Protein tyrosine phosphatase receptor type Q in cerebrospinal fluid reflects ependymal cell dysfunction and is a potential biomarker for adult chronic hydrocephalus.

BACKGROUND AND PURPOSE: Protein tyrosine phosphatase receptor type Q (PTPRQ) was extracted from the cerebrospinal fluid (CSF) of patients with probable idiopathic normal-pressure hydrocephalus (iNPH) by proteome analysis. We aimed to assess the feasibility of using CSF PTPRQ concentrations for the additional diagnostic criterion of iNPH in Japanese and Finnish populations. METHODS: We compared PTPRQ concentrations among patients with probable iNPH and neurologically healthy individuals (normal control [NC] group), patients with normal-pressure hydrocephalus (NPH) of acquired and congenital/developmental aetiologies, patients with Alzheimer's disease and patients with Parkinson's disease in a Japanese analysis cohort. A corresponding iNPH group and NC group in a Finnish cohort was used for validation. Patients in the Finnish cohort who underwent biopsy were classified into two groups based on amyloid and/or tau deposition. We measured PTPRQ expression levels in autopsied brain specimens of iNPH patients and the NC group. RESULTS: Cerebrospinal fluid PTPRQ concentrations in the patients with NPH of idiopathic, acquired and congenital/developmental aetiologies were significantly higher than those in the NC group and those with Parkinson's disease, but iNPH showed no significant differences when compared with those in the Alzheimer's disease group. For the patients with iNPH, the area under the receiver-operating characteristic curve was 0.860 in the Japanese iNPH and 0.849 in the Finnish iNPH cohorts. Immunostaining and in situ hybridization revealed PTPRQ expression in the ependymal cells and choroid plexus. It is highly possible that the elevated PTPRQ levels in the CSF are related to ependymal dysfunction from ventricular expansion. CONCLUSIONS: Cerebrospinal fluid PTPRQ levels indicated the validity of this assay for auxiliary diagnosis of adult chronic hydrocephalus.

Health-related quality-of-life outcome in patients with idiopathic normal-pressure hydrocephalus - a 1-year follow-up study.

BACKGROUND AND PURPOSE: This prospective study explored the factors affecting the health-related quality-of-life (HRQoL) outcome in patients with idiopathic normal-pressure hydrocephalus (iNPH) 1 year after the installation of the cerebrospinal fluid shunt. METHODS: The HRQoL outcome was evaluated using a 15D instrument, in which the minimum clinically significant change/difference has been estimated to be ±0.015. The follow-up data (15D, Mini-Mental State Examination, Beck Depression Inventory, iNPH Grading Scale), frontal cortical biopsy, Charlson Age Comorbidity Index and body mass index of 145 patients diagnosed with iNPH by clinical and radiological examination were analyzed. RESULTS: At 1-year follow-up, 63 (43%) patients had experienced a clinically significant improvement in HRQoL. Multivariate binary logistic regression analysis indicated that the absence of amyloid-ß and hyperphosphorylated tau pathology in the frontal cortical biopsy (53% vs. 33%; absolute risk difference, 20%; adjusted odds ratio, 2.27; 95% confidence interval, 1.07-4.84; P < 0.05) and lower body mass index (adjusted odds ratio, 0.90, 95% confidence interval, 0.82-0.98; P < 0.05) predicted favorable HRQoL outcome 1 year after the shunting. CONCLUSIONS: Less than half of the patients with iNPH experienced clinically significant favorable HRQoL outcome, partly explained by the patient's characteristics and comorbidities. The HRQoL approach reveals aspects that are important for the patient's well-being, but may also improve the quality of the outcome assessment of cerebrospinal fluid shunting. Study results may help clinicians to estimate which patients will benefit shunt surgery.

Adipokines played a limited role in predicting temporary growth differences between very low birthweight infants with and without bronchopulmonary dysplasia.

AIMS: This study explored whether growth was poorer among very low birthweight (VLBW) infants with bronchopulmonary dysplasia (BPD) and assessed adipokine levels as predictors of early growth. METHODS: We studied 53 VLBW infants born in Tampere University Hospital up to 12 months of corrected age (CA). The median gestational age of the 21 infants with BPD and 32 infants without BPD was 29 weeks, and the median birthweights were 930 (635-1470) and 1185 (650-1470) grams. Growth parameters, macronutrients intake and plasma levels of adipokines were measured. RESULTS: Bronchopulmonary dysplasia infants were lighter than controls until 36 weeks of CA, with catch-up growth achieved by three months of CA. Adipsin levels were lower in BPD infants at 28 days of postnatal age. High leptin levels seemed protective for low weight for height at nine months of CA. The duration of ventilator therapy predicted low weight for height, length for age and body mass index and BPD predicted low length for age at 12 months of CA. CONCLUSIONS: Catch-up growth in VLBW infants with BPD was achieved by three months of CA, but adipokines played a limited role in predicting growth. Shortening ventilator therapy could help growth in VLBW infants.

Health-related quality of life in patients with idiopathic normal pressure hydrocephalus.

BACKGROUND AND PURPOSE: Factors affecting health-related quality of life (HRQoL) were explored in patients with idiopathic normal pressure hydrocephalus (iNPH). METHODS: Using the 15D instrument HRQoL was evaluated in 132 patients diagnosed with iNPH by clinical and neuroradiological examinations. The severity of iNPH symptoms was measured with the iNPH grading scale (iNPHGS), depressive symptoms with the Beck Depression Inventory (BDI-21) and cognitive impairment with the Mini-Mental State Examination. RESULTS: The mean (SD) 15D score (on a 0-1 scale) of patients with iNPH was significantly lower than that of an age- and gender-matched sample of the general population [0.718 (0.103) vs. 0.870 (0.106); P < 0.001]. The mean 15D score was lower in iNPH patients with moderate or severe depressive symptoms than in patients without depressive symptoms (P = 0.003). According to stepwise multiple linear regression analysis, a higher total iNPHGS score (b = -0.62, P < 0.001) and a higher BDI-21 total score (ß = -0.201, P = 0.025) predicted a lower 15D score; in combination, these explained 51% of the variance in the 15D score (R(2)  = 0.506, P < 0.001). CONCLUSIONS: Idiopathic normal pressure hydrocephalus impairs patients' HRQoL on multiple dimensions, similarly to other chronic diseases. Potentially treatable depressive symptoms contribute greatly to the HRQoL impairment of iNPH patients, but only if they are moderate or severe. The 15D portrayed HRQoL dimensions affected by iNPH in a similar way to broader assessment batteries and thus is a potentially useful tool for treatment evaluation and cost-utility analysis.

Positron emission tomography with [18F]flutemetamol and [11C]PiB for in vivo detection of cerebral cortical amyloid in normal pressure hydrocephalus patients.

BACKGROUND AND PURPOSE: This study determined the correlation between uptake of the amyloid positron emission tomography (PET) imaging agent [(18) F]flutemetamol and amyloid-ß measured by immunohistochemical and histochemical staining in a frontal cortical biopsy. METHODS: Fifteen patients with possible normal pressure hydrocephalus (NPH) and previous brain biopsy obtained during intracranial pressure monitoring underwent [18F]flutemetamol PET. Seven of these patients also underwent [11C] Pittsburgh compound B (PiB) PET. [18F]Flutemetamol and [11C]PiB uptake was quantified using standardized uptake value ratio (SUVR) with the cerebellar cortex as a reference region. Tissue amyloid-ß was evaluated using the monoclonal antibody 4G8, Thioflavin-S and Bielschowsky silver stain. RESULTS: [18F]Flutemetamol and [11C]PiB SUVRs correlated with biopsy specimen amyloid-ß levels contralateral (r = 0.86, P < 0.0001; r = 0.96, P = 0.0008) and ipsilateral (r = 0.82, P = 0.0002; r = 0.87, P = 0.01) to the biopsy site. Association between cortical composite [(18) F]flutemetamol SUVRs and [11C]PiB SUVRs was highly significant (r = 0.97, P = 0.0003). CONCLUSIONS: [18F]Flutemetamol detects brain amyloid-ß in vivo with moderate to high sensitivity and high specificity. This agent, therefore, represents a valuable new tool to study and verify the presence of amyloid-ß pathology, both in patients with possible NPH and among the wider population.

Umbilically and Peripherally Inserted Thin Central Venous Catheters Have Similar Risks of Complications in Very Low-Birth-Weight Infants.

Catheter complications can be life-threatening in very low-birth-weight (VLBW) infants. We retrospectively evaluated non-elective removals of the first thin (1-2F) umbilical vein catheters (tUVCs (n = 92)) and peripherally inserted central venous catheters (PICCs (n = 103)) among 195 VLBW infants. Catheters were removed non-electively in 78 infants (40%), typically due to suspected infection (n = 42) or catheter dislocation (n = 30). Infants with complications had lower birth weights and gestational ages than others. The frequencies and causes of catheter removal were similar in the tUVC and PICC groups. Thirty-one infants had true catheter infections. The number of infections/1000 catheter days was higher in the tUVC group than in the PICC group. In a multivariable analysis, gestational age was associated with catheter infection, but catheter type was not. The odds of catheter complications decreased with increasing gestational age, but no clear association with thin catheter type was found.

Post-mortem findings in 10 patients with presumed normal-pressure hydrocephalus and review of the literature.

AIMS: Neuropathological features of idiopathic normal-pressure hydrocephalus (iNPH) are poorly characterized. Brain biopsy during life may help in the differential diagnosis of dementia, but post-mortem validation of biopsy findings is scarce. Here we review and report brain biopsy and post-mortem neuropathological findings in patients with presumed NPH. METHODS: We evaluated 10 patients initially investigated by intraventricular pressure monitoring and a frontal cortical biopsy for histological and immunohistochemical assessment as a diagnostic procedure for presumed NPH. RESULTS: Out of the 10 patients, eight were shunted and seven benefited. Until death, six had developed severe and two mild cognitive impairment. One was cognitively unimpaired, and one was mentally retarded. Three subjects displayed amyloid-ß (Aß) aggregates in their frontal cortical biopsy obtained at the initial procedure. One of these patients developed Alzheimer's disease during a follow-up time of nearly 10 years. One patient with cognitive impairment and NPH suffered from corticobasal degeneration. In six patients various vascular lesions were seen at the final neuropathological investigation. Five of them were cognitively impaired, and in four vascular lesions were seen sufficient in extent to be considered as causative regarding their symptoms. CONCLUSIONS: The frequent finding of vascular pathology in NPH is intriguing, suggesting that vascular alterations might be causative of cognitive impairment in a notable number of patients with NPH and dementia. Brain biopsy can be used to detect Aß aggregates, but neuropathological characteristics of iNPH as a distinct disease still need to be discovered.

Rightward bias in right hemisphere infarct patients with or without thrombolytic treatment and in healthy controls.

Right hemisphere (RH) infarct patients have a tendency to begin visual scanning from the right side of a given stimulus. Our aim was to find out whether RH patients with (T+) or without (T-) thrombolytic treatment and healthy controls differ in their starting points in three cancellation tasks. Our sample comprised of 77 patients and 62 controls. Thirty-four patients received thrombolysis. Rightward orientation bias was more evident in the T- group than in the T+ group. The T+ group showed a robust tendency to start all cancellation tasks more often on the right side than the controls. Regardless of whether they had visual neglect, patients in the T+ group showed still defective rightward orienting, possibly indicating residual attentional problems. The analyses of starting points in visual cancellation tasks provide additional information on residual symptoms of attention difficulties after stroke.

Predictors of functional outcome after right hemisphere stroke in patients with or without thrombolytic treatment.

The purpose of this study was to assess the predictors of functional outcome after right hemisphere stroke at 6-month follow up in patients with or without thrombolytic treatment. Thrombolysis did not predict functional outcome in instrumental activities of daily living (IADL). Lower acute phase basic activities of daily living (ADL) measured by the Barthel Index was a statistically significant predictor of IADL when adjusted for age and education (p = .015) and had borderline significance (p = .076) as a predictor of functional outcome when adjusted for severity of stroke at admission. When stroke severity was taken into account also higher age became a statistically significant (p = .039) predictor of functional outcome. The acute phase neuropsychological symptoms predicted the functional outcome in unadjusted analyses but when adjusted for age, education, and severity of stroke no independent association was found.

The presence of visual neglect after thrombolytic treatment in patients with right hemisphere stroke.

Visual neglect (VN) is a common consequence of right hemisphere (RH) stroke. The aims of this study were to explore the presence of VN after RH stroke in the patients with (T+) or without (T-) thrombolytic treatment, and to determine whether thrombolysis is a predictor of VN. The study group consisted of 77 RH infarct patients. VN was evaluated with six conventional subtests of the Behavioural Inattention Test (BIT). Stroke severity was assessed using the National Institute of Health Stroke Scale (NIHSS). In the neuropsychological examination, 22% of all RH stroke patients had VN. VN was present in 15% of the patients in the T+ group and in 28% of the patients in the T- group, but the difference was not statistically significant. Despite that, patients in the T- group had a higher risk of VN than patients in the T+ group. Our results suggest that thrombolysis independently predicted absence of VN.

5-Year health-related quality of life outcome in patients with idiopathic normal pressure hydrocephalus.

BACKGROUND: Health-related quality of life (HRQoL) is severely impaired in persons with idiopathic normal pressure hydrocephalus (iNPH). The HRQoL improves in a number of patients after the placement of a cerebrospinal fluid (CSF) shunt, but long-term follow-up of HRQoL is rare. METHODS: Extended follow-up (60 months) of a prospective cohort study involving 189 patients with iNPH who underwent shunt surgery. Preoperative variables were used to predict favorable HRQoL outcome (improvement or non-deterioration) measured by the 15D instrument 5 years after shunting. RESULTS: Out of the 189 initially enrolled study participants, 88 had completed 5-year HRQoL follow-up (46%), 64 had died (34%), and 37 (20%) failed to complete the HRQoL follow-up but were alive at the end of the study. After initial post-operative HRQoL improvement, HRQoL deteriorated so that 37/88 participants (42%) had a favorable HRQoL outcome 5 years after shunting. Multivariate binary logistic regression analysis indicated that younger age (adjusted OR 0.86, 95% CI 0.77-0.95; p < 0.005), lower body mass index (adjusted OR 0.87, 95% CI 0.77-0.98; p < 0.05) and better Mini-Mental State Examination performance (adjusted OR 1.16, 95% CI 1.01-1.32; p < 0.05) before surgery predicted favorable 5-year outcome. CONCLUSIONS: This extended follow-up showed that the self-evaluated HRQoL outcome is associated with iNPH patients' pre-operative cognitive status, overweight and age. The post-operative deterioration may reflect the natural progression of iNPH, but also derive from aging and comorbidities. It indicates a need for long-term follow-up.

Network structures and temporal stability of self- and informant-rated affective symptoms in Alzheimer's disease.

BACKGROUND: Affective symptoms in Alzheimer's disease (AD) can be rated with both informant- and self-ratings. Information from these two modalities may not converge. We estimated network structures of affective symptoms in AD with both rating modalities and assessed the longitudinal stability of the networks. METHODS: Network analyses combining self-rated and informant-rated affective symptoms were conducted in 3198 individuals with AD at two time points (mean follow-up 387 days), drawn from the NACC database. Self-rated symptoms were assessed by Geriatric Depression Scale, and informant-rated symptoms included depression, apathy and anxiety questions from Neuropsychiatric Inventory Questionnaire. RESULTS: Informant-rated symptoms were mainly connected to symptoms expressing lack of positive affect, but not to the more central symptoms of self-rated worthlessness and helplessness. Networks did not differ in structure (p = .71), or connectivity (p = .92) between visits. Symptoms formed four clinically meaningful clusters of depressive symptoms and decline, lack of positive affect, informant-rated apathy and anxiety and informant-rated depression. LIMITATIONS: The symptom dynamics in our study could have been present before AD diagnosis. The lack of positive affect cluster may represent a methodological artefact rather than a theoretically meaningful subgroup. Requiring follow-up lead to a selection of patients with less cognitive decline. CONCLUSIONS: Informant rating may only capture the more visible affective symptoms, such as not being in good spirits, instead of more central and severe symptoms, such as hopelessness and worthlessness. Future research should continue to be mindful of differences between self- and informant-rated symptoms even in earlier stages of AD.

The Kuopio idiopathic normal pressure hydrocephalus protocol: initial outcome of 175 patients.

BACKGROUND: The Kuopio University Hospital (KUH) idiopathic normal pressure hydrocephalus (iNPH) cerebrospinal fluid (CSF) shunting protocol is described together with the initial outcomes of 175 patients with probable iNPH treated according to this protocol from a defined population. Our secondary aim was to display the variety of differential diagnoses referred to the KUH iNPH outpatient clinic from 2010 until 2017. METHODS: Patients were divided into four groups according to the prognostic tests: tap test (positive or negative) and infusion test (positive or negative). The short-term outcome was compared between groups. The 3-month outcome following shunt surgery was assessed by measuring gait speed improvement, using a 12-point iNPH grading scale (iNPHGS) and the 15D instrument. RESULTS: From 341 patients suspected of iNPH, 88 patients were excluded from further research mostly due to deviation from the protocol's gait assessment guidelines. Hence 253 patients with suspected iNPH were included in the study, 177/253 (70%) of whom were treated with a CSF shunt. A favorable clinical outcome following surgery was observed in 79-93% of patients depending on the prognostic group. A moderate association (Cramer's V = 0.32) was found between the gait speed improvement rate and the prognostic group (X2, p = 0.003). Patients with a positive tap test had the highest gait speed improvement rate (75%). In addition, an improvement in walking speed was observed in 4/11 patients who had both a negative tap test and a negative infusion test. Other outcome measures did not differ between the prognostic groups. Conditions other than iNPH were found in 25% of the patients referred to iNPH outpatient clinic, with the most prevalent being Alzheimer's disease. CONCLUSIONS: Our results emphasize the importance of a systematic diagnostic and prognostic workup especially in cases with an atypical presentation of iNPH. Additional diagnostic testing may be required, but should not delay adequate care. Active surgical treatment is recommended in patients with a high clinical probability of iNPH. Other neurological conditions contributed to most of the non iNPH diagnoses.

Genetic study between SIRT1, PPARD, PGC-1alpha genes and Alzheimer's disease.

Single nucleotide polymorphisms (SNPs) in three diabetes-related genes (SIRT1, PPARD, PGC-1alpha) were investigated with a case-control approach. To examine the genetic association of those genes with Alzheimer's disease (AD) risk, we used the TaqMan technique to genotype five SNP sites for SIRT1, six for PPARD and eight for the PGC-1alpha gene, in 326 Finnish AD cases and 463 controls and conducted a single allele and genotypic distribution comparison as well as estimated haplotype frequencies between cases and controls. No significant differences in AD risk were found in single SNP and haplotype analyses for any of the three genes between 326 cases and 463 controls. However, in a subgroup of women older than 65 years, the frequencies of three SNPs in the SIRT1 gene were significantly different between AD and controls. We conclude that there is no real association with SNPs available in the present study between SIRT1, PPARD or PGC-1alpha genes and AD risk in the Finnish population.

Fluctuation in spontaneous recovery of left visual neglect: a 1-year follow-up.

Spontaneous recovery and possible fluctuation in left visual neglect, and its relation to stroke severity, basic activities of daily living (ADL) and extended ADL were examined at 10 days, at 3, 6, and 12 months after onset. Twenty-one of 56 right hemisphere stroke patients had visual neglect. Three visual neglect recovery groups were identified: continuous, fluctuating and poor recovery. We concentrated on the comparison of the continuous and the fluctuating recovery groups. At the acute phase the fluctuating recovery group had larger infarcts, more severe neglect and stroke, and a lower level of basic ADL compared to the continuous recovery group. In the continuous recovery group stable recovery was detected up to 6 months, whereas in the fluctuating recovery group recovery was incoherent in neglect and in extended ADL. A minimum follow-up period of 6 months including the evaluation of extended ADL is recommended for neglect patients due to possible fluctuation in visual neglect.

Cigarette smoking in long-term schizophrenia.

PURPOSE: Cigarette smoking is a great health problem and prevalent among subjects with schizophrenia. Our aim was to investigate the prevalence and associations of cigarette smoking in patients with long-term schizophrenia. METHODS: Seven hundred and sixty schizophrenia patients were interviewed and their cigarette smoking was recorded. RESULTS: Smoking was more prevalent men than in women patients. In logistic regression analysis, male gender, duration of illness (DUI) from 10 to 19 years, being divorced or separated, lower education and high daily doses of neuroleptics (DDN) associated significantly with regular smoking. Heavy smoking associated, in men, with hospital treatment. CONCLUSIONS: In schizophrenia patients, smoking is associated with long DUI, high DDN and institutional care. Interventions for cessation and/or reduction of cigarette smoking should be a part of the treatment for patients with schizophrenia.

Altered complexity and correlation properties of R-R interval dynamics before the spontaneous onset of paroxysmal atrial fibrillation.

BACKGROUND: Trigger mechanisms for the onset of paroxysmal atrial fibrillation (AF) in patients without structural heart disease are not well established. New analysis methods of heart rate (HR) variability based on nonlinear system theory may reveal features and abnormalities in R-R interval behavior that are not detectable by traditional analysis methods. The purpose of this study was to reveal possible alterations in the dynamics of R-R intervals before the spontaneous onset of paroxysmal AF. METHODS AND RESULTS: Traditional time and frequency domain HR variability indices, along with the short-term scaling exponent alpha(1) and approximate entropy (ApEn), were analyzed in 20-minute intervals before 92 episodes of spontaneous, paroxysmal AF in 22 patients without structural heart disease. Traditional HR variability measures showed no significant changes before the onset of AF. A progressive decrease occurred both in ApEn (1.09+/-0.26 120 to 100 minutes before AF; 0.88+/-0.24 20 to 0 minutes before AF; P<0.001) and in alpha(1) (1.01+/-0.28 120 to 100 minutes before AF, 0.89+/-0.28 20 to 0 minutes before AF; P<0.05) before the AF episodes. Both ApEn (0. 89+/-0.27 versus 1.02+/-0.30; P<0.05) and alpha(1) (0.91+/-0.28 versus 1.27+/-0.21; P<0.001) were also lower before the onset of AF compared with values obtained from matched healthy control subjects. CONCLUSIONS: A decrease in the complexity of R-R intervals and altered fractal properties in short-term R-R interval dynamics precede the spontaneous onset of AF in patients with no structural heart disease. Further studies are needed to determine the physiological correlates of these new, nonlinear HR variability measures.

Bone structure and volumetric density in young adults born prematurely: a peripheral quantitative computed tomography study.

Prematurity is known to be associated with reduced bone mineral density (BMD) in childhood, but whether this condition has long-term detrimental consequences on adult bone structure is not known. In this study, we measured with peripheral quantitative computed tomography (pQCT) the total bone cross-sectional area, cortical area and wall thickness, cortical and trabecular density, and a density-weighed polar section modulus as a bone strength index (BSI) at distal and shaft sites of right radius and tibia in a group of 40 prematurely born, otherwise normally developed and healthy young adults (17 women and 23 men, aged 18 to 27 years) and compared their data to corresponding data obtained from a group of 42 control subjects born term (20 women and 22 men, aged 18 to 28 years). Body height and weight were similar in both groups, but the preterm group had significantly lower BSI values at distal sites of tibia (approximately -16%) and radius (approximately -13%) and at tibial shaft (approximately -11%) as compared to control group. In the weight-bearing tibia, BMC was lower and the lower BSI values were mainly due to smaller total bone cross-sectional area. For unknown reason, this prematurity-associated detrimental effect seemed to concern more men than women. In contrast, prematurity was not associated with volumetric trabecular and cortical densities at any measured bone site while the typical sex differences in bone density were observed. We conclude that prematurity is associated with somewhat smaller cross-sectional bone dimensions in terms of body size in young adulthood. Due to the cross-sectional design, this study could not reveal specific reasons but they may pertain to nutrition during the neonatal period and living habits in general.

Identification of a novel 4.6-kb genomic deletion in presenilin-1 gene which results in exclusion of exon 9 in a Finnish early onset Alzheimer's disease family: an Alu core sequence-stimulated recombination?

Mutations in the presenilin-1 (PS-1) gene have been shown to cause early onset Alzheimer's disease (EOAD) in an autosomal dominant manner. We have identified a novel 4.6-kb genomic deletion in the PS-1 gene in a Finnish EOAD family, which leads to an inframe exclusion of exon9 (delta9) from the mRNA transcript. This germline mutation results in a similar alteration in mRNA level as previously described with the variant AD and the delta9 splice-site mutations. In this present EOAD family, the clinical and neuropathological phenotype of patients are those of the typical AD without indications of spastic paraparesis or 'cotton wool' plaques, which are the hallmarks of the variant AD. A sequence analysis of the deletion crossover site of the mutant and corresponding wild type regions revealed complete homology with the recombigenic 26 bp Alu core sequence at intron 8. In addition, a segment at the intron 9 breakpoint displayed homology with the core sequence, but comparison of the 5' and 3' breakpoint sequences did not reveal significant identity favouring involvement of Alu core sequence-stimulated non-homologous recombination rather than Alu-mediated homologous pairing of the fragments. This study shows that large genomic rearrangements can affect the EOAD gene PS-1 through a mechanism, which may involve Alu core sequence-stimulated recombination.

Linkage disequilibrium in the 13q12 region in Finnish late onset Alzheimer's disease patients.

Alzheimer's disease (AD) is a complex neurodegenerative disorder, for which several disease-associated loci have been located on different chromosomes. We have used a population-based linkage disequilibrium mapping approach in order to find potential AD-associated loci on chromosome 13. To avoid population stratification, late onset AD patients and age-matched controls were carefully chosen from the same geographical area in Eastern Finland, where the population is mainly descended from a small group of original founders. During the initial screening with chromosome 13-specific microsatellite markers, tetranucleotide marker D13S787 was found to be in linkage disequilibrium in the 13q12 region. Screening this region with additional microsatellite markers revealed that marker D13S292 was also significantly associated with AD. Stratification of the AD patients and controls into groups according to apolipoprotein E, sex, and familial/sporadic status indicated that the 13q12 locus was associated with female familial AD patients regardless of ApoE genotype. Based on the physical data from the region 13q12, markers D13S292 and D13S787 were estimated to reside in a 810kb long YAC clone 754h7 together with two infant brain-derived ESTs and the H,K-ATPase alpha-subunit protein gene (ATP1AL1). The localisation of these sequences at the linkage disequilibrium region suggests that they may be candidate genes involved in a sex-specific effect during development of AD.