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Introduction A better understanding of the earliest stages of Alzheimer’s disease (AD) could expedite the development or administration of treatments. Large population biobanks hold the promise to identify individuals at an elevated risk of AD and related dementias based on health registry information. Here, we establish the protocol for an observational clinical recall and biomarker study called TWINGEN with the aim to identify individuals at high risk of AD by assessing cognition, health and AD-related biomarkers. Suitable candidates were identified and invited to participate in the new study among THL Biobank donors according to TWINGEN study criteria.Methods and analysis A multi-centre study (n=800) to obtain blood-based biomarkers, telephone-administered and web-based memory and cognitive parameters, questionnaire information on lifestyle, health and psychological factors, and accelerometer data for measures of physical activity, sedentary behaviour and sleep. A subcohort is being asked to participate in an in-person neuropsychological assessment (n=200) and wear an Oura ring (n=50). All participants in the TWINGEN study have genome-wide genotyping data and up to 48 years of follow-up data from the population-based older Finnish Twin Cohort (FTC) study of the University of Helsinki. The data collected in TWINGEN will be returned to THL Biobank from where it can later be requested for other biobank studies such as FinnGen that supported TWINGEN.Ethics and dissemination This recall study consists of FTC/THL Biobank/FinnGen participants whose data were acquired in accordance with the Finnish Biobank Act. The recruitment protocols followed the biobank protocols approved by Finnish Medicines Agency. The TWINGEN study plan was approved by the Ethics Committee of Hospital District of Helsinki and Uusimaa (number 16831/2022). THL Biobank approved the research plan with the permission no: THLBB2022_83.

Background: Amyotrophic lateral sclerosis (ALS) is a progressive disease for which no curative treatment is currently available. Objective: This study aimed to investigate whether cortico-spinal transcranial direct current stimulation (tDCS) could mitigate symptoms in ALS patients via a randomized, double-blind, sham-controlled trial, followed by an open-label phase. Methods: Thirty-one participants were randomized into two groups for the initial controlled phase. At baseline (T0), Group 1 received placebo stimulation (sham tDCS), while Group 2 received cortico-spinal stimulation (real tDCS) for five days/week for two weeks (T1), with an 8-week (T2) follow-up (randomized, double-blind, sham-controlled phase). At the 24-week follow-up (T3), all participants (Groups 1 and 2) received a second treatment of anodal bilateral motor cortex and cathodal spinal stimulation (real tDCS) for five days/week for two weeks (T4). Follow-up evaluations were performed at 32-weeks (T5) and 48-weeks (T6) (open-label phase). At each time point, clinical assessment, blood sampling, and intracortical connectivity measures using transcranial magnetic stimulation (TMS) were evaluated. Additionally, we evaluated survival rates. Results: Compared to sham stimulation, cortico-spinal tDCS significantly improved global strength, caregiver burden, and quality of life scores, which correlated with the restoration of intracortical connectivity measures. Serum neurofilament light levels decreased among patients who underwent real tDCS but not in those receiving sham tDCS. The number of completed 2-week tDCS treatments significantly influenced patient survival. Conclusions: Cortico-spinal tDCS may represent a promising therapeutic and rehabilitative approach for patients with ALS. Further larger-scale studies are necessary to evaluate whether tDCS could potentially impact patient survival. Clinical trial registration: NCT04293484.

Abstract Successful development of novel therapies requires that clinical trials are conducted in patient cohorts with the highest benefit-to-risk ratio. Population-based biobanks with comprehensive health and genetic data from large numbers of individuals hold promise to facilitate identification of trial participants, particularly when interventions need to start while symptoms are still mild, such as for Alzheimer’s disease (AD). This study describes a process for clinical recall studies from FinnGen. We demonstrate the feasibility to systematically ascertain customized clinical data from FinnGen participants with ICD10 diagnosis of AD or mild cognitive disorder (MCD) in a single-center cross-sectional study testing blood-based biomarkers and cognitive functioning in-person, computer-based and remote. As a result, 19% (27/140) of a pre-specified FinnGen subcohort were successfully recalled and completed the study. Hospital records largely validated registry entries. For 8/12 MCD patients, other reasons than AD were identified as underlying diagnosis. Cognitive measures correlated across platforms, with highest consistencies for dementia screening (r = 0.818) and semantic fluency (r = 0.764), respectively, for in-person versus telephone-administered tests. Glial fibrillary acidic protein (GFAP) (p

Abstract Background Idiopathic Normal pressure hydrocephalus (iNPH) is a form of adult hydrocephalus that is clinically characterized by progressive gait impairment, cognitive dysfunction, and urinary incontinence. The current standard method of treatment involves surgical installation of a CSF diversion shunt. However, only a fraction of patients shows an alleviation of symptoms from shunt surgery. Thus, the purpose of this prospective explorative proteomic study was to identify prognostic CSF biomarkers to predict shunt responsiveness in iNPH patients. Further, we evaluated the ability of the core Alzheimer’s disease (AD) CSF biomarkers phosphorylated (p)-tau, total (t)-tau, and amyloid-β 1–42 (Aβ1–42) to serve as predictors of shunt response. Methods We conducted a tandem mass tag (TMT) proteomic analysis of lumbar CSF from 68 iNPH patients, sampled pre-shunt surgery. Tryptic digests of CSF samples were labelled with TMTpro reagents. The TMT multiplex samples were fractionated in 24 concatenated fractions by reversed-phase chromatography at basic pH and analysed by liquid chromatography coupled to mass spectrometry (LC–MS) on an Orbitrap Lumos mass spectrometer. The relative abundances of the identified proteins were correlated with (i) iNPH grading scale (iNPHGS) and (ii) gait speed change 1 year after surgery from baseline to identify predictors of shunt responsiveness. Results We identified four CSF biomarker candidates which correlated most strongly with clinical improvement on the iNPHGS and were significantly changed in shunt-responsive compared to shunt-unresponsive iNPH patients 1 year post-surgery: FABP3 (R = − 0.46, log2(fold change (FC)) = − 0.25, p

Abstract Background Frontotemporal dementia (FTD) covers a spectrum of neurodegenerative disorders with various clinical and neuropathological subtypes. The two major pathological proteins accumulating in the brains of FTD patients, depending on their genetic background, are TDP-43 and tau. We aimed to evaluate whether total TDP-43 levels measured from the serum associate with the genotype or clinical phenotype of the FTD patients and whether serum TDP-43 provides prognostic or diagnostic value in the FTD spectrum disorders. Methods The study cohort included 254 participants with a clinical diagnosis of FTD (including all major genotypes and clinical phenotypes) and 105 cognitively healthy controls. Serum total TDP-43 levels measured with a single-molecule array (Simoa) were compared within the FTD group according to the genotype, clinical phenotype, and predicted neuropathological subtype of the patients. We also evaluated the associations between the TDP-43 levels and disease severity or survival in FTD. Results Total TDP-43 levels in the serum were significantly lower in the FTD group as compared to the healthy control group (275.3 pg/mL vs. 361.8 pg/mL, B = 0.181, 95%CI = 0.014–0.348, p = 0.034). The lowest TDP-43 levels were observed in the subgroup of FTD patients harboring predicted TDP-43 brain pathology (FTD-TDP, 241.4 pg/mL). The low levels in the FTD-TDP group were especially driven by C9orf72 repeat expansion carriers (169.2 pg/mL) and FTD patients with concomitant motoneuron disease (FTD-MND, 113.3 pg/mL), whereas GRN mutation carriers did not show decreased TDP-43 levels (328.6 pg/mL). Serum TDP-43 levels showed no correlation with disease severity nor progression in FTD. Conclusions Our results indicate that the total levels of TDP-43 in the serum are decreased especially in FTD patients with the C9orf72 repeat expansion or FTD-MND phenotype, both subtypes strongly associated with TDP-43 type B brain pathology. Serum-based measurement of TDP-43 could represent a useful tool in indicating C9orf72 repeat expansion and FTD-MND-related TDP-43 neuropathology for future diagnostics and intervention studies.

Abstract Background Idiopathic normal pressure hydrocephalus (iNPH) is a clinico-radiological syndrome of elderly individuals likely sustained by different neurodegenerative changes as copathologies. Since iNPH is a potentially reversible condition, assessing neurodegenerative pathologies in vitam through CSF biomarkers and their influence on clinical features and surgical outcome represents crucial steps. Methods We measured α-synuclein seeding activity related to Lewy body (LB) pathology by the real-time quaking-induced conversion assay (RT-QuIC) and Alzheimer disease core biomarkers (proteins total-tau, phospho-tau, and amyloid-beta) by immunoassays in the cerebrospinal fluid (CSF) of 293 iNPH patients from two independent cohorts. To compare the prevalence of LB copathology between iNPH participants and a control group representative of the general population, we searched for α-synuclein seeding activity in 89 age-matched individuals who died of Creutzfeldt-Jakob disease (CJD). Finally, in one of the iNPH cohorts, we also measured the CSF levels of neurofilament light chain protein (NfL) and evaluated the association between all CSF biomarkers, baseline clinical features, and surgery outcome at 6 months. Results Sixty (20.5%) iNPH patients showed α-synuclein seeding activity with no significant difference between cohorts. In contrast, the prevalence observed in CJD was only 6.7% (p = 0.002). Overall, 24.0% of iNPH participants showed an amyloid-positive (A+) status, indicating a brain co-pathology related to Aβ deposition. At baseline, in the Italian cohort, α-synuclein RT-QuIC positivity was associated with higher scores on axial and upper limb rigidity (p = 0.003 and p = 0.011, respectively) and lower MMSEc scores (p = 0.003). A+ patients showed lower scores on the MMSEc (p = 0.037) than A- patients. Higher NfL levels were also associated with lower scores on the MMSEc (rho = -0.213; p = 0.021). There were no significant associations between CSF biomarkers and surgical outcome at 6 months (i.e. responders defined by decrease of 1 point on the mRankin scale). Conclusions Prevalent LB- and AD-related neurodegenerative pathologies affect a significant proportion of iNPH patients and contribute to cognitive decline (both) and motor impairment (only LB pathology) but do not significantly influence the surgical outcome at 6 months. Their effect on the clinical benefit after surgery over a more extended period remains to be determined.

The rare A673T variant was the first variant found within the amyloid precursor protein (APP) gene conferring protection against Alzheimer's disease (AD). Thereafter, different studies have discovered that the carriers of the APP A673T variant show reduced levels of amyloid beta (Aβ) in the plasma and better cognitive performance at high age. Here, we analyzed cerebrospinal fluid (CSF) and plasma of APP A673T carriers and control individuals using a mass spectrometry-based proteomics approach to identify differentially regulated targets in an unbiased manner. Furthermore, the APP A673T variant was introduced into 2D and 3D neuronal cell culture models together with the pathogenic APP Swedish and London mutations. Consequently, we now report for the first time the protective effects of the APP A673T variant against AD-related alterations in the CSF, plasma, and brain biopsy samples from the frontal cortex. The CSF levels of soluble APPβ (sAPPβ) and Aβ42 were significantly decreased on average 9–26% among three APP A673T carriers as compared to three well-matched controls not carrying the protective variant. Consistent with these CSF findings, immunohistochemical assessment of cortical biopsy samples from the same APP A673T carriers did not reveal Aβ, phospho-tau, or p62 pathologies. We identified differentially regulated targets involved in protein phosphorylation, inflammation, and mitochondrial function in the CSF and plasma samples of APP A673T carriers. Some of the identified targets showed inverse levels in AD brain tissue with respect to increased AD-associated neurofibrillary pathology. In 2D and 3D neuronal cell culture models expressing APP with the Swedish and London mutations, the introduction of the APP A673T variant resulted in lower sAPPβ levels. Concomitantly, the levels of sAPPα were increased, while decreased levels of CTFβ and Aβ42 were detected in some of these models. Our findings emphasize the important role of APP-derived peptides in the pathogenesis of AD and demonstrate the effectiveness of the protective APP A673T variant to shift APP processing towards the non-amyloidogenic pathway in vitro even in the presence of two pathogenic mutations.

Abstract Neurofilament light chain (NfL) is a novel biomarker reflecting neuroaxonal damage and associates with brain atrophy, and glial fibrillary acidic protein (GFAP) is a marker of astrocytic activation, associated with several neurodegenerative diseases. Since obesity is associated with increased risk for several neurodegenerative disorders, we hypothesized that circulating NfL and GFAP levels could reflect neuronal damage in obese patients. 28 morbidly obese and 18 lean subjects were studied with voxel based morphometry (VBM) MRI to assess gray and white matter densities. Serum NfL and GFAP levels were determined with single-molecule array. Obese subjects were re-studied 6 months after bariatric surgery. Morbidly obese subjects had lower absolute concentrations of circulating NfL and GFAP compared to lean individuals. Following bariatric surgery-induced weight loss, both these levels increased. Both at baseline and after weight loss, circulating NfL and GFAP values correlated inversely with eGFR. Cross-sectionally, circulating NfL levels correlated inversely with gray matter (GM) density, and this association remained significant also when accounting for age and total eGFR. GFAP values did not correlate with GM density. Our data suggest that when determining circulating NfL and GFAP levels, eGFR should also be measured since renal function can affect these measurements. Despite the potential confounding effect of renal function on NfL measurement, NfL correlated inversely with gray matter density in this group of subjects with no identified neurological disorders, suggesting that circulating NfL level may be a feasible biomarker of cerebral function even in apparently neurologically healthy subjects.

Abstract Background The relationship between cerebrospinal fluid (CSF) biomarkers and the clinical features of idiopathic normal pressure hydrocephalus (iNPH) has been inconclusive. We aimed to evaluate CSF biomarkers reflecting Alzheimer’s disease (AD)-related amyloid β (Aβ) aggregation, tau pathology, neuroinflammation and axonal degeneration in relation to the clinical features of pre- and post-shunt surgery in iNPH patients. Methods Mini Mental State Examination (MMSE) scores and gait velocity were evaluated pre- and postoperatively in cohorts of 65 Finnish (FIN) and 82 Swedish (SWE) iNPH patients. Lumbar CSF samples were obtained prior to shunt surgery and analysed for soluble amyloid precursor protein alpha (sAPPα) and beta (sAPPβ); amyloid-β isoforms of 42, 40 and 38 (Aβ42, Aβ40, Aβ38); total tau (T-tau); phosphorylated tau (P-tau181); neurofilament light (NfL) and monocyte chemoattractant protein 1 (MCP1). Results Preoperative patient characteristics showed no significant differences between patients in the FIN and SWE cohorts. Patients in both cohorts had significantly improved gait velocity after shunt surgery (p

BackgroundThe usefulness of neurofilament light (NfL) as a biomarker for small vessel disease has not been established. We examined the relationship between NfL, neuroimaging changes, and clinical findings in subjects with varying degrees of white matter hyperintensity (WMH).MethodsA subgroup of participants (n = 35) in the Helsinki Small Vessel Disease Study underwent an analysis of NfL in cerebrospinal fluid (CSF) as well as brain magnetic resonance imaging (MRI) and neuropsychological and motor performance assessments. WMH and structural brain volumes were obtained with automatic segmentation.ResultsCSF NfL did not correlate significantly with total WMH volume (r = 0.278, p = 0.105). However, strong correlations were observed between CSF NfL and volumes of cerebral grey matter (r = −0.569, p

The use of dipeptidyl peptidase 4 (DPP4) inhibitors, (also known as gliptins), is associated with an increased risk of bullous pemphigoid (BP), an autoimmune blistering skin disease. To explore the mechanism behind gliptin-associated BP we investigated circulating autoantibodies against the major BP autoantigen BP180 in serum samples from patients with type 2 diabetes (T2D) with preceding gliptin medication (n = 136) or without (n = 136). Sitagliptin was the most frequently prescribed gliptin (125/136 patients). Using an ELISA assay, we showed that IgG autoantibodies against the immunodominant NC16A domain of BP180 were found in 5.9% of gliptin treated and in 6.6% of non-gliptin treated T2D patients. We found that 28% of gliptin treated patients had IgG autoantibodies recognizing the native full-length BP180 in ELISA, but among non-gliptin treated the seropositivity was even higher, at 32%. Further ELISA analysis of additional serum samples (n = 57) found no major changes in the seropositivity against BP180 during a follow-up period of about nine years. In immunoblotting, full-length BP180 was recognized by 71% of gliptin treated and 89% of non-gliptin treated T2D patients, but only by 46% of the age-and sex-matched controls. The chemokine stromal derived factor-1(SDF-1/CXCL12) is one of the major substrates of DPP4. Immunostainings showed that the expression of SDF-1 was markedly increased in the skin of BP patients, but not affected by prior gliptin treatment. We found that the use of gliptins decreased the serum level of SDF-1α in both BP and T2D patients. Our results indicate that the autoantibodies against the linear full-length BP180 are common in patients with T2D, but seropositivity is unaffected by the use of sitagliptin.

Abstract Objective The aim of the present study was to compare the levels of serum neurofilament light chain (sNfL) in frontotemporal lobar degeneration (FTLD) patients of different clinical subtypes (bvFTD, PPA, and FTLD‐MND) and with or without the C9orf72 repeat expansion, and to correlate sNfL levels to disease progression, assessed by the brain atrophy rate and survival time. Methods The sNfL levels were determined from 78 FTLD patients (C9orf72 repeat expansion carriers [n = 26] and non‐carriers [n = 52]) with Single Molecule Array (SIMOA). The progression of brain atrophy was evaluated using repeated T1‐weighted MRI scans and the survival time from medical records. Results In the total FTLD cohort, sNfL levels were significantly higher in C9orf72 repeat expansion carriers compared to non‐carriers. Considering clinical phenotypes, sNfL levels were higher in the C9orf72 repeat expansion carriers than in the non‐carriers in bvFTD and PPA groups. Furthermore, sNfL levels were the highest in the FTLD‐MND group (median 105 pg/mL) and the lowest in the bvFTD group (median 27 pg/mL). Higher sNfL levels significantly correlated with frontal cortical atrophy rate and subcortical grey matter atrophy rate. The higher sNfL levels also associated with shorter survival time. Interpretation Our results indicate that the C9orf72 repeat expansion carriers show elevated sNFL levels compared to non‐carriers and that the levels differ among different clinical phenotypes of FTLD. Higher sNfL levels correlated with a shorter survival time and cortical and subcortical atrophy rates. Thus, sNfL could prove as a potential prognostic biomarker in FTLD.

Neurofilament light (NFL) is one of the proteins forming multimeric neuron-specific intermediate filaments, neurofilaments, which fill the axonal cytoplasm, establish caliber growth, and provide structural support. Dominant missense mutations and recessive nonsense mutations in the neurofilament light gene (NEFL) are among the causes of Charcot–Marie–Tooth (CMT) neuropathy, which affects the peripheral nerves with the longest axons. We previously demonstrated that a neuropathy-causing homozygous nonsense mutation in NEFL led to the absence of NFL in patient-specific neurons. To understand the disease-causing mechanisms, we investigate here the functional effects of NFL loss in human motor neurons differentiated from induced pluripotent stem cells (iPSC). We used genome editing to generate NEFL knockouts and compared them to patient-specific nonsense mutants and isogenic controls. iPSC lacking NFL differentiated efficiently into motor neurons with normal axon growth and regrowth after mechanical axotomy and contained neurofilaments. Electrophysiological analysis revealed that motor neurons without NFL fired spontaneous and evoked action potentials with similar characteristics as controls. However, we found that, in the absence of NFL, human motor neurons 1) had reduced axonal caliber, 2) the amplitude of miniature excitatory postsynaptic currents (mEPSC) was decreased, 3) neurofilament heavy (NFH) levels were reduced and no compensatory increases in other filament subunits were observed, and 4) the movement of mitochondria and to a lesser extent lysosomes was increased. Our findings elaborate the functional roles of NFL in human motor neurons. NFL is not only a structural protein forming neurofilaments and filling the axonal cytoplasm, but our study supports the role of NFL in the regulation of synaptic transmission and organelle trafficking. To rescue the NFL deficiency in the patient-specific nonsense mutant motor neurons, we used three drugs, amlexanox, ataluren (PTC-124), and gentamicin to induce translational read-through or inhibit nonsense-mediated decay. However, the drugs failed to increase the amount of NFL protein to detectable levels and were toxic to iPSC-derived motor neurons.

Plasma neurofilament light chain (NF-L) levels were assessed as a diagnostic biomarker for traumatic brain injury (TBI) and as a prognostic biomarker for somatomotor recovery, cognitive decline, and epileptogenesis. Rats with severe TBI induced by lateral fluid-percussion injury (n = 26, 13 with and 13 without epilepsy) or sham-operation (n = 8) were studied. During a 6-month follow-up, rats underwent magnetic resonance imaging (MRI) (day (D) 2, D7, and D21), composite neuroscore (D2, D6, and D14), Morris-water maze (D35–D39), and a 1-month-long video-electroencephalogram to detect unprovoked seizures during the 6th month. Plasma NF-L levels were assessed using a single-molecule assay at baseline (i.e., naïve animals) and on D2, D9, and D178 after TBI or a sham operation. Plasma NF-L levels were 483-fold higher on D2 (5072.0 ± 2007.0 pg/mL), 89-fold higher on D9 (930.3 ± 306.4 pg/mL), and 3-fold higher on D176 32.2 ± 8.9 pg/mL after TBI compared with baseline (10.5 ± 2.6 pg/mL; all p < 0.001). Plasma NF-L levels distinguished TBI rats from naïve animals at all time-points examined (area under the curve [AUC] 1.0, p < 0.001), and from sham-operated controls on D2 (AUC 1.0, p < 0.001). Plasma NF-L increases on D2 were associated with somatomotor impairment severity (ρ = −0.480, p < 0.05) and the cortical lesion extent in MRI (ρ = 0.401, p < 0.05). Plasma NF-L increases on D2 or D9 were associated with the cortical lesion extent in histologic sections at 6 months post-injury (ρ = 0.437 for D2; ρ = 0.393 for D9, p < 0.05). Plasma NF-L levels, however, did not predict somatomotor recovery, cognitive decline, or epileptogenesis (p > 0.05). Plasma NF-L levels represent a promising noninvasive translational diagnostic biomarker for acute TBI and a prognostic biomarker for post-injury somatomotor impairment and long-term structural brain damage.

Abstract Background In clinical practice, it is often difficult to predict which patients with cognitive complaints or impairment will progress or remain stable. We assessed the impact of using a clinical decision support system, the PredictND tool, to predict progression in patients with subjective cognitive decline (SCD) and mild cognitive impairment (MCI) in memory clinics. Methods In this prospective multicenter study, we included 429 patients with SCD (n = 230) and MCI (n = 199) (female 54%, age 67 ± 9, MMSE 28 ± 2) and followed them for at least 12 months. Based on all available patient baseline data (demographics, cognitive tests, cerebrospinal fluid biomarkers, and MRI), the PredictND tool provides a comprehensive overview of the data and a classification defining the likelihood of progression. At baseline, a clinician defined an expected follow-up diagnosis and estimated the level of confidence in their prediction using a visual analogue scale (VAS, 0–100%), first without and subsequently with the PredictND tool. As outcome measure, we defined clinical progression as progression from SCD to MCI or dementia, and from MCI to dementia. Correspondence between the expected and the actual clinical progression at follow-up defined the prognostic accuracy. Results After a mean follow-up time of 1.7 ± 0.4 years, 21 (9%) SCD and 63 (32%) MCI had progressed. When using the PredictND tool, the overall prognostic accuracy was unaffected (0.4%, 95%CI − 3.0%; + 3.9%; p = 0.79). However, restricting the analysis to patients with more certain classifications (n = 203), we found an increase of 3% in the accuracy (95%CI − 0.6%; + 6.5%; p = 0.11). Furthermore, for this subgroup, the tool alone showed a statistically significant increase in the prognostic accuracy compared to the evaluation without tool (6.4%, 95%CI 2.1%; 10.7%; p = 0.004). Specifically, the negative predictive value was high. Moreover, confidence in the prediction increased significantly (∆VAS = 4%, p

Abstract Objectives Serum neurofilament light chain (sNfL) is a promising biomarker of MS activity, progression, and treatment response. The aim of the present study was to address whether sNfL concentrations are affected by supplementation of vitamin D and correlate with disease activity in interferon‐beta‐1b (IFNb‐1b)‐treated Finnish MS. Materials and Methods Serum samples were available of 32 participants of the Finnish vitamin D randomized controlled trial (17 vitamin D/15 placebo). Serum 25 hydroxyvitamin D was measured using radioimmunoassay and sNfL using single‐molecule array (Simoa). Correlation of sNfL with brain magnetic resonance imaging (MRI) activity, burden of disease (BOD, mm3), and disability was assessed at the study baseline and at 52 weeks. Results Serum NfL concentrations were similar in the patients randomized to high‐dose vitamin D and placebo at the study baseline and at month 12 follow‐up (p‐value). Concentrations of sNfL were higher in patients with Gadolinium‐enhancing lesions in brain MRI: median (95% CI) sNfL was 14.84 (9.9–42.5) pg/ml and 11.39 (8.9–13.2) pg/ml in patients without Gd+ lesions (p = .0144) and correlated with enhancing lesion volume (Pearson r = .36, p = .037) at the study baseline but not at week 52. Serum NfL did not correlate with the MRI BOD or disability measured by expanded disability status scale and 25‐foot walk test. Conclusion In this small cohort of clinically stable IFN‐treated Finnish MS patients, sNfL levels were similarly low in patients supplemented with high‐dose vitamin D or placebo. Subclinical disease activity in MRI was associated with higher sNfL levels.

INTRODUCTION:An accurate and timely diagnosis for Alzheimer's disease (AD) is important, both for care and research. The current diagnostic criteria allow the use of CSF biomarkers to provide pathophysiological support for the diagnosis of AD. How these criteria should be operationalized by clinicians is unclear. Tools that guide in selecting patients in which CSF biomarkers have clinical utility are needed. We evaluated computerized decision support to select patients for CSF biomarker determination. METHODS:We included 535 subjects (139 controls, 286 Alzheimer's disease dementia, 82 frontotemporal dementia and 28 vascular dementia) from three clinical cohorts. Positive (AD like) and negative (normal) CSF biomarker profiles were simulated to estimate whether knowledge of CSF biomarkers would impact (confidence in) diagnosis. We applied these simulated CSF values and combined them with demographic, neuropsychology and MRI data to initiate CSF testing (computerized decision support approach). We compared proportion of CSF measurements and patients diagnosed with sufficient confidence (probability of correct class ≥0.80) based on an algorithm with scenarios without CSF (only neuropsychology, MRI and APOE), CSF according to the appropriate use criteria (AUC) and CSF for all patients. RESULTS:The computerized decision support approach recommended CSF testing in 140 (26%) patients, which yielded a diagnosis with sufficient confidence in 379 (71%) of all patients. This approach was more efficient than CSF in none (0% CSF, 308 (58%) diagnosed), CSF selected based on AUC (295 (55%) CSF, 350 (65%) diagnosed) or CSF in all (100% CSF, 348 (65%) diagnosed). CONCLUSIONS:We used a computerized decision support with simulated CSF results in controls and patients with different types of dementia. This approach can support clinicians in making a balanced decision in ordering additional biomarker testing. Computer-supported prediction restricts CSF testing to only 26% of cases, without compromising diagnostic accuracy.

Abstract Introduction Web‐based cognitive tests have potential for standardized screening in neurodegenerative disorders. We examined accuracy and consistency of cCOG, a computerized cognitive tool, in detecting mild cognitive impairment (MCI) and dementia. Methods Clinical data of 306 cognitively normal, 120 mild cognitive impairment (MCI), and 69 dementia subjects from three European cohorts were analyzed. Global cognitive score was defined from standard neuropsychological tests and compared to the corresponding estimated score from the cCOG tool containing seven subtasks. The consistency of cCOG was assessed comparing measurements administered in clinical settings and in the home environment. Results cCOG produced accuracies (receiver operating characteristic‐area under the curve [ROC‐AUC]) between 0.71 and 0.84 in detecting MCI and 0.86 and 0.94 in detecting dementia when administered at the clinic and at home. The accuracy was comparable to the results of standard neuropsychological tests (AUC 0.69–0.77 MCI/0.91–0.92 dementia). Discussion cCOG provides a promising tool for detecting MCI and dementia with potential for a cost‐effective approach including home‐based cognitive assessments.

Abstract Idiopathic normal pressure hydrocephalus (iNPH) is a neuropathology with unknown cause characterised by gait impairment, cognitive decline and ventriculomegaly. These patients often present comorbidity with Alzheimer’s disease (AD), including AD pathological hallmarks such as amyloid plaques mainly consisting of amyloid β-peptide and neurofibrillary tangles consisting of hyperphosphorylated tau protein. Even though some of the molecular mechanisms behind AD are well described, little is known about iNPH. Several studies have reported that mitochondria-endoplasmic reticulum contact sites (MERCS) regulate amyloid β-peptide metabolism and conversely that amyloid β-peptide can influence the number of MERCS. MERCS have also been shown to be dysregulated in several neurological pathologies including AD. In this study we have used transmission electron microscopy and show, for the first time, several mitochondria contact sites including MERCS in human brain biopsies. These unique human brain samples were obtained during neurosurgery from 14 patients that suffer from iNPH. Three of these 14 patients presented comorbidities with other dementias: one patient with AD, one with AD and vascular dementia and one patient with Lewy body dementia. Furthermore, we report that the numbers of MERCS are increased in biopsies obtained from patients diagnosed with dementia. Moreover, the presence of both amyloid plaques and neurofibrillary tangles correlates with decreased contact length between endoplasmic reticulum and mitochondria, while amyloid plaques alone do not seem to affect endoplasmic reticulum-mitochondria apposition. Interestingly, we report a significant positive correlation between the number of MERCS and ventricular cerebrospinal fluid amyloid β-peptide levels, as well as with increasing age of iNPH patients.

Abstract Body fluid biomarkers have great potential for different clinical purposes, including diagnosis, prognosis, patient stratification and treatment effect monitoring. This is exemplified by current use of several excellent biomarkers, such as the Alzheimer’s disease cerebrospinal fluid (CSF) biomarkers, anti-neuromyelitis optica antibodies and blood neurofilament light. We still, however, have a strong need for additional biomarkers and several gaps in their development and implementation should be filled. Examples of such gaps are i) limited knowledge of the causes of neurological diseases, and thus hypotheses about the best biomarkers to detect subclinical stages of these diseases; ii) the limited success translating discoveries obtained by e.g. initial mass spectrometry proteomic low-throughput studies into immunoassays for widespread clinical implementation; iii) lack of interaction among all stakeholders to optimise and adapt study designs throughout the biomarker development process to medical needs, which may change during the long period needed for biomarker development. The Society for CSF Analysis and Clinical Neurochemistry (established in 2015) has been founded as a concerted follow-up of large standardisation projects, including BIOMARKAPD and SOPHIA, and the BioMS-consortium. The main aims of the CSF society are to exchange high level international scientific experience, to facilitate the incorporation of CSF diagnostics into clinical practice and to give advice on inclusion of CSF analysis into clinical guidelines. The society has a broad scope, as its vision is that the gaps in development and implementation of biomarkers are shared among almost all neurological diseases and thus they can benefit from the activities of the society.

Abstract Background From earlier studies it is known that the APOE ε2/ε3/ε4 polymorphism modulates the concentrations of cerebrospinal fluid (CSF) beta-amyloid1–42 (Aβ42) in patients with cognitive decline due to Alzheimer’s disease (AD), as well as in cognitively healthy controls. Here, in a large cohort consisting solely of cognitively healthy individuals, we aimed to evaluate how the effect of APOE on CSF Aβ42 varies by age, to understand the association between APOE and the onset of preclinical AD. Methods APOE genotype and CSF Aβ42 concentration were determined in a cohort comprising 716 cognitively healthy individuals aged 17–99 from nine different clinical research centers. Results CSF concentrations of Aβ42 were lower in APOE ε4 carriers than in noncarriers in a gene dose-dependent manner. The effect of APOE ε4 on CSF Aβ42 was age dependent. The age at which CSF Aβ42 concentrations started to decrease was estimated at 50 years in APOE ε4-negative individuals and 43 years in heterozygous APOE ε4 carriers. Homozygous APOE ε4 carriers showed a steady decline in CSF Aβ42 concentrations with increasing age throughout the examined age span. Conclusions People possessing the APOE ε4 allele start to show a decrease in CSF Aβ42 concentration almost a decade before APOE ε4 noncarriers already in early middle age. Homozygous APOE ε4 carriers might deposit Aβ42 throughout the examined age span. These results suggest that there is an APOE ε4-dependent period of early alterations in amyloid homeostasis, when amyloid slowly accumulates, that several years later, together with other downstream pathological events such as tau pathology, translates into cognitive decline.

Background: Data on the association of memory performance with cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) are inconsistent. The Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery (CERAD-NB) is a commonly used validated cognitive tool; however, only few studies have examined its relationship with CSF biomarkers for AD. We studied the correlation of pathological changes in CSF biomarkers with various CERAD-NB subtests and total scores. Methods: Out of 79 subjects (36 men, mean age 70.5 years), 63 had undergone an assessment of cognitive status with CERAD-NB and a CSF biomarker analysis due to a suspected memory disorder, and 16 were controls with no memory complaint.Results: In women we found a significant correlation between CSF amyloid-beta (Aβ1-42) and several subtests measuring delayed recall. Word List Recall correlated with all markers: Aβ1-42 (r = 0.323, p = 0.035), tau (r = -0.304, p = 0.050) and hyperphosphorylated tau (r = -0.331, p = 0.046). No such correlations were found in men. Conclusions: CSF biomarkers correlate with delayed memory scores in CERAD-NB in women, and women may have more actual AD pathology at the time of the investigations than men.

Background: Disease State Index (DSI) and its visualization, Disease State Fingerprint (DSF), form a computer-assisted clinical decision making tool that combines patient data and compares them with cases with known outcomes. Aims: To investigate the ability of the DSI to diagnose frontotemporal dementia (FTD) and Alzheimer's disease (AD). Methods: The study cohort consisted of 38 patients with FTD, 57 with AD and 22 controls. Autopsy verification of FTD with TDP-43 positive pathology was available for 14 and AD pathology for 12 cases. We utilized data from neuropsychological tests, volumetric magnetic resonance imaging, single-photon emission tomography, cerebrospinal fluid biomarkers and the APOE genotype. The DSI classification results were calculated with a combination of leave-one-out cross-validation and bootstrapping. A DSF visualization of a FTD patient is presented as an example. Results: The DSI distinguishes controls from FTD (area under the receiver-operator curve, AUC = 0.99) and AD (AUC = 1.00) very well and achieves a good differential diagnosis between AD and FTD (AUC = 0.89). In subsamples of autopsy-confirmed cases (AUC = 0.97) and clinically diagnosed cases (AUC = 0.94), differential diagnosis of AD and FTD performs very well. Conclusions: DSI is a promising computer-assisted biomarker approach for aiding in the diagnostic process of dementing diseases. Here, DSI separates controls from dementia and differentiates between AD and FTD.

Background: TDP-43 is the main protein component of ubiquitinated inclusions in a subgroup of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) patients. The C9ORF72 hexanucleotide expansion is one of the main mutations associated with TDP-43 pathology in FTLD and ALS. Our aim was to analyze cerebrospinal fluid (CSF) TDP-43 levels and Alzheimer's disease biomarkers in FTLD and ALS patients and to test whether the C9ORF72 expansion carrier status affects these variables. Methods: The patient cohort consisted of 90 clinically well-characterized FTLD (n = 69) and ALS (n = 21) patients. There were 30 patients with the C9ORF72 expansion and 60 patients without the expansion. CSF TDP-43, Aβ1-42, t-tau, and phospho-tau levels were measured using commercial ELISA kits. Results: There was no difference in CSF TDP-43 levels between the C9ORF72 expansion carriers and the noncarriers. CSF TDP-43 levels were higher in ALS patients than in FTLD patients, and this finding was independent of the C9ORF72 expansion carrier status. Males had significantly higher TDP-43 levels than females (p = 0.008 in the total cohort). Conclusion: CSF TDP-43 does not seem to distinguish the C9ORF72 expansion carriers from noncarriers. However, higher CSF TDP-43 levels were detected in ALS than in FTLD, which might be an indicator of a more rapid progression of TDP-43 pathology in ALS.

Background/Aims: The diagnosis of frontotemporal lobar degeneration (FTLD) is based on neuropsychological examination in addition to clinical symptoms and brain imaging. There is no simple, validated, cognitive tool available in screening for FTLD. The Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery (CERAD-NB) was originally devised to identify the early cognitive changes related to Alzheimer's disease (AD). Our aim was to investigate the utility of the CERAD-NB in FTLD. Methods: Patients with FTLD (n = 95) and AD (n = 90) were assessed with the CERAD-NB, Trail Making Test parts A and B and single-letter Phonemic Fluency. Results: FTLD patients were more severely impaired in the Verbal Fluency subtest in the CERAD-NB and Trail Making Test part A compared to AD patients. In addition, AD patients were more impaired in memory subtests compared to FTLD patients. Conclusion: The CERAD-NB may be a useful tool in screening for FTLD. Impaired performance in Verbal Fluency with moderately well-preserved Delayed Recall and Memory Tests may help in identifying patients with probable FTLD and discriminating FTLD from AD. Adding the Trail Making Test to the battery might enhance its value as a screening instrument for FTLD.

Background/Aim: Alzheimer’s disease (AD) causes impairment in memory and other cognitive functions as well as neuropsychiatric symptoms and limitations in the activities of daily living (ADL). The aim of this study was to examine whether demographic variables, dementia severity, ADL and neuropsychiatric symptoms are associated with cognition in very mild or mild AD. Methods: We analyzed the baseline data of 236 patients with very mild or mild AD participating in a prospective AD follow-up study (ALSOVA). The Consortium to Establish a Registry for Alzheimer’s Disease neuropsychological battery total score was used in the evaluation of the global cognitive performance. Results: Cognition was associated with dementia severity and ADL but not with neuropsychiatric symptoms. ADL functions were associated with both cognitive performance and neuropsychiatric symptoms. Conclusion: Even patients with very mild or mild AD may exhibit neuropsychiatric symptoms not related to cognitive impairment. The results of this study emphasize the importance of taking a multidimensional approach to the diagnostic and prognostic evaluation of AD patients already in the early stages of the disease.

To relate levels of β-amyloid42 (Aβ42) in the cerebrospinal fluid (CSF) and brain in early Alzheimer's disease, we repeatedly measured CSF Aβ42 levels in transgenic mice carrying Swedish amyloid precursor protein and presenilin-1 mutations, at ages before and after amyloid deposition. Hippocampal Aβ42 levels were measured at the endpoints. In APPswe/PS1(A246E) mice, CSF Aβ42 levels significantly increased between 5 and 7 months of age but did not change between 8 and 13 months despite a rapid increase in brain Aβ42. Furthermore, a decline in CSF Aβ42 levels was observed between 6 and 9 months in APPswe/PS1dE9 mice with faster pathology. Interestingly, the initial CSF Aβ42 concentrations correlated more strongly with brain Aβ42 levels than the endpoint CSF Aβ42. Our results suggest that the levels of CSF Aβ42 initially reflect the rate of Aβ42 production, but after reaching a critical concentration stay in equilibrium, until plaque formation leads to decreased CSF Aβ42 levels.

BackgroundThe significance of amyloid precursor protein (APP) and neuroinflammation in idiopathic normal pressure hydrocephalus (iNPH) and Alzheimer's disease (AD) is unknown.ObjectiveTo investigate the role of soluble APP (sAPP) and amyloid beta (Aβ) isoforms, proinflammatory cytokines, and biomarkers of neuronal damage in the cerebrospinal fluid (CSF) in relation to brain biopsy Aβ and hyperphosphorylated tau (HPτ) findings.MethodsThe study population comprised 102 patients with possible NPH with cortical brain biopsies, ventricular and lumbar CSF samples, and DNA available. The final clinical diagnoses were: 53 iNPH (91% shunt-responders), 26 AD (10 mixed iNPH+AD), and 23 others. Biopsy samples were immunostained against Aβ and HPτ. CSF levels of AD-related biomarkers (Aβ42, p-tau, total tau), non-AD-related Aβ isoforms (Aβ38, Aβ40), sAPP isoforms (sAPPα, sAPPβ), proinflammatory cytokines (several interleukins (IL), interferon-gamma, monocyte chemoattractant protein-1, tumor necrosis factor-alpha) and biomarkers of neuronal damage (neurofilament light and myelin basic protein) were measured. All patients were genotyped for APOE.ResultsLumbar CSF levels of sAPPα were lower (pConclusionsThe role of sAPP isoforms in iNPH seems to be independent from the amyloid cascade. No neuroinflammatory background was observed in iNPH or AD.

OBJECTIVES: To understand the relation between risk genes for Alzheimer's disease (AD) and their influence on biomarkers for AD, we examined the association of AD in the Finnish cohort with single nucleotide polymorphisms (SNPs) from top AlzGene loci, genome-wide association studies (GWAS), and candidate gene studies; and tested the correlation between these SNPs and AD markers Aβ(1-42), total tau (t-tau), and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF). METHODS: We tested 25 SNPs for genetic association with clinical AD in our cohort comprised of 890 AD patients and 701-age matched healthy controls using logistic regression. For the correlational study with biomarkers, we tested 36 SNPs in a subset of 222 AD patients with available CSF using mixed models. Statistical analyses were adjusted for age, gender and APOE status. False discovery rate for multiple testing was applied. All participants were from academic hospital and research institutions in Finland. RESULTS: APOE-ε4, CLU rs11136000, and MS4A4A rs2304933 correlated with significantly decreased Aβ(1-42) (corrected p0.05). CONCLUSIONS: We provide evidence that APOE-ε4, CLU and MS4A4A, which have been identified in GWAS to be associated with AD, also significantly reduced CSF Aβ1-42 in AD. None of the other AlzGene and GWAS loci showed significant effects on CSF tau. The effects of other SNPs on CSF biomarkers and clinical AD diagnosis did not reach statistical significance. Our findings suggest that APOE-ε4, CLU and MS4A4A influence both AD risk and CSF Aβ1-42.

PURPOSE:To compare the accuracies of predicting AD conversion by using a decision support system (PredictAD tool) and current research criteria of prodromal AD as identified by combinations of episodic memory impairment of hippocampal type and visual assessment of medial temporal lobe atrophy (MTA) on MRI and CSF biomarkers. METHODS:Altogether 391 MCI cases (158 AD converters) were selected from the ADNI cohort. All the cases had baseline cognitive tests, MRI and/or CSF levels of Aβ1-42 and Tau. Using baseline data, the status of MCI patients (AD or MCI) three years later was predicted using current diagnostic research guidelines and the PredictAD software tool designed for supporting clinical diagnostics. The data used were 1) clinical criteria for episodic memory loss of the hippocampal type, 2) visual MTA, 3) positive CSF markers, 4) their combinations, and 5) when the PredictAD tool was applied, automatically computed MRI measures were used instead of the visual MTA results. The accuracies of diagnosis were evaluated with the diagnosis made 3 years later. RESULTS:The PredictAD tool achieved the overall accuracy of 72% (sensitivity 73%, specificity 71%) in predicting the AD diagnosis. The corresponding number for a clinician's prediction with the assistance of the PredictAD tool was 71% (sensitivity 75%, specificity 68%). Diagnosis with the PredictAD tool was significantly better than diagnosis by biomarkers alone or the combinations of clinical diagnosis of hippocampal pattern for the memory loss and biomarkers (p≤0.037). CONCLUSION:With the assistance of PredictAD tool, the clinician can predict AD conversion more accurately than the current diagnostic criteria.

The prevalence of Parkinson's disease (PD) increases with age. Up to 50% of PD show cognitive decline in terms of a mild cognitive impairment already in early stages that predict the development of dementia, which can occur in up to 80% of PD patients over the long term, called Parkinson's disease dementia (PDD). So far, diagnosis of PD/PDD is made according to clinical and neuropsychological examinations while laboratory data is only used for exclusion of other diseases. The aim of this study was the identification of possible biomarkers in cerebrospinal fluid (CSF) of PD, PDD and controls (CON) which predict the development of dementia in PD. For this, a proteomic approach optimized for CSF was performed using 18 clinically well characterized patients in a first step with subsequent validation using 84 patients. Here, we detected differentially sialylated isoforms of Serpin A1 as marker for differentiation of PD versus PDD in CSF. Performing 2D-immunoblots, all PDD patients could be identified correctly (sensitivity 100%). Ten out of 24 PD patients showed Serpin A1 isoforms in a similar pattern like PDD, indicating a specificity of 58% for the test-procedure. In control samples, no additional isoform was detected. On the basis of these results, we conclude that differentially sialylated products of Serpin A1 are an interesting biomarker to indicate the development of a dementia during the course of PD.

BACKGROUND: MRI is an important clinical tool for diagnosing dementia-like diseases such as Frontemporal Dementia (FTD). However there is a need to develop more accurate and standardized MRI analysis methods. OBJECTIVE: To compare FTD with Alzheimer's Disease (AD) and Mild Cognitive Impairment (MCI) with three automatic MRI analysis methods - Hippocampal Volumetry (HV), Tensor-based Morphometry (TBM) and Voxel-based Morphometry (VBM), in specific regions of interest in order to determine the highest classification accuracy. METHODS: Thirty-seven patients with FTD, 46 patients with AD, 26 control subjects, 16 patients with progressive MCI (PMCI) and 48 patients with stable MCI (SMCI) were examined with HV, TBM for shape change, and VBM for gray matter density. We calculated the Correct Classification Rate (CCR), sensitivity (SS) and specificity (SP) between the study groups. RESULTS: We found unequivocal results differentiating controls from FTD with HV (hippocampus left side) (CCR = 0.83; SS = 0.84; SP = 0.80), with TBM (hippocampus and amygdala (CCR = 0.80/SS = 0.71/SP = 0.94), and with VBM (all the regions studied, especially in lateral ventricle frontal horn, central part and occipital horn) (CCR = 0.87/SS = 0.81/SP = 0.96). VBM achieved the highest accuracy in differentiating AD and FTD (CCR = 0.72/SS = 0.67/SP = 0.76), particularly in lateral ventricle (frontal horn, central part and occipital horn) (CCR = 0.73), whereas TBM in superior frontal gyrus also achieved a high accuracy (CCR = 0.71/SS = 0.68/SP = 0.73). TBM resulted in low accuracy (CCR = 0.62) in the differentiation of AD from FTD using all regions of interest, with similar results for HV (CCR = 0.55). CONCLUSION: Hippocampal atrophy is present not only in AD but also in FTD. Of the methods used, VBM achieved the highest accuracy in its ability to differentiate between FTD and AD.

Cerebrospinal fluid (CSF) samples from 33 patients with Alzheimer dementia (AD), 21 patients with mild cognitive impairment who converted to AD during followup (MCI-AD), 25 patients with stable mild cognitive impairment (MCI-stable), and 16 nondemented subjects (ND) were analyzed with a chemiluminescence immunoassay to assess the levels of the mitogen-activated protein kinase ERK1/2 (extracellular signal-regulated kinase 1/2). The results were evaluated in relation to total Tau (tTau), phosphorylated Tau (pTau), and beta-amyloid 42 peptide (Aβ42). CSF-ERK1/2 was significantly increased in the AD group as compared to stable MCI patients and the ND group. Western blot analysis of a pooled cerebrospinal fluid sample revealed that both isoforms, ERK1 and ERK2, and low amounts of doubly phosphorylated ERK2 were detectable. As a predictive diagnostic AD biomarker, CSF-ERK1/2 was inferior to tTau, pTau, and Aβ42.