Your search for: 'author:("Lai, Mitchell K.P.")' has returned 8 results. (0.011s) Save search

Authors: Miura, Yumako | Miyaji, Kazuki | Chai, Yuek Ling | Chen, Christopher L.H. | Lai, Mitchell K.P. | Yuki, Nobuhiro

Article Type: Research Article

Abstract: A few studies have reported the association of autoantibodies to GM1 or GQ1bα with Alzheimer's disease (AD) or vascular dementia. Here we investigated whether patients with AD or vascular dementia had high titers of the anti-ganglioside antibodies. Sera were obtained from patients with AD (n = 22), vascular dementia (n = 14), Guillain–Barré syndrome, and multifocal motor neuropathy as well as normal controls. Enzyme-linked immunosorbent assay showed titers of IgG and IgM anti-GM1, anti-GQ1bα, and anti-GT1aα antibodies did not differ among AD, vascular dementia, and normal controls, and being remarkably lower than those in Guillain–Barré syndrome and multifocal motor neuropathy. …The anti-ganglioside antibodies are not biological markers of AD. Show more

Keywords: Alzheimer's disease, anti-ganglioside antibody, biological marker, ganglioside

DOI: 10.3233/JAD-140474

Citation: Journal of Alzheimer's Disease, vol. 42, no. 4, pp. 1165-1169, 2014

Authors: Mohamed, Nur-Ezan | Lee, Jasinda H. | Francis, Paul T. | Esiri, Margaret M. | Chen, Christopher P. | Lai, Mitchell K.P.

Article Type: Research Article

Abstract: Background: Glutamatergic deficits are well-established neurochemical findings in Alzheimer's disease (AD) and are thought to underlie both cognitive and behavioral symptoms of the disease. However, it is unclear whether subcortical ischemic vascular dementia (SIVD) and mixed SIVD/AD (MixD) manifest similar changes in the glutamatergic system. Objective: To measure the immunoreactivities of NMDA receptor GluN1, GluN2A, and GluN2B subunits in SIVD and MixD. Methods: Postmortem neocortical tissues from a cohort of well-characterized, longitudinally followed-up patients with SIVD and MixD, together with age-matched controls, were processed for immunoblotting with GluN subunit-specific antibodies. Results: There was a significant reduction of GluN1 only in …MixD, while significant increases of GluN2A and GluN2B were found only in SIVD. Furthermore, GluN1 loss and GluN2A/2B upregulation was associated respectively with higher Braak stages and lacunar infarct scores. Conclusions: Our data suggest that the differential alterations of GluN subunits in SIVD and MixD may result from separate, interacting disease processes, and point to the potential utility of glutamatergic approaches for pharmacotherapy. Show more

Keywords: Alzheimer's disease, GluN receptors, mixed dementia, neurochemistry, subcortical ischemic vascular dementia

DOI: 10.3233/JAD-141764

Citation: Journal of Alzheimer's Disease, vol. 44, no. 2, pp. 431-437, 2015

Authors: Chai, Yuek Ling | Xing, Huayang | Chong, Joyce R. | Francis, Paul T. | Ballard, Clive G. | Chen, Christopher P. | Lai, Mitchell K.P.

Article Type: Research Article

Abstract: Background: The translocase of the outer membrane (TOM) is a vital mitochondrial transport system facilitating the importation of nuclear encoded proteins into the organelle. While mitochondrial dysfunction, including perturbation of oxidative phosphorylation (OXPHOS) complex, is evident in Alzheimer’s disease (AD), it remains unclear whether the observed OXPHOS deficits may be associated with TOM alterations. Objectives: To correlate TOM subunits with OXPHOS complex proteins in AD. Methods: Postmortem neocortex (BA40) from AD and age-matched controls were processed to obtain mitochondrial enriched homogenates for the measurement of Tom20, Tom22, Tom40, and Tom70 as well as components of OXPHOS complex I–V by immunoblotting. …Results: Tom20 and Tom70 immunoreactivities were significantly reduced in AD, as were components of OXPHOS complex I and III. Both Tom20 and Tom70 positively correlated with complex III and V, while Tom20 also correlated withcomplex IV. Conclusion: Reductions in certain TOM subunits and their correlations with specific OXPHOS complex proteins suggest that an impaired mitochondrial transportation system may contribute to previously observed oxidative phosphorylation deficits in AD. Follow-up studies are needed to corroborate the present correlative study. Show more

Keywords: Alzheimer’s disease, mitochondria, oxidative phosphorylation, translocase of the outer membrane

DOI: 10.3233/JAD-170613

Citation: Journal of Alzheimer's Disease, vol. 61, no. 2, pp. 793-801, 2018

Authors: Marcos, Beatriz | García-Alloza, Mónica | Gil-Bea, Francisco J. | Chuang, Tsu T. | Francis, Paul T. | Chen, Christopher P. | Tsang, Shirley W.T.Y. | Lai, Mitchell K.P. | Ramirez, María J.

Article Type: Research Article

Abstract: We studied the hypothesis that disturbances in 5-HT6 receptor function in the temporal cortex may contribute to clinical symptoms of Alzheimer’s disease (AD). 5-HT6 density and 5-HT levels were significantly decreased in a cohort of AD patients prospectively assessed for cognitive/behavioral symptoms. cAMP formation after stimulation with the selective 5-HT6 receptor agonist E-6801 was significantly lower (p < 0.01 ) in AD (170.02 ± 27.53 pmol/mg prot.) compared to controls (823.33 ± 196.67 ). In addition, the ratio cAMP formation after stimulation with E-6801/5-HT6 receptor density was significantly lower (p < 0.01 ) in AD (6.67 ± 0.83 ) compared …to controls (16.67 ± 3.33 ). Splitting these results by sex, 5-HT6 receptor activation was significantly lower (p < 0.01 ) in AD females compared to males (21.67 ± 30.02 vs. 231.67 ± 34.17 pmol/mg prot). 5-HT6 density and 5-HT levels were significantly correlated (p ⩽ 0.01 ) in both controls and AD patients, although in AD, this correlation was lost in females. Psychosis factor was the best predictor of reduced 5-HT levels or adenylate cyclase activity after E-6801 stimulation, the former result being due to females. It may be suggested that psychotic symptoms may be related to a dysregulation of 5-HT6 activation by 5-HT in the temporal cortex. These results are discussed in terms of purported influence of sex and therapeutical approaches to psychosis in AD. Show more

Keywords: Adenylate cyclase, gender, neocortex, psychosis

DOI: 10.3233/JAD-2008-14104

Citation: Journal of Alzheimer's Disease, vol. 14, no. 1, pp. 43-50, 2008

Authors: Chong, Joyce R. | Chai, Yuek Ling | Lee, Jasinda H. | Howlett, David | Attems, Johannes | Ballard, Clive G. | Aarsland, Dag | Francis, Paul T. | Chen, Christopher P. | Lai, Mitchell K.P.

Article Type: Research Article

Abstract: Background: Of the three transforming growth factor (TGF)-β isoforms known, TGFβ1 deficits have been widely reported in Alzheimer’s disease (AD) and studied as a potential therapeutic target. In contrast, the status of TGFβ2, which has been shown to mediate amyloid-β (Aβ)-mediated neuronal death, are unclear both in AD and in Lewy body dementias (LBD) with differential neuritic plaque and neurofibrillary tangle burden. Objective: To measure neocortical TGFβ2 levels and their correlations with neuropathological and clinical markers of disease severity in a well-characterized cohort of AD as well as two clinical subtypes of LBD, dementia with Lewy bodies (DLB) and Parkinson’s …disease dementia (PDD), known to manifest relatively high and low Aβ plaque burden, respectively. Methods: Postmortem samples from temporal cortex (BA21) were measured for TGFβ2 using a Luminex-based platform, and correlated with scores for neuritic plaques, neurofibrillary tangles, α-synuclein pathology, dementia severity (as measured by annual decline of Mini-Mental State Examination scores) as well as soluble and total fractions of brain Aβ42 . Results: TGFβ2 was significantly increased in AD and DLB, but not in PDD. TGFβ2 also correlated with scores for neurofibrillary tangles, Lewy bodies (within the LBD group), dementia severity, and soluble Aβ42 concentration, but not with neuritic plaque scores, total Aβ42 , or monomeric α-synuclein immunoreactivity. Conclusions: TGFβ2 is increased in the temporal cortex of AD and DLB, and its correlations with neuropathological and clinical markers of disease severity as well as with soluble Aβ42 load suggest a potential pathogenic role in mediating the neurotoxicity of non-fibrillar Aβ. Our study also indicates the potential utility of targeting TGFβ2 in pharmacotherapeutic approaches to AD and DLB. Show more

Keywords: Alzheimer’s disease, amyloid-β, dementia with Lewy bodies, Parkinson’s disease dementia, transforming growth factor β2

DOI: 10.3233/JAD-160781

Citation: Journal of Alzheimer's Disease, vol. 56, no. 1, pp. 157-166, 2017

Authors: Wu, Liu-Yun | Chong, Joyce R. | Chong, Jenny P.C. | Hilal, Saima | Venketasubramanian, Narayanaswamy | Tan, Boon Yeow | Richards, Arthur Mark | Chen, Christopher P. | Lai, Mitchell K.P.

Article Type: Research Article

Abstract: Background: Concomitant cerebrovascular diseases (CeVD) have been identified as an important determinant of Alzheimer’s disease (AD) progression. Development of robust blood-based biomarkers will provide critical tools to evaluate prognosis and potential interventional strategies for AD with CeVD. Objective: This study investigated circulating placental growth factor (PlGF), a potent pro-angiogenic factor related to endothelial dysfunction and vascular inflammation, in an Asian memory clinic cohort of non-demented individuals as well as AD, including its associations with neuroimaging markers of CeVD. Methods: 109 patients with AD, 76 cognitively impaired with no dementia (CIND), and 56 non-cognitively impaired (NCI) were included in this cross-sectional …study. All subjects underwent 3T brain magnetic resonance imaging to assess white matter hyperintensities (WMH), lacunes, cortical infarcts, and cerebral microbleeds (CMBs). Serum PlGF concentrations were measured by electrochemiluminescence immunoassays. Results: Serum PlGF was elevated in AD, but not CIND, compared to the NCI controls. Adjusted concentrations of PlGF were associated with AD only in the presence of significant CeVD. Elevated PlGF was significantly associated with higher burden of WMH and with CMBs in AD patients. Conclusions: Serum PlGF has potential utility as a biomarker for the presence of CeVD, specifically WMH and CMBs, in AD. Further studies are needed to elucidate the underlying pathophysiological mechanisms linking PlGF to CeVD, as well as to further assess PlGF’s clinical utility. Show more

Keywords: Alzheimer’s disease, blood biomarkers, cerebral microbleeds, cerebrovascular disease, placental growth factor, white matter hyperintensities

DOI: 10.3233/JAD-230811

Citation: Journal of Alzheimer's Disease, vol. 97, no. 3, pp. 1289-1298, 2024

Authors: Lee, Jasinda H. | Francis, Paul T. | Ballard, Clive G. | Aarsland, Dag | Kalaria, Raj N. | Wong, Peter T.-H. | Chen, Christopher P. | Lai, Mitchell K.P.

Article Type: Research Article

Abstract: Background: Postsynaptic cholinergic deficits, including reduced cortical muscarinic M1 receptor coupling to G-proteins, are neurochemical findings postulated to underlie the limited efficacy of presynaptically-targeted cholinergic replacement therapies in Alzheimer’s disease (AD). While the loss of M1-G-protein coupling has been associated with β-amyloid (Aβ) burden in AD, the status of M1 coupling to G-proteins in Parkinson’s disease-related or mixed dementias is unclear. Objective: To test the hypothesis that M1 receptor uncoupling is correlated with Aβ burden, we aimed to study muscarinic M1 neurochemical parameters in neurodegenerative dementias characterized by low and high Aβ loads. Methods: M1 receptors, M1 coupling to G-proteins …as well as Aβ were measured in postmortem frontal cortex of a cohort of longitudinally assessed patients with Parkinson’s Disease Dementia (PDD, low Aβ load) and AD with significant subcortical cerebrovascular disease (AD + CVD, high Aβ load). Results: We found unchanged levels of M1 receptors in both dementia groups, while M1 coupling was reduced only in AD + CVD (p  < 0.01). Furthermore, Aβ concentration was significantly increased only in AD + CVD, and correlated negatively with M1-G-protein coupling in the dementia groups. Conclusions: Our study suggests that loss of M1 coupling to G-proteins may be a neurochemical feature of neurodegenerative dementias with high cortical Aβ burden, and that cholinergic replacement therapies may be more efficacious for PDD due to low Aβ burden. Show more

Keywords: Parkinson’s Disease Dementia, Alzheimer’s Disease, cerebrovascular disease, muscarinic M1 receptors, G-protein coupling, β-amyloid

DOI: 10.3233/JPD-160932

Citation: Journal of Parkinson's Disease, vol. 6, no. 4, pp. 733-739, 2016

Authors: Teoh, Nicole Shu Ning | Gyanwali, Bibek | Lai, Mitchell K.P. | Chai, Yuek Ling | Chong, Joyce R. | Chong, Eddie Jun Yi | Chen, Christopher | Tan, Chuen Seng | Hilal, Saima

Article Type: Research Article

Abstract: Background: Neuroinflammation has been postulated to play an important role in cognitive impairment, cognitive decline, and dementia. Inflammatory biomarkers such as interleukin-6 (IL-6) and IL-8 are found to be associated with the neuro-inflammatory process and worse cognitive function. However, it is unknown whether these interleukins are associated with long-term cognitive function. Objective: To investigate the association of baseline IL-6 and IL-8 with cognitive function at baseline as well as its association with cognitive decline over five-year follow-up. Methods: 387 patients were recruited from an ongoing memory clinic-based study who underwent comprehensive physical, medical, neuropsychological and blood assessments together with brain …MRI. IL-6 and IL-8 were measured using LUMINEX assays. The National Institute of Neurological Disorders and Stroke-Canadian Stroke Network neuropsychological battery was used to assess cognitive decline across multiple domains. Results: Among the 387 (mean age = 72.9 years and 53.7% males) participants, 322 had at least two follow-up assessments and were included in the longitudinal analysis. Negative linear trend associations were found between tertiles of IL-8 with baseline global cognition (p-trend< 0.001), attention (p-trend = 0.005), executive function (p-trend< 0.001), and visuospatial function (p-trend = 0.002) domains. No association was found between baseline IL-8 and cognitive decline. IL-6 was not associated with both baseline and follow-up cognition. Conclusion: IL-8 was associated with worse cognition especially in attention, executive function, and visuospatial function, suggesting the role of neuroinflammation in cognitive impairment. Hence, blood inflammatory biomarkers may be useful indicators in identifying patients at risk of cognitive impairment and warrant consideration for inclusion in treatment trials. Show more

Keywords: Blood biomarker, cognitive decline, inflammation mediators, interleukin-6, interleukin-8, memory clinic

DOI: 10.3233/JAD-220971

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 445-455, 2023