Clinical Continuum Research Articles

Blood phosphorylated tau 181 as a biomarker for Alzheimer's disease: a diagnostic performance and prediction modelling study using data from four prospective cohorts.

CSF and PET biomarkers of amyloid β and tau accurately detect Alzheimer's disease pathology, but the invasiveness, high cost, and poor availability of these detection methods restrict their widespread use as clinical diagnostic tools. CSF tau phosphorylated at threonine 181 (p-tau181) is a highly specific biomarker for Alzheimer's disease pathology. We aimed to assess whether blood p-tau181 could be used as a biomarker for Alzheimer's disease and for prediction of cognitive decline and hippocampal atrophy. We developed and validated an ultrasensitive blood immunoassay for p-tau181. Assay performance was evaluated in four clinic-based prospective cohorts. The discovery cohort comprised patients with Alzheimer's disease and age-matched controls. Two validation cohorts (TRIAD and BioFINDER-2) included cognitively unimpaired older adults (mean age 63-69 years), participants with mild cognitive impairment (MCI), Alzheimer's disease, and frontotemporal dementia. In addition, TRIAD included healthy young adults (mean age 23 years) and BioFINDER-2 included patients with other neurodegenerative disorders. The primary care cohort, which recruited participants in Montreal, Canada, comprised control participants from the community without a diagnosis of a neurological condition and patients referred from primary care physicians of the Canadian National Health Service for specialist care. Concentrations of plasma p-tau181 were compared with established CSF and PET biomarkers and longitudinal measurements using Spearman correlation, area under the curve (AUC), and linear regression analyses. We studied 37 individuals in the discovery cohort, 226 in the first validation cohort (TRIAD), 763 in the second validation cohort (BioFINDER-2), and 105 in the primary care cohort (n=1131 individuals). In all cohorts, plasma p-tau181 showed gradual increases along the Alzheimer's disease continuum, from the lowest concentrations in amyloid β-negative young adults and cognitively unimpaired older adults, through higher concentrations in the amyloid β-positive cognitively unimpaired older adults and MCI groups, to the highest concentrations in the amyloid β-positive MCI and Alzheimer's disease groups (p<0·001, Alzheimer's disease vs all other groups). Plasma p-tau181 distinguished Alzheimer's disease dementia from amyloid β-negative young adults (AUC=99·40%) and cognitively unimpaired older adults (AUC=90·21-98·24% across cohorts), as well as other neurodegenerative disorders, including frontotemporal dementia (AUC=82·76-100% across cohorts), vascular dementia (AUC=92·13%), progressive supranuclear palsy or corticobasal syndrome (AUC=88·47%), and Parkinson's disease or multiple systems atrophy (AUC=81·90%). Plasma p-tau181 was associated with PET-measured cerebral tau (AUC=83·08-93·11% across cohorts) and amyloid β (AUC=76·14-88·09% across cohorts) pathologies, and 1-year cognitive decline (p=0·0015) and hippocampal atrophy (p=0·015). In the primary care cohort, plasma p-tau181 discriminated Alzheimer's disease from young adults (AUC=100%) and cognitively unimpaired older adults (AUC=84·44%), but not from MCI (AUC=55·00%). Blood p-tau181 can predict tau and amyloid β pathologies, differentiate Alzheimer's disease from other neurodegenerative disorders, and identify Alzheimer's disease across the clinical continuum. Blood p-tau181 could be used as a simple, accessible, and scalable test for screening and diagnosis of Alzheimer's disease. Alzheimer Drug Discovery Foundation, European Research Council, Swedish Research Council, Swedish Alzheimer Foundation, Swedish Dementia Foundation, Alzheimer Society Research Program.

Value-Based Analysis of Virtual Versus Traditional Surgical Planning for Orthognathic Surgery.

In orthognathic surgery, virtual surgical planning (VSP) is gaining popularity over traditional surgical planning (TSP); however, concerns about cost of VSP have slowed adoption of this technology. This study investigates the clinical value of VSP versus TSP over the entire clinical care continuum. Retrospective cohort study was conducted for patients undergoing maxillomandibular surgery between 2005 and 2016 at a tertiary pediatric hospital. Clinical value, defined as patient outcomes per unit cost, was analyzed between the 2 groups with appropriate statistics. The VSP (n = 19) and TSP (n = 10) cohorts had statistically similar hospital lengths of stay, rates of complications, readmissions, and duration of postoperative orthodontic treatment (P = 0.518, P > 0.999, P > 0.999, P = 0.812, respectively). VSP maxillomandibular procedures trended towards shorter operative times (P = 0.052). Total hospital charges were statistically similar between the TSP and VSP cohorts (P = 0.160). Medication, laboratory and testing, and room charges were also statistically similar between the TSP and VSP cohorts (P = 0.169, P = 0.953, and P = 0.196 respectively). Indexed patient outcomes and costs incurred for maxillomandibular procedures were statistically similar between those utilizing TSP or VSP leading us to conclude that these 2 methods are associated with similar clinical value. This retrospective analysis should be followed with prospective data to give patients and insurers the best estimate of clinical value utilizing TSP and VSP.

Nonepileptic attack disorder and functional movement disorder: A clinical continuum?

Nonepileptic attack disorder (NEAD) and functional movement disorder (FMD) are functional neurological disorders commonly seen in neuropsychiatry services. Although their initial referral pathways involve epileptologists (NEAD) and specialists in movement disorders (FMD), these conditions are currently classified as two possible manifestations of a single underlying conversion disorder. We set out to compare the characteristics of patients with NEAD and patients with FMD in order to quantify the degree of overlap between these patient groups. We retrospectively reviewed comprehensive clinical data from 146 consecutive patients with functional neurological disorders (NEAD: n = 117; FMD: n = 29) attending a specialist Neuropsychiatry Clinic run by a single Consultant in Behavioral Neurology. The two clinical groups were directly compared with regard to demographic and clinical characteristics, as well as somatic and psychiatric presentations. The results showed that in most features, there were no significant differences between patients with NEAD and patients with FMD. However, patients with NEAD reported an earlier age at onset (p = 0.033) and a higher proportion of acute onset (p = 0.037), alterations of consciousness (p = 0.001), and headache (p = 0.042), whereas patients with FMD reported a higher prevalence of childhood abuse (p = 0.008), as well as mobility problems (p = 0.007) and comorbid functional symptoms (dysarthria, p = 0.004; dizziness, p = 0.035; weakness, p = 0.049). Despite different phenotypic presentations, NEAD and FMD might represent a clinical continuum, with relevant implications in terms of both diagnostic strategies and treatment approaches.

Cortical Microstructural Alterations in Mild Cognitive Impairment and Alzheimer's Disease Dementia.

In Alzheimer's disease (AD), neurodegenerative processes are ongoing for years prior to the time that cortical atrophy can be reliably detected using conventional neuroimaging techniques. Recent advances in diffusion-weighted imaging have provided new techniques to study neural microstructure, which may provide additional information regarding neurodegeneration. In this study, we used neurite orientation dispersion and density imaging (NODDI), a multi-compartment diffusion model, in order to investigate cortical microstructure along the clinical continuum of mild cognitive impairment (MCI) and AD dementia. Using gray matter-based spatial statistics (GBSS), we demonstrated that neurite density index (NDI) was significantly lower throughout temporal and parietal cortical regions in MCI, while both NDI and orientation dispersion index (ODI) were lower throughout parietal, temporal, and frontal regions in AD dementia. In follow-up ROI analyses comparing microstructure and cortical thickness (derived from T1-weighted MRI) within the same brain regions, differences in NODDI metrics remained, even after controlling for cortical thickness. Moreover, for participants with MCI, gray matter NDI-but not cortical thickness-was lower in temporal, parietal, and posterior cingulate regions. Taken together, our results highlight the utility of NODDI metrics in detecting cortical microstructural degeneration that occurs prior to measurable macrostructural changes and overt clinical dementia.

Primary lateral sclerosis: consensus diagnostic criteria

Primary lateral sclerosis (PLS) is a neurodegenerative disorder of the adult motor system. Characterised by a slowly progressive upper motor neuron syndrome, the diagnosis is clinical, after exclusion of structural,...

Preeclampsia: The Need for a Biological Definition and Diagnosis.

The centuries-old approach to the prevention of eclampsia and its associated maternal morbidity and mortality is based on the recognition of the presence of premonitory signs and symptoms such as hypertension and proteinuria. The spectrum of preceding signs and symptoms came to be known as preeclampsia, which is debatably considered to be an early stage on a clinical continuum possibly leading to eclampsia. The premonitory signs and symptoms were then construed as diagnostic criteria for the poorly understood syndrome of preeclampsia, and this led to a perpetual debate that remains subject to wide disagreement and periodic updates. In this commentary, we will draw attention to the fact that the criteria for preeclampsia should be viewed from the prism of a screening test rather than as diagnostic of a condition in itself. Focusing research on developing better diagnostic and screening methods for what is clinically important, namely maternal and perinatal morbidity and mortality from hypertensive disorders of pregnancy, a long overdue upgrade from what was possible centuries ago, will ultimately lead to better management approaches to what really matters.

Visual snow syndrome: A clinical and phenotypical description of 1,100 cases.

ObjectiveTo validate the current criteria of visual snow and to describe its common phenotype using a substantial clinical database.MethodsWe performed a web-based survey of patients with self-assessed visual snow (n = 1,104), with either the complete visual snow syndrome (n = 1,061) or visual snow without the syndrome (n = 43). We also describe a population of patients (n = 70) with possible hallucinogen persisting perception disorder who presented clinically with visual snow syndrome.ResultsThe visual snow population had an average age of 29 years and had no sex prevalence. The disorder usually started in early life, and ≈40% of patients had symptoms for as long as they could remember. The most commonly experienced static was black and white. Floaters, afterimages, and photophobia were the most reported additional visual symptoms. A latent class analysis showed that visual snow does not present with specific clinical endophenotypes. Severity can be classified by the amount of visual symptoms experienced. Migraine and tinnitus had a very high prevalence and were independently associated with a more severe presentation of the syndrome.ConclusionsClinical characteristics of visual snow did not differ from the previous cohort in the literature, supporting validity of the current criteria. Visual snow likely represents a clinical continuum, with different degrees of severity. On the severe end of the spectrum, it is more likely to present with its common comorbid conditions, migraine and tinnitus. Visual snow does not depend on the effect of psychotropic substances on the brain.

From first-trimester screening to risk stratification of evolving pre-eclampsia in second and third trimesters of pregnancy: comprehensive approach.

Preeclampsia and associated hypertensive disorders of pregnancy represent a leading cause of global maternal and neonatal morbidity and mortality. Identification of women at high risk for developing preterm-preeclampsia and prophylaxis with low-dose aspirin has the potential to significantly reduce the rate of preterm-preeclampsia. In addition, risk assessment and monitoring of women in the second and third trimester of pregnancy, to aid in early detection of evolving disease, timely referral to specialist care, and active monitoring of women with confirmed or suspected preeclampsia is essential for improving maternal and neonatal outcomes. The angiogenesis-related biomarkers sFlt-1 and PlGF have been shown to have clinical value to aid in the prediction, diagnosis, and risk stratification of preeclampsia when used either alone or in combination with other risk factors. However, currently there is no consensus on the optimum strategy to link first trimester screening for preterm-preeclampsia with appropriate second and third trimester risk assessment strategies. This opinion paper will outline the current evidence for first trimester preeclampsia screening and prevention, as well as the evidence for various risk stratification approaches for detection of evolving preeclampsia through the second and third trimesters of pregnancy, and proposes a potential model integrating these tools. This article is protected by copyright. All rights reserved.

Association of Cognitive and Behavioral Features Between Adults With Tuberous Sclerosis and Frontotemporal Dementia

Individuals with tuberous sclerosis complex can develop a progressive neuropsychiatric syndrome known as tuberous sclerosis-associated neuropsychiatric disorders. Tuberous sclerosis-associated neuropsychiatric disorders symptoms overlap with clinical criteria for frontotemporal dementia, yet the association between the 2 has not been explored. To investigate the potential association between tuberous sclerosis-associated neuropsychiatric disorders and frontotemporal dementia. Case-control study that enrolled patients with tuberous sclerosis complex with normal IQs in an observational clinical study at the University of California, San Francisco, from 2017 to 2019 where they underwent a comprehensive clinical evaluation including neuropsychologic testing, cerebral spinal fluid biomarker profiling, and structural neuroimaging. The study included adults who fulfilled the clinical criteria for tuberous sclerosis complex and had normal IQs, had frontotemporal dementia, or were healthy control individuals. Tuberous sclerosis-associated neuropsychiatric disorders checklist severity score, neuropsychologic test scores, cerebral spinal fluid concentrations of phosphorylated tau181, total tau, amyloid-β 42, and neurofilament light chain. Amyloid and tau positron emission tomography scans were obtained in a subset of patients. Eighteen patients with tuberous sclerosis complex (mean [SD] age, 48 years [9.54]; 13 women [72%]), 16 with frontotemporal dementia (60 [6.93] years; 7 women [44%]) and 18 healthy control individuals (63 [3.85] years; 9 women [50%]) were included. The tuberous sclerosis-associated neuropsychiatric disorders checklist and neuropsychological test results were not significantly different when the tuberous sclerosis complex and frontotemporal dementia cohorts were compared. The tuberous sclerosis complex cohort exhibited elevated cerebral spinal fluid phosphorylated tau181 and neurofilament light chain with a mean of 32 pg/mL and 2300 pg/mL, respectively, when compared to healthy control individuals. All 3 patients with tuberous sclerosis complex who underwent fluorine 1B-labeled flortaucipir tau positron emission tomographic neuroimaging showed punctate foci of elevated [18F]flortaucipir binding in the frontal and temporal regions. Adults with tuberous sclerosis complex showed phenotypic overlap with frontotemporal dementia. The results support a possible clinical continuum between tuberous sclerosis-associated neuropsychiatric disorders and frontotemporal dementia and highlights a potential pathophysiological link between neurodevelopmental and neurodegenerative processes. Quantitative neuropsychological testing and the tuberous sclerosis-associated neuropsychiatric disorders checklist, potentially supplemented by cerebral spinal fluid and imaging biomarkers, could be used to screen and prognosticate for risk of a neurodegenerative process in adult patients with tuberous sclerosis complex.

Longitudinal transcriptomic analysis of altered pathways in a CHMP2Bintron5-based model of ALS-FTD

Amyotrophic lateral sclerosis and frontotemporal dementia are two neurodegenerative diseases with currently no cure. These two diseases share a clinical continuum with overlapping genetic causes. Mutations in the CHMP2B gene are found in patients with ALS, FTD and ALS-FTD. To highlight deregulated mechanisms occurring in ALS-FTD linked to the CHMP2B gene, we performed a whole transcriptomic study on lumbar spinal cord from CHMP2Bintron5 mice, a model that develops progressive motor alterations associated with dementia symptoms reminiscent of both ALS and FTD. To gain insight into the transcriptomic changes taking place during disease progression this study was performed at three stages: asymptomatic, symptomatic and end stage. We showed that before appearance of motor symptoms, the major disrupted mechanisms were linked with the immune system/inflammatory response and lipid metabolism. These processes were progressively replaced by alterations of neuronal electric activity as motor symptoms appeared, alterations that could lead to motor neuron dysfunction.To investigate overlapping alterations in gene expression between two ALS-causing genes, we then compared the transcriptome of symptomatic CHMP2Bintron5 mice with the one of symptomatic SOD1G86R mice and found the same families deregulated providing further insights into common underlying dysfunction of biological pathways, disrupted or disturbed in ALS.Altogether, this study provides a database to explore potential new candidate genes involved in the CHMP2Bintron5-based pathogenesis of ALS, and provides molecular clues to further understand the functional consequences that diseased neurons expressing CHMP2B mutant may have on their neighbor cells.

Schizophrenia-schizoaffective-bipolar spectra: an epistemological perspective.

For decades clinicians and researchers have been thinking and writing about the spectrum of schizophrenia disorders. Indeed both Kraepelin and Bleuler believed in schizophrenia as a spectrum, both in a clinical (individual) and hereditary (family) continuum, from just some exquisite personality traits to unquestionable chronic and debilitating psychosis. Other authors would put the schizophrenia spectrum disorders on different levels of continuum: developmental, psychofunctional, existential, and genetic. Here, we would like to present an historical chronology for the schizophrenia-schizoaffective-bipolar spectra plus a tridimensional model for these spectra: the first axis for categories (affective versus nonaffective psychoses), the second axis for dimensions (personality versus full blown psychosis), and a third axis for biomarkers (remission versus relapse). We believe that without the schizophrenia-schizoaffective-bipolar spectra concept in our minds all our efforts will keep failing one the hardest quest: searching for biomarkers in schizophrenia and related disorders.

398. Description of a Large Pediatric Lyme Arthritis Cohort in an Endemic Region

BackgroundIn endemic areas, Lyme arthritis (LA) is a leading cause of joint swelling. Due to the shared inflammatory nature and common clinical features, acute LA is often misdiagnosed as septic arthritis (SA) while recurrent disease is at times difficult to differentiate from other causes of chronic arthritis. In Minnesota, there has been a steady increase in cases of Lyme disease. This has not been met by a clear guideline and there is no consensus for the management of pediatric arthritis. In this context, we sought to characterize the epidemiology and clinical presentation of a large local cohort.MethodsThis is a retrospective review of medical charts from children with confirmed LA, presented at a large academic medical organization in the Upper Midwest between January 2011 to December 2017. Demographic, clinical, and laboratory data were collected and analyzed.ResultsLyme arthritis was confirmed in 109 children. Acute presentation was more common (67) while the rest (42) had either persistence or reoccurrence of symptoms [Figure 1]. Elevated inflammatory markers and synovial pleocytosis were common, unlike fever and refusal to bear weight which were seen occasionally [Figure 2]. Seasonal distribution and the clinical setting for initial presentation as well as admissions are summarized in Figure 3. The knee was involved in all but 2 patients, both had acute monoarthritis (elbow and hip) [Figure 4].ConclusionLA causes a spectrum of disease, is seen year round, and across the clinical setting continuum. Acute knee monoarthritis is the most common presentation (54% in our cohort) and is often misdiagnosed as SA leading to unnecessary hospitalizations and aggressive interventions. This occurs more frequently at the ED setting and for children with significant synovial pleocytosis. When evaluating a child with arthritis, laboratory findings are none specific and should be used in caution. Pediatric providers in endemic regions, especially those in primary, hospital, or emergency care must be familiar with the clinical presentation and have a high index of suspicion for LA in order to prevent mismanagement. Disclosures All authors: No reported disclosures.

Brain atrophy and patch-based grading in individuals from the CIMA-Q study: a progressive continuum from subjective cognitive decline to AD

It has been proposed that individuals developing Alzheimer’s disease (AD) first experience a phase expressing subjective complaints of cognitive decline (SCD) without objective cognitive impairment. Using magnetic resonance imaging (MRI), our objective was to verify whether SNIPE probability grading, a new MRI analysis technique, would distinguish between clinical dementia stage of AD: Cognitively healthy controls without complaint (CH), SCD, mild cognitive impairment, and AD. SNIPE score in the hippocampus and entorhinal cortex was applied to anatomical T1-weighted MRI of 143 participants from the Consortium pour l’identification précoce de la maladie Alzheimer - Québec (CIMA-Q) study and compared to standard atrophy measures (volumes and cortical thicknesses). Compared to standard atrophy measures, SNIPE score appeared more sensitive to differentiate clinical AD since differences between groups reached a higher level of significance and larger effect sizes. However, no significant difference was observed between SCD and CH groups. Combining both types of measures did not improve between-group differences. Further studies using a combination of biomarkers beyond anatomical MRI might be needed to identify individuals with SCD who are on the beginning of the clinical continuum of AD.

Lysosomal acid lipase activity and liver fibrosis in the clinical continuum of non-alcoholic fatty liver disease.

Recent evidence showed a reduced activity of the lysosomal acid lipase (LAL) in patients with non-alcoholic fatty liver disease (NAFLD) and cryptogenic cirrhosis (CC). However, the relationship between LAL activity and liver fibrosis has never been investigated. Cross-sectional study including 575 outpatients referred for the management of cardio-metabolic and liver disease. The absence of liver fibrosis was defined by a FIB-4<1.30 and NAFLD fibrosis score (NFS) <-1.455. LAL activity was measured with dried blood spot technique. Overall, 515 patients had a diagnosis of NAFLD (454 NAFL and 61 biopsy-proven NASH) and 60 of CC. The value of LAL activity progressively decreased from healthy subjects to NAFL/NASH patients to CC (P<.001). LAL activity was reduced by 10% in patients with NAFL, by 20% in NASH and by 50% in CC. The prevalence of CC decreased across the tertiles of LAL activity: 22.2% in the lowest, 4.6% in the intermediate and 0.5% in the highest tertile. In NAFLD patients, 69.9% had a FIB4<1.30, and 43.1% a NFS <-1.455. Multivariate logistic regression analysis showed that Log(LAL activity) was associated with FIB-4<1.30 (Odds ratio [OR] 2.19 95% confidence interval [CI] 1.33-3.62, P=.002) and NFS < -1.455 (OR 2.43, 95% CI 1.51-3.91, P<.001) after adjustment for confounding factors. We found a progressive reduction of LAL activity according to liver disease severity. LAL activity was inversely associated with markers of liver fibrosis in patients with NAFLD.

Reduced lysosomal acid lipase activity: A new marker of liver disease severity across the clinical continuum of non-alcoholic fatty liver disease?

Lysosomal acid lipase (LAL) plays a key role in intracellular lipid metabolism. Reduced LAL activity promotes increased multi-organ lysosomal cholesterol ester storage, as observed in two recessive autosomal genetic diseases, Wolman disease and Cholesterol ester storage disease. Severe liver steatosis and accelerated liver fibrosis are common features in patients with genetic LAL deficiency. By contrast, few reliable data are available on the modulation of LAL activity in vivo and on the epigenetic and metabolic factors capable of regulating its activity in subjects without homozygous mutations of the Lipase A gene. In the last few years, a less severe and non-genetic reduction of LAL activity was reported in children and adults with non-alcoholic fatty liver disease (NAFLD), suggesting a possible role of LAL reduction in the pathogenesis and progression of the disease. Patients with NAFLD show a significant, progressive reduction of LAL activity from simple steatosis to non-alcoholic steatohepatitis and cryptogenic cirrhosis. Among cirrhosis of different etiologies, those with cryptogenic cirrhosis show the most significant reductions of LAL activity. These findings suggest that the modulation of LAL activity may become a possible new therapeutic target for patients with more advanced forms of NAFLD. Moreover, the measurement of LAL activity may represent a possible new marker of disease severity in this clinical setting.

Autosomal recessive Bethlem myopathy: A clinical, genetic and functional study

Bethlem myopathy (BM) represents the milder form of the spectrum of Collagen VI-related dystrophies, which are characterized by a clinical continuum between the two extremities, the BM and the Ullrich congenital muscular dystrophy, and include less defined intermediate phenotypes. BM is mainly an autosomal dominant disorder and the causing mutations occur in the COL6A genes encoding for the α1 (COL6A1), α2 (COL6A2) and α3 (COL6A3) chains. However, few cases of recessive inheritance have been also reported. We here describe clinical, genetic and functional findings in a recessive BM family harbouring two novel pathogenic mutations in the COL6A2 gene. Two adult siblings presented with muscle weakness and wasting, elbows and Achilles tendon retractions, lumbar hyperlordosis, waddling gait and positive Gowers' sign. Muscle biopsy showed a dystrophic pattern. Molecular analysis of the COL6A2 gene revealed the novel paternally-inherited nonsense p.Gln889* mutation and the maternally-inherited p.Pro260_Lys261insProPro small insertion. Fibroblast studies in both affected patients showed the concomitant reduction in the amount of normal Collagen VI (p.Gln889*) and impairment of Collagen VI secretion and assembly (p.Pro260_Lys261insProPro). Each of the two variants behave as a recessive mutation as shown by the asymptomatic heterozygous parents, while their concomitant effects determined a relatively mild BM phenotype. This study confirms the occurrence of recessive inherited BM and expands the genetic heterogeneity of this group of muscle diseases.

Autosomal recessive Bethlem myopathy: A clinical, genetic and functional study

Bethlem myopathy represents the milder form of the spectrum of Collagen VI-related dystrophies, which are characterized by a clinical continuum between the two extremities, the Bethlem myopathy and the Ullrich congenital muscular dystrophy, and include less defined intermediate phenotypes. Bethlem myopathy is mainly an autosomal dominant disorder and the causing mutations occur in the COL6A genes encoding for the α1 (COL6A1), α2 (COL6A2) and α3 (COL6A3) chains. However, few cases of recessive inheritance have been also reported. We here describe clinical, genetic and functional findings in a recessive Bethlem myopathy family harbouring two novel pathogenic mutations in the COL6A2 gene. Two adult siblings presented with muscle weakness and wasting, elbows and Achilles tendon retractions, lumbar hyperlordosis, waddling gait and positive Gowers' sign. Muscle biopsy showed a dystrophic pattern. Molecular analysis of the COL6A2 gene revealed the novel paternally-inherited nonsense p.Gln889* mutation and the maternally-inherited p.Pro260_Lys261insProPro small insertion. Fibroblast studies in both affected patients showed the concomitant reduction in the amount of normal Collagen VI (p.Gln889*) and impairment of Collagen VI secretion and assembly (p.Pro260_Lys261insProPro). Each of the two variants behave as a recessive mutation as shown by the asymptomatic heterozygous parents, while their concomitant effects determined a relatively mild Bethlem myopathy phenotype. This study confirms the occurrence of recessive inherited Bethlem myopathy and expands the genetic heterogeneity of this group of muscle diseases.

Liver disease predominates in a mouse model for mild human Zellweger spectrum disorder

Zellweger spectrum disorders (ZSDs) are autosomal recessive diseases caused by defective peroxisome assembly. They constitute a clinical continuum from severe early lethal to relatively milder presentations in adulthood. Liver disease is a prevalent symptom in ZSD patients. The underlying pathogenesis for the liver disease, however, is not fully understood. We report a hypomorphic ZSD mouse model, which is homozygous for Pex1-c.2531G>A (p.G844D), the equivalent of the most common pathogenic variant found in ZSD, and which predominantly presents with liver disease. After introducing the Pex1-G844D allele by knock-in, we characterized homozygous Pex1-G844D mice for survival, biochemical parameters, including peroxisomal and mitochondrial functions, organ histology, and developmental parameters. The first 20 post-natal days (P20) were critical for survival of homozygous Pex1-G844D mice (~20% survival rate). Lethality was likely due to a combination of cholestatic liver problems, liver dysfunction and caloric deficit, probably as a consequence of defective bile acid biosynthesis. Survival beyond P20 was nearly 100%, but surviving mice showed a marked delay in growth. Surviving mice showed similar hepatic problems as described for mild ZSD patients, including hepatomegaly, bile duct proliferation, liver fibrosis and mitochondrial alterations. Biochemical analyses of various tissues showed the absence of functional peroxisomes accompanied with aberrant levels of peroxisomal metabolites predominantly in the liver, while other tissues were relatively spared.ur findings show that homozygous Pex1-G844D mice have a predominant liver disease phenotype, mimicking the hepatic pathology of ZSD patients, and thus constitute a good model to study pathogenesis and treatment of liver disease in ZSD patients.

A New Approach to Measure Adherence to Medicines Using Biomarkers and Sensors.

Approximately one in two patients with a chronic disease does not take their medicines as prescribed. Poor adherence is a worldwide epidemic and a major source of variability in pharmacokinetics (PK) and pharmacodynamics. Without addressing adherence, precision medicine is unlikely to come to fruition. In drug development, poor adherence confounds the estimates for efficacy and safety of drug candidates. Accurate and high-resolution measurement of adherence is a first step toward effective interventions against poor adherence. We describe a new cross-technology platform to measure adherence. The approach involves, first, building PK models to explain dose-exposure relationships. The model incorporates PK biomarkers by genotyping or phenotyping of drug metabolism, transport and other drug clearance pathways. Importantly, dose-exposure data for model building are obtained in healthy volunteer and/or patient cohorts who are ascertained for full adherence, using edible ingestion sensors (IS) that digitize orally administered medicines. Second, the built model is harnessed to back calculate the dose actually ingested by patients, given the empirically observed drug exposure, PK biomarker, demographic, and other patient data. The proposed platform is envisioned to result in development of both drug and drug-specific companion software for adherence measurement. In terms of feasibility, the new approach overlaps with current drug development timelines spanning the Phase 1 to 4 clinical trial continuum, and thus, could conceivably be implemented without requiring significant changes to the time sensitive clinical trial processes. For the IS-powered tools, the proposed platform creates a new space for applications in clinical trials to ensure adherence.

The Evolving Landscape of Immunotherapy in Advanced Prostate Cancer

Prostate cancer exists in a clinical continuum of hormone-sensitive to castration-resistant disease. Despite the use of chemotherapy and androgen synthesis inhibitors in the castration-resistant setting, this remains a lethal disease. The advent of immune checkpoint blockade has changed the outlook for cancer treatment and survival for several tumors since its first approval in 2011; however, the clinical benefit in castration-resistant prostate cancer (CRPC) is rather limited. Currently, Sipuleucel-T remains the only immune modality to be approved in CRPC setting. Such immune resistance likely exists due to low immunogenicity of prostate tumor cells and an immunosuppressive tumor microenvironment. In this review, we describe the early experiences of immune checkpoint blockade and therapeutic vaccines in CRPC. We then outline strategies currently being implemented to overcome immune resistance, as well as genomic biomarker investigation to identify patients that may harbor more immunogenic tumors. At last, we preview emerging immunotherapeutic platforms.