Progression to corticobasal syndrome: a longitudinal study of patients with nonfluent primary progressive aphasia and primary progressive apraxia of speech.

BACKGROUND AND OBJECTIVES: Nonfluent variant primary progressive aphasia (nfvPPA) and primary progressive apraxia of speech (PPAOS) can be precursors to corticobasal syndrome (CBS). Details on their progression remain unclear. We aimed to examine the clinical and neuroimaging evolution of nfvPPA and PPAOS into CBS. METHODS: We conducted a retrospective longitudinal study in 140 nfvPPA or PPAOS patients and applied the consensus criteria for possible and probable CBS for every visit, evaluating limb rigidity, akinesia, limb dystonia, myoclonus, ideomotor apraxia, alien limb phenomenon, and nonverbal oral apraxia (NVOA). Given the association of NVOA with AOS, we also modified the CBS criteria by excluding NVOA and assigned every patient to either a progressors or non-progressors group. We evaluated the frequency of every CBS feature by year from disease onset, and assessed gray and white matter volume loss using SPM12. RESULTS: Asymmetric akinesia, NVOA, and limb apraxia were the most common CBS features that developed; while limb dystonia, myoclonus, and alien limb were rare. Eighty-two patients progressed to possible CBS; only four to probable CBS. nfvPPA and PPAOS had a similar proportion of progressors, although nfvPPA progressed to CBS earlier (p-value = 0.046), driven by an early appearance of limb apraxia (p-value = 0.0041). The non-progressors and progressors both showed premotor/motor cortex involvement at baseline, with spread into prefrontal cortex over time. DISCUSSION: An important proportion of patients with nfvPPA and PPAOS progress to possible CBS, while they rarely develop features of probable CBS even after long follow-up.

A systematic review of progranulin concentrations in biofluids in over 7,000 people-assessing the pathogenicity of GRN mutations and other influencing factors.

BACKGROUND: Pathogenic heterozygous mutations in the progranulin gene (GRN) are a key cause of frontotemporal dementia (FTD), leading to significantly reduced biofluid concentrations of the progranulin protein (PGRN). This has led to a number of ongoing therapeutic trials aiming to treat this form of FTD by increasing PGRN levels in mutation carriers. However, we currently lack a complete understanding of factors that affect PGRN levels and potential variation in measurement methods. Here, we aimed to address this gap in knowledge by systematically reviewing published literature on biofluid PGRN concentrations. METHODS: Published data including biofluid PGRN concentration, age, sex, diagnosis and GRN mutation were collected for 7071 individuals from 75 publications. The majority of analyses (72%) had focused on plasma PGRN concentrations, with many of these (56%) measured with a single assay type (Adipogen) and so the influence of mutation type, age at onset, sex, and diagnosis were investigated in this subset of the data. RESULTS: We established a plasma PGRN concentration cut-off between pathogenic mutation carriers and non-carriers of 74.8 ng/mL using the Adipogen assay based on 3301 individuals, with a CSF concentration cut-off of 3.43 ng/mL. Plasma PGRN concentration varied by GRN mutation type as well as by clinical diagnosis in those without a GRN mutation. Plasma PGRN concentration was significantly higher in women than men in GRN mutation carriers (p = 0.007) with a trend in non-carriers (p = 0.062), and there was a significant but weak positive correlation with age in both GRN mutation carriers and non-carriers. No significant association was seen with weight or with TMEM106B rs1990622 genotype. However, higher plasma PGRN levels were seen in those with the GRN rs5848 CC genotype in both GRN mutation carriers and non-carriers. CONCLUSIONS: These results further support the usefulness of PGRN concentration for the identification of the large majority of pathogenic mutations in the GRN gene. Furthermore, these results highlight the importance of considering additional factors, such as mutation type, sex and age when interpreting PGRN concentrations. This will be particularly important as we enter the era of trials for progranulin-associated FTD.

Evaluation of a hybrid protocol using continuous glucose monitoring and point-of-care testing in non-critically ill patients in a community hospital.

PURPOSE: Inpatient glycemic management typically involves use of point-of-care (POC) glucose measurements to inform insulin dosing decisions. This study evaluated a hybrid monitoring protocol using real-time continuous glucose monitoring (rtCGM) supplemented with POC testing at a community hospital. METHODS: Adult inpatients receiving POC glucose testing were monitored using rtCGM in a telemetry unit. The hybrid monitoring protocol required a once-daily POC test but otherwise primarily relied on rtCGM values for insulin dosing decisions. Outcomes assessment included surveillance error grid (SEG) and Clarke Error Grid (CEG) analysis results, the mean absolute relative difference (MARD) for available rtCGM-POC value pairs before and after study protocol application, the number of POC tests avoided, and the number of hypoglycemic events involving a blood glucose value of <70 mg/dL identified by rtCGM and POC values. RESULTS: Data were collected from 30 inpatients (the mean age was 69.4 years, 77% were female, 80% had type 2 diabetes, and 37% were at-home insulin users). With the protocol applied, a total of 202 rtCGM-POC pairs produced a MARD of 12.5%. SEG analysis showed 2 pairs in the "moderate" risk category, with all other pairs in the "none" or "slight" risk categories. CEG analysis showed 99% of paired values to be in the clinically acceptable range. Six hypoglycemic events in 5 patients were resolved without incident. Three hundred three POC tests were avoided, a 60% reduction for the study duration. CONCLUSION: Use of a hybrid monitoring protocol of rtCGM and POC testing in a community hospital demonstrated sustained rtCGM accuracy and was found to reduce the frequency of POC testing to manage inpatient glycemia.

Molecular fragment characteristics and distribution of tangle associated TDP-43 (TATs) and other TDP-43 lesions in Alzheimer's disease.

TAR DNA binding protein 43 (TDP-43) pathology is a defining feature of frontotemporal lobar degeneration (FTLD). In FTLD-TDP there is a moderate-to-high burden of morphologically distinctive TDP-43 immunoreactive inclusions distributed throughout the brain. In Alzheimer's disease (AD), similar TDP-43 immunoreactive inclusions are observed. In AD, however, there is a unique phenomenon of neurofibrillary tangle-associated TDP-43 (TATs) whereby TDP-43 intermingles with neurofibrillary tangles. Little is known about the characteristics and distribution of TATs, or how burden and distribution of TATs compares to burden and distribution of other FTLD-TDP-like lesions observed in AD. Here we characterize molecular fragment characteristics, burden and distribution of TATs and assess how these features compare to features of other TDP-43 lesions. We performed TDP-43 immunohistochemistry with anti-phosphorylated, C- and N-terminal TDP-43 antibodies in 20 high-probability AD cases and semi-quantitative burden of seven inclusion types within five brain regions (entorhinal cortex, subiculum, CA1 and dentate gyrus of hippocampus, occipitotemporal cortex). Hierarchical cluster analysis was used to analyze the dataset that consisted of 75 different combinations of neuropathological features. TATs were nonspherical with heterogeneous staining patterns and present in all regions except hippocampal dentate. All three antibodies detected TATs although N-terminal antibody sensitivity was low. Three clusters were identified: Cluster-1 had mild-moderate TATs, moderate-frequent neuronal cytoplasmic inclusions, dystrophic neurites, neuronal intranuclear inclusions and fine neurites, and perivascular and granular inclusions identified only with the N-terminal antibody throughout the brain; Cluster-2 had scant TATs in limbic regions and Cluster-3 mild-moderate TATs and mild-moderate neuronal cytoplasmic inclusions and dystrophic neurites throughout the brain and moderate fine neurites. Only 17% of cluster 1 cases had the TMEM106b GG (protective) haplotype and 83% had hippocampal sclerosis. Both features differed across clusters (p=0.03 & p=0.01). TATs have molecular characteristics, distribution and burden, and genetic and pathologic associations like FTLD-TDP lesions.

Evaluating Factors Explaining U.S. Consumers' Behavioral Intentions toward Irradiated Ground Beef.

Although food irradiation is deemed safe and endorsed by health-related organizations worldwide, consumers are reluctant to accept the technology. Yet, consumer acceptance is critical as food irradiation has significant potential for increasing the safety and availability of food globally. To communicate about food irradiation, science communicators should understand the psychology behind consumers' decision making related to irradiated foods. Using empirical research, we developed a theoretical model and used structural equation modeling to determine how nine variables affect consumers' behavioral intentions toward irradiated ground beef. We purchased a national quota sample from Qualtrics and surveyed N = 1102 U.S. consumers. The model explained 60.3% of the variance in consumers' attitudes toward food irradiation and 55.4% of their behavioral intentions toward irradiated ground beef. Attitude had the largest positive, total effect on consumers' behavioral intentions, which was followed by subjective social norm and perceived benefit. Perceived risk had the largest negative, total effect on behavioral intentions. Attitude mediated the effect of subjective social norm, perceived benefit, perceived risk, objective knowledge, and food technology neophobia. Environmental concern and health consciousness did not significantly affect behavioral intention. Science communicators should develop messaging strategies that seek to improve consumer acceptance with these factors in mind.

The SERPINA5 coding variant E228Q does not contribute to clinicopathologic characteristics in Alzheimer's disease: A cross-sectional study.

We previously demonstrated that increased expression of the SERPINA5 gene is associated with hippocampal vulnerability in Alzheimer's disease (AD) brains. SERPINA5 was further demonstrated to be a novel tau-binding partner that colocalizes within neurofibrillary tangles. Our goal was to determine whether genetic variants in the SERPINA5 gene contributed to clinicopathologic phenotypes in AD. To screen for SERPINA5 variants, we sequenced 103 autopsy-confirmed young-onset AD cases with a positive family history of cognitive decline. To further assess the frequency of a rare missense variant, SERPINA5 p.E228Q, we screened an additional 1114 neuropathologically diagnosed AD cases. To provide neuropathologic context in AD, we immunohistochemically evaluated SERPINA5 and tau in a SERPINA5 p.E228Q variant carrier and a matched noncarrier. In the initial SERPINA5 screen, we observed 1 individual with a rare missense variant (rs140138746) that resulted in an amino acid change (p.E228Q). In our AD validation cohort, we identified an additional 5 carriers of this variant, resulting in an allelic frequency of 0.0021. There was no significant difference between SERPINA5 p.E228Q carriers and noncarriers in terms of demographic or clinicopathologic characteristics. Although not significant, on average SERPINA5 p.E228Q carriers were 5 years younger at age of disease onset than noncarriers (median: 66 [60-73] vs 71 [63-77] years, P = .351). In addition, SERPINA5 p.E228Q carriers exhibited a longer disease duration than noncarriers that approached significance (median: 12 [10-15]) vs 9 [6-12] years, P = .079). More severe neuronal loss was observed in the locus coeruleus, hippocampus, and amygdala of the SERPINA5 p.E228Q carrier compared to noncarrier, although no significant difference in SERPINA5-immunopositive lesions was observed. Throughout the AD brain in either carrier or noncarrier, areas with early pretangle pathology or burnt-out ghost tangle accumulation did not reveal SERPINA5-immunopositive neurons. Mature tangles and newly formed ghost tangles appeared to correspond well with SERPINA5-immunopositive tangle-bearing neurons. SERPINA5 gene expression was previously associated with disease phenotype; however, our findings suggest that SERPINA5 genetic variants may not be a contributing factor to clinicopathologic differences in AD. SERPINA5-immunopositive neurons appear to undergo a pathologic process that corresponded with specific levels of tangle maturity.

Impact of Postsurgical Opioid Prescription Reduction in General Surgery Patients.

Purpose: Recent studies suggest a large percentage of post-surgical opioid prescriptions are not utilized. This surplus of opioids provides supply for diversion or entry into the waste cycle. Recommendations are available for general surgery procedures which may optimize prescribed quantity while maintaining patient satisfaction which this work was initiated to investigate. Methods: This retrospective patient survey was conducted with Institutional Review Committee approval following adjustments to discharge opioid prescription quantities in an individual General Surgeon practice. Patients were contacted via phone to assess the impact of the reduced opioid quantities. Patients were categorized based on whether they utilized the entire prescription or opioid remained. Data collected include baseline demographics, inpatient stay characteristics, opioid use patterns, and satisfaction with overall pain control. The primary endpoint was to determine if patients were satisfied with their pain control based on response. Secondary endpoints included if patient characteristics could be identified that signal larger opioid quantity use, and whether unused opioids were disposed. Results: Thirty patients utilized all opioid prescribed, 60 had some quantity remaining. Baseline data appear similar aside from age with younger patients using more opioid. Patients were satisfied with their overall pain control in 93% of respondents. A total of 960 opioid tablets (11.4 ± 4.8 tabs/patient) were not prescribed, 8% required refill. Opioid disposal yet to occur in 85% of patients. Conclusion: An evidence-based reduction in opioid discharge prescriptions following general surgery procedures resulted in nearly 1000 opioid tablets not being dispensed without having a negative impact on patient satisfaction.

C-terminal TMEM106B fragments in human brain correlate with disease-associated TMEM106B haplotypes.

Transmembrane protein 106B (TMEM106B) is a tightly regulated glycoprotein predominantly localized to endosomes and lysosomes. Genetic studies have implicated TMEM106B haplotypes in the development of multiple neurodegenerative diseases with the strongest effect in frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP), especially in progranulin (GRN) mutation carriers. Recently, cryo-electron microscopy studies showed that a C-terminal fragment (CTF) of TMEM106B (amino acid residues 120-254) forms amyloid fibrils in the brain of patients with FTLD-TDP, but also in brains with other neurodegenerative conditions and normal ageing brain. The functional implication of these fibrils and their relationship to the disease-associated TMEM106B haplotype remain unknown. We performed immunoblotting using a newly developed antibody to detect TMEM106B CTFs in the sarkosyl-insoluble fraction of post-mortem human brain tissue from patients with different proteinopathies (n = 64) as well as neuropathologically normal individuals (n = 10) and correlated the results with age and TMEM106B haplotype. We further compared the immunoblot results with immunohistochemical analyses performed in the same study population. Immunoblot analysis showed the expected ∼30 kDa band in the sarkosyl-insoluble fraction of frontal cortex tissue in at least some individuals with each of the conditions evaluated. Most patients with GRN mutations showed an intense band representing TMEM106B CTF, whereas in most neurologically normal individuals it was absent or much weaker. In the overall cohort, the presence of TMEM106B CTFs correlated strongly with both age (rs = 0.539, P < 0.001) and the presence of the TMEM106B risk haplotype (rs = 0.469, P < 0.001). Although there was a strong overall correlation between the results of immunoblot and immunohistochemistry (rs = 0.662, P < 0.001), 27 cases (37%) were found to have higher amounts of TMEM106B CTFs detected by immunohistochemistry, including most of the older individuals who were neuropathologically normal and individuals who carried two protective TMEM106B haplotypes. Our findings suggest that the formation of sarkosyl-insoluble TMEM106B CTFs is an age-related feature which is modified by TMEM106B haplotype, potentially underlying its disease-modifying effect. The discrepancies between immunoblot and immunohistochemistry in detecting TMEM106B pathology suggests the existence of multiple species of TMEM106B CTFs with possible biological relevance and disease implications.

Accumulation of TMEM106B C-terminal fragments in neurodegenerative disease and aging.

Several studies using cryogenic electron microscopy (cryo-EM) techniques recently reported the isolation and characterization of novel protein filaments, composed of a C-terminal fragment (CTF) of the endolysosomal transmembrane protein 106B (TMEM106B), from human post-mortem brain tissue with various neurodegenerative conditions and normal aging. Genetic variation in TMEM106B is known to influence the risk and presentation of several neurodegenerative diseases, especially frontotemporal dementia (FTD) caused by mutations in the progranulin gene (GRN). To further elucidate the significance of TMEM106B CTF, we performed immunohistochemistry with antibodies directed against epitopes within the filament-forming C-terminal region of TMEM106B. Accumulation of TMEM106B C-terminal immunoreactive (TMEM-ir) material was a common finding in all the conditions evaluated, including frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP), Alzheimer's disease, tauopathies, synucleinopathies and neurologically normal aging. TMEM-ir material was present in a wide range of brain cell types and in a broad neuroanatomical distribution; however, there was no co-localization of TMEM-ir material with other neurodegenerative proteins in cellular inclusions. In most conditions, the presence and abundance of TMEM-ir aggregates correlated strongly with patient age and showed only a weak correlation with the TMEM106B haplotype or the primary pathological diagnosis. However, all patients with FTD caused by GRN mutations were found to have high levels of TMEM-ir material, including several who were relatively young (< 60 years). These findings suggest that the accumulation of TMEM106B CTF is a common age-related phenomenon, which may reflect lysosomal dysfunction. Although its significance in most neurodegenerative conditions remains uncertain, the consistent finding of extensive TMEM-ir material in cases of FTLD-TDP with GRN mutations further supports a pathomechanistic role of TMEM106B and lysosomal dysfunction in this specific disease population.

Practical implementation of remote continuous glucose monitoring in hospitalized patients with diabetes.

PURPOSE: Inpatient diabetes management involves frequent assessment of glucose levels for treatment decisions. Here we describe a program for inpatient real-time continuous glucose monitoring (rtCGM) at a community hospital and the accuracy of rtCGM-based glucose estimates. METHODS: Adult inpatients with preexisting diabetes managed with intensive insulin therapy and a diagnosis of coronavirus disease 2019 (COVID-19) were monitored via rtCGM for safety. An rtCGM system transmitted glucose concentration and trending information at 5-minute intervals to nearby smartphones, which relayed the data to a centralized monitoring station. Hypoglycemia alerts were triggered by rtCGM values of ≤85 mg/dL, but rtCGM data were otherwise not used in management decisions; insulin dosing adjustments were based on blood glucose values measured via fingerstick blood sampling. Accuracy was evaluated retrospectively by comparing rtCGM values to contemporaneous point-of-care (POC) blood glucose values. RESULTS: A total of 238 pairs of rtCGM and POC data points from 10 patients showed an overall mean absolute relative difference (MARD) of 10.3%. Clarke error grid analysis showed 99.2% of points in the clinically acceptable range, and surveillance error grid analysis showed 89.1% of points in the lowest risk category. It was determined that for 25% of the rtCGM values, discordances in rtCGM and POC values would likely have resulted in different insulin doses. Insulin dose recommendations based on rtCGM values differed by 1 to 3 units from POC-based recommendations. CONCLUSION: rtCGM for inpatient diabetes monitoring is feasible. Evaluation of individual rtCGM-POC paired values suggested that using rtCGM data for management decisions poses minimal risks to patients. Further studies to establish the safety and cost implications of using rtCGM data for inpatient diabetes management decisions are warranted.

FDG-PET in presymptomatic C9orf72 mutation carriers.

OBJECTIVE: Our aim is to investigate patterns of brain glucose metabolism using fluorodeoxyglucose positron emission tomography (FDG-PET) in presymptomatic carriers of the C9orf72 repeat expansion to better understand the early preclinical stages of frontotemporal dementia (FTD). METHODS: Structural MRI and FDG-PET were performed on clinically asymptomatic members of families with FTD caused by the C9orf72 repeat expansion (15 presymptomatic mutation carriers, C9orf72+; 20 non-carriers, C9orf72-). Regional glucose metabolism in cerebral and cerebellar gray matter was compared between groups. RESULTS: The mean age of the C9orf72+ and C9orf72- groups were 45.3 ± 10.6 and 56.0 ± 11.0 years respectively, and the mean age of FTD onset in their families was 56 ± 7 years. Compared to non-carrier controls, the C9orf72+ group exhibited regional hypometabolism, primarily involving the cingulate gyrus, frontal and temporal neocortices (left > right) and bilateral thalami. CONCLUSIONS: The C9orf72 repeat expansion is associated with changes in brain glucose metabolism that are demonstrable up to 10 years prior to symptom onset and before changes in gray matter volume become significant. These findings indicate that FDG-PET may be a particularly sensitive and useful method for investigating and monitoring the earliest stages of FTD in individuals with this underlying genetic basis.

Longitudinal clinical, neuropsychological, and neuroimaging characterization of a kindred with a 12-octapeptide repeat insertion in PRNP: the next generation.

BACKGROUND: Highly penetrant inherited mutations in the prion protein gene (PRNP) offer a window to study the pathobiology of prion disorders. METHOD: Clinical, neuropsychological, and neuroimaging characterization of a kindred. RESULTS: Three of four mutation carriers have progressed to a frontotemporal dementia phenotype. Declines in neuropsychological function coincided with changes in FDG-PET at the identified onset of cognitive impairment. CONCLUSIONS AND RELEVANCE: Gene silencing treatments are on the horizon and when they become available, early detection will be crucial. Longitudinal studies involving familial mutation kindreds can offer important insights into the initial neuropsychological and neuroimaging changes necessary for early detection.

Clinicopathologic correlations in a family with a TBK1 mutation presenting as primary progressive aphasia and primary lateral sclerosis.

Mutations in the TANK binding kinase 1 gene (TBK1) are associated with amyotrophic lateral sclerosis and/or frontotemporal dementia; however, the range of clinical phenotypes and neuropathological changes associated with these mutations have not yet been completely elucidated. We present the detailed clinical, neuroimaging, and neuropathological features of two brothers carrying the TBK1 p.Gly272_Thr331del mutation. Both presented with very similar and unusual clinical features including primary progressive aphasia and asymmetric-onset primary lateral sclerosis (PLS). Repeated electrophysiological studies failed to reveal any lower motor neuron involvement. Neuropathological evaluation of both cases revealed frontotemporal lobar degeneration with TDP-43 proteinopathy type B and selective involvement of upper motor neurons with TDP-43 inclusions. The stereotypical clinical presentation and neuropathological findings in these cases widen the phenotypic spectrum of TBK1 mutations and provide insights into the pathogenesis of PLS.

Coexistence of Progressive Supranuclear Palsy With Pontocerebellar Atrophy and Myotonic Dystrophy Type 1.

Progressive supranuclear palsy with predominant cerebellar ataxia (PSP-C) has been reported as a rare clinical subtype, but the underlying pathology of its cerebellar ataxia remains unclear. Here, we report a patient with the coexistence of PSP with pontocerebellar atrophy and myotonic dystrophy type 1 (DM1). A 73-year-old man who was an asymptomatic carrier of DM1 (66 CTG repeats) started developing ataxic gait with multiple falls, visual blurring, double vision, and word finding difficulty at age 62 and was initially diagnosed with multiple system atrophy (MSA). Subsequently, the diagnosis was changed to PSP due to hypometric downward gaze, reduced blink frequency, symmetric bradykinesia, rigidity, and the absence of autonomic dysfunction. He eventually developed delayed grip opening with percussion myotonia at age 72. At autopsy, severe neuronal degeneration and astrogliosis in the pontocerebellar structures suggested MSA, but immunohistochemistry for α-synuclein did not reveal neuronal or glial cytoplasmic inclusions. Immunohistochemistry for phospho-tau and 4-repeat tau confirmed a neuropathological diagnosis of PSP with exceptionally numerous coiled bodies and threads in the pontine base and cerebellar white matter. This unusual distribution of 4-repeat tau pathology and neuronal degeneration with astrogliosis is a plausible clinicopathological substrate of PSP-C.

Genome-wide analyses as part of the international FTLD-TDP whole-genome sequencing consortium reveals novel disease risk factors and increases support for immune dysfunction in FTLD.

Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) represents the most common pathological subtype of FTLD. We established the international FTLD-TDP whole-genome sequencing consortium to thoroughly characterize the known genetic causes of FTLD-TDP and identify novel genetic risk factors. Through the study of 1131 unrelated Caucasian patients, we estimated that C9orf72 repeat expansions and GRN loss-of-function mutations account for 25.5% and 13.9% of FTLD-TDP patients, respectively. Mutations in TBK1 (1.5%) and other known FTLD genes (1.4%) were rare, and the disease in 57.7% of FTLD-TDP patients was unexplained by the known FTLD genes. To unravel the contribution of common genetic factors to the FTLD-TDP etiology in these patients, we conducted a two-stage association study comprising the analysis of whole-genome sequencing data from 517 FTLD-TDP patients and 838 controls, followed by targeted genotyping of the most associated genomic loci in 119 additional FTLD-TDP patients and 1653 controls. We identified three genome-wide significant FTLD-TDP risk loci: one new locus at chromosome 7q36 within the DPP6 gene led by rs118113626 (p value = 4.82e - 08, OR = 2.12), and two known loci: UNC13A, led by rs1297319 (p value = 1.27e - 08, OR = 1.50) and HLA-DQA2 led by rs17219281 (p value = 3.22e - 08, OR = 1.98). While HLA represents a locus previously implicated in clinical FTLD and related neurodegenerative disorders, the association signal in our study is independent from previously reported associations. Through inspection of our whole-genome sequence data for genes with an excess of rare loss-of-function variants in FTLD-TDP patients (n ≥ 3) as compared to controls (n = 0), we further discovered a possible role for genes functioning within the TBK1-related immune pathway (e.g., DHX58, TRIM21, IRF7) in the genetic etiology of FTLD-TDP. Together, our study based on the largest cohort of unrelated FTLD-TDP patients assembled to date provides a comprehensive view of the genetic landscape of FTLD-TDP, nominates novel FTLD-TDP risk loci, and strongly implicates the immune pathway in FTLD-TDP pathogenesis.

Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations: a genome-wide association study.

BACKGROUND: Loss-of-function mutations in GRN cause frontotemporal lobar degeneration (FTLD). Patients with GRN mutations present with a uniform subtype of TAR DNA-binding protein 43 (TDP-43) pathology at autopsy (FTLD-TDP type A); however, age at onset and clinical presentation are variable, even within families. We aimed to identify potential genetic modifiers of disease onset and disease risk in GRN mutation carriers. METHODS: The study was done in three stages: a discovery stage, a replication stage, and a meta-analysis of the discovery and replication data. In the discovery stage, genome-wide logistic and linear regression analyses were done to test the association of genetic variants with disease risk (case or control status) and age at onset in patients with a GRN mutation and controls free of neurodegenerative disorders. Suggestive loci (p<1 × 10-5) were genotyped in a replication cohort of patients and controls, followed by a meta-analysis. The effect of genome-wide significant variants at the GFRA2 locus on expression of GFRA2 was assessed using mRNA expression studies in cerebellar tissue samples from the Mayo Clinic brain bank. The effect of the GFRA2 locus on progranulin concentrations was studied using previously generated ELISA-based expression data. Co-immunoprecipitation experiments in HEK293T cells were done to test for a direct interaction between GFRA2 and progranulin. FINDINGS: Individuals were enrolled in the current study between Sept 16, 2014, and Oct 5, 2017. After quality control measures, statistical analyses in the discovery stage included 382 unrelated symptomatic GRN mutation carriers and 1146 controls free of neurodegenerative disorders collected from 34 research centres located in the USA, Canada, Australia, and Europe. In the replication stage, 210 patients (67 symptomatic GRN mutation carriers and 143 patients with FTLD without GRN mutations pathologically confirmed as FTLD-TDP type A) and 1798 controls free of neurodegenerative diseases were recruited from 26 sites, 20 of which overlapped with the discovery stage. No genome-wide significant association with age at onset was identified in the discovery or replication stages, or in the meta-analysis. However, in the case-control analysis, we replicated the previously reported TMEM106B association (rs1990622 meta-analysis odds ratio [OR] 0·54, 95% CI 0·46-0·63; p=3·54 × 10-16), and identified a novel genome-wide significant locus at GFRA2 on chromosome 8p21.3 associated with disease risk (rs36196656 meta-analysis OR 1·49, 95% CI 1·30-1·71; p=1·58 × 10-8). Expression analyses showed that the risk-associated allele at rs36196656 decreased GFRA2 mRNA concentrations in cerebellar tissue (p=0·04). No effect of rs36196656 on plasma and CSF progranulin concentrations was detected by ELISA; however, co-immunoprecipitation experiments in HEK293T cells did suggest a direct binding of progranulin and GFRA2. INTERPRETATION: TMEM106B-related and GFRA2-related pathways might be future targets for treatments for FTLD, but the biological interaction between progranulin and these potential disease modifiers requires further study. TMEM106B and GFRA2 might also provide opportunities to select and stratify patients for future clinical trials and, when more is known about their potential effects, to inform genetic counselling, especially for asymptomatic individuals. FUNDING: National Institute on Aging, National Institute of Neurological Disorders and Stroke, Canadian Institutes of Health Research, Italian Ministry of Health, UK National Institute for Health Research, National Health and Medical Research Council of Australia, and the French National Research Agency.

Identification of compound heterozygous variants in OPTN in an ALS-FTD patient from the CReATe consortium: a case report.

Homozygous loss-of-function mutations in optineurin (OPTN) are a rare cause of amyotrophic lateral sclerosis (ALS), whereas heterozygous loss-of-function mutations have been suggested to increase ALS disease risk. We report a patient with ALS and frontotemporal dementia (FTD) from the Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium carrying compound heterozygous loss-of-function variants in OPTN. Quantitative real-time mRNA expression analyses revealed a 75-80% reduction in OPTN expression in blood in the OPTN carrier as compared to controls, suggesting at least partial nonsense-mediated decay of the mutant transcripts. This case report illustrates the diverse inheritance patterns and variable clinical presentations associated with OPTN mutations, and underscores the importance of complete OPTN gene screening in patients with ALS and related disorders, especially in the context of clinical genetic testing.

Clinical and neuropathological features of ALS/FTD with TIA1 mutations.

Mutations in the stress granule protein T-cell restricted intracellular antigen 1 (TIA1) were recently shown to cause amyotrophic lateral sclerosis (ALS) with or without frontotemporal dementia (FTD). Here, we provide detailed clinical and neuropathological descriptions of nine cases with TIA1 mutations, together with comparisons to sporadic ALS (sALS) and ALS due to repeat expansions in C9orf72 (C9orf72+). All nine patients with confirmed mutations in TIA1 were female. The clinical phenotype was heterogeneous with a range in the age at onset from late twenties to the eighth decade (mean = 60 years) and disease duration from one to 6 years (mean = 3 years). Initial presentation was either focal weakness or language impairment. All affected individuals received a final diagnosis of ALS with or without FTD. No psychosis or parkinsonism was described. Neuropathological examination on five patients found typical features of ALS and frontotemporal lobar degeneration (FTLD-TDP, type B) with anatomically widespread TDP-43 proteinopathy. In contrast to C9orf72+ cases, caudate atrophy and hippocampal sclerosis were not prominent. Detailed evaluation of the pyramidal motor system found a similar degree of neurodegeneration and TDP-43 pathology as in sALS and C9orf72+ cases; however, cases with TIA1 mutations had increased numbers of lower motor neurons containing round eosinophilic and Lewy body-like inclusions on HE stain and round compact cytoplasmic inclusions with TDP-43 immunohistochemistry. Immunohistochemistry and immunofluorescence failed to demonstrate any labeling of inclusions with antibodies against TIA1. In summary, our TIA1 mutation carriers developed ALS with or without FTD, with a wide range in age at onset, but without other neurological or psychiatric features. The neuropathology was characterized by widespread TDP-43 pathology, but a more restricted pattern of neurodegeneration than C9orf72+ cases. Increased numbers of round eosinophilic and Lewy-body like inclusions in lower motor neurons may be a distinctive feature of ALS caused by TIA1 mutations.