis of Multiple Sclerosis

Protein composition of myelin and white matter was analysed in 8 multiple sclerosis (MS), 2 sub- acute sclerosing panencephalitis and 1 postvaccinal leucoencephalitis autopsy samples. Special attentio

SELENIUM, VITAMIN E AND COPPER IN MULTIPLE SCLEROSIS

There has been accumulation of the nutritional muscular dystrophy of the cattle in a certain western district of Finland where the prevalence of multiple sclerosis (MS) is also highest. This animal disease is due to lack of selenium (Se) and vitamin E. The Se content of whole blood was low (52.8 ± 11.3 ng/ml) in MS patients from this high‐risk area compared to the controls (68.8 ± 11.0). The data for serum failed to confirm this tendency. All Se values appeared to he lower than international values suggested. The values for hoth vitamin E and copper were within the international normal range.

Serum and Cerebrospinal Fluid Proteins and the Blood-Brain Barrier in Alzheimer’s Disease and Multi-Infarct Dementia

Serum concentrations of IgG, IgA, IgM, haptoglobin, transferrin, prealbumin and albumin quantitated nephelometrically in 22 patients with Alzheimers disease (AD), 29 patients with multi-infarct dementia (MID) and their age-matched controls were normal. Cerebrospinal fluid (CSF) albumin and CSF/serum ratio for albumin were higher in AD and MID patients compared to controls, but no significant differences were found between AD and MID. Patients with MID had elevated CSF IgG, IgA, IgM and prealbumin levels compared to controls and to AD. An increased CSF IgG index was found in 5 MID patients but none of the AD patients. Thus, the blood-brain barrier permeability is often increased in MID as well as in AD. There is no increased intrathecal IgG synthesis in AD but it may occur in MID.