Stephen Sikkink

Publications (5)38.83 Total impact

• Article: TDP-43 pathological changes in early onset familial and sporadic Alzheimer's disease, late onset Alzheimer's disease and Down's syndrome: association with age, hippocampal sclerosis and clinical phenotype.

  Yvonne S Davidson, Samantha Raby, Penelope G Foulds, Andrew Robinson, Jennifer C Thompson, Stephen Sikkink, Imran Yusuf, Hanan Amin, Daniel DuPlessis, Claire Troakes, Safa Al-Sarraj, Carolyn Sloan, Margaret M Esiri, Vee P Prasher, David Allsop, David Neary, Stuart M Pickering-Brown, Julie S Snowden, David M A Mann
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  ABSTRACT: TDP-43 immunoreactive (TDP-43-ir) pathological changes were investigated in the temporal cortex and hippocampus of 11 patients with autosomal dominant familial forms of Alzheimer's disease (FAD), 169 patients with sporadic AD [85 with early onset disease (EOAD) (i.e before 65 years of age), and 84 with late onset after this age (LOAD)], 50 individuals with Down's Syndrome (DS) and 5 patients with primary hippocampal sclerosis (HS). TDP-43-ir pathological changes were present, overall, in 34/180 of AD cases. They were present in 1/11 (9%) FAD, and 9/85 (10%) EOAD patients but were significantly more common (p = 0.003) in LOAD where 24/84 (29%) patients showed such changes. There were no demographic differences, other than onset age, between AD patients with or without TDP-43-ir pathological changes. Double immunolabelling indicated that these TDP-43-ir inclusions were frequently ubiquitinated, but were only rarely AT8 (tau) immunoreactive. Only 3 elderly DS individuals and 4/5 cases of primary HS showed similar changes. Overall, 21.7% of AD cases and 6% DS cases showed hippocampal sclerosis (HS). However, only 9% FAD cases and 16% EOAD cases showed HS, but 29% LOAD cases showed HS. The proportion of EOAD cases with both TDP-43 pathology and HS tended to be greater than those in LOAD, where nearly half of all the cases with TDP-43 pathology did not show HS. The presence of TDP-43-ir changes in AD and DS may therefore be a secondary phenomenon, relating more to ageing than to AD itself. Nevertheless, a challenge to such an interpretation comes from the finding in AD of a strong relationship between TDP-43 pathology and cognitive phenotype. Patients with TDP-43 pathology were significantly more likely to present with an amnestic syndrome than those without (p < 0.0001), in keeping with pathological changes in medial temporal lobe structures. HS was also associated more commonly with an amnestic presentation (p < 0.005), but this association disappeared when TDP-43-positive cases were excluded from the analysis. TDP-43 may, after all, be integral to the pathology of AD, and to some extent determine the clinical phenotype present.
  Acta Neuropathologica 12/2011; 122(6):703-13. · 9.32 Impact Factor
• Article: Effect of topographical distribution of α-synuclein pathology on TDP-43 accumulation in Lewy body disease.

  Osamu Yokota, Yvonne Davidson, Tetsuaki Arai, Masato Hasegawa, Haruhiko Akiyama, Hideki Ishizu, Seishi Terada, Stephen Sikkink, Stuart Pickering-Brown, David M A Mann
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  ABSTRACT: It has been reported that the development of TDP-43 pathology in cases of Lewy body disease (LBD) might be associated with the severity of tau pathology. However, the impact of α-synuclein pathology on TDP-43 accumulation in LBD remains unclear. To clarify whether α-synuclein pathology has an effect on TDP-43 accumulation, independent of tau pathology, we examined by immunohistochemistry 56 cases of LBD using a phosphorylation-dependent TDP-43 antibody. The frequency of TDP-43 pathology in all LBD cases was 18% (10/56). In 37 LBD cases with no or low tau burden (LBD-Ltau; Braak NFT stages 0-II), the frequency of TDP-43 pathology was 19% (7/37). The frequency of TDP-43 pathology in diffuse neocortical type LBD-Ltau cases was 36% (4/11), which was higher than those in limbic and brain stem-predominant types (11-14%). The amygdala and entorhinal cortex were the most frequently affected sites of TDP-43 pathology in LBD-Ltau cases. In LBD-Ltau cases, the proportion of diffuse neocortical type LBD was higher in the TDP-43-positive cases, than that in TDP-43-negative cases (57 vs. 23%). In all LBD cases, α-synuclein pathology in the temporal cortex was significantly more severe in TDP-43-positive cases, and significantly correlated with the severity of TDP-43 pathology in the amygdala. In a multivariate model, the presence of severe α-synuclein pathology was significantly associated with the development of TDP-43 pathology independent of age at death and tau pathology. In the amygdala, TDP-43 was often colocalized with α-synuclein or tau. Given these findings, we suggest that α-synuclein pathology is associated with TDP-43 accumulation in LBD cases.
  Acta Neuropathologica 12/2010; 120(6):789-801. · 9.32 Impact Factor
• Article: Phosphorylated TDP-43 pathology and hippocampal sclerosis in progressive supranuclear palsy.

  Osamu Yokota, Yvonne Davidson, Eileen H Bigio, Hideki Ishizu, Seishi Terada, Tetsuaki Arai, Masato Hasegawa, Haruhiko Akiyama, Stephen Sikkink, Stuart Pickering-Brown, David M A Mann
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  ABSTRACT: TDP-43 is characteristically accumulated in TDP-43 proteinopathies such as frontotemporal lobar degeneration and motor neurone disease, but is also present in some tauopathies, including Alzheimer's disease, argyrophilic grain disease, and corticobasal degeneration (CBD). However, several studies have suggested that cases of progressive supranuclear palsy (PSP) lack TDP-43 pathology. We have therefore examined limbic regions of the brain in 19 PSP cases, as well as in 12 CBD cases, using phosphorylation-dependent anti-TDP-43 antibodies. We observed TDP-43-positive inclusions in five PSP cases (26%), as well as in two CBD cases (17%). The amygdala and hippocampal dentate gyrus were most frequently affected in PSP. Regional tau burden tended to be higher in TDP-43-positive PSP cases, and a significant correlation between tau and TDP-43 burden was noted in the occipitotemporal gyrus. Hippocampal sclerosis (HS) was found in 3/5 TDP-43-positive PSP cases, but HS was significantly more frequent in TDP-43-positive than TDP-43 negative PSP cases. Dementia was present in 13/19 (58%) of the PSP cases, in 4/5 TDP-43-positive cases, in all 3 TDP-43-positive cases with HS, in 1/2 TDP-43-positive cases without HS, and 7/14 cases lacking both. TDP-43 and tau were frequently colocalized in the amygdala, but not in the hippocampal dentate gyrus. Immunoblotting demonstrated the characteristic (for TDP-43 proteinopathies) 45 and 25 kDa bands and high molecular weight smear in the TDP-43-positive PSP case. These findings suggest that (1) although PSP is nominally a tauopathy, pathological TDP-43 can accumulate in the limbic system in some cases, and (2) TDP-43 pathology may be concurrent with HS.
  Acta Neuropathologica 07/2010; 120(1):55-66. · 9.32 Impact Factor
• Article: Ubiquitin associated protein 1 is a risk factor for frontotemporal lobar degeneration.

  Sara Rollinson, Patrizia Rizzu, Stephen Sikkink, Matthew Baker, Nicola Halliwell, Julie Snowden, Bryan J Traynor, Dina Ruano, Nigel Cairns, Jonathan D Rohrer, [......], Karen E Morrison, Pau Pastor, Elena Alonso, Pablo Martinez-Lage, Neil Graff-Radford, David Neary, Peter Heutink, David M A Mann, John Van Swieten, Stuart M Pickering-Brown
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  ABSTRACT: Frontotemporal lobar degeneration (FTLD) is now recognised as a common form of early onset dementia. Up to 40% of patients have a family history of disease demonstrating a large genetic component to its etiology. Linkage to chromosome 9p21 has recently been reported in families with this disorder. We undertook a large scale two-stage linkage disequilibrium mapping approach of this region in the Manchester FTLD cohort. We identified association of ubiquitin associated protein 1 (UBAP1; OR 1.42 95% CI 1.08-1.88, P=0.013) with FTLD in this cohort and we replicated this finding in an additional two independent cohorts from the Netherlands (OR 1.33 95% CI 1.04-1.69, P=0.022), the USA (OR 1.4 95% CI 1.02-1.92, P=0.032) and a forth Spanish cohort approached significant association (OR 1.45 95% CI 0.97-2.17, P=0.064). However, we failed to replicate in a fifth cohort from London (OR 0.99 95% CI 0.72-1.37, P=0.989). Quantitative analysis of UBAP1 mRNA extracted from tissue from the Manchester cases demonstrated a significant reduction of expression from the disease-associated haplotype. In addition, we identified a case of familial FTLD that demonstrated colocalisation of UBAP1 and TDP-43 in the neuronal cytoplasmic inclusions in the brain of this individual. Our data for the first time identifies UBAP1 as a genetic risk factor for FTLD and suggests a mechanistic relationship between this protein and TDP-43.
  Neurobiology of aging 03/2009; 30(4):656-65. · 5.94 Impact Factor
• Article: The genetics of frontotemporal lobar degeneration.

  Stephen Sikkink, Sara Rollinson, Stuart M Pickering-Brown
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  ABSTRACT: This review addresses the latest developments in the genetics of frontotemporal lobar degeneration. 'Frontotemporal lobar degeneration' is the clinical term used to describe a heterogeneous neurodegenerative syndrome that includes frontotemporal dementia, semantic dementia, progressive nonfluent aphasia and progressive apraxia. Up to 40% of patients with frontotemporal lobar degeneration have a family history of a similar disorder in a first-degree relative, highlighting a significant genetic contribution to the aetiology of this disorder. Four genes that cause autosomal frontotemporal lobar degeneration have already been identified, including two that are only 1.7 megabases apart on chromosome 17. Although much progress has been made in our understanding of the genetics of frontotemporal lobar degeneration in recent years, the majority of the genetic causes of this syndrome remains to be identified.
  Current Opinion in Neurology 01/2008; 20(6):693-8. · 4.94 Impact Factor