Novel hormonal therapy versus standard of care-A registry-based comparative effectiveness evaluation for mCRPC-patients.

BACKGROUND: This paper presents results from one of the few comparative effectiveness evaluations of novel antiandrogen medications (NHT) against standard of care (SoC) for patients suffering from metastatic castrate-resistant prostate cancer (mCRPC). METHODS: The design and the analysis are published in a protocol before accessing outcome data. Two groups of patients are balanced on hundreds of important covariates measured before the prostate cancer diagnosis and up to the date of the prescription. While the design yields balance on the observed covariates, one cannot discard the possibility that unobserved confounders are not balanced. The unconfoundedness assumption is assessed by estimating placebo regressions on two health measures, not included in the design but added together with the outcome data after protocol publication. RESULTS: We find a substantial (64 percent) increase in mortality for patients prescribed with NHT rather than SoC. However, based on the results from one of the two placebo regressions, we cannot rule out that the difference in mortality may be due to confounding. Using a bounding strategy of the effect, we can, however, rule out that NHT reduces mortality compared to SoC. Under an empirical valid assumption that most mCRPC patients who die suffer from bone metastases, we have a strong indication of increased skeleton-related events in patients if prescribed NHT against SoC. CONCLUSIONS: Generally, the SoC for this group of patients is docetaxel. Given the substantially higher costs of many of the NHT, the finding of no positive effects from NHT on both mortality and SRE is important. More comparative studies, including studies analysing quality of life outcomes, are thus needed.

Sex steroid levels in corresponding cerebrospinal fluid and serum samples quantified by mass spectrometry in men.

Objective: Sex steroids exert important biological functions within the CNS, but the underlying mechanisms are poorly understood. The contribution of circulating sex steroids to the levels in CNS tissue and cerebrospinal fluid (CSF) has been sparsely investigated in human and with inconclusive results. This could partly be due to lack of sensitive validated assays. To address this, we validated a gas chromatography-tandem mass spectrometry (GC-MS/MS) assay for quantification of sex steroid hormones/precursors in CSF. Methods: GC-MS/MS quantification of dihydrotestosterone (DHT, CSF lower limit of quantification, 1.5 pg/mL), testosterone (4.9), estrone (E1, 0.88), estradiol (E2, 0.25), dehydroepiandrosterone (DHEA, 38.4), androstenedione (4D, 22.3), and progesterone (P, 4.2) in CSF, and corresponding serum samples from 47 men. Results: Analyses of CSF revealed that DHEA was the major sex steroid (73.5 ± 31.7 pg/mL) followed by 4D (61.4 ± 29.6 pg/mL) and testosterone (49.5 ± 18.9 pg/mL). The CSF levels of DHT, E2, and E1 were substantially lower, and P was in general not detectable in CSF. For all sex steroids except E2, strong associations between corresponding CSF and serum levels were observed. We propose that testosteronein CSF is derived from circulating testosterone, DHT in CSF is from local conversion from testosterone, while E2 in CSF is from local conversion from 4D in CNS. Conclusions: We describe the first thoroughly validated highly sensitive mass spectrometric assay for a broad sex steroid hormone panel suitable for human CSF. This assay constitutes a new tool for investigation of the role of sex steroid hormones in the human CNS. Significance statement: In this study, a fully validated highly sensitive mass spectrometric assay for sex steroids was applied to human CSF. The results were used to describe the relative contribution of peripheral circulating sex steroids together with locally transformation of sex steroids to the levels in CSF. The results are of importance to understand the biological processes of the human brain.

Causal inferences and real-world evidence: A comparative effectiveness evaluation of abiraterone acetate against enzalutamide.

Regulatory authorities are recognizing the need for real-world evidence (RWE) as a complement to randomized controlled trials in the approval of drugs. However, RWE needs to be fit for regulatory purposes. There is an ongoing discussion regarding whether pre-publication of a protocol on appropriate repositories, e.g. ClinicalTrials.gov, would increase the quality of RWE or not. This paper illustrates that an observational study based on a pre-published protocol can entail the same level of detail as a protocol for a randomized experiment. The strategy is exemplified by designing a comparative effectiveness evaluation of abiraterone acetate against enzalutamide in clinical practice. These two cancer drugs are prescribed to patients with advanced prostate cancer. Two complementary designs, including pre-analysis plans, were published before data on outcomes and proxy-outcomes were obtained. The underlying assumptions are assessed and both analyses show an increased mortality risk from being prescribed abiraterone acetate compared to enzalutamide.

Development of the Swedish anticholinergic burden scale (Swe-ABS).

BACKGROUND: Drugs with anticholinergic properties are associated with cognitive adverse effects, especially in patients vulnerable to central muscarinic antagonism. A variety of drugs show weak, moderate or strong anticholinergic effects. Therefore, the cumulative anticholinergic burden should be considered in patients with cognitive impairment. This study aimed to develop a Swedish Anticholinergic Burden Scale (Swe-ABS) to be used in health care and research. METHODS: A systematic literature review was conducted in PubMed and Ovid Embase to identify previously published tools quantifying anticholinergic drug burden (i.e., exposure). Drugs and grading scores (0-3, no to high anticholinergic activity) were extracted from identified lists. Enteral and parenteral drugs authorized in Sweden were included. Drugs with conflicting scores in the existing lists were assessed by an expert group. Two drugs that were not previously assessed were also added to the evaluation process. RESULTS: The systematic literature search identified the following nine anticholinergic burden scales: Anticholinergic Activity Scale, Anticholinergic Burden Classification, updated Anticholinergic Cognitive Burden scale, Anticholinergic Drug Scale, Anticholinergic Load Scale, Anticholinergic Risk Scale, updated Clinician-rated Anticholinergic Scale, German Anticholinergic Burden Scale and Korean Anticholinergic Burden Scale. A list of drugs with significant anticholinergic effects provided by The Swedish National Board of Health and Welfare was included in the process. The suggested Swe-ABS consists of 104 drugs scored as having weak, moderate or strong anticholinergic effects. Two hundred and fifty-six drugs were listed as having no anticholinergic effects based on evaluation in previous scales. In total, 62 drugs were assessed by the expert group. CONCLUSIONS: Swe-ABS is a simplified method to quantify the anticholinergic burden and is easy to use in clinical practice. Publication of this scale might make clinicians more aware of drugs with anticholinergic properties and patients' total anticholinergic burden. Further research is needed to validate the Swe-ABS and evaluate anticholinergic exposure versus clinically significant outcomes.

Vagococcus proximus sp. nov. and Vagococcus intermedius sp. nov., originating from modified atmosphere packaged broiler meat.

During our studies on spoilage microbiomes of modified atmosphere packaged broiler meat, we isolated three strains (PNs007T, STAA11T and STAA25) of unknown identity. In this present polyphasic taxonomy study, including genome-based analyses, we discovered that these isolates represent two novel species belonging to the genus Vagococcus. In all phylogenetic analyses, PNs007T was positioned very close to Vagococcus fessus but both the average nucleotide identity (ANI; 89.5 %) and digital DNA-DNA hybridization (dDDH; 38.3 %) values distinguished it as a novel vagococcal species. STAA11T and STAA25 were genetically highly similar (16S rRNA, ANI and dDDH 100 %). The phylogenetic position of STAA11T was adjacent to but out of the cluster containing V. fessus, Vagococcus coleopterorum and PNs007T. According to the ANI (76.2-76.4 %) and dDDH (<22.6 %) values it also represented a novel vagococcal species. Phenotypic characteristics and chemotaxonomic properties of both novel species were typical for vagococci and they contained C16 : 0 (25.5-30.1 %) and C18 : 1 ω9c (67.3-73.0 %) as the major cellular fatty acids. The streptomycin-resistant genotype of STAA11T and STAA25 allowing the growth on streptomycin thallous acetate actidione medium was considered to result from a modification in codon 104 of the rpsL gene leading to P104A substitution. The ability of STAA11T and STAA25 to produce ammonia from arginine separated them from PNs007T, which did not show arginine deiminase activity. We propose the names Vagococcus proximus sp. nov. (type strain PNs007T=DSM 115185T=CCUG 76696T) and Vagococcus intermedius sp. nov. (type strain STAA11T=DSM 115183T=CCUG 76697T) for these novel species.

Sickness Absence and Disability Pension Among Patients With Chronic Pain in Interdisciplinary Treatment or Unspecified Interventions.

Interdisciplinary treatment is a widely implemented strategy for the rehabilitation of patients with chronic pain. A primary treatment objective is to decrease the load on the social insurance system; however, it is questionable whether interdisciplinary treatment reduces sickness absence and disability pension (SA/DP). This register-based observational study compared SA and DP between patients in interdisciplinary treatment and unspecified interventions. With data from 7,752 Swedish specialist health care patients in their prime working age, we analyzed total net SA/DP days over 3 years from the first visit to a pain rehabilitation center. A zero-one-inflated beta model, adjusted for theoretically substantiated confounders, was used to estimate the mean differences in total days and the proportions of patients with both zero and maximum days. Compared with unspecified interventions, interdisciplinary treatment resulted in a mean (95% confidence interval) absolute increase of 50 (37, 62) total days, a 13.0% (11.3%, 14.6%) decrease in patients with zero days, and a 1.5% (.2%, 2.8%) decrease in patients with the maximum days. These findings support that interdisciplinary treatment increases SA/DP compared to less intensive interventions but reduces the risk of maximum days, implying that it is advantageous for patients with the highest absence. This highlights the need for improved patient selection procedures and the adaptation of interdisciplinary treatment programs to more adequately target SA/DP reduction. PERSPECTIVES: This study provides an accessible overview of SA/DP among working-age patients with chronic pain in Swedish specialist health care. It also shows that interdisciplinary treatment does not decrease SA/DP more than alternative treatments in most patients but is advantageous for the patients with the longest absence.

Microbiological quality and safety of vacuum-packaged white-tailed deer meat stored at 4 °C.

Vacuum packaging is widely used for extending the shelf life of commercial fresh meat products. It also ensures product hygiene during distribution and storage. However, very little information exists concerning the effects of vacuum packaging on the shelf life of deer meat. One of our aims was to evaluate how storage under vacuum at 4 °C affects the microbial quality and safety of white-tailed deer (Odocoileus virginianus) meat cuts. This was assessed in a longitudinal study based on sensory analyses and measurements of (1) mesophilic aerobic bacteria (MAB), (2) lactic acid bacteria (LAB), (3) enterobacteria (EB), (4) and Escherichia coli (EC) counts, and the presence of foodborne pathogens (Campylobacter, Salmonella, stx-harbouring E. coli (STEC), Yersinia and Listeria). Microbiomes were additionally investigated by 16S rRNA gene amplicon sequencing at the time of spoilage. In total, 50 vacuum-packaged meat cuts from the carcasses of 10 wild white-tailed deer harvested in southern Finland in December 2018 were analysed. A significant (p < 0.001) drop in the odour and appearance scores and a significant increase in MAB (p < 0.001) and LAB (p = 0.001) counts of the vacuum-packaged meat cuts were observed after 3 weeks of storage at 4 °C. A very strong correlation (rs = 0.9444, p < 0.001) between the MAB and LAB counts were found during the 5-week sampling period. Clear spoilage changes, manifested as sour off-odours (odour scores ≤2) and pale colour, were detected in the meat cuts spoilt after 3-week storage. High (≥8 log10 cfu/g) MAB and LAB counts were also detected. According to the 16S rRNA gene amplicon analyses, Lactobacillus was the dominant bacterial genus in these samples, demonstrating that LAB can cause rapid spoilage of vacuum-packaged deer meat cuts stored at 4 °C. The rest of the samples were spoilt after four or five weeks of storage, and a vast number of bacterial genera were identified in them. Listeria and STEC were detected by PCR in 50 % and 18 % of the meat cut samples, respectively, which may indicate a public health problem. Our results demonstrate that it is very challenging to ensure the quality and safety of vacuum-packaged deer meat stored at 4 °C, and freezing is therefore recommended to prolong the shelf life.

Marination increased tyramine levels in rainbow trout fillet strips packaged under modified atmosphere.

Marinades are increasingly used to manufacture raw fish products. In corresponding meats, marinating is known to have a major effect on the composition of the microbiome, but the effect of marinating on fish is not known as well. This knowledge gap prompted our study of the microbial ecology and amine formation in marinated and unmarinated modified atmosphere commercially packaged rainbow trout fillet strips. According to our findings, marination increased the maximum concentrations (7-8 log CFU/g) of psychrotrophic bacteria by one logarithmic unit and led to 5 times higher average tyramine concentrations than the corresponding unmarinated product. Instead, trimethylamine concentrations were 30 times higher in the unmarinated product than those in the marinated one. According to the 16 S rRNA sequence analyses, lactic acid bacteria (LAB) predominated in the marinated strips one day after the use-by date, whereas in the unmarinated strips Fusobacteriaceae and LAB were the dominating taxa. Based on the culture-dependent analysis, Latilactobacillus fuchuensis was the prevailing LAB in both products. Since the subset of L. fuchuensis strains tested was able to produce tyramine in vitro, we hypothesise that the use of the acidic marinade activated the production of tyrosine-decarboxylating enzymes in L. fuchuensis and led to the increased tyramine concentrations.

Pangenome and genomic taxonomy analyses of Leuconostoc gelidum and Leuconostoc gasicomitatum.

BACKGROUND: Leuconostoc gelidum and Leuconostoc gasicomitatum have dual roles in foods. They may spoil cold-stored packaged foods but can also be beneficial in kimchi fermentation. The impact in food science as well as the limited number of publicly available genomes prompted us to create pangenomes and perform genomic taxonomy analyses starting from de novo sequencing of the genomes of 37 L. gelidum/L. gasicomitatum strains from our culture collection. Our aim was also to evaluate the recently proposed change in taxonomy as well as to study the genomes of strains with different lifestyles in foods. METHODS: We selected as diverse a set of strains as possible in terms of sources, previous genotyping results and geographical distribution, and included also 10 publicly available genomes in our analyses. We studied genomic taxonomy using pairwise average nucleotide identity (ANI) and calculation of digital DNA-DNA hybridisation (dDDH) scores. Phylogeny analyses were done using the core gene set of 1141 single-copy genes and a set of housekeeping genes commonly used for lactic acid bacteria. In addition, the pangenome and core genome sizes as well as some properties, such as acquired antimicrobial resistance (AMR), important due to the growth in foods, were analysed. RESULTS: Genome relatedness indices and phylogenetic analyses supported the recently suggested classification that restores the taxonomic position of L. gelidum subsp. gasicomitatum back to the species level as L. gasicomitatum. Genome properties, such as size and coding potential, revealed limited intraspecies variation and showed no attribution to the source of isolation. The distribution of the unique genes between species and subspecies was not associated with the previously documented lifestyle in foods. None of the strains carried any acquired AMR genes or genes associated with any known form of virulence. CONCLUSION: Genome-wide examination of strains confirms that the proposition to restore the taxonomic position of L. gasicomitatum is justified. It further confirms that the distribution and lifestyle of L. gelidum and L. gasicomitatum in foods have not been driven by the evolution of functional and phylogenetic diversification detectable at the genome level.

Model-based Bayesian inference under computer assisted balance-improving designs.

To improve covariate balance over a complete randomization, a number of methods have been proposed recently to utilize modern computational capabilities to find allocations with balance in observed covariates. Asymptotic inference on treatment effects based on these designs is more complicated than that under complete randomization, and this is why Fisher randomization tests often are suggested. This article suggests model-based Bayesian inference as a general method of inference in these designs, which can deal with complications such as arbitrary covariate balancing criteria and complex estimands. As an illustration, we focus on the case when the outcome is linearly related to the covariates and the estimand of interest is the Sample Average Treatment Effect (SATE). We use a large Monte Carlo simulation to compare the finite sample performance of the model-based Bayesian inference with that of two previous methods which are valid for asymptotic inference of SATE under Mahalanobis distance based rerandomization. We find that for experiments with small to moderate sample sizes, Bayesian inference is to be preferred to the previous methods. As a byproduct, we also find that regression adjustment together with small sample adjusted estimators of standard errors perform better than the previous methods.

Leveraging large multi-center cohorts of Alzheimer disease endophenotypes to understand the role of Klotho heterozygosity on disease risk.

Two genetic variants in strong linkage disequilibrium (rs9536314 and rs9527025) in the Klotho (KL) gene, encoding a transmembrane protein, implicated in longevity and associated with brain resilience during normal aging, were recently shown to be associated with Alzheimer disease (AD) risk in cognitively normal participants who are APOE ε4 carriers. Specifically, the participants heterozygous for this variant (KL-SVHET+) showed lower risk of developing AD. Furthermore, a neuroprotective effect of KL-VSHET+ has been suggested against amyloid burden for cognitively normal participants, potentially mediated via the regulation of redox pathways. However, inconsistent associations and a smaller sample size of existing studies pose significant hurdles in drawing definitive conclusions. Here, we performed a well-powered association analysis between KL-VSHET+ and five different AD endophenotypes; brain amyloidosis measured by positron emission tomography (PET) scans (n = 5,541) or cerebrospinal fluid Aß42 levels (CSF; n = 5,093), as well as biomarkers associated with tau pathology: the CSF Tau (n = 5,127), phosphorylated Tau (pTau181; n = 4,778) and inflammation: CSF soluble triggering receptor expressed on myeloid cells 2 (sTREM2; n = 2,123) levels. Our results found nominally significant associations of KL-VSHET+ status with biomarkers for brain amyloidosis (e.g., CSF Aß positivity; odds ratio [OR] = 0.67 [95% CI, 0.55-0.78], ß = 0.72, p = 0.007) and tau pathology (e.g., biomarker positivity for CSF Tau; OR = 0.39 [95% CI, 0.19-0.77], ß = -0.94, p = 0.007, and pTau; OR = 0.50 [95% CI, 0.27-0.96], ß = -0.68, p = 0.04) in cognitively normal participants, 60-80 years old, who are APOE e4-carriers. Our work supports previous findings, suggesting that the KL-VSHET+ on an APOE ε4 genotype background may modulate Aß and tau pathology, thereby lowering the intensity of neurodegeneration and incidence of cognitive decline in older controls susceptible to AD.

Development of Apathy, Anxiety, and Depression in Cognitively Unimpaired Older Adults: Effects of Alzheimer's Disease Pathology and Cognitive Decline.

BACKGROUND: The impact of Alzheimer's disease (AD) pathology and cognitive deficits on longitudinal neuropsychiatric symptoms is unclear, especially in early disease stages. METHODS: Cognitively unimpaired older adults (N = 356) enrolled in the prospective Swedish BioFINDER study were examined. Neuropsychiatric assessments encompassed the Apathy Evaluation Scale and the Hospital Anxiety and Depression Scale, performed biennially (together with tests of global cognition) for up to 8 years. Biomarkers were measured in cerebrospinal fluid or plasma at baseline. Magnetic resonance imaging quantified white matter lesions. We used linear mixed-effect models to test associations between baseline AD biomarkers (for amyloid-ß [Aß], tau, and neurodegeneration) and white matter lesions with longitudinal neuropsychiatric symptoms (apathy, anxiety, and depressive symptoms). We also tested associations between changes in cognition and changes in neuropsychiatric symptoms. Finally, we tested if change in cognition mediated the effects of different brain pathologies on neuropsychiatric symptoms. RESULTS: Aß pathology at baseline was associated with increasing levels of apathy (ß = -0.284, p = .005) and anxiety (ß = -0.060, p = .011) longitudinally. More rapid decline of cognition over time was related to increasing levels of apathy. The effects of baseline Aß pathology on longitudinal apathy were partly mediated by changes in cognitive performance (proportion mediated 23%). CONCLUSIONS: Aß pathology may drive the development of both apathy and anxiety in very early stages of AD, largely independent of cognitive change. The effect of Aß on apathy is only partially conveyed by worse cognition. Together, these findings highlight certain neuropsychiatric symptoms as early manifestations of AD.

Shock-Induced Endothelial Dysfunction is Present in Patients With Occult Hypoperfusion After Trauma.

BACKGROUND: Shock-induced endothelial dysfunction, evidenced by elevated soluble thrombomodulin (sTM) and syndecan-1 (Syn-1), is associated with poor outcomes after trauma. The association of endothelial dysfunction and overt shock has been demonstrated; it is unknown if hypoperfusion in the setting of normal vital signs (occult hypoperfusion [OH]) is associated with endothelial dysfunction. We hypothesized that sTM and Syn-1 would be elevated in patients with OH when compared to patients with normal perfusion. METHODS: A single-center study of patients requiring highest-level trauma activation (2012-2016) was performed. Trauma bay arrival plasma Syn-1 and sTM were measured by enzyme-linked immunosorbent assay. Shock was defined as systolic blood pressure (SBP) <90 mm Hg or heart rate (HR) ≥120 bpm. OH was defined as SBP ≥ 90, HR < 120, and base excess (BE) ≤-3. Normal perfusion was assigned to all others. Univariate and multivariable analyses were performed. RESULTS: Of 520 patients, 35% presented with OH and 26% with shock. Demographics were similar between groups. Patients with normal perfusion had the lowest Syn-1 and sTM, while patients with OH and shock had elevated levels. OH was associated with increased sTM by 0.97 ng/mL (95% CI 0.39-1.57, p = 0.001) and Syn-1 by 14.3 ng/mL (95% CI -1.5 to 30.2, p = 0.08). Furthermore, shock was associated with increased sTM by 0.64 (95% CI 0.02-1.30, p = 0.04) and with increased Syn-1 by 23.6 ng/mL (95% CI 6.2-41.1, p = 0.008). CONCLUSIONS: Arrival OH was associated with elevated sTM and Syn-1, indicating endothelial dysfunction. Treatments aiming to stabilize the endothelium may be beneficial for injured patients with evidence of hypoperfusion, regardless of vital signs.

Study protocol for a comparative effectiveness evaluation of abiraterone acetate against enzalutamide: a longitudinal study based on Swedish administrative registers.

INTRODUCTION: This paper presents a study protocol for a comparative effectiveness evaluation of abiraterone acetate against enzalutamide in clinical practice, two cancer drugs given to patients suffering from advanced prostate cancer. METHOD AND ANALYSIS: The protocol designs a comparative-effectiveness analysis of abiraterone acetate against enzalutamide. With the substantial number of covariates a two-step procedure is suggested in choosing relevant covariates in the matching design. In the first step, an exploratory factor analysis reduces the dimension of a large set of continuous covariates to nine factors. In the second step, we reduce the dimension of the covariates, interactions and second order terms for the continuous covariates using propensity score estimation. The final design makes use of a genetic matching algorithm. The study protocol provides a detailed statistical analysis plan of the analysis sample derived from the matching design. The analysis will make use of linear regression and robust inference adjusted for multisignificance testing. DISCUSSION: As in a randomised experiment the focus is on the design of the assignment to treatment. This allows the publication of this preanalysis plan before having access to outcome data. This means that the p values will be correct if the maintained assumption of uncounfoundedness is valid. Given that is p-hacking is substantial problem in empirical research, this is a substantial strength of this study. However, while design yields, balance on the observed covariates one cannot discard the possibility that unobserved confounders are not balanced. For that reason, sensitivity tests for the maintained assumption of uncounfoundedness are presented. ETHICS AND DISSEMINATION: The study was approved by the Regional Ethical Review Board in Uppsala, Sweden (Dnr 2017/482). Results will be published in a peer-reviewed journal and distributed to relevant stakeholders in healthcare.

Cerebrospinal fluid biomarker panel for synaptic dysfunction in Alzheimer's disease.

INTRODUCTION: Synaptic dysfunction and degeneration is one of the earliest events in Alzheimer's disease (AD) and the best correlate of cognitive decline. Thus, identification and validation of biomarkers reflecting synaptic degeneration to be used as prognostic biomarkers are greatly needed. METHOD: Solid-phase extraction and parallel reaction monitoring mass spectrometry were used to quantify 17 synaptic proteins in CSF, in two cross-sectional studies including AD (n = 52) and controls (n = 37). RESULTS: Increased concentrations of beta-synuclein, gamma-synuclein, neurogranin, phosphatidylethanolamine-binding protein 1, and 14-3-3 proteins were observed in AD patients compared to controls, while neuronal pentraxin-2 and neuronal pentraxin receptor were decreased. DISCUSSION: We have established a method with a novel panel of synaptic proteins as biomarkers of synaptic dysfunction. The results indicate that several of the proteins included in the panel may serve as synaptic biomarkers for AD.

Mild behavioral impairment and its relation to tau pathology in preclinical Alzheimer's disease.

Mild behavioral impairment (MBI) is suggested as risk marker for neurodegenerative diseases, such as Alzheimer's disease (AD). Recently, pathologic tau deposition in the brain has been shown closely related to clinical manifestations, such as cognitive deficits. Yet, associations between tau pathology and MBI have rarely been investigated. It is further debated if MBI precedes cognitive deficits in AD. Here, we explored potential mechanisms by which MBI is related to AD, this by studying associations between MBI and tau in preclinical AD. In all, 50 amyloid-ß-positive cognitively unimpaired subjects (part of the BioFINDER-2 study) underwent MBI-checklist (MBI-C) to assess MBI, and the Alzheimer's Disease Assessment Scale - Cognitive subscale (ADAS-Cog) delayed word recall (ADAS-DR) to assess episodic memory. Early tau pathology was determined using tau-PET ([18F]RO948 retention in entorhinal cortex/hippocampus) and cerebrospinal fluid (CSF) P-tau181. Regression models were used to test for associations. We found that higher tau-PET signal in the entorhinal cortex/hippocampus and CSF P-tau181 levels were associated with higher MBI-C scores (ß = 0.010, SE = 0.003, p = 0.003 and ß = 1.263, SE = 0.446, p = 0.007, respectively). When MBI-C and ADAS-DR were entered together in the regression models, tau-PET (ß = 0.009, p = 0.009) and CSF P-tau181 (ß = 0.408, p = 0.006) were predicted by MBI-C, but not ADAS-DR. We conclude that in preclinical AD, MBI is associated with tau independently from memory deficits. This denotes MBI as an important early clinical manifestation related to tau pathology in AD.

Brevican and Neurocan Peptides as Potential Cerebrospinal Fluid Biomarkers for Differentiation Between Vascular Dementia and Alzheimer's Disease.

BACKGROUND: Brevican and neurocan are central nervous system-specific extracellular matrix proteoglycans. They are degraded by extracellular enzymes, such as metalloproteinases. However, their degradation profile is largely unexplored in cerebrospinal fluid (CSF). OBJECTIVE: The study aim was to quantify proteolytic peptides derived from brevican and neurocan in human CSF of patients with Alzheimer's disease (AD) and vascular dementia (VaD) compared with controls. METHODS: The first cohort consisted of 75 individuals including 25 patients with AD, 7 with mild cognitive impairment (MCI) diagnosed with AD upon follow-up, 10 patients with VaD or MCI diagnosed with VaD upon follow-up, and 33 healthy controls and cognitively stable MCI patients. In the second cohort, 31 individuals were included (5 AD patients, 14 VaD patients and 12 healthy controls). Twenty proteolytic peptides derived from brevican (n = 9) and neurocan (n = 11) were quantified using high-resolution parallel reaction monitoring mass spectrometry. RESULTS: In the first cohort, the majority of CSF concentrations of brevican and neurocan peptides were significantly decreased inVaDas compared withADpatients (AUC = 0.83.0.93, p≤0.05) and as compared with the control group (AUC = 0.79.0.87, p ≤ 0.05). In the second cohort, CSF concentrations of two brevican peptides (B87, B156) were significantly decreased in VaD compared with AD (AUC = 0.86.0.91, p ≤ 0.05) and to controls (AUC = 0.80.0.82, p ≤ 0.05), while other brevican and neurocan peptides showed a clear trend to be decreased in VaD compared with AD (AUC = 0.64.80, p > 0.05). No peptides differed between AD and controls. CONCLUSION: Brevican and neurocan peptides are potential diagnostic biomarkers for VaD, with ability to separate VaD from AD.

Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.

We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40-64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington's disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered.