Aims

Alzheimer’s disease (AD) and type-2 diabetes share similar pathological characteristics involving amyloid β (Aβ) deposition in the brain in AD and pancreatic amyloid derived from islet amyloid polypeptide (IAPP; amylin) in type-2 diabetes. Accumulating evidence demonstrates the presence of mixed amylin-Aβ deposits in AD brains. Because amylin is synthesized and co-secreted with insulin and hyperinsulinemia (prediabetes) is common in AD, hypersecretion of amylin may influence AD pathogenesis. Here, we tested the hypothesis that the rising level of amylin in the blood (hyperamylinemia) in the setting of AD promotes cerebrovascular amylin-Aβ deposition altering Aβ elimination from the AD brain.

Methods

To test whether blood-borne amyloid-forming human amylin might affect the Aβ transport from brain to blood, we genetically manipulated amylin secretion in APPswe/PS1dE9 (APP/PS1) rats (rodent amylin is non-amyloidogenic). In vitro blood-brain barrier models of Aβ transcytosis with and without amylin-mediated stress were used to describe the mechanism and to test potential ways to reverse amylin-mediated endothelial dysfunction.

Results

In brains of APP/PS1 rats with pancreatic expression of amyloid-forming human amylin, Aβ accumulation within the perivascular space frequently co-localized with deposits of amylin in the vessel wall. Aβ transport proteins in endothelium were downregulated through a miRNA-based translational repression mechanism. This is partially reversed by antisense miRNA.

Conclusions

The rising levels of amylin in the blood during the development of type-2 diabetes promote cerebrovascular amylin deposits blocking the transport of Aβ from brain to blood. Diagnosing hyperamylinemia early in AD and targeting the blood amylin level therapeutically could delay the progression of AD pathology.

Aims

Disturbances of protein O-GlcNAcylation represent a possible link between altered brain metabolism and the progression of neurodegenerative processes. As observed in Alzheimer’s disease (AD), flaws of cerebral glucose uptake translate into reduced HBP flux leading to impaired protein O-GlcNAcylation. Notably, the reduction of O-GlcNAcylated proteins triggers the aberrant increase of tau and APP phosphorylation in AD brain, favouring the formation of neurofibrillary tangles and β-amyloid plaques. Given that Down syndrome (DS) and AD share similar metabolic alterations, charachterized by insulin resistance, and common pathological markers within the brain, it is conceivable to suppose a role for aberrant O-GlcNAcylation in driving DS neurodegeneration.

Methods

We analyzed by proteomics approaches the total and protein-specific levels of O-GlcNacylation, the O-GlcNAc cycling and AD signatures in both DS mice and high fat diet (HFD) mice. Further, we tested the effects of Thiamet-G, an inducer of O-GlcNAcylation, to rescue brain alterations and AD development.

Results

Data on DS mice supported the implications of this PTM in the progression of AD-like pathology. Accordingly, HFD favoured the impairment of protein O-GlcNAcylation, eventually resulting in mitochondrial defects, reduced energy consumption and in the development of AD signatures. At final, the pharmacological modulation of protein O-GlcNAc levels in DS mouse brain managed to recovery global and protein specific O-GlcNAcylation, and to ameliorate alterations occurring at neuronal architecture, stress response mechanisms and energy production.

Conclusions

Our work emphasizes the role of reduced protein O-GlcNAcylation in AD-like pathology and lays the foundations for the involvement of an hypercaloric diet in disease progression.

Aims

Intellectual disability, accelerated aging and early-onset Alzheimer-like neurodegeneration are key brain pathological features of Down syndrome (DS). While growing research aims at the identification of molecular pathways underlying the aging trajectory of DS population data on infants and adolescents with DS are missing.

Methods

Plasma-resident neuronal-derived extracellular vesicles (nEVs) were isolated form healthy donors (HD, n=17) and DS children (n=18) aging from 2 to 17 years who underwent complete clinical workup and routine biochemistry. nEVs were first characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM) and probed for nEVs markers (L1CAM, CD81, Alix and APOA1). Afterwards, nEVs content was interrogated for markers of insulin/mTOR pathways as well as for proteins involved in synaptic plasticity, i.e., sintaxin-1, PSD95 and pCamKIIα-Thr286.

Results

nEVs isolated from DS children were characterized by a significant increase of pIRS1^Ser636, a marker of insulin resistance, and the hyperactivation of the Akt/mTOR/p70S6K axis downstream from IRS1, likely driven by the higher inhibition of PTEN. High levels of pGSK3b^Ser9 were also found. These alterations occur independent of peripheral alterations. Interestingly, the activation of both Akt and mTOR strongly correlate with pCamKIIα-Thr286 levels in nEVs from HD, while this association is lost in DS individuals, suggesting that the aberrant activation of the Akt/mTOR axis may contribute to dysfunctional synaptic plasticity mechanisms in DS through CaMKIIα.

Conclusions

The alteration of the insulin signalling/mTOR pathways represents an early event in DS brain and likely contributes to the cerebral dysfunctions and intellectual disability observed in this unique population.

Aims

α1-adrenoceptor antagonist tamsulosin has been associated with dementia, but the results have been inconsistent. Concerns have been raised about using exposure assessment time too close to the outcome. We investigated the association between α1-adrenoceptor antagonist use and risk of Alzheimer’s disease (AD) using different exposure windows.

Methods

The study population (24,602 cases and 98,397 matched controls) included men from the Finnish nationwide nested case-control study on Medication and Alzheimer’s disease (MEDALZ). Cases received clinically verified AD diagnosis during 2005–2011 and were community-dwelling at the time of diagnosis. Use of α1-adrenoceptor antagonists in 1995–2011 was defined from the Prescription Register. Exposure was categorized based on whether it had occurred within three years before AD diagnosis (lag time) or before that. Dose-response analysis, based on purchased defined daily doses of drug (DDDs), was conducted. Associations were investigated with conditional logistic regression, adjusted for confounders and mediators.

Results

The use of α1-adrenoceptor antagonists before lag time was associated with an increased risk of AD (OR 1.24 [1.20–1.27]). After adjustment for comorbidities and concomitant drug use throughout the assessment time (confounders) and healthcare contacts within the lag period (mediators), the association weakened (aOR 1.10 [1.06–1.14]). We found no evidence of dose-response-relationship when comparing the users of higher than median DDDs to the users of lower than median DDDs.

Conclusions

Our findings, especially the lack of dose-response-relationship and attenuation after mediator adjustment, do not provide strong support for the previous hypothesis on α1-adrenoceptor antagonists as a risk factor for dementia.

Aims

Parkinson’s disease (PD) is the second most common neurodegenerative disease, characterized by the loss of dopamine neurons from the substantia nigra (SN). Aging is the primary risk factor for PD although it remains unclear how aging predisposes an individual to neurodegenerative conditions.

Methods

In this study, we analyzed 71,106 SN nuclei from 32 individuals to compare young, aged, and PD-diagnosed conditions. We analyzed gene expression and chromatin accessibility simultaneously in the same nuclei using paired snRNA-seq and snATAC-seq to identify aging and disease-specific changes in the midbrain.

Results

Our data shows widespread changes in chromatin states over aging that influence gene expression. To investigate the contribution of aging to PD pathogenesis, we adapted pseudotime frameworks to combine RNA and ATAC data and established a pseudopathogenesis trajectory between young, old and PD conditions. This analysis allowed us to identify aging and disease relevant cell type populations, their gene expression patterns and chromatin motifs, and compare them with existing GWAS and SNP databases. Astrocytes and oligodendrocyte precursor cells show significant alterations over aging, but no significant differences during PD pathogenesis, suggesting they have little contribution to PD. Interestingly, although dopamine neurons are sparsely myelinated, oligodendrocyte (ODC) have dramatic changes both over aging and PD. Our analysis shows ODC lose synaptic support and myelination functions and allows us to identify a potential disease-associated ODC subtype.

Conclusions

Our multiomic analysis of single-cell transcriptomic and epigenomic dataset provides an essential resource to further our understanding of how aging affects the midbrain and predisposes it to degeneration in PD.

Aims

PD risk has been associated with exposure to the chlorinated solvents trichloroethylene (TCE) and perchloroethylene (PCE), but data are sparse. We tested whether risk is higher in former US Marines who served at a large military base whose residential water supply was contaminated with TCE and PCE.

Methods

A cohort of 152,521 Marines who resided at Camp Lejeune, North Carolina (water contaminated) and 168,361 who resided at Camp Pendleton, California (water uncontaminated) between 1975-1985 was previously assembled by the US Agency for Toxic Substances and Disease Registry (ATSDR). We searched Veterans Administration healthcare and Medicare databases for all ICD-9 and ICD-10 codes for PD or other forms of parkinsonism and PD-related medications. Diagnoses were confirmed by manual record review. We estimated the relative risk of being diagnosed with PD in former residents of the two camps, adjusting for age, sex, race and ethnicity.

Results

Health data were available for 149,218 (46.5%) individuals through 2/2021. Demographic characteristics were similar between camps, with mean (SD) attained ages of 59.6 (4.5) and 59.8 (4.6) in Lejeune and Pendleton, respectively. PD risk was significantly higher in former residents of Camp Lejeune.

Conclusions

The risk of PD may be higher in persons exposed to TCE and PCE in drinking water four decades ago. Ongoing work will test associations with cumulative exposure metrics for these toxicants.

Aims

To describe the natural history and antipsychotic treatment patterns of adults with dementia-related psychosis (DRP)

Methods

A cohort of patients with newly-diagnosed DRP was identified in United States Medicare claims data during 2013-2018. Baseline demographic and clinical characteristics were described. We estimated the incidence rates (IR) and 95% confidence intervals (CIs) for falls/fractures, infections, healthcare utilization, and death. Antipsychotic initiation and treatment patterns were evaluated

Results

We identified 484,520 patients with newly-diagnosed DRP. At the index date, patients had a mean age of 84 years, and 66% were female. Among those with a specified dementia type (44%), the majority had Alzheimer’s disease (70%), followed by vascular dementia (28%). The most prevalent psychosis symptom was unspecific (70%), followed by hallucinations (23%) and delusions (7%). Most patients had “severe” scores in the Charlson Comorbidity Index (71%) and in the frailty index (61%).

Patients with DRP had high IRs (95% CI) per 100 person-years: emergency department visits (186.04 [185.75-186.33]), oral anti-infectives use (148.27 [148.01-148.53]), and urinary tract infections (121.06 [120.82-121.31]). The mortality rate was 29.64 per 100 person-years [29.53-29.76].

A total of 132,380 (27%) patients with DRP initiated treatment with antipsychotics during follow-up. The mean time to start treatment after DRP diagnosis was 34 weeks. At 6 months of antipsychotic initiation, 32% of patients discontinued treatment

Conclusions

DRP is a complex disorder involving neurological and psychiatric symptoms. Patients with DRP additionally experience a substantial burden of non-neuropsychiatric events after diagnosis, with high rates of emergency department visits, hospital admissions, infections, and death

Aims

Neuropsychiatric symptoms (NPS) are common in the elderly and can precede dementia. They are associated with more rapid cognitive and functional decline. Little is known about the pathophysiological changes underlying NPS. We aimed to investigate systemic and CNS molecular and pathway alterations associated with occurring NPS in general and single neuropsychiatric sub-syndromes, and address relationships with Alzheimer’s disease (AD) pathology and cognitive and functional decline.

Methods

CSF and serum neuroinflammatory markers and CSF proteomics data obtained by sandwich immunoassay and liquid chromatography with tandem mass spectrometry respectively, in a longitudinally followed-up cohort of elderly subjects with normal cognition and memory clinic patients. NPS were assessed using the Neuropsychiatric inventory Questionnaire. Clinical and neuropsychological follow-up was performed at 18 and 36 months from inclusion. We used multivariate and regression analysis along with pathway enrichment to address associations of interest.

Results

Distinct CSF and serum molecular signatures were associated with NPS. Single neuropsychiatric syndromes such as apathy and depression were associated with distinct molecular signatures and pathway alterations related to neuroinflammation, cell adhesion and signal transduction pathways and lipid metabolism. These associations were partially independent of the presence of AD pathology. Several of the identified molecules in both serum and CSF were associated with more severe cognitive decline at follow-up visits.

Conclusions

Differentially altered pathways in NPS and sub-syndromes indicate distinct underlying molecular mechanisms. Neuroinflammation and proteome alterations related to NPS may both represent pathophysiological processes partially independent from AD, and accelerate cognitive decline in older people.