Authors: Francis, Paul T. | Costello, Helen | Hayes, Gillian M.
Article Type: Research Article
Abstract: Brain banking has a long and distinguished past, contributing greatly to our understanding of human neurological and psychiatric conditions. Brain banks have been operationally diverse, collecting primarily end stage disease, with variable quality clinical data available, yet it is now recognized the most informative brain donations are from those in longitudinally studied cohorts. The Brains for Dementia Research (BDR) cohort and program was for planned brain donation across five UK brain banks and one donation point, with standardized operating procedures, following longitudinal clinical and psychometric assessments for people with no cognitive impairment as well as those with dementia. Lay representatives …with experience of dementia were involved from inception of BDR and 74.5% of all enquiries about participation came through routes that were directly attributable to or influenced by lay representatives. Ten years after inception, this ongoing project has received over 700 brain donations from the recruited cohort of 3,276 potential brain donors. At cohort census for this paper, 72.2% of the living cohort have no cognitive impairment by assessment, whereas only 28.3% of the donated cohort were without cognitive impairment. It is important that brain banks are agile and reflect the changing needs of the research community, given that ‘big data’, readiness cohorts, and GWAS demand large sample numbers of highly characterized individuals to facilitate new approaches and understanding of pathological processes in dementia. Show more
Keywords: Brain donation, cohort, control, dementia, research tissue bank
DOI: 10.3233/JAD-180699
Citation: Journal of Alzheimer's Disease, vol. 66, no. 4, pp. 1635-1644, 2018
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: Aisa, Bárbara | Gil-Bea, Francisco J. | Solas, Maite | García-Alloza, Mónica | Chen, Christopher P. | Lai, Mitchell K. | Francis, Paul T. | Ramírez, María Javier
Article Type: Research Article
Abstract: Neurotransmitter system dysfunction and synapse loss have been recognized as hallmarks of Alzheimer's disease (AD). Our hypothesis is that specific neurochemical populations of neurons might be more vulnerable to degeneration in AD due to particular deficits in synaptic plasticity. We have studied, in postmortem brain tissue, the relationship between levels of synaptic markers (NCAM and BDNF), neurochemical measurements (cholinacetyltransferase activity, serotonin, dopamine, GABA, and glutamate levels), and clinical data (cognitive status measured as MMSE score). NCAM levels in frontal and temporal cortex from AD patients were significantly lower than control patients. Interestingly, these reductions in NCAM levels were associated to …an ApoE4 genotype. Levels of BDNF were also significantly reduced in both frontal and temporal regions in AD patients. The ratio between plasticity markers and neurochemical measurements was used to study which of the neurochemical populations was particularly associated to plasticity changes. In both the frontal and temporal cortex, there was a significant reduction in the ChAT/NCAM ratio in AD samples compared to controls. None of the ratios to BDNF were different between control and AD samples. Furthermore, Pearson's product moment showed a significant positive correlation between MMSE score and the ChAT/NCAM ratio in frontal cortex (n=19; r=0.526*; p=0.037) as well as in temporal cortex (n=19; r=0.601*; p=0.018) in AD patients. Altogether, these data suggest a potential involvement of NCAM expressing neurons in the cognitive deficits in AD. Show more
Keywords: BDNF, ChAT, cognitive deficits, frontal cortex (BA10), MMSE, plasticity, temporal cortex (BA20)
DOI: 10.3233/JAD-2010-1398
Citation: Journal of Alzheimer's Disease, vol. 20, no. 2, pp. 659-668, 2010
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: 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: Brookes, Keeley J. | McConnell, George | Williams, Kirsty | Chaudhury, Sultan | Madhan, Gaganjit | Patel, Tulsi | Turley, Christopher | Guetta-Baranes, Tamar | Bras, Jose | Guerreiro, Rita | Hardy, John | Francis, Paul T. | Morgan, Kevin
Article Type: Short Communication
Abstract: The Brains for Dementia Research project is a recently established longitudinal cohort which aims to provide brain tissue for research purposes from neuropathologically defined samples. Here we present the findings from our analysis on the 19 established GWAS index SNPs for Alzheimer’s disease, in order to demonstrate if the BDR sample also displays association to these variants. A highly significant association of the APOE ɛ 4 allele was identified (p = 3.99×10–12 ). Association tests for the 19 GWAS SNPs found that although no SNPs survive multiple testing, nominal significant findings were detected and concordance with the Lambert et al. …GWAS meta-analysis was observed. Show more
Keywords: Alzheimer’s disease, association, Brains for Dementia Research, genome-wide association study, single nucleotide polymorphisms
DOI: 10.3233/JAD-180191
Citation: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 355-362, 2018
Authors: Vallortigara, Julie | Whitfield, David | Quelch, William | Alghamdi, Amani | Howlett, David | Hortobágyi, Tibor | Johnson, Mary | Attems, Johannes | O’Brien, John T. | Thomas, Alan | Ballard, Clive G. | Aarsland, Dag | Francis, Paul T.
Article Type: Research Article
Abstract: Alpha-synuclein (α -syn) aggregations are the key pathological hallmark of dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD), but are also frequently present in Alzheimer’s disease (AD). Much remains unknown about the role of α -syn in the synapse and the wider role of synaptic dysfunction in these dementias. Changes in concentrations of key ‘SNAP (Soluble N-ethylmaleimide Sensitive Factor Attachment Protein) Receptor’ (SNARE) proteins as a consequence of alterations in the aggregation state of α -syn may contribute to synaptic dysfunction in patients with DLB, PDD, and AD and result in impaired cognition. We have studied a large …cohort (n = 130) of autopsy confirmed DLB, PDD, AD, and control brains. Using semi-quantitative western blotting, we have demonstrated significant changes across the diagnostic groups of DLB, PDD, and AD in the SNARE and vesicle proteins syntaxin, Munc18, VAMP2, and monomeric α -syn in the prefrontal cortex, with a significant reduction of Munc18 in AD patients (p < 0.001). This correlated to the final MMSE score before death (p = 0.016). We also identified a significant negative correlation between the duration of dementia and the levels of the binding partners VAMP2 (p = 0.0004) and monomeric α -syn (p = 0.0002). Our findings may indicate that an upregulation of SNARE complex related proteins occurs in the early stages of disease as an attempt at compensating for failing synapses, prior to widespread deposition of pathological α -syn. Show more
Keywords: Alpha-synuclein, Alzheimer’s disease, dementia with lewy bodies, munc18, Parkinson’s disease dementia, SNARE process, synaptic dysfunction, VAMP2
DOI: 10.3233/JAD-150707
Citation: Journal of Alzheimer's Disease, vol. 50, no. 1, pp. 101-110, 2016
Authors: Alghamdi, Amani | Vallortigara, Julie | Howlett, David R. | Broadstock, Martin | Hortobágyi, Tibor | Ballard, Clive | Thomas, Alan J. | O’Brien, John T. | Aarsland, Dag | Attems, Johannes | Francis, Paul T. | Whitfield, David R.
Article Type: Research Article
Abstract: Lewy body dementia is the second most common neurodegenerative dementia and is pathologically characterized by α-synuclein positive cytoplasmic inclusions, with varying amounts of amyloid-β (Aβ) and hyperphosphorylated tau (tau) aggregates in addition to synaptic loss. A dysfunctional ubiquitin proteasome system (UPS), the major proteolytic pathway responsible for the clearance of short lived proteins, may be a mediating factor of disease progression and of the development of α-synuclein aggregates. In the present study, protein expression of a key component of the UPS, the RPT6 subunit of the 19S regulatory complex was determined. Furthermore, the main proteolytic-like (chymotrypsin- and PGPH-) activities have …also been analyzed. The middle frontal (Brodmann, BA9), inferior parietal (BA40), and anterior cingulate (BA24) gyrus’ cortex were selected as regions of interest from Parkinson’s disease dementia (PDD, n = 31), dementia with Lewy bodies (DLB, n = 44), Alzheimer’s disease (AD, n = 16), and control (n = 24) brains. Clinical and pathological data available included the MMSE score. DLB, PDD, and AD were characterized by significant reductions of RPT6 (one-way ANOVA, p < 0.001; Bonferroni post hoc test) in prefrontal cortex and parietal cortex compared with controls. Strong associations were observed between RPT6 levels in prefrontal, parietal cortex, and anterior cingulate gyrus and cognitive impairment (p = 0.001, p = 0.001, and p = 0.008, respectively). These findings highlight the involvement of the UPS in Lewy body dementia and indicate that targeting the UPS may have the potential to slow down or reduce the progression of cognitive impairment in DLB and PDD. Show more
Keywords: Alzheimer’s disease, amyloid-beta, cognitive impairment, dementia with Lewy bodies, Parkinson’s disease with dementia, RPT6, tau, ubiquitin proteasome system
DOI: 10.3233/JAD-160946
Citation: Journal of Alzheimer's Disease, vol. 57, no. 2, pp. 373-386, 2017
