Deficient neurotransmitter systems and synaptic function in frontotemporal lobar degeneration-Insights into disease mechanisms and current therapeutic approaches.

Frontotemporal lobar degeneration (FTLD) comprises a heterogenous group of fatal neurodegenerative diseases and, to date, no validated diagnostic or prognostic biomarkers or effective disease-modifying therapies exist for the different clinical or genetic subtypes of FTLD. Current treatment strategies rely on the off-label use of medications for symptomatic treatment. Changes in several neurotransmitter systems including the glutamatergic, GABAergic, dopaminergic, and serotonergic systems have been reported in FTLD spectrum disease patients.

The effect of adherence on cognition in a multidomain lifestyle intervention (FINGER).

Introduction: Lifestyle interventions may prevent cognitive decline, but the sufficient dose of intervention activities and lifestyle changes is unknown. We investigated how intervention adherence affects cognition in the FINGER trial (pre-specified subgroup analyses).

Methods: FINGER is a multicenter randomized controlled trial examining the efficacy of multidomain lifestyle intervention (ClinicalTrials.

The effects of a physical and cognitive training intervention vs. physical training alone on older adults' physical activity: A randomized controlled trial with extended follow-up during COVID-19.

Background: Executive functions underlie self-regulation and are thus important for physical activity and adaptation to new situations. The aim was to investigate, if yearlong physical and cognitive training (PTCT) had greater effects on physical activity among older adults than physical training (PT) alone, and if executive functions predicted physical activity at baseline, after six (6m) and twelve months (12m) of the interventions, one-year post-intervention follow-up and an extended follow-up during COVID-19 lockdown.

Methods: Data from a single-blinded, parallel-group randomized controlled trial (PASSWORD-study, ISRCTN52388040) were utilized.

Serum GFAP and NfL levels in benign relapsing-remitting multiple sclerosis.

Objective: We aimed to investigate serum glial fibrillary acidic protein (GFAP) and serum neurofilament light chain (NfL) levels as potential discriminative biomarkers between benign relapsing-remitting multiple sclerosis (BRRMS) and aggressive relapsing-remitting MS (ARRMS).

Methods: Serum GFAP and NfL levels were analyzed in patients with BRRMS (n = 34), ARRMS (n = 29), and healthy controls (n = 14) by using Single Molecule Array (Simoa). Patients with ARRMS had been treated with highly effective disease-modifying treatments (DMT) (fingolimod or natalizumab).

Cerebrospinal fluid dynamics in idiopathic intracranial hypertension: a literature review and validation of contemporary findings.

Background: Idiopathic intracranial hypertension (IIH) is a rare disease of unknown aetiology related possibly to disturbed cerebrospinal fluid (CSF) dynamics and characterised by elevated intracranial pressure (ICP) causing optic nerve atrophy if not timely treated. We studied CSF dynamics of the IIH patients based on the available literature and our well-defined cohort.

Method: A literature review was performed from PubMed between 1980 and 2020 in compliance with the PRISMA guideline.

Facilitators and barriers to implementing lifestyle intervention programme to prevent cognitive decline.

Background: The Finnish Intervention Study to Prevent Cognitive Impairment and Disability is a randomized controlled trial that has tested the efficacy of a multidomain intervention targeting modifiable risk factors to prevent cognitive impairment/dementia. A combination of healthy diet, physical, social and cognitive activity, and management of cardiovascular risks was shown to be an effective model to promote brain health among older people. The aim of this qualitative study was to explore healthcare professionals' perceptions of facilitators and barriers to implementing this lifestyle programme into health care.

A Novel Genetic Marker for the C9orf72 Repeat Expansion in the Finnish Population.

Background: C9orf72 repeat expansion (C9exp) is the most common genetic cause underlying frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). However, detection of the C9exp requires elaborative methods.

Objective: Identification of C9exp carriers from genotyped cohorts could be facilitated by using single nucleotide polymorphisms (SNPs) as markers for the C9exp.

A novel CT-based automated analysis method provides comparable results with MRI in measuring brain atrophy and white matter lesions.

Purpose: Automated analysis of neuroimaging data is commonly based on magnetic resonance imaging (MRI), but sometimes the availability is limited or a patient might have contradictions to MRI. Therefore, automated analyses of computed tomography (CT) images would be beneficial.

Methods: We developed an automated method to evaluate medial temporal lobe atrophy (MTA), global cortical atrophy (GCA), and the severity of white matter lesions (WMLs) from a CT scan and compared the results to those obtained from MRI in a cohort of 214 subjects gathered from Kuopio and Helsinki University Hospital registers from 2005 - 2016.

FTLD Patient-Derived Fibroblasts Show Defective Mitochondrial Function and Accumulation of p62.

Frontotemporal lobar degeneration (FTLD) is a clinically, genetically, and neuropathologically heterogeneous group of neurodegenerative syndromes, leading to progressive cognitive dysfunction and frontal and temporal atrophy. C9orf72 hexanucleotide repeat expansion (C9-HRE) is the most common genetic cause of FTLD, but pathogenic mechanisms underlying FTLD are not fully understood. Here, we compared cellular features and functional properties, especially related to protein degradation pathways and mitochondrial function, of FTLD patient-derived skin fibroblasts from C9-HRE carriers and non-carriers and healthy donors.

GFAP as a biomarker in frontotemporal dementia and primary psychiatric disorders: diagnostic and prognostic performance.

Background: Frontotemporal lobar degeneration (FTLD) and primary psychiatric disorders (PPD) are characterised by overlapping clinical features but different aetiologies. Here, we assessed for the first time the potential of blood glial fibrillar acidic protein (GFAP), marker of astrogliosis, as a discriminative and prognostic tool in FTLD and PPD.

Methods: The levels of GFAP in serum (sGFAP) of patients with FTLD (N=107) and PPD (N=44) and GFAP in whole blood samples (bGFAP) from FTLD (N=10), PPD (N=10) and healthy controls (N=18) were measured.

Effect of a Multidomain Lifestyle Intervention on Estimated Dementia Risk.

We investigated the effect of a multidomain lifestyle intervention on the risk of dementia estimated using the validated CAIDE risk score (post-hoc analysis). The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) is a 2-year randomized controlled trial among 1,260 at-risk older adults (60-77 years). Difference in the estimated mean change in CAIDE score at 2 years in the intervention compared to the control group was -0.

Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.

Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene).

Change in CAIDE Dementia Risk Score and Neuroimaging Biomarkers During a 2-Year Multidomain Lifestyle Randomized Controlled Trial: Results of a Post-Hoc Subgroup Analysis.

The CAIDE (Cardiovascular Risk Factors, Aging and Dementia) Risk Score is a validated tool estimating dementia risk. It was previously associated with imaging biomarkers. However, associations between dementia risk scores (including CAIDE) and dementia-related biomarkers have not been studied in the context of an intervention.

State-of-the-Art Methods and Emerging Fluid Biomarkers in the Diagnostics of Dementia-A Short Review and Diagnostic Algorithm.

The most common neurodegenerative dementias include Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD). The correct etiology-based diagnosis is pivotal for clinical management of these diseases as well as for the suitable timing and choosing the accurate disease-modifying therapies when these become available. Enzyme-linked immunosorbent assay (ELISA)-based methods, detecting altered levels of cerebrospinal fluid (CSF) Tau, phosphorylated Tau, and Aβ-42 in AD, allowed the wide use of this set of biomarkers in clinical practice.

Effects of physical and cognitive training on gait speed and cognition in older adults: A randomized controlled trial.

Gait speed is a measure of health and functioning. Physical and cognitive determinants of gait are amenable to interventions, but best practices remain unclear. We investigated the effects of a 12-month physical and cognitive training (PTCT) on gait speed, dual-task cost in gait speed, and executive functions (EFs) compared with physical training (PT) (ISRCTN52388040).

Time Trends of Cerebrospinal Fluid Biomarkers of Neurodegeneration in Idiopathic Normal Pressure Hydrocephalus.

Background: Longitudinal changes in cerebrospinal fluid (CSF) biomarkers are seldom studied. Furthermore, data on biomarker gradient between lumbar (L-) and ventricular (V-) compartments seems to be discordant.

Objective: To examine alteration of CSF biomarkers reflecting Alzheimer's disease (AD)-related amyloid-β (Aβ) aggregation, tau pathology, neurodegeneration, and early synaptic degeneration by CSF shunt surgery in idiopathic normal pressure hydrocephalus (iNPH) in relation to AD-related changes in brain biopsy.

27-Hydroxycholesterol, cognition, and brain imaging markers in the FINGER randomized controlled trial.

Background: 27-Hydroxycholesterol (27-OH), the main circulating oxysterol in humans and the potential missing link between peripheral hypercholesterolemia and Alzheimer's disease (AD), has not been investigated previously in relation to cognition and neuroimaging markers in the context of preventive interventions.

Methods: The 2-year Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) included older individuals (60-77 years) at increased risk for dementia but without dementia or substantial cognitive impairment from the general population. Participants were randomized to a multidomain intervention (diet, exercise, cognitive training, and vascular risk management) or control group (general health advice) in a 1:1 ratio.

Serum Neurofilament Light in Patients with Frontotemporal Dementia Caused by CHMP2B Mutation.

Introduction: The potential of neurofilament light (NfL) as a blood-based biomarker is currently being investigated in autosomal dominant neurodegenerative disease. This study explores the clinical utility of serum-NfL in frontotemporal dementia due to CHMP2B mutation (FTD-3).

Methods: This cross-sectional study included serum and CSF data from 38 members of the Danish FTD-3 family: 12 affected CHMP2B mutation carriers, 10 presymptomatic carriers, and 16 noncarriers.

The ethical implications of genetic testing in neurodegenerative diseases: A systematic review.

Background: Availability of genetic testing in neurodegenerative disorders has developed rapidly. This growing ability is providing specific genetic information to individuals and, in turn, their families, raising ethical concerns. However, family members' perspective is a seldom-studied phenomenon.

Presynaptic Vesicle Protein SEPTIN5 Regulates the Degradation of APP C-Terminal Fragments and the Levels of Aβ.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by aberrant amyloid-β (Aβ) and hyperphosphorylated tau aggregation. We have previously investigated the involvement of SEPTIN family members in AD-related cellular processes and discovered a role for SEPTIN8 in the sorting and accumulation of β-secretase. Here, we elucidated the potential role of SEPTIN5, an interaction partner of SEPTIN8, in the cellular processes relevant for AD, including amyloid precursor protein (APP) processing and the generation of Aβ.

BV-2 Microglial Cells Overexpressing Hexanucleotide Repeat Expansion Produce DPR Proteins and Show Normal Functionality but No RNA Foci.

Hexanucleotide repeat expansion (HRE) in the () gene is the most common genetic cause underpinning frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). It leads to the accumulation of toxic RNA foci and various dipeptide repeat (DPR) proteins into cells. These HRE-specific hallmarks are abundant in neurons.