Anti-GluA3 autoantibodies define a new sub-population of frontotemporal lobar degeneration patients with distinct neuropathological features.

Autoantibodies directed against the GluA3 subunit (anti-GluA3 hIgGs) of AMPA receptors have been identified in 20%-25% of patients with frontotemporal lobar degeneration (FTLD). Data from patients and in vitro/ex vivo pre-clinical studies indicate that anti-GluA3 hIgGs negatively affect glutamatergic neurotransmission. However, whether and how the chronic presence of anti-GluA3 hIgGs triggers synaptic dysfunctions and the appearance of FTLD-related neuropathological and behavioural signature has not been clarified yet. To address this question, we developed and characterized a pre-clinical mouse model of passive immunization with anti-GluA3 hIgGs purified from patients. In parallel, we clinically compared FTLD patients who were positive for anti-GluA3 hIgGs to negative ones. Clinical data showed that the presence of anti-GluA3 hIgGs defined a subgroup of patients with distinct clinical features. In the preclinical model, anti-GluA3 hIgGs administration led to accumulation of phospho-tau in the postsynaptic fraction and dendritic spine loss in the prefrontal cortex. Remarkably, the preclinical model exhibited behavioural disturbances that mostly reflected the deficits proper of patients positive for anti-GluA3 hIgGs. Of note, anti-GluA3 hIgGs-mediated alterations were rescued in the animal model by enhancing glutamatergic neurotransmission with a positive allosteric modulator of AMPA receptors. Overall, our study clarified the contribution of anti-GluA3 autoantibodies to central nervous system symptoms and pathology and identified a specific subgroup of FTLD patients. Our findings will be instrumental in the development of a therapeutic personalised medicine strategy for patients positive for anti-GluA3 hIgGs.

Diverging medical and legal perceptions of the need for legal guardianship in people with dementia: A qualitative study.

BACKGROUND: Dementia is assumed to alter mental capacity, which may necessitate legal guardianship. However, only limited research exists on how dementia affects mental capacity, and most studies have focused solely on a medical perspective and concentrate on memory functions. The aim of this qualitative study was to investigate physicians' and legal experts' perceptions on a broad range of cognitive and neuropsychiatric domains potentially affecting mental capacity and the need for guardianship in people with dementia. METHODS: Physicians (N = 30) and legal experts (N = 20) participated in semi-structured individual interviews. The data were analyzed by using content analysis and further semi-quantified according to the cognitive and neuropsychiatric domains. RESULTS: Physicians considered neuropsychiatric symptoms and executive dysfunction to be the most important deficits in the legal context, while legal experts highlighted episodic memory impairment and dyscalculia. Perceptions regarding the importance of several cognitive and neuropsychiatric symptoms varied between and within the professional groups. CONCLUSIONS: Physicians and legal experts diverged in their perceptions of cognitive and neuropsychiatric domains affecting mental capacity and the need for guardianship. The evaluation and influence of medical evidence among legal experts heavily rely on subjective opinions. Given the substantial potential impact on patients' equal access to their rights, developing standardized guidelines is essential.

Utility of the INECO Frontal Screening and the Frontal Assessment Battery in detecting executive dysfunction in early-onset cognitive impairment and dementia.

OBJECTIVE: The INECO Frontal Screening (IFS) and the Frontal Assessment Battery (FAB) are executive dysfunction (ED) screening tools that can distinguish patients with neurodegenerative disorders from healthy controls and, to some extent, between dementia subtypes. This paper aims to examine the suitability of these tests in assessing early-onset cognitive impairment and dementia patients. METHOD: In a memory clinic patient cohort (age mean = 57.4 years) with symptom onset at ≤65 years, we analyzed the IFS and the FAB results of four groups: early-onset dementia (EOD, n = 49), mild cognitive impairment due to neurological causes (MCI-n, n = 34), MCI due to other causes such as depression (MCI-o, n = 99) and subjective cognitive decline (SCD, n = 14). Data were gathered at baseline and at 6 and 12 months. We also studied the tests' accuracy in distinguishing EOD from SCD patients and ED patients from those with intact executive functioning. Correlations with neuropsychological measures were also studied. RESULTS: The EOD group had significantly (p < .05) lower IFS and FAB total scores than the MCI-o and SCD groups. Compared with the FAB, the IFS showed more statistically significant (p < .05) differences between diagnostic groups, greater accuracy (IFS AUC = .80, FAB AUC = .75, p = .036) in detecting ED and marginally stronger correlations with neuropsychological measures. We found no statistically significant differences in the EOD group scores from baseline up to 6- or 12-months follow-up. CONCLUSIONS: While both tests can detect EOD among memory clinic patients, the IFS may be more reliable in detecting ED than the FAB.

Genotype-phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications.

We report detailed functional analyses and genotype-phenotype correlations in 392 individuals carrying disease-causing variants in SCN8A, encoding the voltage-gated Na+ channel Nav1.6, with the aim of describing clinical phenotypes related to functional effects. Six different clinical subgroups were identified: Group 1, benign familial infantile epilepsy (n = 15, normal cognition, treatable seizures); Group 2, intermediate epilepsy (n = 33, mild intellectual disability, partially pharmaco-responsive); Group 3, developmental and epileptic encephalopathy (n = 177, severe intellectual disability, majority pharmaco-resistant); Group 4, generalized epilepsy (n = 20, mild to moderate intellectual disability, frequently with absence seizures); Group 5, unclassifiable epilepsy (n = 127); and Group 6, neurodevelopmental disorder without epilepsy (n = 20, mild to moderate intellectual disability). Those in Groups 1-3 presented with focal or multifocal seizures (median age of onset: 4 months) and focal epileptiform discharges, whereas the onset of seizures in patients with generalized epilepsy was later (median: 42 months) with generalized epileptiform discharges. We performed functional studies expressing missense variants in ND7/23 neuroblastoma cells and primary neuronal cultures using recombinant tetrodotoxin-insensitive human Nav1.6 channels and whole-cell patch-clamping. Two variants causing developmental and epileptic encephalopathy showed a strong gain-of-function (hyperpolarizing shift of steady-state activation, strongly increased neuronal firing rate) and one variant causing benign familial infantile epilepsy or intermediate epilepsy showed a mild gain-of-function (defective fast inactivation, less increased firing). In contrast, all three variants causing generalized epilepsy induced a loss-of-function (reduced current amplitudes, depolarizing shift of steady-state activation, reduced neuronal firing). Functional effects were known for 170 individuals. All 136 individuals carrying a functionally tested gain-of-function variant had either focal (n = 97, Groups 1-3) or unclassifiable (n = 39) epilepsy, whereas 34 individuals with a loss-of-function variant had either generalized (n = 14), no (n = 11) or unclassifiable (n = 6) epilepsy; only three had developmental and epileptic encephalopathy. Computational modelling in the gain-of-function group revealed a significant correlation between the severity of the electrophysiological and clinical phenotypes. Gain-of-function variant carriers responded significantly better to sodium channel blockers than to other anti-seizure medications, and the same applied for all individuals in Groups 1-3. In conclusion, our data reveal clear genotype-phenotype correlations between age at seizure onset, type of epilepsy and gain- or loss-of-function effects of SCN8A variants. Generalized epilepsy with absence seizures is the main epilepsy phenotype of loss-of-function variant carriers and the extent of the electrophysiological dysfunction of the gain-of-function variants is a main determinant of the severity of the clinical phenotype in focal epilepsies. Our pharmacological data indicate that sodium channel blockers present a treatment option in SCN8A-related focal epilepsy with onset in the first year of life.

Education-Based Cutoffs for Cognitive Screening of Alzheimer's Disease.

INTRODUCTION: The educational background and size of the elderly population are undergoing significant changes in Finland during the 2020s. A similar process is likely to occur also in several European countries. For cognitive screening of early Alzheimer's disease (AD), using outdated norms and cutoff scores may negatively affect clinical accuracy. The aim of the present study was to examine the effects of education, age, and gender on the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery (CERAD-nb) in a large register-based, clinical sample of patients with mild AD and nondemented at-risk persons from the general population (controls) and to examine whether corrected cutoff scores would increase the accuracy of differentiation between the 2 groups. METHODS: CERAD-nb scores were obtained from AD patients (n = 389, 58% women, mean age 74.0 years) and from controls (n = 1,980, 52% women, mean age 68.5 years). The differences in CERAD-nb performance were evaluated by univariate GLM. Differentiation between the 2 groups was evaluated using a receiver operating characteristic (ROC) curve, where a larger area under the ROC curve represents better discrimination. Youden's J was calculated for the overall performance and accuracy of each of the measures. RESULTS: Of the demographic factors, education was the strongest predictor of CERAD-nb performance, explaining more variation than age or gender in both the AD patients and the controls. Education corrected cutoff scores had better diagnostic accuracy in discriminating between the AD patients and controls than existing uncorrected scores. The highest level of discrimination between the 2 groups overall was found for two CERAD-nb total scores. CONCLUSIONS: Education-corrected cutoff scores were superior to uncorrected scores in differentiating between controls and AD patients especially for the highest level of education and should therefore be used in clinical cognitive screening, also as the proportion of the educated elderly is increasing substantially during the 2020s. Our results also indicate that total scores of the CERAD-nb are better at discriminating AD patients from controls than any single subtest score. A digital tool for calculating the total scores and comparing education-based cutoffs would increase the efficiency and usability of the test.

Cardiovascular brain impulses in Alzheimer's disease.

Accumulation of amyloid-ß is a key neuropathological feature in brain of Alzheimer's disease patients. Alterations in cerebral haemodynamics, such as arterial impulse propagation driving the (peri)vascular CSF flux, predict future Alzheimer's disease progression. We now present a non-invasive method to quantify the three-dimensional propagation of cardiovascular impulses in human brain using ultrafast 10 Hz magnetic resonance encephalography. This technique revealed spatio-temporal abnormalities in impulse propagation in Alzheimer's disease. The arrival latency and propagation speed both differed in patients with Alzheimer's disease. Our mapping of arterial territories revealed Alzheimer's disease-specific modifications, including reversed impulse propagation around the hippocampi and in parietal cortical areas. The findings imply that pervasive abnormality in (peri)vascular CSF impulse propagation compromises vascular impulse propagation and subsequently glymphatic brain clearance of amyloid-ß in Alzheimer's disease.

Retigabine and gabapentin restore channel function and neuronal firing in a cellular model of an epilepsy-associated dominant-negative KCNQ5 variant.

KCNQ5 encodes the voltage-gated potassium channel KV7.5, a member of the KV7 channel family, which conducts the M-current. This current is a potent regulator of neuronal excitability by regulating membrane potential in the subthreshold range of action potentials and mediating the medium and slow afterhyperpolarization. Recently, we have identified five loss-of-function variants in KCNQ5 in patients with genetic generalized epilepsy. Using the most severe dominant-negative variant (R359C), we set out to investigate pharmacological therapeutic intervention by KV7 channel openers on channel function and neuronal firing. Retigabine and gabapentin increased R359C-derived M-current amplitudes in HEK cells expressing homomeric or heteromeric mutant KV7.5 channels. Retigabine was most effective in restoring K+ currents. Ten µM retigabine was sufficient to reach the level of WT currents without retigabine, whereas 100 µM of gabapentin showed less than half of this effect and application of 50 µM ZnCl2 only significantly increased M-current amplitude in heteromeric channels. Overexpression of KV7.5-WT potently inhibited neuronal firing by increasing the M-current, whereas R359C overexpression had the opposite effect and additionally decreased the medium afterhyperpolarization current. Both aforementioned drugs and Zn2+ reversed the effect of R359C expression by reducing firing to nearly normal levels at high current injections. Our study shows that a dominant-negative variant with a complete loss-of-function in KV7.5 leads to largely increased neuronal firing which may explain a neuronal hyperexcitability in patients. KV7 channel openers, such as retigabine or gabapentin, could be treatment options for patients currently displaying pharmacoresistant epilepsy and carrying loss-of-function variants in KCNQ5.

A Novel Computerized Flexible Attention Test in Detecting Executive Dysfunction of Patients with Early-Onset Cognitive Impairment and Dementia.

OBJECTIVE: The number of computer-based cognitive tests has increased in recent years, but there is a need for tests focusing on the assessment of executive function (EF), as it can be crucial for the identification of early-onset neurodegenerative disorders. This study aims to examine the ability of the Flexible Attention Test (FAT), a new computer-based test battery for detecting executive dysfunction of early-onset cognitive impairment and dementia patients. METHOD: We analyzed the FAT subtask results in memory clinic patients with cognitive symptom onset at ≤65 years. The patients were divided into four groups: early onset dementia (EOD, n = 48), mild cognitive impairment due to neurological causes (MCI-n, n = 34), MCI due to other causes (MCI-o, n = 99), and subjective cognitive decline (SCD, n = 14). The test accuracy to distinguish EOD patients from other groups was examined, as well as correlations with pen-and-paper EF tests. We also reported the 12-months follow-up results. RESULTS: The EOD and MCI-n patients performed significantly poorer (p ≤ .002) than those in the MCI-o and SCD groups in most of the FAT subtasks. The accuracies of the FAT subtasks to detect EOD from other causes were mainly moderate (0.34 ≤ area under the curve < 0.74). The FAT subtasks correlated logically with corresponding pen-and-paper EF tests (.15 ≤ r ≤ .75). No systematic learning effects were detected in the FAT performance at follow-up. CONCLUSIONS: The FAT appears to be a promising method for the precise evaluation of EF and applicable distinguishing early-onset neurodegenerative disorders from patients with other causes of cognitive problems.

The relative brain signal variability increases in the behavioral variant of frontotemporal dementia and Alzheimer's disease but not in schizophrenia.

Overlapping symptoms between Alzheimer's disease (AD), behavioral variant of frontotemporal dementia (bvFTD), and schizophrenia (SZ) can lead to misdiagnosis and delays in appropriate treatment, especially in cases of early-onset dementia. To determine the potential of brain signal variability as a diagnostic tool, we assessed the coefficient of variation of the BOLD signal (CVBOLD) in 234 participants spanning bvFTD (n = 53), AD (n = 17), SZ (n = 23), and controls (n = 141). All underwent functional and structural MRI scans. Data unveiled a notable increase in CVBOLD in bvFTD patients across both datasets (local and international, p < 0.05), revealing an association with clinical scores (CDR and MMSE, r = 0.46 and r = -0.48, p < 0.0001). While SZ and control group demonstrated no significant differences, a comparative analysis between AD and bvFTD patients spotlighted elevated CVBOLD in the frontopolar cortices for the latter (p < 0.05). Furthermore, CVBOLD not only presented excellent diagnostic accuracy for bvFTD (AUC 0.78-0.95) but also showcased longitudinal repeatability. During a one-year follow-up, the CVBOLD levels increased by an average of 35% in the bvFTD group, compared to a 2% increase in the control group (p < 0.05). Our findings suggest that CVBOLD holds promise as a biomarker for bvFTD, offering potential for monitoring disease progression and differentiating bvFTD from AD and SZ.

Neuropsychological Profiles, Etiologies, and Medical Comorbidities in Early-Onset Dementia and Cognitive Impairment: A Memory Outpatient Clinic Cohort Study.

Background: Although early-onset dementia (EOD) is associated with diagnostic challenges that differ from those of related to late-onset dementia, only limited studies have addressed the neuropsychological and health characteristics or specified the diagnoses underlying early-onset cognitive impairment in a real-world clinical setting. Objective: To investigate the neuropsychological profiles, etiologies, and comorbidities of an unselected cohort of memory clinic patients (≤65 years at symptom onset). Methods: The patients' (n = 210) diagnoses were determined based on comprehensive diagnostic workup. Medical comorbidities and neuropsychological profiles were compared between clinically relevant patient groups, namely early-onset dementia (n = 55), mild cognitive impairment due to vascular or suspected neurodegenerative (MCI-n, n = 35) or non-neurodegenerative (MCI-o, n = 106) etiologies, and subjective cognitive decline (n = 14). Results: The most prevalent diagnoses were Alzheimer's disease (AD, 14%) and depression (11%). Multiple prior medical conditions were common (67%); however, EOD patients had fewer other diagnoses (p = 0.008) than MCI-o patients. Compared to other groups, EOD patients had more severe deficits (p < 0.001) on immediate and delayed memory, processing speed, symptom awareness, and global cognition. AD patients had weaker memory retention ability but less behavioral symptoms than frontotemporal dementia (FTD) patients (p≤0.05). Depression was associated with better immediate memory, symptom awareness, and global cognition than AD and FTD (p < 0.05). Conclusions: EOD is associated with more severe and widespread neuropsychological deficits but fewer prior medical diagnoses than nondegenerative etiologies of cognitive impairment. AD and depression are common etiologies and the neuropsychological profiles are partly overlapping; however, memory, symptom awareness and global cognitive impairment measures may help in the differential diagnosis.

A New Concept of Sustainable Wind Turbine Blades: Bio-Inspired Design with Engineered Adhesives.

In this paper, a new concept of extra-durable and sustainable wind turbine blades is presented. The two critical materials science challenges of the development of wind energy now are the necessity to prevent the degradation of wind turbine blades for several decades, and, on the other side, to provide a solution for the recyclability and sustainability of blades. In preliminary studies by DTU Wind, it was demonstrated that practically all typical wind turbine blade degradation mechanisms (e.g., coating detachment, buckling, spar cap/shell adhesive joint degradation, trailing edge failure, etc.) have their roots in interface degradation. The concept presented in this work includes the development of bio-inspired dual-mechanism-based interface adhesives (combining mechanical interlocking of fibers and chemical adhesion), which ensures, on the one side, extra-strong attachment during the operation time, and on the other side, possible adhesive joint separation for re-use of the blade parts. The general approach and physical mechanisms of adhesive strengthening and separation are described.

Psychopharmacological Medication Use in Frontotemporal Dementia at the Time of Diagnosis: Comparison with Alzheimer's Disease.

BACKGROUND: Due to the significant presence of neuropsychiatric symptoms in patients with frontotemporal dementia (FTD) spectrum disorders, psychiatric misdiagnoses, diagnostic delay, and use of psychiatric treatments are common prior to the FTD diagnosis. Furthermore, treatment of diagnosed FTD patients mainly relies on off-label psychopharmacological approaches. Currently, limited real-world data are available regarding the actual use of psychopharmacological medications in FTD. OBJECTIVE: To evaluate psychopharmacological medication use at the time of FTD diagnosis. METHODS: Psychopharmacological medication use was evaluated in a Finnish FTD cohort containing 222 FTD patients, including the major clinical disease phenotypes (behavioral, language, and motor variants) and genetic patients carrying the C9orf72 repeat expansion. A cohort of 214 Alzheimer's disease (AD) patients was used as a neurodegenerative disease reference group. RESULTS: Active use of psychopharmacological medications at the time of diagnosis was significantly more common in FTD compared to AD, especially in the case of antidepressants (26.1% versus 15.0%, OR = 2.01, p = 0.008), antipsychotics (23.9% versus 9.3%, OR = 3.15, p < 0.001), and mood-stabilizers (6.3% versus 1.9%, OR = 2.93, p = 0.085; not statistically significant), whereas the use of cholinesterase inhibitors or memantine was nearly nonexistent in FTD patients. Female gender and behavioral variant of FTD phenotype alongside with depressive and psychotic symptoms were the most prominent factors associating with the use of these medications among the FTD spectrum patients. CONCLUSION: Use of off-label psychopharmacological medication and polypharmacy is substantially common at the time of FTD diagnosis. This likely reflects the challenges in using symptom-driven treatment approaches, especially prior to the eventual diagnosis.

Traumatic Brain Injury Associates with an Earlier Onset in Sporadic Frontotemporal Dementia.

BACKGROUND: Currently, there are few studies considering possible modifiable risk factors of frontotemporal dementia (FTD). OBJECTIVE: In this retrospective case-control study, we evaluated whether a history of traumatic brain injury (TBI) associates with a diagnosis of FTD or modulates the clinical phenotype or onset age in FTD patients. METHODS: We compared the prevalence of prior TBI between individuals with FTD (N = 218) and age and sex-matched AD patients (N = 214) or healthy controls (HC; N = 100). Based on the patient records, an individual was categorized to the TBI+ group if they were reported to have suffered from TBI during lifetime. The possible associations of TBI with age of onset and disease duration were also evaluated in the whole FTD patient group or separately in the sporadic and genetic FTD groups. RESULTS: The prevalence of previous TBI was the highest in the FTD group (19.3%) when compared to the AD group (13.1%, p = 0.050) or HC group (12%, p = 0.108, not significant). Preceding TBI was more often associated with the sporadic FTD cases than the C9orf72 repeat expansion-carrying FTD cases (p = 0.003). Furthermore, comparison of the TBI+ and TBI- FTD groups indicated that previous TBI was associated with an earlier onset age in the FTD patients (B = 3.066, p = 0.010). CONCLUSION: A preceding TBI associates especially with sporadic FTD and with earlier onset of symptoms. The results of this study suggest that TBI may be a triggering factor for the neurodegenerative processes in FTD. However, understanding the precise underlying mechanisms still needs further studies.

Fatigue and health-related quality of life depend on the disability status and clinical course in RRMS.

BACKGROUND: Fatigue is a prominent and disabling symptom of multiple sclerosis (MS), impairing quality of life. The disease course of relapsing remitting MS (RRMS) is individual. OBJECTIVES: We aimed to study the effects of demographic and clinical characteristics, as well as lifestyle risk factors on experienced fatigue and health-related quality of life (HRQoL) among RRMS patients, comparing benign and severe disease types. METHODS: Altogether 198 Finnish RRMS patients were recruited for this real-life cross-sectional study. Self-reported questionnaires were used to evaluate fatigue and HRQoL by using Fatigue Scale for Motor and Cognitive Functions and 15D health-related quality of life questionnaires. Patients were categorized into subgroups based on the current disability status measured by the Expanded Disability Status Scale (EDSS) cut-off value of 4.5, and by retrospective clinical course divided into benign and aggressive RRMS. RESULTS: All in all, 73% of the RRMS patients suffered from fatigue. Lower HRQoL had a strong correlation with more prominent fatigue (r = -0.719). Higher EDSS was associated with more prominent fatigue and lower HRQoL in the whole RRMS cohort. Older age at the disease onset was associated with more prominent fatigue and decreased HRQoL in the groups of aggressive RRMS and EDSS > 4.5. In the groups of EDSS ≤ 4.5 and benign RRMS, a higher number of used disease-modifying treatments (DMTs) was associated with more pronounced fatigue and reduced HRQoL. In addition, higher BMI was associated with lower HRQoL in patients with benign RRMS. Side effects (45 %) and lack of efficacy (26 %) were the most common reasons for discontinuing a DMT. Cessation due to side effects was the only reason that was significantly associated with more prominent fatigue and lower HRQoL. Use of nicotine products, gender, or disease duration were not associated with fatigue or HRQoL. CONCLUSIONS: Individuals with severe RRMS and higher EDSS scores are more prone to experience fatigue and lower HRQoL. In addition, fatigue and lower HRQoL are more commonly observed among RRMS patients with older age at disease onset and in those with multiple DMT switches.

The Cognitive Function at Work Questionnaire in memory clinic setting: a validation study.

INTRODUCTION: As there is a trend toward more people seeking medical help due to cognitive symptoms, validated and targeted questionnaires are increasingly important in the clinical evaluation process. The Cognitive Function at Work Questionnaire (CFWQ) was developed to identify and rate subjective cognitive symptoms of individuals active in working life. However, its psychometric characteristics have not been previously studied in a memory clinic setting. METHOD: The factorial structure, internal consistency, test-retest reliability, and convergent validity of the CFWQ were studied in a memory clinic setting (N = 113). We also investigated the instrument's ability to identify cognitive symptoms in a cohort of early-onset dementia (EOD, N = 22), mild cognitive impairment-neurological (MCI-n, N = 18), MCI due to mood, sleep, or other physical health problems (MCI-o, N = 59), and subjective cognitive decline (SCD, N = 14) patients. RESULTS: Based on factor analysis, eight cognitive subscales were identified covering main cognitive domains: Memory, Language, Executive Function, Speed of Processing, Cognitive Control, Name Memory, Visuospatial/Praxis and Attention. The internal consistency (α = .93) and the test-retest reliability (ICC = .91) were high. Several correlations (r = .19 - .33, p < .05) were documented between neuropsychological impairment level and CFWQ scores. EOD, MCI-n, MCI-o, and SCD groups did not differ statistically significantly in the levels of cognitive symptoms as measured by the CFWQ Total score. EOD group scored higher (p = .009) than other patient groups on the Visuospatial/Praxis subscale, but the difference between EOD and MCI-o groups turned insignificant after correcting for multiple testing. CONCLUSIONS: The results of the study support the validity and reliability characteristics of the CFWQ in a memory clinic setting. The instrument is easy-to-use and has clinical utility in capturing the subjective cognitive symptoms of patients active in working life and who need a referral to a more detailed evaluation.

Serum Cathepsin S Levels Do Not Show Alterations in Different Clinical, Neuropathological, or Genetic Subtypes of Frontotemporal Dementia Patients nor in Comparison to Healthy Control Individuals.

Frontotemporal dementia (FTD) can manifest as diverse clinical phenotypes and is frequently caused by mutations in different genes, complicating differential diagnosis. This underlines the urgent need for valid biomarkers. Altered lysosomal and immune functions proposedly contribute to FTD pathogenesis. Cathepsins, including cathepsin S, are enzymes preferentially expressed in brain in microglia, which influence lysosomal and immune function. Here, we examined whether alterations in serum cathepsin S levels associate with specific clinical, genetic, or neuropathological FTD subgroups, but no such alterations were observed. However, further research on other lysosomal proteins may reveal new biologically relevant biomarkers in FTD.

Incidence of Syndromes Associated With Frontotemporal Lobar Degeneration in 9 European Countries.

Importance: Diagnostic incidence data for syndromes associated with frontotemporal lobar degeneration (FTLD) in multinational studies are urgent in light of upcoming therapeutic approaches. Objective: To assess the incidence of FTLD across Europe. Design, Setting, and Participants: The Frontotemporal Dementia Incidence European Research Study (FRONTIERS) was a retrospective cohort study conducted from June 1, 2018, to May 31, 2019, using a population-based registry from 13 tertiary FTLD research clinics from the UK, the Netherlands, Finland, Sweden, Spain, Bulgaria, Serbia, Germany, and Italy and including all new FTLD-associated cases during the study period, with a combined catchment population of 11 023 643 person-years. Included patients fulfilled criteria for the behavioral variant of frontotemporal dementia (BVFTD), the nonfluent variant or semantic variant of primary progressive aphasia (PPA), unspecified PPA, progressive supranuclear palsy, corticobasal syndrome, or frontotemporal dementia with amyotrophic lateral sclerosis (FTD-ALS). Data were analyzed from July 19 to December 7, 2021. Main Outcomes and Measures: Random-intercept Poisson models were used to obtain estimates of the European FTLD incidence rate accounting for geographic heterogeneity. Results: Based on 267 identified cases (mean [SD] patient age, 66.70 [9.02] years; 156 males [58.43%]), the estimated annual incidence rate for FTLD in Europe was 2.36 cases per 100 000 person-years (95% CI, 1.59-3.51 cases per 100 000 person-years). There was a progressive increase in FTLD incidence across age, reaching its peak at the age of 71 years, with 13.09 cases per 100 000 person-years (95% CI, 8.46-18.93 cases per 100 000 person-years) among men and 7.88 cases per 100 000 person-years (95% CI, 5.39-11.60 cases per 100 000 person-years) among women. Overall, the incidence was higher among men (2.84 cases per 100 000 person-years; 95% CI, 1.88-4.27 cases per 100 000 person-years) than among women (1.91 cases per 100 000 person-years; 95% CI, 1.26-2.91 cases per 100 000 person-years). BVFTD was the most common phenotype (107 cases [40.07%]), followed by PPA (76 [28.46%]) and extrapyramidal phenotypes (69 [25.84%]). FTD-ALS was the rarest phenotype (15 cases [5.62%]). A total of 95 patients with FTLD (35.58%) had a family history of dementia. The estimated number of new FTLD cases per year in Europe was 12 057. Conclusions and Relevance: The findings suggest that FTLD-associated syndromes are more common than previously recognized, and diagnosis should be considered at any age. Improved knowledge of FTLD incidence may contribute to appropriate health and social care planning and in the design of future clinical trials.

A randomised, double blind, placebo controlled trial with vitamin D3 as an add on treatment to interferon ß-1b in patients with multiple sclerosis.

OBJECTIVES: To study the safety and efficacy of vitamin D3 as an add on therapy to interferon ß-1b (IFNB) in patients with multiple sclerosis (MS). METHODS: 1 year, double blind, placebo controlled, randomised study in 66 MS patients. The primary outcomes were T2 burden of disease (BOD) on MRI scans, proportion of patients with serum levels of 25-hydroxyvitamin D (25(OH)D) ≥85 nmol/l or intact parathyroid hormone (PTH) ≤20 ng/l, and number of adverse events. Secondary outcomes were number of MRI enhancing T1 lesions and new T2 lesions, annual relapse rate, changes in the Expanded Disability Status Scale score, timed 25 foot walk test and timed 10 foot tandem walk tests. RESULTS: Median change in BOD was 287 mm(3) in the placebo group and 83 mm(3) in the vitamin D group (p=0.105). Serum levels of 25(OH)D increased from a mean of 54 (range 19-82) nmol/l to 110 (range 67-163) nmol/l in the vitamin D group. 84% of patients reached a serum 25(OH)D level >85 nmol/l in the vitamin D group and 3% in the placebo group (p<0.0001). Patients in the vitamin D group showed fewer new T2 lesions (p=0.286) and a significantly lower number of T1 enhancing lesions (p=0.004), as well as a tendency to reduced disability accumulation (p=0.071) and to improved timed tandem walk (p=0.076). There were no significant differences in adverse events or in the annual relapse rate. CONCLUSION: Vitamin D3 add on treatment to IFNB reduces MRI disease activity in MS. TRIAL REGISTRATION NUMBER: EudraCT number 2007-001958-99 and ClinicalTrialsGov number NCT01339676.

Molecular genetic analysis of the APP, PSEN1, and PSEN2 genes in Finnish patients with early-onset Alzheimer disease and frontotemporal lobar degeneration.

Mutations in 3 genes, amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2), have been identified as causing a proportion of early-onset Alzheimer disease (eoAD) cases. A few PSEN mutations have also been previously detected in patients with frontotemporal lobar degeneration (FTLD). In order to evaluate the role of these genes in a clinical series of Finnish eoAD and FTLD patients, we sequenced exons 16 and 17 of the APP gene and the coding regions of the PSEN1 and PSEN2 genes in 140 eoAD and 66 FTLD patients. No pathogenic mutations were identified in the cohort. The E318G variant was detected with similar frequencies in the cases with eoAD and FTLD and the healthy controls, therefore, showing no association between E318G and eoAD. Furthermore, the PSEN2 R71W variant seems to be nonpathogenic, because it was present in our healthy controls. Mutations in the PSEN1, PSEN2, and APP genes seem to be rare in this population, as these genes exhibited no pathogenic mutations in our cohort of eoAD and FTLD patients even though about 40% of the cases were familial ones. This suggests the involvement of other, still unknown genetic factors in the pathogenesis of these diseases.

NDUFA1 p.Gly32Arg variant in early-onset dementia.

Early-onset dementia (EOD) is highly heritable. However, in many EOD cases the genetic etiology remains unknown. Mitochondrial dysfunction is associated with neurodegeneration and the complex I (CI) deficiency is the most common enzyme deficiency in diseases related to oxidative phosphorylation. The X-chromosomal NDUFA1 gene is essential for the activity of CI. Mutations in NDUFA1 are associated with mitochondrial diseases especially with Leigh syndrome. CI deficiency is also associated with neurodegenerative diseases, such as Alzheimer's disease (AD). The aim of this study was to evaluate the role of NDUFA1 variants in EOD patients. Next-generation sequencing panel was used to screen NDUFA1 variants in a cohort of 37 EOD patients with a family history of dementia or an atypical or rapidly progressive course of disease. We identified a hemizygous p.Gly32Arg variant in two brothers with AD. Subsequent screening of the variant in a larger cohort of EOD patients (n = 279) revealed three additional variant carriers (one male and two heterozygote females), suggesting that NDUFA1 variant p.Gly32Arg may play a role in neurodegenerative dementia.