Serum Thioredoxin-80 is associated with age, ApoE4, and neuropathological biomarkers in Alzheimer’s disease: a potential early sign of AD

[EN] Background: Thioredoxin-80 (Trx80) is a cleavage product from the redox-active protein Thioredoxin-1 and has been previously described as a pro-inflammatory cytokine secreted by immune cells. Previous studies in our group reported that Trx80 levels are depleted in Alzheimer's disease (AD) brains. However, no studies so far have investigated peripheral Trx80 levels in the context of AD pathology and whether could be associated with the main known AD risk factors and biomarkers. Methods: Trx80 was measured in serum samples from participants from two different cohorts: the observational memory clinic biobank (GEDOC) (N = 99) with AD CSF biomarker data was available and the population-based lifestyle multidomain intervention trial Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) (N = 47), with neuroimaging data and blood markers of inflammation available. The GEDOC cohort consists of participants diagnosed with subjective cognitive impairment (SCI), mild cognitive impairment (MCI), and AD, whereas the FINGER participants are older adults at-risk of dementia, but without substantial cognitive impairment. One-way ANOVA and multiple comparison tests were used to assess the levels of Trx80 between groups. Linear regression models were used to explore associations of Trx80 with cognition, AD CSF biomarkers (A beta 42, t-tau, p-tau and p-tau/t-tau ratio), inflammatory cytokines, and neuroimaging markers. Results: In the GEDOC cohort, Trx80 was associated to p-tau/t-tau ratio in the MCI group. In the FINGER cohort, serum Trx80 levels correlated with lower hippocampal volume and higher pro-inflammatory cytokine levels. In both GEDOC and FINGER cohorts, ApoE4 carriers had significantly higher serum Trx80 levels compared to non-ApoE4 carriers. However, Trx80 levels in the brain were further decreased in AD patients with ApoE4 genotype. Conclusion: We report that serum Trx80 levels are associated to AD disease stage as well as to several risk factors for AD such as age and ApoE4 genotype, which suggests that Trx80 could have potential as serum AD biomarker. Increased serum Trx80 and decreased brain Trx80 levels was particularly seen in ApoE4 carriers. Whether this could contribute to the mechanism by which ApoE4 show increased vulnerability to develop AD would need to be further investigated.Open access funding provided by Karolinska Institute. This research was supported by the Margaretha af Ugglas Foundation, the Karolinska institutet KID funding, Gun och Bertil Stohnes Stiftelse, Stiftelsen Syskonen Svenssons, the Karolinska Institutet fund for geriatric research Stiftelsen Gamla Tjanarinnor, and the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet

Blood β-synuclein is related to amyloid PET positivity in memory clinic patients

Introduction: β-synuclein is an emerging blood biomarker to study synaptic degeneration in Alzheimer´s disease (AD), but its relation to amyloid-β (Αβ) pathology is unclear. Methods: We investigated the association of plasma β-synuclein levels with [18F]flutemetamol positron emission tomography (PET) in patients with AD dementia (n = 51), mild cognitive impairment (MCI–Aβ+ n = 18, MCI– Aβ– n = 30), non-AD dementias (n = 22), and non-demented controls (n = 5). Results: Plasma β-synuclein levels were higher in Aβ+ (AD dementia, MCI–Aβ+) than in Aβ– subjects (non-AD dementias, MCI–Aβ−) with good discrimination of Aβ+ from Aβ– subjects and prediction of Aβ status in MCI individuals. A positive correlation between plasma β-synuclein and Aβ PET was observed in multiple cortical regions across all lobes. Discussion: Plasma β-synuclein demonstrated discriminative properties for Aβ PET positive and negative subjects. Our data underline that β-synuclein is not a direct marker of Aβ pathology and suggest different longitudinal dynamics of synaptic degeneration versus amyloid deposition across the AD continuum. Highlights: Blood and CSF β-synuclein levels are higher in Aβ+ than in Aβ− subjects. Blood β-synuclein level correlates with amyloid PET positivity in multiple regions. Blood β-synuclein predicts Aβ status in MCI individuals

Blood β-synuclein is related to amyloid PET positivity in memory clinic patients

INTRODUCTION: β-synuclein is an emerging blood biomarker to study synaptic degeneration in Alzheimer´s disease (AD), but its relation to amyloid-β (Αβ) pathology is unclear. METHODS: We investigated the association of plasma β-synuclein levels with [18F] flutemetamol positron emission tomography (PET) in patients with AD dementia (n = 51), mild cognitive impairment (MCI-Aβ+ n = 18, MCI- Aβ- n = 30), non-AD dementias (n = 22), and non-demented controls (n = 5). RESULTS: Plasma β-synuclein levels were higher in Aβ+ (AD dementia, MCI-Aβ+) than in Aβ- subjects (non-AD dementias, MCI-Aβ-) with good discrimination of Aβ+ from Aβ- subjects and prediction of Aβ status in MCI individuals. A positive correlation between plasma β-synuclein and Aβ PET was observed in multiple cortical regions across all lobes. DISCUSSION: Plasma β-synuclein demonstrated discriminative properties for Aβ PET positive and negative subjects. Our data underline that β-synuclein is not a direct marker of Aβ pathology and suggest different longitudinal dynamics of synaptic degeneration versus amyloid deposition across the AD continuum. HIGHLIGHTS: Blood and CSF β-synuclein levels are higher in Aβ+ than in Aβ- subjects. Blood β-synuclein level correlates with amyloid PET positivity in multiple regions. Blood β-synuclein predicts Aβ status in MCI individuals

27-Hydroxycholesterol, cognition, and brain imaging markers in the FINGER randomized controlled trial

Background: 27-Hydroxycholesterol (27-OH), the main circulating oxysterol in humans and the potential missing link between peripheral hypercholesterolemia and Alzheimer's disease (AD), has not been investigated previously in relation to cognition and neuroimaging markers in the context of preventive interventions.Methods: The 2-year Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) included older individuals (60-77 years) at increased risk for dementia but without dementia or substantial cognitive impairment from the general population. Participants were randomized to a multidomain intervention (diet, exercise, cognitive training, and vascular risk management) or control group (general health advice) in a 1:1 ratio. Outcome assessors were masked to group allocation. This FINGER exploratory sub-study included 47 participants with measures of 27-OH, cognition, brain MRI, brain FDG-PET, and PiB-PET. Linear regression models were used to assess the cross-sectional and longitudinal associations between 27-OH, cognition, and neuroimaging markers, considering several potential confounders/intervention effect modifiers.Results: 27-OH reduction during the intervention was associated with improvement in cognition (especially memory). This was not observed in the control group. The intervention reduced 27-OH particularly in individuals with the highest 27-OH levels and younger age. No associations were found between changes in 27-OH levels and neuroimaging markers. However, at baseline, a higher 27-OH was associated with lower total gray matter and hippocampal volume, and lower cognitive scores. These associations were unaffected by total cholesterol levels. While sex seemed to influence associations at baseline, it did not affect longitudinal associations.Conclusion: 27-OH appears to be a marker not only for dementia/AD risk, but also for monitoring the effects of preventive interventions on cholesterol metabolism

Tau hyperphosphorylation induces oligomeric insulin accumulation and insulin resistance in neurons

Insulin signalling deficiencies and insulin resistance have been directly linked to the progression of neurodegenerative disorders like Alzheimer's disease. However, to date little is known about the underlying molecular mechanisms or insulin state and distribution in the brain under pathological conditions. Here, we report that insulin is accumulated and retained as oligomers in hyperphosphorylated tau-bearing neurons in Alzheimer's disease and in several of the most prevalent human tauopathies. The intraneuronal accumulation of insulin is directly dependent on tau hyperphosphorylation, and follows the tauopathy progression. Furthermore, cells accumulating insulin show signs of insulin resistance and decreased insulin receptor levels. These results suggest that insulin retention in hyperphosphorylated tau-bearing neurons is a causative factor for the insulin resistance observed in tauopathies, and describe a novel neuropathological concept with important therapeutic implications

Mitochondrial Alterations in PINK1 Deficient Cells Are Influenced by Calcineurin-Dependent Dephosphorylation of Dynamin-Related Protein 1

PTEN-induced novel kinase 1 (PINK1) mutations are associated with autosomal recessive parkinsonism. Previous studies have shown that PINK1 influences both mitochondrial function and morphology although it is not clearly established which of these are primary events and which are secondary. Here, we describe a novel mechanism linking mitochondrial dysfunction and alterations in mitochondrial morphology related to PINK1. Cell lines were generated by stably transducing human dopaminergic M17 cells with lentiviral constructs that increased or knocked down PINK1. As in previous studies, PINK1 deficient cells have lower mitochondrial membrane potential and are more sensitive to the toxic effects of mitochondrial complex I inhibitors. We also show that wild-type PINK1, but not recessive mutant or kinase dead versions, protects against rotenone-induced mitochondrial fragmentation whereas PINK1 deficient cells show lower mitochondrial connectivity. Expression of dynamin-related protein 1 (Drp1) exaggerates PINK1 deficiency phenotypes and Drp1 RNAi rescues them. We also show that Drp1 is dephosphorylated in PINK1 deficient cells due to activation of the calcium-dependent phosphatase calcineurin. Accordingly, the calcineurin inhibitor FK506 blocks both Drp1 dephosphorylation and loss of mitochondrial integrity in PINK1 deficient cells but does not fully rescue mitochondrial membrane potential. We propose that alterations in mitochondrial connectivity in this system are secondary to functional effects on mitochondrial membrane potential

Mechanism of action of autosomal recessive juvenile parkinsonism gene mutations

Parkinson Disease (PD) is the most common neurodegenerative movement disorder. Although PD is a largely sporadic disease, several genes has been linked to familial forms of PD. This thesis focuses on the mechanism of function of the Autosomal Recessively Juvenile Parkinsonism (AR-JP) associated genes parkin, PTEN induced kinase 1 (PINK1) and DJ-1. In Paper I we described a novel interaction between the E3 ubiquitin ligase parkin and phospholipase C-gamma1 (PLCgamma1). We further demonstrated that parkin ubiquitinates and regulates PLCgamma1 levels. Impairment in calcium homeostasis has been suggested to be associated to PD related cell death. Since PLCgamma1 is an important enzyme for regulating calcium, we continued by studying the downstream consequences of parkin impairment in the context of PLCgamma1-mediated signaling. This study resulted in Paper II where we established that parkin deficiency leads to increased lipid hydrolysis and cytosolic calcium levels due to altered PLCgamma1 activity. When we blocked calcium release from intracellular stores in parkin-mutant cells, the viability after exposure to oxidative stress was increased. Previous studies suggest that mitochondrial dysfunction is related to neurodegeneration in PD. In Paper III and IV, we elucidated the roles of DJ-1 and PINK1 in mitochondrial morphology and dynamics. We showed that DJ-1 or PINK1 knock-down (KD) increased mitochondrial fragmentation and that blocking fission could reverse these phenotypes. In DJ-1 KD, we found that fission was related to oxidative stress, whereas in PINK1-deficient cells the mitochondrial abnormality was likely a consequence of a loss of mitochondrial membrane potential and increased calcineurin activity. In Paper V we analyzed mitochondrial motility in differentiated cells. By live imaging we demonstrated that KD of either DJ-1 or PINK1 decreased the rate of mitochondrial motility in neurites. Blocking fission eliminated the difference between the control cells and parkinsonism associated KD cells, suggesting that balanced mitochondrial dynamics is important for neuritic motility. In conclusion, PD is a multi-factorial disorder involving several degenerative processes and signaling pathways. The AR-JP studies presented in this thesis may help to bring light to the understanding of the underlying mechanisms of PD and to develop novel treatment strategies

Gastric carcinoma in young Hong Kong Chinese

Gastric carcinomas usually occur in older people. Those occurring in the young are uncommon. The pathological and clinical features of gastric carcinomas were reviewed in 42 Chinese patients who were 35 years of age and younger. The data were obtained from the record files of the University Department of Pathology, Queen Mary Hospital for the period 1976-85. The patients comprised 4% of the total cases of gastric carcinomas in that period. These patients (age range: 20-35 years, mean: 30 years) showed a male to female ratio of 1:2.5 which differs from the usual male preponderance seen in gastric carcinoma. Among the 27 cases with known staging, 22 (81.5%) were stage III or IV. Twenty-five cases had an ulcerative appearance. All were adenocarcinomas and the majority (83.3%) were poorly differentiated. Associated dysplasia was found in 35 (83.3%) cases, although only 14 of these were in association with poorly differentiated adenocarcinomas. Intestinal metaplasia was found in 13 cases and, when present, involved less than 30% of the mucosa. Only two cases were of type III metaplasia. The findings show that gastric carcinoma in young Chinese tended to occur more frequently in females, presented at late stages, showed poor glandular differentiation, was frequently associated with gastric dysplasia and had minimal association with intestinal metaplasia.link_to_subscribed_fulltex