Biomedical subjects

Jillian Kril

Publications and source records attributed to Jillian Kril.

5 recordsLinked to original sources

PubMed2006

Mutations in progranulin explain atypical phenotypes with variants in MAPT.

Mutations in presenilin-1 (PSEN1) cause autosomal dominant Alzheimer's disease and mutations in MAPT cause the familial tauopathy Frontotemporal dementia linked to chromosome 17 (FTDP-17). However, there have been reports of mutations in PSEN1 and MAPT associated with cases of FTD with ubiquitin-positive tau-negative inclusion pathology. Here, we demonstrate that the MAPT variants are almost certainly rare benign polymorphisms as all of these cases harbour mutations in Progranulin (PGRN). Mutations in PGRN were recently shown to cause ubiquitin-positive FTDP-17.

Base Sequence↗

PubMed2005

Pathologically proven frontotemporal dementia presenting with severe amnesia.

Early and severe memory impairment is generally held to be an exclusion criterion for the clinical diagnosis of frontotemporal dementia (FTD). However, clinical experience suggests that some patients with otherwise typical FTD can be amnesic from presentation, or even present solely with amnesia. A review of severe amnesia at presentation in patients with pathologically proven FTD is therefore warranted. The present study examined the records of all patients in the joint Cambridge-Sydney neuropathological series of patients with dementia and a pathological diagnosis of FTD to identify those for whom memory complaints were dominant at presentation. Eight of 71 patients met these criteria. For two patients, memory loss was the only complaint; for one patient, memory loss was accompanied by personality change; for two patients, memory loss was accompanied by prominent dysexecutive symptoms; and for three patients, memory loss was accompanied by apathy but no other behavioural changes. In seven patients local specialist teams initially diagnosed Alzheimer's disease; four patients entered anticholinesterase drug trials. All eight later developed behavioural features: in four, the diagnosis was revised to FTD, while in four the diagnosis of FTD was made only on neuropathological examination after death. In conclusion, severe amnesia at presentation in FTD is commoner than previously thought and the clinical consensus criteria for the diagnosis of FTD may need to be revised. The underlying basis of the memory impairments in patients with FTD may be heterogeneous, with different explanations in different subgroups.

Adult↗

PubMed2005

High-resolution MRI reflects myeloarchitecture and cytoarchitecture of human cerebral cortex.

Maps of cytoarchitectonically defined cortical areas have proven to be a valuable tool for anatomic localization of activated brain regions revealed by functional imaging studies. However, architectonic data require observations in a sample of postmortem brains. They can only be used reliably for comparison with functional data as probabilistic maps after spatial normalization to a common reference space. The complete architectonic analysis of an individual living brain has not been achievable to date, because the relationship remains unclear between laminar gray value changes of cerebral cortex in magnetic resonance (MR) images and those of cyto- and myeloarchitectonic histologic sections. We examined intensity profiles through the cortex in five imaging modalities: in vivo T1 and postmortem T2 MRI, one cell body stain, and two myelin stains. After visualizing the dissimilarities in the shapes of these profiles using a canonical analysis, differences between the profiles from the different image modalities were compared quantitatively. Subsequently, the profiles extracted from the in vivo T1-weighted images were estimated from profiles extracted from cyto- and myeloarchitectonic sections using linear combinations. We could verify statistically the mixed nature of the cortical T1 signal obtained in vivo: The MR intensity profiles were significantly more similar to myeloarchitectonic than to cytoarchitectonic profiles, but a weighted sum of both fitted the T1 profiles best.

Brain Mapping↗

PubMed2004

Astrocytic degeneration relates to the severity of disease in frontotemporal dementia.

The main unifying feature of cases with frontotemporal dementia (FTD) is the pattern of brain atrophy. Surprisingly, there are a variety of underlying histopathologies in cases with the clinical features and typical pattern of atrophy characterizing FTD. This suggests that the degenerative mechanism(s) associated with pyramidal cell loss and gliosis in FTD is likely to be similar in the different histopathological forms of the disease. In this study we tested this hypothesis by analysing a common cell death mechanism, apoptosis, in cases of FTD with either Pick's disease (PiD) (n = 9) or frontotemporal lobar degeneration (FTLD) (n = 7) compared with normal controls (n = 10). Tissue sections from previously analysed cases were stained using anti-activated caspase-3 immunohistochemistry, TUNEL, propidium iodide, and cell- and pathology-specific labels. These markers of apoptosis identified both astrocytes and neurons in regions vulnerable to degeneration in all cases of FTD. However, neuronal apoptosis was rare (<2% of neurons), even at early disease stages where there is considerably less frontotemporal atrophy or pyramidal cell loss. This suggests that other cell death mechanisms account for the progressive neuronal loss in FTD. In contrast, astrocytes with beaded processes and other apoptotic features were very frequent in both PiD and FTLD, with the severity of astrocytosis and astrocytic apoptosis correlating with both the degree of neuronal loss and the stage of disease. These findings provide evidence that astrocytic apoptosis occurs as an early event in different histopathological forms of FTD. Furthermore, this astrocytic apoptosis directly relates to the degree of degeneration in FTD, and becomes the overwhelming pathological feature as the disease progresses.

Aged↗

PubMed2002

Influence of plasminogen deficiency on the contribution of polymorphonuclear leucocytes to fibrin/ogenolysis: studies in plasminogen knock-out mice.

Plasminogen knock-out (PG(-/-)) mice provide an unique opportunity for the study of alternative mediators of fibrinolysis. Polymorpho-nuclear leucocytes (PMNs) contain non-plasmin fibrinolytic proteases, however the degree to which these cells contribute to fibrin(ogen) degradation in these animals is not known. Thrombi were generated in carotid arteries and jugular veins of PG(-/-) and wild type (PG(+/+)) mice following adventitial application of a 20% ferric chloride solution. PMNs, identified histologically on H&E staining and by immunohistochemistry using anti-mouse PMN RB6-8C5 antibody, accumulated within the thrombus by 6 h after the injury and peaked at 24 h. There was significantly greater retention of PMNs within the thrombi of PG(-/-) mice from 48 to 72 h than in the PG(+/+) controls (at 72 h: PG(-/-)255 +/- 41 cell/mm(2) (n = 5), PG(+/+) 61 +/- 10 cell/mm(2) (n = 5), p<0.01 in the arterial thrombi; PG(-/-) 252 +/- 50 cell/mm(2) (n = 5), PG(+/+) 100 +/- 36 cell/mm(2) (n = 5), p<0.05 in the venous thrombi), providing potential for more PMN derived fibrinolytic enzymes to be present at late times after a thrombotic challenge in PG(-/-) mice relative to the PG(+/+) controls. Intact PMNs were elicited from the peritoneal cavities of PG(-/-) and PG(+/+) mice following 4% thioglycolate stimulation. In vitro studies showed PMNs from PG(-/-) mice to release greater quantities of 10% trichloroacetic acid (TCA)-soluble fibrinopeptides from I(125)-labeled fibrinogen, than cells from PG(+/+) controls although these differences did not become apparent until after 24 h of incubation (at 72 h incubation: PG(-/-) 918 n/10 x 10(6) cells/0.5 ml, PG(+/+) 589 ng/10 10(6) cells/0.5 ml p = 0.005). Furthermore, autoradiographic analysis of the I(125)-labeled fibrinogen degradation products showed the cleavage pattern by PG(-/-) PMNs to be distinct from that produced by PG(+/+) PMNs. These data suggest that a relatively greater role for PMNs-initiated fibrinolysis exists in the setting of plasminogen deficiency, although this prominence only becomes evident more than 24 h after the thrombotic insult. In addition, mechanisms responsible for the process in PG(-/-) mice may be distinct from those primarily responsible for the process in PMNs from PG(+/+) mice.

Animals↗