Haploinsufficiency of the progranulin (PGRN)‐encoding gene (GRN) causes frontotemporal lobar degeneration (GRN‐FTLD) and results in microglial hyperactivation, TREM2 activation, lysosomal ...dysfunction, and TDP‐43 deposition. To understand the contribution of microglial hyperactivation to pathology, we used genetic and pharmacological approaches to suppress TREM2‐dependent transition of microglia from a homeostatic to a disease‐associated state. Trem2 deficiency in Grn KO mice reduced microglia hyperactivation. To explore antibody‐mediated pharmacological modulation of TREM2‐dependent microglial states, we identified antagonistic TREM2 antibodies. Treatment of macrophages from GRN‐FTLD patients with these antibodies led to reduced TREM2 signaling due to its enhanced shedding. Furthermore, TREM2 antibody‐treated PGRN‐deficient microglia derived from human‐induced pluripotent stem cells showed reduced microglial hyperactivation, TREM2 signaling, and phagocytic activity, but lysosomal dysfunction was not rescued. Similarly, lysosomal dysfunction, lipid dysregulation, and glucose hypometabolism of Grn KO mice were not rescued by TREM2 ablation. Synaptic loss and neurofilament light‐chain (NfL) levels, a biomarker for neurodegeneration, were further elevated in the Grn/Trem2 KO cerebrospinal fluid (CSF). These findings suggest that TREM2‐dependent microglia hyperactivation in models of GRN deficiency does not promote neurotoxicity, but rather neuroprotection.
SYNOPSIS
Patients suffering from progranulin (PGRN) associated frontotemporal lobar degeneration (GRN‐FTLD) exhibit hyperactivated microglia, lysosomal dysfunction and TDP‐43 deposition.
Suppression of TREM2 reverses hyperactivation of microglia in models of PGRN deficiency.
Hyperactivated microglia in models of PGRN deficiency retain neuroprotective functions.
Lysosomal dysfunction is independent of microglia activation stages.
TREM2‐dependent hyperactivated microglia retain neuroprotective functions in the neurodegenerative disorder GRN‐FTLD.
Behavioral variant of frontotemporal dementia (bvFTD) is common among young‐onset dementia patients. While bvFTD‐specific multivariate metabolic brain pattern (bFDRP) has been identified previously, ...little is known about its temporal evolution, internal structure, effect of atrophy, and its relationship with nonspecific resting‐state networks such as default mode network (DMN). In this multicenter study, we explored FDG‐PET brain scans of 111 bvFTD, 26 Alzheimer's disease, 16 Creutzfeldt‐Jakob's disease, 24 semantic variant primary progressive aphasia (PPA), 18 nonfluent variant PPA and 77 healthy control subjects (HC) from Slovenia, USA, and Germany. bFDRP was identified in a cohort of 20 bvFTD patients and age‐matched HC using scaled subprofile model/principle component analysis and validated in three independent cohorts. It was characterized by hypometabolism in frontal cortex, insula, anterior/middle cingulate, caudate, thalamus, and temporal poles. Its expression in bvFTD patients was significantly higher compared to HC and other dementia syndromes (p < .0004), correlated with cognitive decline (p = .0001), and increased over time in longitudinal cohort (p = .0007). Analysis of internal network organization by graph‐theory methods revealed prominent network disruption in bvFTD patients. We have further found a specific atrophy‐related pattern grossly corresponding to bFDRP; however, its contribution to the metabolic pattern was minimal. Finally, despite the overlap between bFDRP and FDG‐PET‐derived DMN, we demonstrated a predominant role of the specific bFDRP. Taken together, we validated the bFDRP network as a diagnostic/prognostic biomarker specific for bvFTD, provided a unique insight into its highly reproducible internal structure, and proved that bFDRP is unaffected by structural atrophy and independent of normal resting state networks loss.
Behavioral variant of the frontotemporal dementia (bvFTD) specific metabolic brain pattern (bFDRP) is a robust metabolic biomarker validated on three different populations. Its internal structure is characterized by prominent network disruption and inefficient information transfer in bvFTD patients. Despite overlapping with the default mode network, bFDRP is an independent network with highly reproducible changes.
Objective
Perirolandic atrophy occurs in corticobasal syndrome (CBS) but is not specific versus progressive supranuclear palsy (PSP). There is heterogeneity in the locations of atrophy outside the ...perirolandic cortex and it remains unknown why atrophy in different locations would cause the same CBS‐specific symptoms. In prior work, we used a wiring diagram of the brain called the human connectome to localize lesion‐induced disorders to symptom‐specific brain networks. Here, we use a similar technique termed “atrophy network mapping” to localize single‐subject atrophy maps to symptom‐specific brain networks.
Methods
Single‐subject atrophy maps were generated by comparing cortical thickness in patients with CBS versus controls. Next, we performed seed‐based functional connectivity using a large normative connectome to determine brain regions functionally connected to each patient's atrophied locations.
Results
Patients with CBS had perirolandic atrophy versus controls at the group level, but locations of atrophy in CBS were heterogeneous outside of the perirolandic cortex at the single‐subject level (mean spatial correlation = 0.04). In contrast, atrophy occurred in locations functionally connected to the perirolandic cortex in all patients with CBS (spatial correlation = 0.66). Compared with PSP, patients with CBS had atrophy connected to a network of higher‐order sensorimotor regions beyond perirolandic cortex, matching a CBS atrophy network from a recent meta‐analysis. Finally, atrophy network mapping identified a symptom‐specific network for alien limb, matching a lesion‐induced alien limb network and a network associated with agency in healthy subjects.
Interpretation
We identified a syndrome‐specific network for CBS and symptom‐specific network for alien limb using single‐subject atrophy maps and the human connectome. ANN NEUROL 2020;88:1118–1131
Microglia adopt numerous fates with homeostatic microglia (HM) and a microglial neurodegenerative phenotype (MGnD) representing two opposite ends. A number of variants in genes selectively expressed ...in microglia are associated with an increased risk for neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD). Among these genes are progranulin (GRN) and the triggering receptor expressed on myeloid cells 2 (TREM2). Both cause neurodegeneration by mechanisms involving loss of function. We have now isolated microglia from Grn−/− mice and compared their transcriptomes to those of Trem2−/− mice. Surprisingly, while loss of Trem2 enhances the expression of genes associated with a homeostatic state, microglia derived from Grn−/− mice showed a reciprocal activation of the MGnD molecular signature and suppression of gene characteristic for HM. The opposite mRNA expression profiles are associated with divergent functional phenotypes. Although loss of TREM2 and progranulin resulted in opposite activation states and functional phenotypes of microglia, FDG (fluoro‐2‐deoxy‐d‐glucose)‐μPET of brain revealed reduced glucose metabolism in both conditions, suggesting that opposite microglial phenotypes result in similar wide spread brain dysfunction.
Synopsis
Microglia from Grn−/− & Trem2−/− mice display opposite molecular signatures. While microglia are either locked in a hyperactivated or homeostatic state, Grn−/− & Trem2−/− mice both show reduced glucose metabolism, suggesting that opposite microglial phenotypes result in similar brain dysfunction.
First demonstration that microglia from both extremes of their functional stages cause brain wide dysfunctions.
This study indicates that the therapeutic window for microglial modulation is rather narrow and care must be taken to balance microglial activity.
Microglia from Grn−/− & Trem2−/− mice display opposite molecular signatures. While microglia are either locked in a hyperactivated or homeostatic state, Grn−/− & Trem2−/− mice both show reduced glucose metabolism, suggesting that opposite microglial phenotypes result in similar brain dysfunction.
Objective
To estimate the prevalence of amyloid positivity, defined by positron emission tomography (PET)/cerebrospinal fluid (CSF) biomarkers and/or neuropathological examination, in primary ...progressive aphasia (PPA) variants.
Methods
We conducted a meta‐analysis with individual participant data from 1,251 patients diagnosed with PPA (including logopenic lvPPA, n = 443, nonfluent nfvPPA, n = 333, semantic svPPA, n = 401, and mixed/unclassifiable n = 74 variants of PPA) from 36 centers, with a measure of amyloid‐β pathology (CSF n = 600, PET n = 366, and/or autopsy n = 378) available. The estimated prevalence of amyloid positivity according to PPA variant, age, and apolipoprotein E (ApoE) ε4 status was determined using generalized estimating equation models.
Results
Amyloid‐β positivity was more prevalent in lvPPA (86%) than in nfvPPA (20%) or svPPA (16%; p < 0.001). Prevalence of amyloid‐β positivity increased with age in nfvPPA (from 10% at age 50 years to 27% at age 80 years, p < 0.01) and svPPA (from 6% at age 50 years to 32% at age 80 years, p < 0.001), but not in lvPPA (p = 0.94). Across PPA variants, ApoE ε4 carriers were more often amyloid‐β positive (58.0%) than noncarriers (35.0%, p < 0.001). Autopsy data revealed Alzheimer disease pathology as the most common pathologic diagnosis in lvPPA (76%), frontotemporal lobar degeneration–TDP‐43 in svPPA (80%), and frontotemporal lobar degeneration–TDP‐43/tau in nfvPPA (64%).
Interpretation
This study shows that the current PPA classification system helps to predict underlying pathology across different cohorts and clinical settings, and suggests that age and ApoE genotype should be considered when interpreting amyloid‐β biomarkers in PPA patients. Ann Neurol 2018;84:737–748
The C9orf72 GGGGCC repeat expansion is a major cause of amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD). Non‐conventional repeat translation results in five dipeptide repeat ...proteins (DPRs), but their clinical utility, overall significance, and temporal course in the pathogenesis of c9ALS/FTD are unclear, although animal models support a gain‐of‐function mechanism. Here, we established a poly‐GP immunoassay from cerebrospinal fluid (CSF) to identify and characterize C9orf72 patients. Significant poly‐GP levels were already detectable in asymptomatic C9orf72 mutation carriers compared to healthy controls and patients with other neurodegenerative diseases. The poly‐GP levels in asymptomatic carriers were similar to symptomatic c9ALS/FTD cases. Poly‐GP levels were not correlated with disease onset, clinical scores, and CSF levels of neurofilaments as a marker for axonal damage. Poly‐GP determination in CSF revealed a C9orf72 mutation carrier in our cohort and may thus be used as a diagnostic marker in addition to genetic testing to screen patients. Presymptomatic expression of poly‐GP and likely other DPR species may contribute to disease onset and thus represents an alluring therapeutic target.
Synopsis
The C9orf72 hexanucleotide repeat expansion causing amyotrophic lateral sclerosis and frontotemporal dementia is translated into five dipeptide repeat (DPR) proteins, including poly‐GP. Analysis of poly‐GP levels in the CSF of patients and presymptomatic carriers support an early role of DPRs in pathogenesis.
Monoclonal immunoassay detects poly‐GP in CSF of C9orf72 patients.
Poly‐GP levels in asymptomatic carriers and c9ALS/FTD patients are similar.
Neurofilaments but not poly‐GP levels correlate with clinical disease progression.
The C9orf72 hexanucleotide repeat expansion causing amyotrophic lateral sclerosis and frontotemporal dementia is translated into five dipeptide repeat (DPR) proteins, including poly‐GP. Analysis of poly‐GP levels in the CSF of patients and presymptomatic carriers support an early role of DPRs in pathogenesis.
Introduction
Human herpes simplex virus 1 (HSV1) is discussed to induce amyloid‐β (Aβ) accumulation and neurofibrillary tangles of hyperphosphorylated tau (pTau) in Alzheimer's disease (AD) in cell ...culture and animal models. Aβ appears to be virostatic. We investigated the association between intrathecal antibodies against HSV or cytomegalovirus (CMV) and cerebrospinal fluid (CSF) AD biomarkers.
Methods
Aβ42/Aβ40 ratio, pTau, and tTau were measured in CSF of 117 patients with early AD positive for amyloid pathology (A+) and 30 healthy controls (A‐). CSF‐to‐serum anti‐HSV1/2‐IgG antibody indices (AI‐IgGHSV1/2) and CMV (AI‐IgGCMV) were determined by enzyme‐linked immunosorbent assay (ELISA).
Results
Exclusively in HSV1‐seropositive AD, pTau was positively and significantly predicted by AI‐IgGHSV1/2 and negatively by the Aβ42/Aβ40 ratio in both univariate and multivariate regression analyses. Furthermore, a significant and negative interaction between the AI‐IgGHSV1/2 and Aβ42/Aβ40 ratio on pTau was found.
Discussion
The results support the hypothesis that HSV infection contributes to AD.
Highlights
HSV antibody index is positively associated with tau pathology in patients with AD.
HSV antibody index is negatively associated with cerebral FDG metabolism.
Amyloid modulates the association of HSV antibody index with CSF‐pTau.
HSV in AD offers a pathophysiological model connecting tau and amyloid.
ABSTRACT
We assessed the geographical distribution of C9orf72 G4C2 expansions in a pan‐European frontotemporal lobar degeneration (FTLD) cohort (n = 1,205), ascertained by the European Early‐Onset ...Dementia (EOD) consortium. Next, we performed a meta‐analysis of our data and that of other European studies, together 2,668 patients from 15 Western European countries. The frequency of the C9orf72 expansions in Western Europe was 9.98% in overall FTLD, with 18.52% in familial, and 6.26% in sporadic FTLD patients. Outliers were Finland and Sweden with overall frequencies of respectively 29.33% and 20.73%, but also Spain with 25.49%. In contrast, prevalence in Germany was limited to 4.82%. In addition, we studied the role of intermediate repeats (7–24 repeat units), which are strongly correlated with the risk haplotype, on disease and C9orf72 expression. In vitro reporter gene expression studies demonstrated significantly decreased transcriptional activity of C9orf72 with increasing number of normal repeat units, indicating that intermediate repeats might act as predisposing alleles and in favor of the loss‐of‐function disease mechanism. Further, we observed a significantly increased frequency of short indels in the GC‐rich low complexity sequence adjacent to the G4C2 repeat in C9orf72 expansion carriers (P < 0.001) with the most common indel creating one long contiguous imperfect G4C2 repeat, which is likely more prone to replication slippage and pathological expansion.
We assessed the geographical distribution of C9orf72 G4C2 expansions in a pan‐European FTLD cohort. The overall FTLD frequency was 9.98% with frequencies of 18.52% in familial 6.26% in sporadic patients. We demonstrated that C9orf72 transcriptional activity significantly decreased with increasing number of repeats of intermediate length (7 to 24 units), suggesting that they might act as predisposing alleles. Notably, we observed in expansion carriers increased frequencies of short indels in a GC‐rich, low complexity sequence adjacent to the G4C2 repeat.
ABSTRACT
We investigated the mutation spectrum of the TANK‐Binding Kinase 1 (TBK1) gene and its associated phenotypic spectrum by exonic resequencing of TBK1 in a cohort of 2,538 patients with ...frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), or FTD plus ALS, ascertained within the European Early‐Onset Dementia Consortium. We assessed pathogenicity of predicted protein‐truncating mutations by measuring loss of RNA expression. Functional effect of in‐frame amino acid deletions and missense mutations was further explored in vivo on protein level and in vitro by an NFκB‐induced luciferase reporter assay and measuring phosphorylated TBK1. The protein‐truncating mutations led to the loss of transcript through nonsense‐mediated mRNA decay. For the in‐frame amino acid deletions, we demonstrated loss of TBK1 or phosphorylated TBK1 protein. An important fraction of the missense mutations compromised NFκB activation indicating that at least some functions of TBK1 are lost. Although missense mutations were also present in controls, over three times more mutations affecting TBK1 functioning were found in the mutation fraction observed in patients only, suggesting high‐risk alleles (P = 0.03). Total mutation frequency for confirmed TBK1 LoF mutations in the European cohort was 0.7%, with frequencies in the clinical subgroups of 0.4% in FTD, 1.3% in ALS, and 3.6% in FTD‐ALS.
TANK‐binding kinase 1 (TBK1) mutation spectrum in frontotemporal dementia and amyotrophic lateral sclerosis. Transcript analysis of TBK1 p.Arg127* nonsense mutation indicating degradation of the mutant cDNA (A). Neuropathology features of FTD‐ALS patient with TBK1 in‐frame deletion mutation p.Thr79del showing abundant TDP‐43 protein aggregates in neurons and oligodendroglial cells (B). Impact of TBK1 in‐frame deletions and missense mutations on NFκB activity in the IFN pathway (C).
Background
Recent data support beta‐synuclein as a blood biomarker to study synaptic degeneration in Alzheimer's disease (AD).
Methods
We provide a detailed comparison of serum beta‐synuclein ...immunoprecipitation – mass spectrometry (IP‐MS) with the established blood markers phosphorylated tau 181 (p‐tau181) (Simoa) and neurofilament light (NfL) (Ella) in the German FTLD consortium cohort (n = 374) and its relation to brain atrophy (magnetic resonance imaging) and cognitive scores.
Results
Serum beta‐synuclein was increased in AD but not in frontotemporal lobar degeneration (FTLD) syndromes. Beta‐synuclein correlated with atrophy in temporal brain structures and was associated with cognitive impairment. Serum p‐tau181 showed the most specific changes in AD but the lowest correlation with structural alterations. NfL was elevated in all diseases and correlated with frontal and temporal brain atrophy.
Discussion
Serum beta‐synuclein changes differ from those of NfL and p‐tau181 and are strongly related to AD, most likely reflecting temporal synaptic degeneration. Beta‐synuclein can complement the existing panel of blood markers, thereby providing information on synaptic alterations.
Highlights
Blood beta‐synuclein is increased in Alzheimer's disease (AD) but not in frontotemporal lobar degeneration (FTLD) syndromes.
Blood beta‐synuclein correlates with temporal brain atrophy in AD.
Blood beta‐synuclein correlates with cognitive impairment in AD.
The pattern of blood beta‐synuclein changes in the investigated diseases is different to phosphorylated tau 181 (p‐tau181) and neurofilament light (NfL).
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