Biomedical subjects

Caroline Lindholm

Publications and source records attributed to Caroline Lindholm.

7 recordsLinked to original sources

PubMed2006

Familial frontotemporal dementia with neuronal intranuclear inclusions is not a polyglutamine expansion disease.

BACKGROUND: Many cases of frontotemporal dementia (FTD) are familial, often with an autosomal dominant pattern of inheritance. Some are due to a mutation in the tau- encoding gene, on chromosome 17, and show an accumulation of abnormal tau in brain tissue (FTDP-17T). Most of the remaining familial cases do not exhibit tau pathology, but display neuropathology similar to patients with dementia and motor neuron disease, characterized by the presence of ubiquitin-immunoreactive (ub-ir), dystrophic neurites and neuronal cytoplasmic inclusions in the neocortex and hippocampus (FTLD-U). Recently, we described a subset of patients with familial FTD with autopsy-proven FTLD-U pathology and with the additional finding of ub-ir neuronal intranuclear inclusions (NII). NII are a characteristic feature of several other neurodegenerative conditions for which the genetic basis is abnormal expansion of a polyglutamine-encoding trinucleotide repeat region. The genetic basis of familial FTLD-U is currently not known, however the presence of NII suggests that a subset of cases may represent a polyglutamine expansion disease. METHODS: We studied DNA and post mortem brain tissue from 5 affected members of 4 different families with NII and one affected individual with familial FTLD-U without NII. Patient DNA was screened for CAA/CAG trinucleotide expansion in a set of candidate genes identified using a genome-wide computational approach. Genes containing CAA/CAG trinucleotide repeats encoding at least five glutamines were examined (n = 63), including the nine genes currently known to be associated with human disease. CAA/CAG tract sizes were compared with published normal values (where available) and with those of healthy controls (n = 94). High-resolution agarose gel electrophoresis was used to measure allele size (number of CAA/CAG repeats). For any alleles estimated to be equal to or larger than the maximum measured in the control population, the CAA/CAG tract length was confirmed by capillary electrophoresis. In addition, immunohistochemistry using a monoclonal antibody that recognizes proteins containing expanded polyglutamines (1C2) was performed on sections of post mortem brain tissue from subjects with NII. RESULTS: No significant polyglutamine-encoding repeat expansions were identified in the DNA from any of our FTLD-U patients. NII in the FTLD-U cases showed no 1C2 immunoreactivity. CONCLUSION: We find no evidence to suggest that autosomal dominant FTLD-U with NII is a polyglutamine expansion disease.

Brain↗

PubMed2006

Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17.

Frontotemporal dementia (FTD) is the second most common cause of dementia in people under the age of 65 years. A large proportion of FTD patients (35-50%) have a family history of dementia, consistent with a strong genetic component to the disease. In 1998, mutations in the gene encoding the microtubule-associated protein tau (MAPT) were shown to cause familial FTD with parkinsonism linked to chromosome 17q21 (FTDP-17). The neuropathology of patients with defined MAPT mutations is characterized by cytoplasmic neurofibrillary inclusions composed of hyperphosphorylated tau. However, in multiple FTD families with significant evidence for linkage to the same region on chromosome 17q21 (D17S1787-D17S806), mutations in MAPT have not been found and the patients consistently lack tau-immunoreactive inclusion pathology. In contrast, these patients have ubiquitin (ub)-immunoreactive neuronal cytoplasmic inclusions and characteristic lentiform ub-immunoreactive neuronal intranuclear inclusions. Here we demonstrate that in these families, FTD is caused by mutations in progranulin (PGRN) that are likely to create null alleles. PGRN is located 1.7 Mb centromeric of MAPT on chromosome 17q21.31 and encodes a 68.5-kDa secreted growth factor involved in the regulation of multiple processes including development, wound repair and inflammation. PGRN has also been strongly linked to tumorigenesis. Moreover, PGRN expression is increased in activated microglia in many neurodegenerative diseases including Creutzfeldt-Jakob disease, motor neuron disease and Alzheimer's disease. Our results identify mutations in PGRN as a cause of neurodegenerative disease and indicate the importance of PGRN function for neuronal survival.

Cell Survival↗

PubMed2006

A family with tau-negative frontotemporal dementia and neuronal intranuclear inclusions linked to chromosome 17.

Over 30 different mutations have now been identified in MAPt that cause frontotemporal dementia (FTD). However, there are several families with FTD that show definite linkage to the region on chromosome 17 that contains MAPt, in which no mutation(s) has been identified. Although these families could have a complex mutation of the MAPt locus that has evaded detection it is also possible that another gene in this region is associated with FTD. This possibility is supported by neuropathological findings in these families, which consist of neuronal inclusions that are immunoreactive for ubiquitin (ub-ir) but not for tau. In addition to neuronal cytoplasmic inclusions, several chromosome 17-linked families are reported to have ub-ir neuronal intranuclear inclusions (NII); a finding which is uncommon in sporadic FTD. Here, we describe detailed clinical and neuropathological findings in a new large, multigenerational family with autosomal dominant FTD and autopsy proven tau-negative, ub-ir neuronal cytoplasmic and intranuclear inclusions. We have demonstrated that this family is linked to a 19.06 cM region of chromosome 17q21 with a maximum multipoint LOD score of 3.911 containing MAPt. By combining the results of our genetic analysis with those previously published for other families with similar pathology, we have further refined the minimal region to a 3.53 cM region of chromosome 17q21. We did not identify point mutations in MAPt by direct sequencing or any gross MAPt gene alterations using fluorescent in situ hybridization. In addition, tau protein extracted from members of this family was unremarkable in size and quantity as assessed by western blotting. Neuropathological characterization of the ub-ir NII in this family shows that they are positive for promyelocytic leukaemia protein (PML) and SUMO-1 that suggests that these inclusions form in the nuclear body and suggests a possible mechanism of neurodegeneration in tau-negative FTD linked to chromosome 17q21.

Aged↗

PubMed2006

The neuropathology of frontotemporal lobar degeneration caused by mutations in the progranulin gene.

The most common pathology in frontotemporal dementia (FTD) is tau-negative, ubiquitin-immunoreactive (ub-ir) neuronal inclusions (FTLD-U). Recently, we identified mutations in the progranulin (PGRN) gene as the cause of autosomal dominant FTLD-U linked to chromosome 17. Here, we describe the neuropathology in 13 patients from 6 different families, each with FTD caused by a different PGRN mutation. The most consistent feature was the presence of ub-ir lentiform neuronal intranuclear inclusions (NII) in the neocortex and striatum. In addition, the neocortex showed moderate-to-severe superficial laminar spongiosis, chronic degenerative changes, ub-ir neurites and well-defined ub-ir neuronal cytoplasmic inclusions (NCI). In the striatum, there were numerous ub-ir neurites. NCI in the hippocampus usually had a granular appearance. In contrast, familial FTLD-U cases without PGRN mutations had no NII, less severe neocortical and striatal pathology and hippocampal NCI that were more often solid. Eight cases in which genetic analysis was not available also had NII and an overall pathology similar to those with proven mutations. None of our cases of FTLD-U without NII showed the same pattern of pathology as those with mutations. These findings suggest that FTD caused by PGRN mutations has a recognizable pathology with the most characteristic feature being ub-ir NII.

Aged↗

PubMed2006

Endothelial function in post-menopausal former elite athletes.

OBJECTIVE: To characterize endothelial function in postmenopausal former elite athletes in comparison to sedentary controls and to study the influence of hormone replacement therapy (HRT) on endothelial function in these groups of women. DESIGN: Cross-sectional study. SETTING: Research unit at a university hospital. PARTICIPANTS: Twenty postmenopausal former elite but still active endurance female athletes and 19 age-matched sedentary controls. The group of athletes and control subjects were each subdivided into two groups on the basis of utilization or non-utilization of HRT involving estrogen and gestagen. METHODS: Flow-mediated vasodilatation (FMD) was employed as an indicator of endothelial function. Fasting blood samples were analyzed for lipids and body composition determined by dual-energy x-ray absorptiometry. MAIN OUTCOME MEASURES: FMD, blood lipids and body composition. RESULTS: Former elite athletes not utilizing HRT demonstrated the highest FMD of all four subgroups, their values being significantly higher than those of control subjects not utilizing HRT (P < 0.05), whereas this difference was not seen between the subgroups of athletes and control subjects using HRT. Serum levels of cholesterol and low-density lipoprotein (LDL) and the percentage of fat mass were significantly lower in the former elite athletes than in the control group (P < 0.05 in all cases). However, these variables were not related to FMD. CONCLUSION: This investigation documents enhanced endothelial function in postmenopausal former elite endurance athletes not utilizing HRT, whereas the use of HRT equalizes FMD in former athletes and sedentary control subjects. Our findings suggest that long-term strenuous exercise has beneficial effects on endothelial function in postmenopausal women but that no further improvement can be obtained with HRT.

Case-Control Studies↗

PubMed2005

Pregnancy and neonatal outcomes in women with eating disorders.

OBJECTIVE: This study was initiated to examine pregnancy and neonatal outcomes in women with past or current eating disorders as compared with a control group. METHODS: Forty-nine nulliparous nonsmoking women previously diagnosed with eating disorders (24 anorexia nervosa, 20 bulimia nervosa, 5 eating disorders not otherwise specified) and 68 controls were recruited in early pregnancy. Data on antenatal complications, mode of delivery, and neonatal outcome variables were collected. For comparisons between groups 1-way analysis of variance or chi(2) test was used. RESULTS: Twenty-two percent of the patients had a verified relapse in eating disorders during pregnancy. Women with past or current eating disorders were at increased risk of hyperemesis (P < .01) and delivered infants with significantly lower birth weight (P < .01) and smaller head circumference (P < .001) as compared with controls. They were also at greater risk of delivering infants with microcephaly (P < .05) and small for gestational age infants (P < .05). CONCLUSION: Pregnant women with past or active eating disorders seem to be at greater risk for delivering infants with lower birth weight, smaller head circumference, microcephaly, and small for gestational age. LEVEL OF EVIDENCE: II-2.

Adult↗

PubMed2005

Athlete's heart in postmenopausal former elite endurance female athletes.

OBJECTIVE: To investigate cardiac structure and function and exercise capacity in senior former elite athlete women. DESIGN: Cross-sectional study. PARTICIPANTS: Twenty postmenopausal former elite endurance athletes and 19 age-matched sedentary controls. METHODS: All subjects underwent transthoracic Doppler echocardiography and maximal exercise test on a bicycle ergometer. MAIN OUTCOME MEASURES: Cardiac chamber dimensions, wall thickness, cardiac function, and exercise capacity. RESULTS: The athletes had a greater exercise capacity (183 +/- 26 vs. 144 +/- 36 W; P < 0.01) compared with controls. Three of 20 (15%) athletes and 9 of 19 (47%) controls exhibited ST depressions during exercise test (P < 0.05). Echocardiographic measurements demonstrated larger left ventricular diameter (2.9 +/- 0.3 vs. 2.6 +/- 0.2 cm/m; P < 0.01), left ventricular volume (64 +/- 14 vs. 54 +/- 8 mL/m; P < 0.05), right ventricular diameter (1.6 +/- 0.2 vs. 1.4 +/- 0.2 cm/m; P < 0.01), left atrial volume (20.8 +/- 6 vs. 16.6 +/- 3.6 mL/m; P < 0.05), and stroke volume (45 +/- 10 vs. 36 +/- 5 mL/m; P < 0.01) in athletes than controls, whereas interventricular septum (9.3 +/- 1.7 vs. 10.1 +/- 1.8 mm; P > 0.05) and posterior wall thickness (9.0 +/- 1.6 vs. 9.2 +/- 1.0 mm; P > 0.05) did not differ between the groups. CONCLUSIONS: This study demonstrates cardiac enlargement without increased wall thickness in postmenopausal former elite endurance athlete women. Our results also indicate that long-term training maintains a high level of cardiovascular fitness in the aging female athletes.

Cardiac Output↗