alpha-Synuclein pathology in the spinal cord autonomic nuclei associates with alpha-synuclein pathology in the brain: a population-based Vantaa 85+ study.

In most subjects with Parkinson's disease and dementia with Lewy bodies, alpha-synuclein (alphaS) immunoreactive pathology is found not only in the brain but also in the autonomic nuclei of the spinal cord. However, neither has the temporal course of alphaS pathology in the spinal cord in relation to the brain progression been established, nor has the extent of alphaS pathology in the spinal cord been analyzed in population-based studies. Using immunohistochemistry, the frequency and distribution of alphaS pathology were assessed semiquantitatively in the brains and spinal cord nuclei of 304 subjects who were aged at least 85 in the population-based Vantaa 85+ study. alphaS pathology was common in the spinal cord; 102 (34%) subjects had classic alphaS pathology in the thoracic and/or sacral autonomic nuclei. Moreover, 134 (44%) subjects showed grain- or dot-like immunoreactivity in neuropil (mini-aggregates) without classic Lewy neurites or Lewy bodies (LBs). The latter type of alphaS accumulation is associated with age, but also the classic alphaS pathology was found more often in the oldest compared to the youngest age group. The severity of alphaS pathology in the spinal cord autonomic nuclei is significantly associated with the extent and severity of alphaS pathology in the brain. Of the subjects, 60% with moderate to severe thoracic alphaS pathology and up to 89% with moderate to severe sacral alphaS pathology had diffuse neocortical type of LB pathology in the brain. alphaS pathology exclusively in the spinal cord was rare. Our study indicates that in general alphaS pathology in the spinal cord autonomic nuclei is associated with similar pathology in the brain.

30-year trends in asthma and the trends in relation to hospitalization and mortality.

INTRODUCTION: The present study examines how trends in the prevalence of asthma during the past three decades associate with hospitalization and mortality during the same period. METHODS: Altogether 54 320 subjects aged 25-74 years were examined in seven independent cross-sectional population surveys repeated every five years between 1982 and 2012 in Finland. The study protocol included a standardized questionnaire on self-reported asthma, smoking habits and other risk factors, and clinical measurements at the study site. Data on hospitalizations were obtained from the Care Register for Health Care, and data on mortality from the National Causes of Death register. RESULTS: During the study, the prevalence of asthma increased - especially in women. In asthmatic compared with non-asthmatic subjects, hospitalization was significantly higher for all causes, respiratory causes, cardiovascular causes and lung cancer. In addition, particularly in asthmatic subjects, mean yearly hospital days in the 5-year periods after each survey diminished. In asthmatic subjects, the decrease in yearly all-cause hospital days was from 4.45 (between 1982 and 1987) to 1.11 (between 2012 and 2015) and in subjects without asthma the corresponding decrease was from 1.77 to 0.60 (p < 0.001). Similarly between 1982 and 2015, COPD hospitalization decreased more in asthmatic than in non-asthmatic subjects. Generally in the present study, all-cause mortality decreased between 1982 and 2015, though mortality in asthmatic subjects compared with non-asthmatics was higher from all causes, respiratory causes and lung cancer. CONCLUSION: There was an increasing trend in the prevalence of asthma and a declining trend in hospitalization, especially in asthmatic subjects.

Association of allergy, asthma and IgE sensitisation to adenoidectomy and infections in children.

OBJECTIVE: To find out whether previous adenoidectomy is associated with asthma, allergic symptoms or allergen-specific IgE antibodies. RECRUITMENT AND METHODS: We recruited 213 paediatric patients admitted for elective tonsillectomy and 155 paediatric controls. Using a structured questionnaire, we recorded their respiratory symptoms, allergies, bronchial asthma and environmental factors. Serum IgE antibodies against respiratory allergens were screened. Patients were divided into those previously adenoidectomised (n = 100) or not adenoidectomised (n = 113). RESULTS: Any allergy (p = 0.007) and non-antibiotic allergy diagnosed by a doctor (p = 0.015), and asthma (p = 0.015) were more common among adenoidectomised than non-adenoidectomised children under the age of seven. Between ages 7 and 11, neither any kind of allergy nor asthma were associated with earlier adenoidectomy. In the oldest age group (12 to 17), only antibiotic allergy was more common in adenoidectomised children. Recurrent otitis media (p < 0.001) and recurrent sinusitis (p = 0.007) were more common in adenoidectomised children. After controlling for recurrent respiratory infections, doctor-diagnosed allergy remained significantly associated with adenoidectomy in the youngest age group. Prevalence of specific IgE did not differ between the patient groups, or between school-aged patients and controls. CONCLUSIONS: Our results suggest that hypersensitivity disorders and infections may share aetiological factors. However, as adenoidectomised children of any age did not have higher levels of specific IgE, it seems possible that allergy is either clinically over-diagnosed or insufficiently detected by serology among young adenoidectomised children.

Chronic bronchitis in relation to hospitalization and mortality over three decades.

BACKGROUND: The study examines the predictive value of chronic bronchitis for all cause and cause-specific hospitalizations and for mortality during the last three decades. METHODS: The study population consists of altogether 47 896 men and women aged 25-74 years who participated in the National FINRISK Study between 1982 and 2007. The study protocol included a standardized questionnaire on the symptoms of chronic bronchitis, smoking habits and other risk factors and clinical measurements at the study site. Data on hospitalizations were obtained from the National Hospital Discharge Registry, and data on the underlying causes of deaths from the National Causes of Death register. The study cohorts were followed up until the end of 2011. RESULTS: In study subjects with symptoms of chronic bronchitis the mean annual days of hospitalization were almost two-fold higher than in study subjects without chronic bronchitis. The increase was seen in all age -groups and both in 5-year periods for each cohort and during the whole 30-year follow-up. More specifically, hospitalizations were increased for respiratory diseases and cancer. Chronic bronchitis increased hospitalizations more in smokers and ex-smokers than in never smokers. Furthermore, chronic bronchitis was associated with increased all-cause mortality (hazard ratio (HR) 1.23) and mortality from respiratory causes, cardiovascular diseases and cancer. Smokers and ex-smokers with chronic bronchitis had an increased risk to die (HRs 2.89 and 1.69, respectively) compared with never-smokers without chronic bronchitis. CONCLUSION: Symptoms of chronic bronchitis can help to identify individuals who are at risk for increased hospitalizations and mortality.

Population-based analysis of pathological correlates of dementia in the oldest old.

OBJECTIVE: The aim of this study was to analyze brain pathologies which cause dementia in the oldest old population. METHODS: All 601 persons aged ≥85 years living in the city of Vantaa (Finland), on April 1st, 1991 formed the study population of the Vantaa85 +  study, 300 of whom were autopsied during follow-up (79.5% females, mean age-at-death 92 ± 3.7 years). Alzheimer's disease (AD) pathology (tau and beta-amyloid [Aß]), cerebral amyloid angiopathy (CAA) and Lewy-related pathologies were analyzed. Brain infarcts were categorized by size (<2 mm, 2-15 mm, >15 mm) and by location. Brain hemorrhages were classified as microscopic (<2 mm) and macroscopic. RESULTS: 195/300 (65%) were demented. 194/195 (99%) of the demented had at least one neuropathology. Three independent contributors to dementia were identified: AD-type tau-pathology (Braak stage V-VI), neocortical Lewy-related pathology, and cortical anterior 2-15 mm infarcts. These were found in 34%, 21%, and 21% of the demented, respectively, with the multivariate odds ratios (OR) for dementia 5.5, 4.5, and 3.4. Factor analysis investigating the relationships between different pathologies identified three separate factors: (1) AD-spectrum, which included neurofibrillary tau, Aß plaque, and neocortical Lewy-related pathologies and CAA (2) >2 mm cortical and subcortical infarcts, and (3) <2 mm cortical microinfarcts and microhemorrhages. Multipathology was common and increased the risk of dementia significantly. INTERPRETATION: These results indicate that AD-type neurodegenerative processes play the most prominent role in twilight cognitive decline. The high prevalence of both neurodegenerative and vascular pathologies indicates that multiple preventive and therapeutic approaches are needed to protect the brains of the oldest old.

Thirty-year cumulative incidence of chronic bronchitis and COPD in relation to 30-year pulmonary function and 40-year mortality: a follow-up in middle-aged rural men.

PURPOSE: To describe the 30-year cumulative incidence of chronic bronchitis and COPD in relation to smoking habits. The effect of chronic bronchitis on pulmonary function and mortality was also examined. METHODS: Middle-aged men belonging to two rural Finnish cohorts of the Seven Countries Study (n = 1,711 in 1959) were followed up for up to 40 years until 2000. Standard questionnaires were used to measure chronic bronchitis, and repeated spirometry was used to evaluate pulmonary function during the 30 years. Forty-year mortality data were examined. RESULTS: The cumulative incidence of chronic bronchitis and COPD was 42% and 32%, respectively, in continuous smokers, compared to 26% and 14% in ex-smokers and 22% and 12% in never-smokers. During the follow-up, subjects with chronic bronchitis had on average 252 mL (95% confidence interval, 211 to 293 mL) lower forced expiratory volume than those without it. The decrease in forced expiratory volume attributable to chronic bronchitis was most pronounced in those with persistent symptoms and in smokers. In subjects with chronic bronchitis, all-cause mortality was increased by a hazard ratio of 1.30 (95% confidence interval, 1.02 to 1.65). Smokers with chronic bronchitis who decreased their daily cigarette consumption increased their median life span by 2.4 years. CONCLUSIONS: The lifetime risk of chronic bronchitis among smokers is approximately two in five, and almost one half of smokers who have chronic bronchitis also acquire COPD. Chronic bronchitis is related to earlier death, also in never-smokers, probably partly through a rapid decline in pulmonary function.

Mental disorders and harmful substance use in children of substance abusing parents: A longitudinal register-based study on a complete birth cohort born in 1991.

INTRODUCTION AND AIMS: Adverse childhood experiences and their accumulation over childhood have negative outcomes to children, yet earlier findings on the independent effect of parental substance abuse seem inconsistent. Our aims were to examine: (i) whether parental substance abuse is associated with children's mental disorders in mid-childhood (7-12 years) and mental disorders and own substance use in adolescence (13-17 years); and (ii) whether children are affected differently by a mother or father's substance abuse. DESIGN AND METHODS: A register-based longitudinal data on a complete birth cohort of children born in Finland in 1991 (n = 65 117) and their biological parents. The children were followed until their 18th birthday. Data were derived from the Finnish administrative registries. Bivariate and multivariate logistic regression models were used in the analysis. RESULTS: Maternal, paternal and both parents' substance abuse were significant predictors of mental disorders and harmful substance use in children aged 13-17 years, even after controlling for other adverse childhood experiences, parental education and child's gender. Parental substance abuse predicted mental disorders in children aged 7-12 years in bivariate model but in multivariate model the association disappeared. Maternal substance abuse had stronger effect on harmful substance use in adolescent children than paternal. There were no significant interactions between substance abusing parents' gender and the child's gender. DISCUSSION AND CONCLUSIONS: Early identification, prevention and treatment of substance abuse in families with children in primary health care, child welfare and other services are crucial in preventing intergenerational transmission of the problems associated with parental substance abuse. [Jääskeläinen M, Holmila M, Notkola I-L, Raitasalo K. Mental disorders and harmful substance use in children of substance abusing parents: A longitudinal register-based study on a complete birth cohort born in 1991. Drug Alcohol Rev 2016;35:728-740].

Causes of death and life span in Finnish gelsolin amyloidosis.

BACKGROUND: Finnish type of hereditary gelsolin amyloidosis (AGel amyloidosis) is an autosomal dominant disorder. Until recently, there has only been little knowledge of fatal complications of the disease and its possible impact on the patients' life span. METHODS: We identified 272 deceased patients based on patient interviews and genealogical data. After collecting their death certificates, we recorded the patients' underlying and immediate causes of death (CoD) and life span and compared them to the general Finnish population. We then calculated proportional mortality ratios (PMR), standardised for age and sex, for the CoDs. RESULTS: The underlying CoD in 20% of the patients was AGel amyloidosis (PMR = 114.2; 95% CI: 85.6-149.4). The frequency of fatal cancers (10%) was significantly diminished (PMR = 0.47; 95% CI: 0.31-0.69). Renal complications were overrepresented as the immediate CoD in female patients (PMR = 2.82 95% CI: 1.13-5.81). The mean life span for male patients was 73.9 years (95% CI: 72.0-75.6) and 78.0 years for female patients (95% CI: 76.4-79.5) compared to 72.1 and 80.1 years for the general population. CONCLUSIONS: Our results suggest that the disease increases the risk of fatal renal complications but does not substantially shorten the life span, possibly due to the significantly lower frequency of fatal cancers. Key Messages AGel amyloidosis may increase the risk of renal complications, especially among female patients. The frequency of fatal cancers is significantly lower. The patients' life span is comparable to that of the general population.

Physical functioning in elderly Europeans: 10 year changes in the north and south: the HALE project.

OBJECTIVES: To examine age related changes in physical functioning in elderly men and women. DESIGN: Prospective, population based study. SETTING: Population of 15 rural and urban centres in 10 European countries. PARTICIPANTS: Altogether 3496 men and women born between 1900 and 1920 who participated in the baseline survey of the HALE project in 1988-1991. The study population was examined again about five (in 1993-1995) and 10 (in 1999-2001) years after the baseline examination. MAIN OUTCOME MEASURES: Physical functioning was measured by means of a self administered questionnaire of activities of daily living (ADL). Dichotomised prevalence of disability and need for help in self care and mobility ADL were used as dependent variables in the analyses. RESULTS: Prevalence of disability and need for help tended to be higher in women than in men and in mobility abilities than in self care activities. Disability and need for help increased with advancing age but ameliorated over time from one birth cohort to another. In longitudinal analyses this beneficial time trend was independent of the effect of age, study, and region in self care disability in men and women (OR 0.85, 95% CI 0.75 to 0.97 and OR 0.64, 95% CI 0.43 to 0.97, respectively) and self care need for help in men (OR 0.83, 95% CI 0.70 to 0.96). Mobility disability among men and self care disability among women decreased more in the south than in the north. CONCLUSION: While European populations are aging, the proportions of elderly people with disability are decreasing. These results suggest that dynamics of functioning may differ across cultures. Future studies are needed to clarify which potentially modifiable and culturally determined factors protect against functional decline.

Chromosome 21 BACE2 haplotype associates with Alzheimer's disease: a two-stage study.

Genetic linkage studies have provided evidence for a late-onset Alzheimer's disease (AD) susceptibility locus on chromosome 21q. We have tested, in a two-stage association study, whether allelic or haplotype variation of the beta-amyloid cleaving enzyme-2 (BACE2) locus on chromosome 21q affects the risk of late-onset AD. In stage-1, an unselected population-based sample of Finns aged 85 years or over (n=515) was analysed. Neuropathologic examination including beta-amyloid load quantification was possible in over 50% (n=264) of these subjects. AD patients (n=100) and controls (n=48) were defined by modified neuropathological NIA-RI criteria. Positive associations were taken as a hypothesis, and tested in stage-2 using 483 AD families from the USA. Four single nucleotide polymorphisms (SNPs) of BACE2 gene were tested in stage-1. A SNP close to exon-6 was associated with neuropathologically verified AD (p=0.02) and also with beta-amyloid load in non-selected autopsied subjects after conditioning with APOE genotype (p=0.001). In haplotype analysis a specific, relatively common haplotype (H5) was found to associate with AD (p=0.004) and a second haplotype (H7) showed a weaker association with protection against AD (p=0.04). In stage-2, the SNP association was not replicated, whereas the haplotype H5 association was replicated (p=0.004) and a trend to association was found with the putative protective haplotype H7 (two-sided p=0.08). BACE2 haplotype association with AD in two independent datasets provides further evidence for an AD susceptibility locus on chromosome 21q within or close to BACE2.

Neuromuscular pathology in hereditary gelsolin amyloidosis.

Hereditary gelsolin amyloidosis (AGel amyloidosis) is a systemic disorder reported worldwide in kindreds with a G654A or G654T gelsolin gene mutation. The clinically characteristic peripheral nerve involvement has been poorly characterized morphologically, and its pathogenesis remains unknown. We studied peripheral nerve and skeletal muscle biopsy or autopsy specimens of 35 patients with a G654A gelsolin gene mutation. Histological, immunohistochemical, and electron microscopic studies showed consistent deposition of gelsolin amyloid (AGel), particularly in the vascular walls and perineurial sheaths. Nerve roots were more severely affected than distal nerves. The amyloid deposits also displayed variable immunoreactivity for apolipoprotein E, amyloid P component, cystatin C, and alpha-smooth muscle actin. Sural nerve morphometry showed preferential age-related large myelinated nerve fiber loss and reduction of myelin sheath cross-sectional area. There was evidence of denervation atrophy and fiber type grouping in skeletal muscle. Our study shows that marked proximal nerve involvement with AGel angiopathy is an essential feature of AGel amyloidosis. The preferential large fiber loss, not generally seen in amyloid neuropathy, may be caused by ischemia due to AGel angiopathy. Deficient actin modulation by variant gelsolin in neurons and Schwann cells, however, may alter axonal transport and myelination and contribute to AGel polyneuropathy.

Tracking of systolic blood pressure during childhood: a 15-year follow-up population-based family study in eastern Finland.

OBJECTIVES: To investigate the tracking of systolic arterial blood pressure (SBP) during childhood. DESIGN AND SETTING: All children born during 1981-82 in a rural community of eastern Finland were followed at the ages of 6 months, 7 and 15 years (SBP-6m, SBP-7y, SBP-15y). One hundred and thirty-eight out of 205 children completed the full follow-up period, of which 100 (45 girls) were included in the analysis with complete data. MAIN OUTCOME MEASURES: SBP (mmHg). RESULTS: SBP-6m was associated with SBP-7y (r = 0.715; P < 0.001) and with SBP-15y (r = 0.238; P = 0.017) and SBP-7y was associated with SBP-15y (r = 0.348; P < 0.001). Adjustment for confounders did not change these results. Children at the highest tertile of SBP-6m had a higher probability of being at the highest tertile of SBP-7y [relative risk (RR) = 4.3; 95% confidence interval (CI), (2.4-7.6)] and SBP-15y [RR = 1.9; 95% CI, (1.1-3.3)]. Children at the highest tertile of SBP-7y had a higher probability of being at the highest tertile of SBP-15y [RR = 2.6 (1.5-4.6)]. The regression analysis showed a significant main effect on SBP-15y for birth weight (negative association), male gender, current body mass index (BMI), change of BMI between the ages of 7 years and 15 years, SBP-6m, SBP-7y and the mean SBP between the ages of 6 months and 7 years (all with positive association). Children with family history of hypertension appear to have a higher SBP during childhood; however, this association did not reach a significant level. CONCLUSIONS: The study confirmed the tracking of SBP during childhood. Birth weight was inversely associated with SBP-15y. Family history of hypertension was not significantly associated with SBP during childhood.

ApoE epsilon3-haplotype modulates Alzheimer beta-amyloid deposition in the brain.

ApoE epsilon4 allele increases the risk of late-onset Alzheimer disease (AD) as well as the amount of beta-amyloid deposition in the brain. Because half of AD patients do not have ApoE epsilon4, it is important to search for other determinants of ApoE that modify AD risk. We tested whether the haplotype background of the most common ApoE allele, epsilon3, influences brain amyloid deposition or the risk of neuropathologically verified AD in a population-based sample of elderly Finns. To exclude the effects of ApoE protein polymorphism we focused these analyses on subjects homozygous for epsilon3. Haplotypes were defined using polymorphisms at positions - 491 and -219 of the ApoE promoter and at position +113 of intron-1. We found that epsilon3-haplotypes containing the promoter allele -219T were associated with reduced amyloid deposition and reduced risk of neuropathologically verified AD as compared to epsilon3-haplotypes containing -219G. The functional polymorphism(s) responsible for the haplotypic difference remains to be identified. These results indicate that there is significant allelic variation in the ApoE gene region, which modulates brain amyloid deposition and AD risk, independent of the ApoE protein polymorphism.

Twenty-five year trends in prevalence of chronic bronchitis and the trends in relation to smoking.

INTRODUCTION: The present study examines how the trends in the prevalence of chronic bronchitis during the last three decades associate with changes in smoking habits during the same period. METHODS: Altogether 47 896 subjects aged 25-74 years were examined in six independent cross-sectional population surveys repeated every five years between 1982 and 2007 in Finland. The presence of chronic bronchitis, smoking habits and other risk factors were measured by standard questionnaires. RESULTS: During the study, the prevalence of chronic bronchitis was significantly higher in men than in women. In men aged 25-64 years, the prevalence of chronic bronchitis decreased from 19% in 1982 to 13% in 2007 (p for trend <0.001). The corresponding decrease in women aged 25-64 years was from 13% to 11% (p for trend 0.009). In men aged 65-74 years, the prevalence of chronic bronchitis decreased from 24% to 19% (p for trend 0.032). Simultaneously, male smoking decreased and smoking in middle-aged women increased. However, adjusting for the changes in smoking habits did not change the declining trends in the prevalence of chronic bronchitis. The significant declining trend in chronic bronchitis was seen separately in male current smokers and in male and female never smokers aged 45-74 years and the declining trend was the greatest in male current smokers. In general, female smokers with chronic bronchitis had smoked less than their male counterparts. CONCLUSION: There was a declining trend in the prevalence of chronic bronchitis which was probably explained by both a decrease in smoking and by other factors.

Apolipoprotein E (APOE) and lipoprotein lipase (LPL) gene variants and carotid atherosclerotic lesions in the oldest old: a population-based autopsy study.

We investigated the association between histologically defined atherosclerotic lesions in the carotid arteries and the genetic variants of APOE and LPL in a population-based sample of Finns aged 85 or over. Post-mortem analysis of carotid arteries was performed in 240 subjects. Atherosclerotic lesions were categorized according to the modified American Heart Association criteria, and classified into four different categories: pathological intimal thickening (PIT), fibrous cap atheromas (FCA), calcified lesions (CL), and atherosclerotic burden (AB) (a combination of the other three categories). APOE epsilon4 genetic variant was associated with PIT (p=0.018) and AB (p=0.006) in the carotid arteries, and its effect was independent of the serum lipid levels. The genetic variant LPL Ser447Ter was protective against FCA (p=0.031) and AB (p=0.012), while APOE epsilon2 was protective against FCA (p=0.035). Our results suggest that the APOE epsilon4, epsilon2 and LPL Ser447Ter variants may have different roles in the atherosclerotic process and their effects are seen even in the oldest old population.

Neuropathologic findings of dementia with lewy bodies (DLB) in a population-based Vantaa 85+ study.

The consortium on dementia with Lewy bodies has established consensus guidelines for the neuropathologic diagnosis of dementia with Lewy bodies (DLB) including the likelihood that the neuropathologic findings associate with the clinical syndrome. Nevertheless, clinico-pathological correlations remain controversial. We applied the consensus guidelines for determining Lewy-related pathology (LRP) and evaluated the clinical presentation in the prospective, population-based Vantaa 85+ study consisting of individuals at least 85 years of age. LRP was seen in 36% of 304 subjects and categorized as follows: 3% brainstem-predominant, 14% limbic, 15% diffuse neocortical type (4% could not be categorized). The likelihood that the neuropathology predicts the DLB clinical syndrome was low in 6%, intermediate in 13%, and high in 13% of all 304 subjects. In the latter two groups, 77% were demented, 35% had at least one extrapyramidal symptom, and 15% had visual hallucinations. Surprisingly, DLB clinical features associated better with high neurofibrillary stage than with diffuse neocortical LRP. Moreover, the neurofibrillary stage, substantia nigra neuron loss, and grade of Lewy neurites in hippocampal CA2-3 region, each showed a significant association with the extent of LRP. In conclusion, the neuropathologic DLB in this very elderly population was common, but the clinical symptoms tended to associate better with severe neurofibrillary pathology than with extensive LRP.

Widespread unilateral pain associated with herpes simplex virus infections.

UNLABELLED: We describe a patient group with unexplained widespread pain on one side of the body and pain exacerbations during active labial or genital herpes and during herpetic central nervous system infections. The patients had no visible lesion of the central nervous system on magnetic resonance imaging or abnormality in electrophysiological studies. To understand the nature of the pain and its possible relation to herpes simplex virus (HSV) infections, a clinical neurological examination was performed and quantitative sensory testing and skin biopsies were assessed in 17 patients. The levels of serum total immunoglobulins and IgG subclasses and the frequencies of the immune response genes at the IGH@, HLA-A, -B, -DRB1, C4A, and C4B loci were analyzed in the patients and in control subjects. The patients manifested a uniform clinical syndrome with unilateral pain that was best described as neuropathic and that was exacerbated by HSV reactivations. Low plasma IgG3 concentrations, the presence of either low plasma IgG1 or IgG3 or both, and high anti-HSV-2-IgG titers were more common in the patients than in the control subjects, which rendered the patients more vulnerable to HSV recurrences. PERSPECTIVE: We suggest that low immunoglobulin subclass levels and certain MHC alleles render the patients susceptible to recurring HSV infections. HSV reactivations and the accompanying inflammatory process cause dysfunction of the central nervous system that manifests as neuropathic pain. Studies using functional brain imaging are needed to clarify this syndrome.

Senile systemic amyloidosis affects 25% of the very aged and associates with genetic variation in alpha2-macroglobulin and tau: a population-based autopsy study.

BACKGROUND: Senile systemic amyloidosis (SSA) is characterized by deposition of wild-type transthyretin (TTR)-based amyloid in parenchymal organs in elderly individuals. Previously, no population-based studies have been performed on SSA. METHODS: Here we have studied the prevalence and risk factors for SSA in a Finnish autopsied population aged 85 or over, as part of the population-based Vantaa 85+ Autopsy Study (n = 256). The diagnosis of SSA was based on histological examination of myocardial samples stained with Congo red and anti-TTR immunohistochemistry. The genotype frequencies of 20 polymorphisms in 9 genes in subjects with and without SSA were compared. RESULTS: The prevalence of SSA was 25%. SSA was associated with age, myocardial infarctions, the G/G (Val/Val) genotype of the exon 24 polymorphism in the alpha2-macroglobulin (alpha2M), and the H2 haplotype of the tau gene (P-values 0.002, 0.004, 0.042, and 0.016). CONCLUSION: This population-based study shows that SSA is very common in old individuals, affecting one-quarter of people aged over 85 years. Myocardial infarctions and variation in the genes for alpha2M and tau may be associated with SSA.

Incidence of dementia in very elderly individuals: a clinical, neuropathological and molecular genetic study.

AIMS: To evaluate the effect of medical record use on figures for the incidence of dementia and the effect of apolipoprotein E (APOE) polymorphism on this incidence and neuropathologically defined Alzheimer's disease (AD) in very elderly individuals. METHODS: Cognitive functions were examined in a cohort of 328 (92% of the very elderly people of a town participated in this study) nondemented Finnish elderly individuals 85 years of age or more in 1991. The examination was repeated in survivors in 1994, 1996, 1999 and 2001. Medical notes and social work records were evaluated. All these individuals were genotyped for APOE. Neuropathological analysis of AD-type pathology was performed on 159 of 303 subjects who died during the follow-up. RESULTS: Age group, gender or APOE did not significantly affect the incidence of dementia, which was over 20% higher (85 vs. 69 per 1,000 person-years) if the cognitive status at death was ascertained by medical and social work records than without this evaluation. The APOE upsilon4 allele was highly significantly (p=0.002) and age almost significantly (p=0.06) associated with neuropathological AD in nondemented individuals. CONCLUSIONS: Medical records should be analyzed in studies on the incidence of dementia in very elderly individuals. APOE polymorphism does not affect the incidence of dementia in this age group. However, clinical dementia diagnosis in very elderly individuals does not necessarily correlate well with the presence of neuropathological AD which, even in this age group, is significantly associated with the APOE upsilon4 allele.

Subtly impaired humoral immunity predisposes to frequently recurring genital herpes simplex virus type 2 infection and herpetic neuralgia.

BACKGROUND: Immunogenetic factors predisposing to recurrent genital herpes remain poorly characterized. METHODS: In a prospective case-control study, 52 consecutive patients with frequently recurring outbreaks of genital herpes were compared with 80 herpes simplex virus (HSV)-seropositive (types 1 and 2) and 70 HSV-seronegative control subjects. Immunoglobulins (Igs), type-specific anti-HSV-2 IgG and IgG subclass antibodies against glycoprotein G, levels of C3 and C4, and classical pathway hemolytic complement activity were measured, and IgG1 and IgG3 allotyping; C4 immunophenotyping; C4* real-time polymerase chain reaction (PCR) genotyping; and HLA-A*, B*, and DR* typing were performed. RESULTS: The G3m(g),G1m(a/a(x)) haplotype was more frequent in patients than in HSV-seronegative control subjects (P=.047). Compared with all control subjects, low levels of total IgG1 (odds ratio [OR], 4.9 [95% confidence interval {CI}, 2.0-12.5]; P=.001) and IgG3 (OR 3.6 [95% CI 1.7-7.8]; P=.001), but not of anti-HSV-2 antibodies, were associated with recurrences. Levels of complement were lowest in patients. The C4* null type was negatively associated with neuralgia (OR, 0.2 [95% CI, 0.06-0.81]; P=.022). CONCLUSIONS: Low levels of antibody-dependent cellular cytotoxicity-mediating IgG1 and IgG3 antibodies, partly dependent of allotype, may predispose to recurrent genital herpes. Antibodies produced by T helper type 1 responses, potentially against an unknown epitope, appear to be relevant in recurrences. In patients, C4* deficiencies are associated with protection from herpetic neuralgias, possibly through reduced inflammation.