Proteomic profile and predictive markers of outcome in patients with subarachnoid hemorrhage.

BACKGROUND: The molecular mechanisms underlying development of posthemorrhagic hydrocephalus (PHH) following subarachnoid hemorrhage (SAH) remain incompletely understood. Consequently, treatment strategies tailored towards the individual patient remain limited. This study aimed to identify proteomic cerebrospinal fluid (CSF) biomarkers capable of predicting shunt dependency and functional outcome in patients with SAH in order to improve informed clinical decision making. METHODS: Ventricular CSF samples were collected twice from 23 patients with SAH who required external ventricular drain (EVD) insertion (12 patients with successful EVD weaning, 11 patients in need of permanent CSF shunting due to development of PHH). The paired CSF samples were collected acutely after ictus and later upon EVD removal. Cisternal CSF samples were collected from 10 healthy control subjects undergoing vascular clipping of an unruptured aneurysm. All CSF samples were subjected to mass spectrometry-based proteomics analysis. Proteomic biomarkers were quantified using area under the curve (AUC) estimates from a receiver operating curve (ROC). RESULTS: CSF from patients with SAH displayed a distinct proteomic profile in comparison to that of healthy control subjects. The CSF collected acutely after ictus from patients with SAH was moreover distinct from that collected weeks later but appeared similar in the weaned and shunted patient groups. Sixteen unique proteins were identified as potential predictors of shunt dependency, while three proteins were identified as potential predictors of functional outcome assessed six months after ictus with the modified Rankin Scale. CONCLUSIONS: We here identified several potential proteomic biomarkers in CSF from patients with SAH capable of predicting (i) shunt dependency and thus development of PHH and (ii) the functional outcome assessed six months after ictus. These proteomic biomarkers may have the potential to aid clinical decision making by predicting shunt dependency and functional outcome following SAH.

Ventricular CSF proteomic profiles and predictors of surgical treatment outcome in chronic hydrocephalus.

BACKGROUND: By applying an unbiased proteomic approach, we aimed to search for cerebrospinal fluid (CSF) protein biomarkers distinguishing between obstructive and communicating hydrocephalus in order to improve appropriate surgical selection for endoscopic third ventriculostomy vs. shunt implants. Our second study purpose was to look for potential CSF biomarkers distinguishing between patients with adult chronic hydrocephalus benefitting from surgery (responders) vs. those who did not (non-responders). METHODS: Ventricular CSF samples were collected from 62 patients with communicating hydrocephalus and 28 patients with obstructive hydrocephalus. CSF was collected in relation to the patients' surgical treatment. As a control group, CSF was collected from ten patients with unruptured aneurysm undergoing preventive surgery (vascular clipping). RESULTS: Mass spectrometry-based proteomic analysis of the samples identified 1251 unique proteins. No proteins differed significantly between the communicating hydrocephalus group and the obstructive hydrocephalus group. Four proteins were found to be significantly less abundant in CSF from communicating hydrocephalus patients compared to control subjects. A PCA plot revealed similar proteomic CSF profiles of obstructive and communicating hydrocephalus and control samples. For obstructive hydrocephalus, ten proteins were found to predict responders from non-responders. CONCLUSION: Here, we show that the proteomic profile of ventricular CSF from patients with hydrocephalus differs slightly from control subjects. Furthermore, we find ten predictors of response to surgical outcome (endoscopic third ventriculostomy or ventriculo-peritoneal shunt) in patients with obstructive hydrocephalus.

Increasing O-GlcNAcylation Attenuates tau Hyperphosphorylation and Behavioral Impairment in rTg4510 Tauopathy Mice.

BACKGROUND: Tauopathies such as Alzheimer's disease (AD) are characterized by abnormal hyperphosphorylation of the microtubule-associated protein tau (MAPT) aggregating into neurofibrillary tangles (NFTs). O-linked ß-N-acetylglucosamine (O-GlcNAc) modifications have been suggested to regulate tau phosphorylation and aggregation and N-acetylglucosaminidase (OGA) removes GlcNAc moieties from proteins. METHODS: We investigated effects of the OGA inhibitor Thiamet G in rTg4510 primary neuronal cultures and in rTg4510 mice. The rTg4510 mice overexpress human tau harboring the P301L mutation and display an age-dependent progression of tau pathology including hyperphosphorylated tau species and NFTs. Aged rTg4510 mice exhibit a non-mnemonic behavioral defect involving a hyperactive phenotype that is associated with the progression of tau pathology. RESULTS: Thiamet G increased overall O-GlcNAc levels and crossed the blood brain barrier in rTg4510 mice. The free fraction of Thiamet G in the brain was 22-fold above the half maximal effective concentration (EC50) measured in rTg4510 primary neurons. Chronic Thiamet G treatment (18 weeks) initiated in young 6 week old rTg4510 mice increased brain O-GlcNAc levels and this corresponded with a significant reduction in soluble and insoluble hyperphosphorylated tau in aged 24 week old rTg4510 mice. Levels of normally phosphorylated P301L tau were not altered under these conditions. Reduction of hyperphosphorylated tau species by increased O-GlcNAcylation was associated with significant attenuation of hyperactivity in 24 week old rTg4510 mice. CONCLUSIONS: Our findings support the pharmacological inhibition of OGA as a potential therapeutic approach for the treatment of AD and other tauopathies.

Posthemorrhagic Hydrocephalus in Patients with Subarachnoid Hemorrhage Occurs Independently of CSF Osmolality.

The molecular mechanisms underlying the development of posthemorrhagic hydrocephalus (PHH) remain incompletely understood. As the disease pathogenesis often cannot be attributed to visible cerebrospinal fluid (CSF) drainage obstructions, we here aimed to elucidate whether elevated CSF osmolality following subarachnoid hemorrhage (SAH) could potentiate the formation of ventricular fluid, and thereby contribute to the pathological CSF accumulation observed in PHH. The CSF osmolality was determined in 32 patients with acute SAH after external ventricular drainage (EVD) placement and again upon EVD removal and compared with the CSF osmolality from 14 healthy control subjects undergoing vascular clipping of an unruptured aneurism. However, we found no evidence of elevated CSF osmolality or electrolyte concentration in patients with SAH when compared to that of healthy control subjects. We detected no difference in CSF osmolality and electrolyte content in patients with successful EVD weaning versus those that were shunted due to PHH. Taken together, elevated CSF osmolality does not appear to underlie the development of PHH following SAH. The pathological CSF accumulation observed in this patient group must thus instead be attributed to other pathological alterations associated with the abnormal presence of blood within the CSF compartments following SAH.

SCA28: Novel Mutation in the AFG3L2 Proteolytic Domain Causes a Mild Cerebellar Syndrome with Selective Type-1 Muscle Fiber Atrophy.

The spinocerebellar ataxias (SCA) are a group of rare inherited neurodegenerative diseases characterized by slowly progressive cerebellar ataxia, resulting in unsteady gait, clumsiness, and dysarthria. The disorders are predominantly inherited in an autosomal dominant manner. Mutations in the gene AFG3L2 that encodes a subunit of the mitochondrial m-AAA protease have previously been shown to cause spinocerebellar ataxia type 28 (SCA28). Here, we present the clinical phenotypes of three patients from a family with autosomal dominant cerebellar ataxia and show by molecular genetics and in silico modelling that this is caused by a novel missense mutation in the AFG3L2 gene. Furthermore, we show, for the first time, fluorodeoxyglucose-positron emission tomography (FDG-PET) scans of the brain and selective type I fiber atrophy of skeletal muscle of SCA28 patients indicating non-nervous-system involvement in SCA28 as well.

Regulation of glycine receptor diffusion properties and gephyrin interactions by protein kinase C.

Glycine receptors (GlyRs) can dynamically exchange between synaptic and extrasynaptic locations through lateral diffusion within the plasma membrane. Their accumulation at inhibitory synapses depends on the interaction of the ß-subunit of the GlyR with the synaptic scaffold protein gephyrin. An alteration of receptor-gephyrin binding could thus shift the equilibrium between synaptic and extrasynaptic GlyRs and modulate the strength of inhibitory neurotransmission. Using a combination of dynamic imaging and biochemical approaches, we have characterised the molecular mechanism that links the GlyR-gephyrin interaction with GlyR diffusion and synaptic localisation. We have identified a protein kinase C (PKC) phosphorylation site within the cytoplasmic domain of the ß-subunit of the GlyR (residue S403) that causes a reduction of the binding affinity between the receptor and gephyrin. In consequence, the receptor's diffusion in the plasma membrane is accelerated and GlyRs accumulate less strongly at synapses. We propose that the regulation of GlyR dynamics by PKC thus contributes to the plasticity of inhibitory synapses and may be involved in maladaptive forms of synaptic plasticity.

Cerebrospinal Fluid Biomarkers in Familial Forms of Alzheimer's Disease and Frontotemporal Dementia.

As dementia is a fast-growing health care problem, it is becoming an increasingly urgent need to provide an early diagnosis in order to offer patients the best medical treatment and care. Validated biomarkers which reflect the pathology and disease progression are essential for diagnosis and are important when developing new therapies. Today, the core protein biomarkers amyloid-ß42, total tau and phosphorylated tau in the cerebrospinal fluid (CSF) are used to diagnose Alzheimer's disease (AD), because these biomarkers have shown to reflect the underlying amyloid and tau pathology. However, the biomarkers have proved insufficient predictors of dementias with a different pathology, e.g. frontotemporal dementia (FTD); furthermore, the biomarkers are not useful for early AD diagnosis. Familial dementias with a known disease-causing mutation can be extremely valuable to study; yet the biomarker profiles in patients with familial dementias are not clear. This review summarizes CSF biomarker findings from studies on symptomatic and presymptomatic individuals carrying a mutation in one of the genes known to cause early-onset familial AD or FTD. In conclusion, the biomarker profile of inherited AD is quite similar between carriers of different mutations as well as similar to the profile found in sporadic AD, whereas familial FTD does not seem to have a clear biomarker profile. Hence, new biomarkers are needed for FTD.

Inflammatory Markers as Predictors of Shunt Dependency and Functional Outcome in Patients with Aneurysmal Subarachnoid Hemorrhage.

The mechanisms underlying post-hemorrhagic hydrocephalus (PHH) development following subarachnoid hemorrhage (SAH) are not fully understood, which complicates informed clinical decisions regarding the duration of external ventricular drain (EVD) treatment and prevents the prediction of shunt-dependency in the individual patient. The aim of this study was to identify potential inflammatory cerebrospinal fluid (CSF) biomarkers of PHH and, thus, shunt-dependency and functional outcome in patients with SAH. This study was a prospective observational study designed to evaluate inflammatory markers in ventricular CSF. In total, 31 Patients with SAH who required an EVD between June 2019 and September 2021 at the Department of Neurosurgery, Rigshospitalet, Copenhagen, Denmark, were included. CSF samples were collected twice from each patient and analyzed for 92 inflammatory markers via proximity extension assay (PEA), and the prognostic ability of the markers was investigated. In total, 12 patients developed PHH, while 19 were weaned from their EVD. Their 6-month functional outcome was determined with the modified Rankin Scale. Of the 92 analyzed inflammatory biomarkers, 79 were identified in the samples. Seven markers (SCF, OPG, LAP TGFß1, Flt3L, FGF19, CST5, and CSF1) were found to be predictors of shunt dependency, and four markers (TNFα, CXCL5, CCL20, and IL8) were found to be predictors of functional outcome. In this study, we identified promising inflammatory biomarkers that are able to predict (i) the functional outcome in patients with SAH and (ii) the development of PHH and, thus, the shunt dependency of the individual patients. These inflammatory markers may have the potential to be employed as predictive biomarkers of shunt dependency and functional outcome following SAH and could, as such, be applied in the clinic.

Distinct Cerebrospinal Fluid Lipid Signature in Patients with Subarachnoid Hemorrhage-Induced Hydrocephalus.

Patients with subarachnoid hemorrhage (SAH) may develop posthemorrhagic hydrocephalus (PHH), which is treated with surgical cerebrospinal fluid (CSF) diversion. This diversion is associated with risk of infection and shunt failure. Biomarkers for PHH etiology, CSF dynamics disturbances, and potentially subsequent shunt dependency are therefore in demand. With the recent demonstration of lipid-mediated CSF hypersecretion contributing to PHH, exploration of the CSF lipid signature in relation to brain pathology is of interest. Despite being a relatively new addition to the omic's landscape, lipidomics are increasingly recognized as a tool for biomarker identification, as they provide a comprehensive overview of lipid profiles in biological systems. We here employ an untargeted mass spectroscopy-based platform and reveal the complete lipid profile of cisternal CSF from healthy control subjects and demonstrate its bimodal fluctuation with age. Various classes of lipids, in addition to select individual lipids, were elevated in the ventricular CSF obtained from patients with SAH during placement of an external ventricular drain. The lipidomic signature of the CSF in the patients with SAH suggests dysregulation of the lipids in the CSF in this patient group. Our data thereby reveal possible biomarkers present in a brain pathology with a hemorrhagic event, some of which could be potential future biomarkers for hypersecretion contributing to ventriculomegaly and thus pharmacological targets for pathologies involving disturbed CSF dynamics.

Differential proteomic profile of lumbar and ventricular cerebrospinal fluid.

BACKGROUND: Pathological cerebral conditions may manifest in altered composition of the cerebrospinal fluid (CSF). Although diagnostic CSF analysis seeks to establish pathological disturbances in the brain proper, CSF is generally sampled from the lumbar compartment for reasons of technical ease and ethical considerations. We here aimed to compare the molecular composition of CSF obtained from the ventricular versus the lumbar CSF compartments to establish a relevance for employing lumbar CSF as a proxy for the CSF bathing the brain tissue. METHODS: CSF was collected from 46 patients with idiopathic normal pressure hydrocephalus (iNPH) patients during their diagnostic workup (lumbar samples) and in connection with their subsequent CSF diversion shunt surgery (ventricular samples). The mass-spectrometry-based proteomic profile was determined in these samples and in addition, selected biomarkers were quantified with ELISA (S100B, neurofilament light (NfL), amyloid-ß (Aß40, Aß42), and total tau (T-tau) and phosphorylated tau (P-tau) forms). The latter analysis was extended to include paired porcine samples obtained from the lumbar compartment and the cerebromedullary cistern closely related to the ventricles. RESULTS: In total 1231 proteins were detected in the human CSF. Of these, 216 distributed equally in the two CSF compartments, whereas 22 were preferentially (or solely) present in the ventricular CSF and four in the lumbar CSF. The selected biomarkers of neurodegeneration and Alzheimer's disease displayed differential distribution, some with higher (S100B, T-tau, and P-tau) and some with lower (NfL, Aß40, Aß42) levels in the ventricular compartment. In the porcine samples, all biomarkers were most abundant in the lumbar CSF. CONCLUSIONS: The overall proteomic profile differs between the ventricular and the lumbar CSF compartments, and so does the distribution of clinically employed biomarkers. However, for a range of CSF proteins and biomarkers, one can reliably employ lumbar CSF as a proxy for ventricular CSF if or a lumbar/cranial index for the particular molecule has been established. It is therefore important to verify the compartmental preference of the proteins or biomarkers of interest prior to extrapolating from lumbar CSF to that of the ventricular fluid bordering the brain.

Cerebrospinal fluid osmolality cannot predict development or surgical outcome of idiopathic normal pressure hydrocephalus.

BACKGROUND: The etiology of idiopathic normal pressure hydrocephalus (iNPH) is currently unknown. With no visible obstructions, altered cerebrospinal fluid (CSF) dynamics may explain the accumulation of ventricular fluid. We hypothesized that elevated osmolality in the CSF of iNPH patients could potentiate formation of ventricular fluid and thereby cause the disease progression and/or predict the surgical outcome. To address this hypothesis, we determined the lumbar and ventricular CSF osmolality of iNPH patients at different disease stages and compared with lumbar CSF samples obtained from control subjects. METHODS: The osmolality of CSF was determined on a total of 35 iNPH patients at diagnosis and at the subsequent treatment with shunt surgery (n = 20) and compared with the CSF osmolality from 20 control subjects. Simultaneously collected lumbar and ventricular CSF samples from experimental pigs were used to evaluate the compatibility between CSF from different compartments. RESULTS: We found no evidence of increased osmolality in the CSF of iNPH patients upon diagnosis or at the time of shunt treatment months after the diagnosis, compared with control individuals. CSF tapped from the lumbar space could be used as a read-out for ventricular CSF osmolality, as these were similar in both the patient group and in experimental pigs. We further observed no correlation between the CSF osmolality in iNPH patients and their responsiveness to shunt surgeries. CONCLUSIONS: The osmolality of lumbar CSF is a reliable reflection of the ventricular CSF osmolality, and is not elevated in iNPH patients. iNPH therefore does not appear to arise as a function of osmotic imbalances in the CSF system and CSF osmolality cannot serve as a biomarker for iNPH or as a predictive tool for shunt responsiveness.

Lysophosphatidic acid as a CSF lipid in posthemorrhagic hydrocephalus that drives CSF accumulation via TRPV4-induced hyperactivation of NKCC1.

BACKGROUND: A range of neurological pathologies may lead to secondary hydrocephalus. Treatment has largely been limited to surgical cerebrospinal fluid (CSF) diversion, as specific and efficient pharmacological options are lacking, partly due to the elusive molecular nature of the CSF secretion apparatus and its regulatory properties in physiology and pathophysiology. METHODS: CSF obtained from patients with subarachnoid hemorrhage (SAH) and rats with experimentally inflicted intraventricular hemorrhage (IVH) was analyzed for lysophosphatidic acid (LPA) by alpha-LISA. We employed the in vivo rat model to determine the effect of LPA on ventricular size and brain water content, and to reveal the effect of activation and inhibition of the transient receptor potential vanilloid 4 (TRPV4) ion channel on intracranial pressure and CSF secretion rate. LPA-mediated modulation of TRPV4 was determined with electrophysiology and an ex vivo radio-isotope assay was employed to determine the effect of these modulators on choroid plexus transport. RESULTS: Elevated levels of LPA were observed in CSF obtained from patients with subarachnoid hemorrhage (SAH) and from rats with experimentally-inflicted intraventricular hemorrhage (IVH). Intraventricular administration of LPA caused elevated brain water content and ventriculomegaly in experimental rats, via its action as an agonist of the choroidal transient receptor potential vanilloid 4 (TRPV4) channel. TRPV4 was revealed as a novel regulator of ICP in experimental rats via its ability to modulate the CSF secretion rate through its direct activation of the Na+/K+/2Cl- cotransporter (NKCC1) implicated in CSF secretion. CONCLUSIONS: Together, our data reveal that a serum lipid present in brain pathologies with hemorrhagic events promotes CSF hypersecretion and ensuing brain water accumulation via its direct action on TRPV4 and its downstream regulation of NKCC1. TRPV4 may therefore be a promising future pharmacological target for pathologies involving brain water accumulation.

Posthemorrhagic hydrocephalus associates with elevated inflammation and CSF hypersecretion via activation of choroidal transporters.

INTRODUCTION: Posthemorrhagic hydrocephalus (PHH) often develops following hemorrhagic events such as intraventricular hemorrhage (IVH) and subarachnoid hemorrhage (SAH). Treatment is limited to surgical diversion of the cerebrospinal fluid (CSF) since no efficient pharmacological therapies are available. This limitation follows from our incomplete knowledge of the molecular mechanisms underlying the ventriculomegaly characteristic of PHH. Here, we aimed to elucidate the molecular coupling between a hemorrhagic event and the subsequent PHH development, and reveal the inflammatory profile of the PHH pathogenesis. METHODS: CSF obtained from patients with SAH was analyzed for inflammatory markers using the proximity extension assay (PEA) technique. We employed an in vivo rat model of IVH to determine ventricular size, brain water content, intracranial pressure, and CSF secretion rate, as well as for transcriptomic analysis. Ex vivo radio-isotope assays of choroid plexus transport were employed to determine the direct effect of choroidal exposure to blood and inflammatory markers, both with acutely isolated choroid plexus and after prolonged exposure obtained with viable choroid plexus kept in tissue culture conditions. RESULTS: The rat model of IVH demonstrated PHH and associated CSF hypersecretion. The Na+/K+-ATPase activity was enhanced in choroid plexus isolated from IVH rats, but not directly stimulated by blood components. Inflammatory markers that were elevated in SAH patient CSF acted on immune receptors upregulated in IVH rat choroid plexus and caused Na+/K+/2Cl- cotransporter 1 (NKCC1) hyperactivity in ex vivo experimental conditions. CONCLUSIONS: CSF hypersecretion may contribute to PHH development, likely due to hyperactivity of choroid plexus transporters. The hemorrhage-induced inflammation detected in CSF and in the choroid plexus tissue may represent the underlying pathology. Therapeutic targeting of such pathways may be employed in future treatment strategies towards PHH patients.

Inflammatory Markers in Cerebrospinal Fluid from Patients with Hydrocephalus: A Systematic Literature Review.

OBJECTIVE: The aim of this systematic review was to evaluate existing literature on inflammatory markers in CSF from patients with hydrocephalus and identify potential markers capable of promoting hydrocephalus development and progression. METHODS: Relevant studies published before December 3rd 2020 were identified from PubMed, Embase, and reference lists. Studies were screened for eligibility using the predefined inclusion and exclusion criteria. Data from eligible studies were extracted, and sources of bias were evaluated. We included articles written in English investigating inflammatory markers in CSF from patients with hydrocephalus and control subjects. The review was conducted according to the PRISMA guidelines by three independent reviewers. RESULTS: Twenty-two studies analyzed CSF from 311 patients with idiopathic normal pressure hydrocephalus (iNPH), 178 with posthemorrhagic hydrocephalus (PHH), 151 with other hydrocephalus diagnoses, and 394 control subjects. Fifty-eight inflammatory markers were investigated. The CSF of iNPH patients had increased CSF levels of IL-6, IL-1ß, and LRG compared with control subjects, whereas the CSF of PHH patients had increased levels of IL-6, IL-18, and VEGF. CSF from patients with "other hydrocephalus diagnoses" had elevated IFN-γ compared to control subjects, and VEGF was increased in congenital hydrocephalus, spina bifida, and hydrocephalus associated with tuberculous meningitis compared with controls. CONCLUSION: IL-6, IL-1ß, LRG, IL-18, VEGF, and IFN-γ are elevated in CSF from patients with hydrocephalus and may be involved in promotion of hydrocephalus development and progression. They may serve as novel disease biomarkers, and their signaling pathways may represent targets for pharmacological management of hydrocephalus.

Elevated CSF inflammatory markers in patients with idiopathic normal pressure hydrocephalus do not promote NKCC1 hyperactivity in rat choroid plexus.

BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) is a potentially reversible neurological condition of unresolved etiology characterized by a clinical triad of symptoms; gait disturbances, urinary incontinence, and cognitive deterioration. In the present study, we aimed to elucidate the molecular coupling between inflammatory markers and development of iNPH and determine whether inflammation-induced hyperactivity of the choroidal Na+/K+/2Cl- cotransporter (NKCC1) that is involved in cerebrospinal fluid (CSF) secretion could contribute to the iNPH pathogenesis. METHODS: Lumbar CSF samples from 20 iNPH patients (10 with clinical improvement upon CSF shunting, 10 without clinical improvement) and 20 elderly control subjects were analyzed with the novel proximity extension assay technique for presence of 92 different inflammatory markers. RNA-sequencing was employed to delineate choroidal abundance of the receptors for the inflammatory markers found elevated in the CSF from iNPH patients. The ability of the elevated inflammatory markers to modulate choroidal NKCC1 activity was determined by addition of combinations of rat version of these in ex vivo experiments on rat choroid plexus. RESULTS: 11 inflammatory markers were significantly elevated in the CSF from iNPH patients compared to elderly control subjects: CCL28, CCL23, CCL3, OPG, CXCL1, IL-18, IL-8, OSM, 4E-BP1, CXCL6, and Flt3L. One inflammatory marker, CDCP1, was significantly decreased in iNPH patients compared to control subjects. None of the inflammatory markers differed significantly when comparing iNPH patients with and without clinical improvement upon CSF shunting. All receptors for the elevated inflammatory markers were expressed in the rat and human choroid plexus, except CCR4 and CXCR1, which were absent from the rat choroid plexus. None of the elevated inflammatory markers found in the CSF from iNPH patients modulated the choroidal NKCC1 activity in ex vivo experiments on rat choroid plexus. CONCLUSION: The CSF from iNPH patients contains elevated levels of a subset of inflammatory markers. Although the corresponding inflammatory receptors are, in general, expressed in the choroid plexus of rats and humans, their activation did not modulate the NKCC1-mediated fraction of choroidal CSF secretion ex vivo. The molecular mechanisms underlying ventriculomegaly in iNPH, and the possible connection to inflammation, therefore remains to be elucidated.

CSF neurofilament light concentration is increased in presymptomatic CHMP2B mutation carriers.

OBJECTIVE: A rare cause of familial frontotemporal dementia (FTD) is a mutation in the CHMP2B gene on chromosome 3 (FTD-3), described in a Danish family. Here we examine whether CSF biomarkers change in the preclinical phase of the disease. METHODS: In this cross-sectional explorative study, we analyzed CSF samples from 16 mutation carriers and 14 noncarriers from the Danish FTD-3 family. CSF biomarkers included total tau (t-tau) and neurofilament light chain (NfL) as a marker for neurodegeneration, phosphorylated tau (p-tau) as a marker for tau pathology, ß-amyloid (Aß) 38, 40, and 42 (Aß38, Aß40, and Aß42) to monitor Aß metabolism, and YKL-40 as a marker of neuroinflammation. Aß isoform concentrations were measured using a multiplexed immunoassay; t-tau, p-tau, NfL, and YKL-40 concentrations were measured using sandwich ELISAs. RESULTS: CSF NfL concentration was significantly increased in mutation carriers vs noncarriers. Further, CSF NfL concentration was significantly higher in symptomatic mutation carriers compared to presymptomatic carriers, and also significantly higher in presymptomatic carriers compared to noncarriers. No differences in t-tau and p-tau and YKL-40 concentrations between controls and mutation carriers were observed. CSF concentrations of the Aß peptides Aß38 and Aß40 but not Aß42 were significantly lower in mutation carriers compared to noncarriers. CONCLUSIONS: Increased NfL levels in presymptomatic individuals and in symptomatic patients with FTD-3 indicate a continuous process of neurodegeneration from the presymptomatic to symptomatic state. Although not specific for FTD-3 pathology, our data suggest that CSF NfL could serve as a valuable biomarker to detect onset of neurodegeneration in FTD-3 mutation carriers.

TMEM106B and ApoE polymorphisms in CHMP2B-mediated frontotemporal dementia (FTD-3).

Single-nucleotide polymorphisms in the TMEM106B gene have been identified as a risk factor in frontotemporal dementia (FTD). The major allele of SNP rs3173615 is a risk factor in sporadic FTD, whereas the minor allele seems protective in GRN- and C9orf72-mediated FTD. The role of apolipoprotein E (ApoE) in FTD is uncertain, though an established risk factor in Alzheimer's disease. In a unique Danish family, inherited FTD is caused by a mutation in the CHMP2B gene located on chromosome 3 (FTD-3). In this family, both risk factors TMEM106B and ApoE were analyzed and correlated to age at onset (AAO) and progression in terms of age at institutionalization (AAI) and age at death (AAD). Although TMEM106B and CHMP2B share cellular function in that both localize to endolysosomes, TMEM106B genotypes appeared to have no influence on the clinical disease course. ApoE ε4 was found to be a protective factor with later AAO and AAI, whereas ε2 seemed to aggravate the disease with earlier AAO and AAD. These results indicate ApoE ε2 as a risk factor in FTD-3 and suggest a protective role of ε4.