Abstract
Purpose
To characterize a novel neurodevelopmental syndrome due to loss-of-function (LoF) variants in Ankyrin 2 (ANK2), and to explore the effects on neuronal network dynamics and ...homeostatic plasticity in human-induced pluripotent stem cell-derived neurons.
Methods
We collected clinical and molecular data of 12 individuals with heterozygous de novo LoF variants in ANK2. We generated a heterozygous LoF allele of ANK2 using CRISPR/Cas9 in human-induced pluripotent stem cells (hiPSCs). HiPSCs were differentiated into excitatory neurons, and we measured their spontaneous electrophysiological responses using micro-electrode arrays (MEAs). We also characterized their somatodendritic morphology and axon initial segment (AIS) structure and plasticity.
Results
We found a broad neurodevelopmental disorder (NDD), comprising intellectual disability, autism spectrum disorders and early onset epilepsy. Using MEAs, we found that hiPSC-derived neurons with heterozygous LoF of ANK2 show a hyperactive and desynchronized neuronal network. ANK2-deficient neurons also showed increased somatodendritic structures and altered AIS structure of which its plasticity is impaired upon activity-dependent modulation.
Conclusions
Phenotypic characterization of patients with de novo ANK2 LoF variants defines a novel NDD with early onset epilepsy. Our functional in vitro data of ANK2-deficient human neurons show a specific neuronal phenotype in which reduced ANKB expression leads to hyperactive and desynchronized neuronal network activity, increased somatodendritic complexity and AIS structure and impaired activity-dependent plasticity of the AIS.
INTRODUCTION
Cerebrospinal fluid (CSF) biomarkers for specific cellular disease processes are lacking for tauopathies. In this translational study we aimed to identify CSF biomarkers reflecting early ...tau pathology‐associated unfolded protein response (UPR) activation.
METHODS
We employed mass spectrometry proteomics and targeted immunoanalysis in a combination of biomarker discovery in primary mouse neurons in vitro and validation in patient CSF from two independent large multicentre cohorts (EMIF‐AD MBD, n = 310; PRIDE, n = 771).
RESULTS
First, we identify members of the protein disulfide isomerase (PDI) family in the neuronal UPR‐activated secretome and validate secretion upon tau aggregation in vitro. Next, we demonstrate that PDIA1 and PDIA3 levels correlate with total‐ and phosphorylated‐tau levels in CSF. PDIA1 levels are increased in CSF from AD patients compared to controls and patients with tau‐unrelated frontotemporal and Lewy body dementia (LBD).
Highlights
Neuronal unfolded protein response (UPR) activation induces the secretion of protein disulfide isomerases (PDIs) in vitro.
PDIA1 is secreted upon tau aggregation in neurons in vitro.
PDIA1 and PDIA3 levels correlate with total and phosphorylated tau levels in CSF.
PDIA1 levels are increased in CSF from Alzheimer's disease (AD) patients compared to controls.
PDIA1 levels are not increased in CSF from tau‐unrelated frontotemporal dementia (FTD) and Lewy body dementia (LBD) patients.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
OBJECTIVETo develop and evaluate a model for staging cortical amyloid deposition using PET with high generalizability.
METHODSThree thousand twenty-seven individuals (1,763 cognitively unimpaired CU, ...658 impaired, 467 with Alzheimer disease AD dementia, 111 with non-AD dementia, and 28 with missing diagnosis) from 6 cohorts (European Medical Information Framework for AD, Alzheimerʼs and Family, Alzheimerʼs Biomarkers in Daily Practice, Amsterdam Dementia Cohort, Open Access Series of Imaging Studies OASIS-3, Alzheimer’s Disease Neuroimaging Initiative ADNI) who underwent amyloid PET were retrospectively included; 1,049 individuals had follow-up scans. With application of dataset-specific cutoffs to global standard uptake value ratio (SUVr) values from 27 regions, single-tracer and pooled multitracer regional rankings were constructed from the frequency of abnormality across 400 CU individuals (100 per tracer). The pooled multitracer ranking was used to create a staging model consisting of 4 clusters of regions because it displayed a high and consistent correlation with each single-tracer ranking. Relationships between amyloid stage, clinical variables, and longitudinal cognitive decline were investigated.
RESULTSSUVr abnormality was most frequently observed in cingulate, followed by orbitofrontal, precuneal, and insular cortices and then the associative, temporal, and occipital regions. Abnormal amyloid levels based on binary global SUVr classification were observed in 1.0%, 5.5%, 17.9%, 90.0%, and 100.0% of individuals in stage 0 to 4, respectively. Baseline stage predicted decline in Mini-Mental State Examination (MMSE) score (ADNIn = 867, F = 67.37, p < 0.001; OASISn = 475, F = 9.12, p < 0.001) and faster progression toward an MMSE score ≤25 (ADNIn = 787, hazard ratio HRstage1 2.00, HRstage2 3.53, HRstage3 4.55, HRstage4 9.91, p < 0.001; OASISn = 469, HRstage4 4.80, p < 0.001).
CONCLUSIONThe pooled multitracer staging model successfully classified the level of amyloid burden in >3,000 individuals across cohorts and radiotracers and detects preglobal amyloid burden and distinct risk profiles of cognitive decline within globally amyloid-positive individuals.
IMPORTANCE: Plasma phosphorylated tau (p-tau) has proven to be an accurate biomarker for Alzheimer disease (AD) pathologic characteristics, offering a less expensive and less invasive alternative to ...cerebrospinal fluid (CSF) and positron emission tomography biomarkers for amyloid-β and tau. Alzheimer disease comorbid pathologic characteristics are common and are associated with more rapid cognitive decline in patients with dementia with Lewy bodies (DLB); therefore, it is anticipated that plasma p-tau concentrations may have utility in assessing cognitive impairment in individuals with this disorder. OBJECTIVE: To measure the concentrations of plasma p-tau (p-tau181 and p-tau231) and evaluate their associations with cognitive decline in individuals with probable DLB. DESIGN, SETTING, AND PARTICIPANTS: This multicenter longitudinal cohort study included participants from the European-DLB (E-DLB) Consortium cohort enrolled at 10 centers with harmonized diagnostic procedures from January 1, 2002, to December 31, 2020, with up to 5 years of follow-up. A total of 1122 participants with plasma samples were available. Participants with acute delirium or terminal illness and patients with other previous major psychiatric or neurologic disorders were excluded, leaving a cohort of 987 clinically diagnosed participants with probable DLB (n = 371), Parkinson disease (n = 204), AD (n = 207), as well as healthy controls (HCs) (n = 205). MAIN OUTCOMES AND MEASURES: The main outcome was plasma p-tau181 and p-tau231 levels measured with in-house single molecule array assays. The Mini-Mental State Examination (MMSE) was used to measure cognition. RESULTS: Among this cohort of 987 patients (512 men 51.9%; mean SD age, 70.0 8.8 years), patients with DLB did not differ significantly regarding age, sex, or years of education from those in the AD group, but the DLB group was older than the HC group and included more men than the AD and HC groups. Baseline concentrations of plasma p-tau181 and p-tau231 in patients with DLB were significantly higher than those in the HC group but lower than in the AD group and similar to the Parkinson disease group. Higher plasma concentrations of both p-tau markers were found in a subgroup of patients with DLB with abnormal CSF amyloid-β42 levels compared with those with normal levels (difference in the groups in p-tau181, −3.61 pg/mL; 95% CI, −5.43 to −1.79 pg/mL; P = .049; difference in the groups in p-tau231, −2.51 pg/mL; 95% CI, −3.63 to −1.39 pg/mL; P = .02). There was no difference between p-tau181 level and p-tau231 level across confirmed AD pathologic characteristcs based on reduced Aβ42 level in CSF in individuals with DLB. In DLB, a significant association was found between higher plasma p-tau181 and p-tau231 levels and lower MMSE scores at baseline (for p-tau181, −0.092 MMSE points; 95% CI, −0.12 to −0.06 MMSE points; P = .001; for p-tau231, −0.16 MMSE points; 95% CI, −0.21 to −0.12 MMSE points; P < .001), as well as more rapid MMSE decline over time. Plasma p-tau181 level was associated with a decrease of −0.094 MMSE points per year (95% CI, −0.144 to −0.052 MMSE points; P = .02), whereas plasma p-tau231 level was associated with an annual decrease of −0.130 MMSE points (95% CI, −0.201 to −0.071 MMSE points; P = .02), after adjusting for sex and age. CONCLUSIONS AND RELEVANCE: This study suggests that plasma p-tau181 and p-tau231 levels may be used as cost-effective and accessible biomarkers to assess cognitive decline in individuals with DLB.
Introduction
Blood‐based assays to measure brain amyloid beta (Aβ) deposition are an attractive alternative to the cerebrospinal fluid (CSF)–based assays currently used in clinical settings. In this ...study, we examined different blood‐based assays to measure Aβ and how they compare among centers and assays.
Methods
Aliquots from 81 plasma samples were distributed to 10 participating centers. Seven immunological assays and four mass‐spectrometric methods were used to measure plasma Aβ concentrations.
Results
Correlations were weak for Aβ42 while Aβ40 correlations were stronger. The ratio Aβ42/Aβ40 did not improve the correlations and showed weak correlations.
Discussion
The poor correlations for Aβ42 in plasma might have several potential explanations, such as the high levels of plasma proteins (compared to CSF), sensitivity to pre‐analytical sample handling and specificity, and cross‐reactivity of different antibodies. Different methods might also measure different pools of plasma Aβ42. We, however, hypothesize that greater correlations might be seen in future studies because many of the methods have been refined during completion of this study.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
We aimed to investigate the early changes in expression of C-type lectin domain family 9, member A (CLEC9A), a C-type lectin that is specifically expressed by the CD141(+) dendritic cell subset that ...is involved in cross-presentation to CD8(+) T cells, by evaluating gene and/or protein expression in three different compartments skin, synovial tissue (ST) and serum after short-term adalimumab treatment in PsA patients compared with placebo.
Patients with active PsA and psoriasis were randomized to receive adalimumab or placebo for 4 weeks. Synovial and skin biopsies were obtained before and after 4 weeks of treatment and serum samples 4 weeks, 12 weeks and 1 year after treatment. Skin and serum from healthy donors were used as control. CLEC9A expression was assessed by immunohistochemistry, double immunofluorescence using terminal deoxynucleotidyl transferase 2'-deoxyuridine 5'-triphosphate nick-end labelling (TUNEL), quantitative PCR and ELISA.
CLEC9A expression was significantly higher in psoriatic skin compared with healthy donor. In psoriatic skin and PsA ST, CLEC9A(+) cells were in close proximity to TUNEL(+) cells. SF CLEC9A levels were significantly lower compared with paired PsA serum. Adalimumab treatment did not affect CLEC9A serum level and skin expression. However, ST CLEC9A protein expression was significantly decreased after adalimumab treatment compared with the placebo group while CLEC9A gene expression remained unchanged. There was a positive correlation between T cell numbers and ST CLEC9A protein expression. CD141(+) cell numbers and chemokine (C motif) receptor 1 expression were not affected with adalimumab treatment.
Altogether, the present study suggests that the downregulation of synovial CLEC9A might be associated with a novel mechanism by which anti-TNF therapy might reduce CD8-mediated inflammation in PsA patients.
Introduction
Primary progressive aphasia (PPA) is divided into three prototypical subtypes that are all characterized by their single core symptom of aphasia. Although later in their course, other ...cognitive, behavioral, and motor domains may become involved, little is known about the progression profile of each subtype relative to the other subtypes.
Methods
In this longitudinal retrospective cohort study, based on the recent biomarker-supported diagnostic criteria, 24 subjects diagnosed with semantic variant (svPPA), 22 with non-fluent variant (nfvPPA), and 18 with logopenic variant (lvPPA) were collected and followed up for 1–6 years. Symptom distribution, cognitive test and neuropsychiatric inventory scores, and progression into another syndrome were assessed.
Results
Over time, lvPPA progressed with broader language problems (PPA-extended) and nfvPPA progressed to mutism, whereas semantic impairment remained the major problem in svPPA. Apart from linguistic problems, svPPA developed pronounced behavioral disturbances, whereas lvPPA exhibited a greater cognitive decline. By contrast, in nfvPPA motor deficits were more common. Furthermore, within 5 years (IQR = 2.5) after clinical onset, 65.6% of the patients additionally fulfilled the clinical criteria for another neurodegenerative syndrome (PPA-plus). Fourteen out of 24 (58%) svPPA patients additionally met the diagnostic criteria of behavioral variant frontotemporal dementia (5.1 years, IQR = 1.1), whereas the clinical features of 15/18 (83%) lvPPA patients were consistent with Alzheimer disease dementia (4.5 years IQR = 3.4). Furthermore, 12/22 (54%) of the subjects with the nfvPPA progressed to meet the diagnostic criteria of corticobasal syndrome, progressive supranuclear palsy, or motor neuron disease (5.1 years IQR = 3.4).
Discussion
Despite aphasia being the initial and unique hallmark of the syndrome, our longitudinal results showed that PPA is not a language limited disorder and progression differs widely for each subtype, both with respect to the nature of symptoms and disease duration.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
APOE and immunity: Research highlights Kloske, Courtney M.; Barnum, Christopher J.; Batista, Andre F. ...
Alzheimer's & dementia,
June 2023, Volume:
19, Issue:
6
Journal Article
Peer reviewed
Open access
INTRODUCTION
At the Alzheimer's Association's APOE and Immunity virtual conference, held in October 2021, leading neuroscience experts shared recent research advances on and inspiring insights into ...the various roles that both the apolipoprotein E gene (APOE) and facets of immunity play in neurodegenerative diseases, including Alzheimer's disease and other dementias.
METHODS
The meeting brought together more than 1200 registered attendees from 62 different countries, representing the realms of academia and industry.
RESULTS
During the 4‐day meeting, presenters illuminated aspects of the cross‐talk between APOE and immunity, with a focus on the roles of microglia, triggering receptor expressed on myeloid cells 2 (TREM2), and components of inflammation (e.g., tumor necrosis factor α TNFα).
DISCUSSION
This manuscript emphasizes the importance of diversity in current and future research and presents an integrated view of innate immune functions in Alzheimer's disease as well as related promising directions in drug development.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Many Alzheimer's disease (AD) genes including Apolipoprotein E (APOE) are found to be expressed in blood-derived macrophages and thus may alter blood protein levels. We measured 91 neuro-proteins in ...plasma from 316 participants of the Rotterdam Study (incident AD = 161) using Proximity Extension Ligation assay. We studied the association of plasma proteins with AD in the overall sample and stratified by APOE. Findings from the Rotterdam study were replicated in 186 AD patients of the BioFINDER study. We further evaluated the correlation of these protein biomarkers with total tau (t-tau), phosphorylated tau (p-tau) and amyloid-beta (Aβ) 42 levels in cerebrospinal fluid (CSF) in the Amsterdam Dementia Cohort (N = 441). Finally, we conducted a genome-wide association study (GWAS) to identify the genetic variants determining the blood levels of AD-associated proteins. Plasma levels of the proteins, CDH6 (β = 0.638, P = 3.33 × 10
) and HAGH (β = 0.481, P = 7.20 × 10
), were significantly elevated in APOE ε4 carrier AD patients. The findings in the Rotterdam Study were replicated in the BioFINDER study for both CDH6 (β = 1.365, P = 3.97 × 10
) and HAGH proteins (β = 0.506, P = 9.31 × 10
) when comparing cases and controls in APOE ε4 carriers. In the CSF, CDH6 levels were positively correlated with t-tau and p-tau in the total sample as well as in APOE ε4 stratum (P < 1 × 10
). The HAGH protein was not detected in CSF. GWAS of plasma CDH6 protein levels showed significant association with a cis-regulatory locus (rs111283466, P = 1.92 × 10
). CDH6 protein is implicated in cell adhesion and synaptogenesis while HAGH protein is related to the oxidative stress pathway. Our findings suggest that these pathways may be altered during presymptomatic AD and that CDH6 and HAGH may be new blood-based biomarkers.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Interleukin (IL)-17 and tumor necrosis factor-alpha (TNF)-α are key players in psoriatic arthritis (PsA) pathogenesis. While both cytokines can be therapeutically targeted with beneficial clinical ...outcome, it is unclear whether inhibiting one cytokine will affect the other at sites of inflammation. If both act independently, this might provide a rationale for dual or combined inhibition of both cytokines. Here, we evaluated the effect of TNF blockade in PsA patients on IL-17 levels in both skin and synovial tissue biopsies. PsA patients with mild psoriatic skin lesions were randomized to receive either adalimumab or placebo for four weeks. Synovial and skin biopsies were obtained at weeks zero and four. Skin from healthy donors (HDs) was used for comparison. Expression of IL-17A, IL-17F, IL-17RA and IL-17RC was assessed by immunohistochemistry and analyzed with digital image analysis. We found relatively low levels of IL-17 and its receptors in the skin of PsA patients compared to HD, and only IL-17F in the dermis of lesional psoriatic skin was significantly higher compared to HD skin (
= 0.0002). Histologically IL-17A, IL-17F, IL-17RA and IL-17RC in skin and synovial tissue were not downregulated by adalimumab treatment. Thus, in this cohort of PsA patients with mild psoriasis, TNF blockade did not affect the protein levels of IL-17 cytokines and its receptors in skin and synovium, despite reduced cellular inflammation and improved clinical outcome for joint involvement.
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