| 31. |
- Landqvist, Maria, et al.
(författare)
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Somatic complaints in frontotemporal dementia.
- 2014
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Ingår i: American Journal of Neurodegenerative Disease. - 2165-591X. ; 3:2, s. 84-92
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Tidskriftsartikel (refereegranskat)abstract
- Frontotemporal dementia (FTD) is associated with a broad spectrum of clinical characteristics. The objective of this study was to analyze the prevalence of unexplained somatic complaints in neuropathologically verified FTD. We also examined whether the somatic presentations correlated with protein pathology or regional brain pathology and if the patients with these somatic features showed more depressive traits. Ninety-seven consecutively neuropathologically verified FTLD patients were selected. All 97 patients were part of a longitudinal study of FTD and all medical records were systematically reviewed. The somatic complaints focused on were headache, musculoskeletal, gastro/urogenital and abnormal pain response. Symptoms of somatic character (either somatic complaints and/or abnormal pain response) were found in 40.2%. These patients did not differ from the total group with regard to gender, age at onset or duration. Six patients showed exaggerated reactions to sensory stimuli, whereas three patients showed reduced response to pain. Depressive traits were present in 38% and did not correlate with somatic complaints. Suicidal behavior was present in 17 patients, in 10 of these suicidal behavior was concurrent with somatic complaints. No clear correlation between somatic complaints and brain protein pathology, regional pathology or asymmetric hemispherical atrophy was found. Our results show that many FTD patients suffer from unexplained somatic complaints before and/or during dementia where no clear correlation can be found with protein pathology or regional degeneration. Somatic complaints are not covered by current diagnostic criteria for FTD, but need to be considered in diagnostics and care. The need for prospective studies with neuropathological follow up must be stressed as these phenomena remain unexplained, misinterpreted, bizarre and, in many cases, excruciating.
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| 32. |
- Li, Jia-Yi, et al.
(författare)
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Characterization of Lewy body pathology in 12- and 16-year-old intrastriatal mesencephalic grafts surviving in a patient with Parkinson's disease.
- 2010
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Ingår i: Movement Disorders. - : Wiley. - 0885-3185. ; 25:8, s. 1091-1096
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Tidskriftsartikel (refereegranskat)abstract
- We previously reported the occurrence of Lewy bodies in grafted human fetal mesencephalic neurons in two patients with Parkinson's disease. Here, we have used immunohistochemistry and electron microscopy to characterize the development of Lewy bodies in one of these cases. This patient was operated in putamen on both sides at 12 or 16 years before death, respectively. We demonstrate that 2% of the 12-year-old and 5% of the 16-year-old grafted, presumed dopaminergic neurons contained Lewy bodies immunoreactive for alpha-synuclein. Based on morphological analysis, two forms of alpha-synuclein-positive aggregates were distinguished in the grafts, the first a classical and compact Lewy body, the other a loose meshwork aggregate. Lewy bodies in the grafts stained positively for ubiquitin and thioflavin-S, and contained characteristic alpha-synuclein immunoreactive electron dense fibrillar structures on electron microscopy. Our data indicate that Lewy bodies develop gradually in transplanted dopaminergic neurons in a fashion similar to that in dopaminergic neurons in the host substantia nigra. (c) 2010 Movement Disorder Society.
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| 33. |
- Majounie, Elisa, et al.
(författare)
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Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study
- 2012
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Ingår i: Lancet Neurology. - 1474-4465. ; 11:4, s. 323-330
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Tidskriftsartikel (refereegranskat)abstract
- Background We aimed to accurately estimate the frequency of a hexanucleotide repeat expansion in C9orf72 that has been associated with a large proportion of cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Methods We screened 4448 patients diagnosed with ALS (El Escorial criteria) and 1425 patients with FTD (Lund-Manchester criteria) from 17 regions worldwide for the GGGGCC hexanucleotide expansion using a repeat-primed PCR assay. We assessed familial disease status on the basis of self-reported family history of similar neurodegenerative diseases at the time of sample collection. We compared haplotype data for 262 patients carrying the expansion with the known Finnish founder risk haplotype across the chromosomal locus. We calculated age-related penetrance using the Kaplan-Meier method with data for 603 individuals with the expansion. Findings In patients with sporadic ALS, we identified the repeat expansion in 236 (7.0%) of 3377 white individuals from the USA, Europe, and Australia, two (4.1%) of 49 black individuals from the USA, and six (8.3%) of 72 Hispanic individuals from the USA. The mutation was present in 217 (39.3%) of 552 white individuals with familial MS from Europe and the USA. 59 (6.0%) of 981 white Europeans with sporadic FTD had the mutation, as did 99 (24.8%) of 400 white Europeans with familial FTD. Data for other ethnic groups were sparse, but we identified one Asian patient with familial ALS (from 20 assessed) and two with familial FTD (from three assessed) who carried the mutation. The mutation was not carried by the three Native Americans or 360 patients from Asia or the Pacific Islands with sporadic MS who were tested, or by 41 Asian patients with sporadic FTD. All patients with the repeat expansion had (partly or fully) the founder haplotype, suggesting a one-off expansion occurring about 1500 years ago. The pathogenic expansion was non-penetrant in individuals younger than 35 years, 50% penetrant by 58 years, and almost fully penetrant by 80 years. Interpretation A common Mendelian genetic lesion in C9472 is implicated in many cases of sporadic and familial ALS and FTD. Testing for this pathogenic expansion should be considered in the management and genetic counselling of patients with these fatal neurodegenerative diseases.
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| 34. |
- Ozen, Ilknur, et al.
(författare)
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Brain pericytes acquire a microglial phenotype after stroke.
- 2014
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Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 1432-0533 .- 0001-6322. ; 128:3, s. 381-396
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Tidskriftsartikel (refereegranskat)abstract
- Pericytes are located on the abluminal side of endothelial cells lining the microvasculature in all organs. They have been identified as multipotent progenitor cells in several tissues of the body including the human brain. New evidence suggests that pericytes contribute to tissue repair, but their role in the injured brain is largely unknown. Here, we investigate the role of pericytes in ischemic stroke. Using a pericyte-reporter mouse model, we provide unique evidence that regulator of G-protein signaling 5 expressing cells are activated pericytes that leave the blood vessel wall, proliferate and give rise to microglial cells after ischemic brain injury. Consistently, we show that activated pericytes express microglial markers in human stroke brain tissue. We demonstrate that human brain-derived pericytes adopt a microglial phenotype and upregulate mRNA specific for activated microglial cells under hypoxic conditions in vitro. Our study indicates that the vasculature is a novel source of inflammatory cells with a microglial phenotype in brain ischemia and hence identifies pericytes as an important new target for the development of future stroke therapies.
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| 35. |
- Persson, Annette, et al.
(författare)
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Phagocytic properties in tumor astrocytes.
- 2012
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Ingår i: Neuropathology. - : Wiley. - 0919-6544. ; 32, s. 252-260
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Tidskriftsartikel (refereegranskat)abstract
- In glioblastoma multiforme (GBM), the pathophysiological events preceding and promoting an uncontrolled and remarkable growth is largely unknown. Studies on gliomas and macrophage expression have shown high levels of phagocytic cells, that is, microglial cells. It has also been demonstrated that human astrocytic cells and rat glioma cells are capable of phagocytosis. The purpose of this study was to investigate a potential phagocytic property in human GBM cells in tumor biopsies from surgery. With an immunhistochemical double staining using macrophage markers (CD68 and CD163) and human telomerase reverse transcriptase (hTERT) as a marker for neoplastic cells, we found high levels of double positive cells in human GBM. In hematoxylin-erythrosin stained sections, we also identified fragmented cell components in the cytoplasm of tumor cells. In our judgement, many neoplastic cells in GBM are also positive for macrophage markers. We suggest that human astroglial tumor cells may have phagocytic properties or phagocyte-like properties. This may represent a latent capacity of self-defence, evoked under certain circumstances. It is likely that these properties substantially help the tumors thrive and expand.
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| 36. |
- Pourhamidi, Kaveh, et al.
(författare)
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Evaluation of clinical tools and their diagnostic use in distal symmetric polyneuropathy
- 2014
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Ingår i: Primary care diabetes. - : Elsevier. - 1878-0210 .- 1751-9918. ; 8:1, s. 77-84
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: To compare the diagnostic usefulness of tuning fork, monofilament, biothesiometer and skin biopsies in peripheral neuropathy in individuals with varying glucose metabolism.METHODS: Normoglycaemic, impaired glucose tolerance (IGT) and type 2 diabetes (T2DM) individuals were recruited. Nerve conduction studies (NCS) and thermal threshold tests were performed. Vibrotactile sense was tested with a biothesiometer and a 128-Hz tuning fork. Touch/pressure perception was examined with a 10-g monofilament. Skin biopsies were performed and intraepidermal nerve fibres were quantified. Distal symmetric polyneuropathy (DSPN) was defined as neuropathy disability score ≥2 and abnormal NCS. Thermal threshold tests were used to define small nerve fibre neuropathy (sDSPN) in cases where NCS (large nerve fibres) were normal.RESULTS: The prevalence of DSPN and sDSPN in the whole group (n=119) was 18% and 23%, respectively. For the biothesiometer, a cut-off of ≥24.5V had a sensitivity of 82% and specificity of 70% (AUC=0.81, 95% CI 0.71-0.91) when evaluating DSPN. An intraepidermal nerve fibre density cut-off of ≤3.39fibres/mm showed a sensitivity of 74% and specificity of 70% in the detection of sDSPN, whereas the sensitivity of the tuning fork and the biothesiometer were relatively low, 46% and 67%, respectively. When combining skin biopsies with the tuning fork, 10 more sDSPN cases were identified. Adding skin biopsy to the combination of the tuning fork and biothesiometer increased the sensitivity of finding sDSPN cases, but not DSPN, from 81% to 93%.CONCLUSION: Using a biothesiometer in clinical routine might be a sensitive method to detect large nerve fibre dysfunction in the lower extremity, whereas skin biopsies in combination with methods measuring vibrotactile sense could increase the diagnostic sensitivity of detecting peripheral neuropathy at an early stage.
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| 37. |
- Pourhamidi, Kaveh, 1985-, et al.
(författare)
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Intraepidermal nerve fibre density is associated with weight
- 2011
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Background and aims: Intraepidermal nerve fibre density (IENFD) quantification is regarded to be a sensitive and specific measure of small nerve fibre dysfunction and IENFD loss is an early feature in glucose dysregulation. Our aims were to study IENFD in individuals with normal glucose tolerance (NGT), impaired glucose tolerance (IGT) and type 2 diabetes (T2D) and to study if IENFD was associated to metabolic traits, e.g. obesity and dyslipidemia, and to neurophysiologic assessments of nerve function.Materials and methods: Participants were consecutively recruited from the population-based Västerbotten Intervention Program; NGT (n=22), IGT (n=14), T2D (n=24), at the age of 60±1 years. The individuals’ height and weight were measured. Blood glucose and lipids were measured. Nerve conduction studies (NCS) were performed (sural and peroneal nerves) and the results were standardized to z-scores and compiled into a composite Z-score representing the nerve function in the leg. Neuropathy disability score (NDS) was used to evaluate neuropathic signs. In addition, thermal threshold tests (TTT) were performed to assess small nerve fibre function. Skin biopsies were performed using a 3-mm punch taken 10 cm proximal to the lateral malleolus. The intraepidermal nerve fibres were evaluated by routine immunohistochemistry and stained with anti-PGP9.5 (ubiquitin carboxyl-terminal hydrolase) antibodies. Light microscopy was used to identify nerve fibres in thin sections (5 µm) according to a standardized protocol. The IENFD was given as the mean of counts in 3 sections per millimeter of epidermal length. The assessors were blinded to the identity of the samples.Results: Patients with diabetes had lower IENFD (median 2.9 nerves mm-1, IQR 1.2-4.8) than controls (median 4.4 nerves mm-1, IQR 3.5-6.3; Mann-Whitney U test p=0.007). IGT individuals did not differ in IENFD (median 3.2 nerves mm-1, IQR 1.4-5.5) compared to controls (p=0.12) or diabetic patients (p=0.53). IENFD was positively correlated to NCS (r=0.39, p=0.002), but not to TTT and NDS. Individuals in the 3rd tertile of composite Z-score (i.e. better nerve conduction) had higher IENFD (median 4.1 nerves mm-1, IQR 2.7-5.8) than individuals in the 1st tertile (median 2.4 nerves mm-1, IQR 0.7-3.9; p=0.009). Triglycerides and cholesterols were not associated with IENFD. However, a stepwise multiple linear regression analysis revealed that weight was independently associated to IENFD, after adjustment for age, sex, height, and diabetic status (β=-0.419, p<0.001).Conclusion: We conclude that skin biopsies for IENFD quantification in thin sections is a simple useful method for assessing small nerve fibre neuropathy in individuals with diabetes. The association between weight and IENFD indicates that metabolic traits other than glucose dysmetabolism might play a role in the development small nerve fibre neuropathy.
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| 38. |
- Pourhamidi, Kaveh, et al.
(författare)
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No difference in small or large nerve fiber function between individuals with normal glucose tolerance and impaired glucose tolerance
- 2013
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Ingår i: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 36:4, s. 962-964
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE To assess small and large nerve fiber function in people with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and type 2 diabetes (T2D).RESEARCH DESIGN AND METHODS Participants were recruited consecutively from a population-based cohort: NGT (n = 39), IGT (n = 29), and T2D (n = 51). Electrophysiological measures included nerve conduction studies and thermal thresholds. Intraepidermal nerve fiber density (IENFD) in skin biopsies was calculated.RESULTS There was no difference between IGT and NGT in sural nerve conduction, IENFD, and thermal thresholds. IENFD was significantly lower in T2D (median = 2.8 fibers/mm [Interquartile range 1.1–4.7 fibers/mm]) than NGT individuals (4.5 fibers/mm [3.4–6.1 fibers/mm]; P < 0.05). T2D participants had poorer nerve conduction and higher heat thresholds than NGT and IGT.CONCLUSIONS Large and small nerve function in people with IGT did not differ from those with NGT. Our finding does not support the existence of neuropathy in a prediabetic stage.
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| 39. |
- Puschmann, Andreas, et al.
(författare)
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First neuropathological description of a patient with Parkinson's disease and LRRK2 p.N1437H mutation.
- 2012
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Ingår i: Parkinsonism & Related Disorders. - : Elsevier BV. - 1873-5126 .- 1353-8020. ; 18:4, s. 332-338
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Tidskriftsartikel (refereegranskat)abstract
- The c.4309A>C mutation in the LRRK2 gene (LRRK2 p.N1437H) has recently been reported as the seventh pathogenic LRRK2 mutation causing monogenic Parkinson's disease (PD). So far, only two families worldwide have been identified with this mutation. By screening DNA from seven brains of PD patients, we found one individual with seemingly sporadic PD and LRRK2 p.N1437H mutation. Clinically, the patient had levodopa-responsive PD with tremor, and developed severe motor fluctuations during a disease duration of 19 years. There was severe and painful ON-dystonia, and severe depression with suicidal thoughts during OFF. In the advanced stage, cognition was slow during motor OFF, but there was no noticeable cognitive decline. There were no signs of autonomic nervous system dysfunction. Bilateral deep brain stimulation of the subthalamic nucleus had unsatisfactory results on motor symptoms. The patient committed suicide. Neuropathological examination revealed marked cell loss and moderate alpha-synuclein positive Lewy body pathology in the brainstem. There was sparse Lewy pathology in the cortex. A striking finding was very pronounced ubiquitin-positive pathology in the brainstem, temporolimbic regions and neocortex. Ubiquitin positivity was most pronounced in the white matter, and was out of proportion to the comparatively weaker alpha-synuclein immunoreactivity. Immunostaining for tau was mildly positive, revealing non-specific changes, but staining for TDP-43 and FUS was entirely negative. The distribution and shape of ubiquitin-positive lesions in this patient differed from the few previously described patients with LRRK2 mutations and ubiquitin pathology, and the ubiquitinated protein substrate remains undefined.
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| 40. |
- Rauramaa, Tuomas, et al.
(författare)
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Cardiovascular diseases and hippocampal infarcts
- 2011
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Ingår i: Hippocampus. - : Wiley. - 1050-9631 .- 1098-1063. ; 21:3, s. 281-287
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Tidskriftsartikel (refereegranskat)abstract
- The prevalence of hippocampal lesions such as hippocampal infarcts have not been studied in detail even though hippocampal alterations are known to be associated with various clinical conditions such as age-related degenerative disorders and epilepsy. Methods: Here we defined the hippocampal infarcts and assessed the prevalence of this lesion in large unselected population of 1,245 subjects age ranging from 1 to 99 years (mean age 79 +/- 1 S.E.M). Furthermore, we assessed the association of these lesions with various cardio- and cerebro-vascular disorders and other neurodegenerative lesions. The prevalence of hippocampal infarct in the study population of 1,245 subjects was 12%, increasing to 13% when only those with a clinically diagnosed cognitive impairment (n = 311) were analyzed. Large hemispheric brain infarcts were seen in 31% of the study subjects and these lesions were strongly associated with cardiovascular risk factors such as hypertension (43%), coronary disease (32%), myocardial infarct (22%), atrial fibrillation (20%), and heart failure (20%). In contrast, hippocampal infarcts displayed a significant association only with large hemispheric brain infarct, heart failure, and cardiovascular index as assessed postmortem. It is noteworthy that only widespread hippocampal infarcts were associated with clinical symptoms of cognitive impairment or epilepsy. The surprisingly low prevalence of 12% of hippocampal infarcts in aged population found here and the failure to detect an association between this lesion and various cerebro- cardio-vascular lesions is intriguing. Whether susceptibility to ischemia in line with susceptibility to neuronal degeneration in this region is influenced by still undetermined risk- factors need further investigation. Furthermore it should be noted that the size of the hippocampal tissue damage, i.e., small vs. large cystic infarcts is of significance regarding clinical alterations.
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