ObjectiveTo examine the differential diagnostic significance of cerebrospinal fluid (CSF) biomarkers reflecting Alzheimer’s disease-related amyloid β (Aβ) production and aggregation, cortical ...neuronal damage, tau pathology, damage to long myelinated axons and astrocyte activation, which hypothetically separates patients with idiopathic normal pressure hydrocephalus (iNPH) from patients with other neurodegenerative disorders.MethodsThe study included lumbar CSF samples from 82 patients with iNPH, 75 with vascular dementia, 70 with Parkinson’s disease, 34 with multiple system atrophy, 34 with progressive supranuclear palsy, 15 with corticobasal degeneration, 50 with Alzheimer’s disease, 19 with frontotemporal lobar degeneration and 54 healthy individuals (HIs). We analysed soluble amyloid precursor protein alpha (sAPPα) and beta (sAPPβ), Aβ species (Aβ38, Aβ40 and Aβ42), total tau (T-tau), phosphorylated tau, neurofilament light and monocyte chemoattractant protein 1 (MCP-1).ResultsPatients with iNPH had lower concentrations of tau and APP-derived proteins in combination with elevated MCP-1 compared with HI and the non-iNPH disorders. T-tau, Aβ40 and MCP-1 together yielded an area under the curve of 0.86, differentiating iNPH from the other disorders. A prediction algorithm consisting of T-tau, Aβ40 and MCP-1 was designed as a diagnostic tool using CSF biomarkers.ConclusionsThe combination of the CSF biomarkers T-tau, Aβ40 and MCP-1 separates iNPH from cognitive and movement disorders with good diagnostic sensitivity and specificity. This may have important implications for diagnosis and clinical research on disease mechanisms for iNPH.
Chronic low back pain (CLBP) is a leading cause of disability globally. Exercise therapies are one of the commonly prescribed treatment options for CLBP. The specific exercise therapies for CLBP most ...commonly target movement dysfunction, but seldom brain-based pain modulation. Exercise therapies with specific breathing techniques (SBTs) have been shown to influence and enhance brain-based structural and functional pain modulation.
To assess the feasibility of the SBTs protocol, eligibility criteria, randomization, and dropout rates. To quantify the changes in patient outcome measures and choose the most relevant measure for larger-scale study. To quantify self-adherence levels to home exercise and monitor and record possible pain medication and other treatment modality usage, and adverse events during exercise.
A parallel randomised analyst-blinded feasibility trial with two-month follow-up.
Feasibility related to aims and objectives. Multiple pain- and health-related patient-reported outcome measures of pain intensity, disability, central sensitization, anxiety, kinesiophobia, catastrophising, self-efficacy, sleep quality, quality of life, and health and well-being status. Exercise adherence, pain medication and other treatment modality usage, and possible adverse events related to exercises will be monitored and recorded.
Thirty participants will be randomized to movement control exercise with SBTs (15 subjects in experimental group) or movement control exercise without SBTs (15 subjects in control group) in private chiropractic practice setting with two-month follow-up. Trial registration number; NCT05268822.
The clinical difference in effectiveness between practically identical exercise programs in uniform study settings with or without SBTs has not been studied before. This study aims to inform feasibility and help determine whether progression to a full-scale trial is worthwhile.
Idiopathic normal pressure hydrocephalus (iNPH) is characterized clinically by degradation of gait, cognition, and urinary continence. INPH is progressive (Andrén et al, 2014), still probably ...underdiagnosed (Williams et al, 2019) but potentially treatable by CSF diversion (Kazui et al, 2015). Familial aggregation is a strong indicator of genetic regulation in the disease process iNPH (Fig 1). Enlargement of brain ventricles is associated with failed cerebrospinal (CSF) homeostasis by so far mostly unknown mechanisms. A mutation of the cilia gene CFAP43 in iNPH family, confirmed by a knocked‐out mouse model (Morimoto et al, 2019), allelic variation of NME8 (Huovinen et al, 2017), a segmental copy number loss in SFMBT1 in selected iNPH patients (Sato et al, 2016), and current results by Yang et al (2021) indicate that cilia dysfunction is one of the key mechanisms behind iNPH.
T. Kuulasmaa, M. Hiltunen and V. Leinonen discuss novel genetic and functional findings related to two loss of function deletions in CWH43 gene in patients with Idiopathic normal pressure hydrocephalus by M. Johnson and colleagues, in this issue of EMBO Mol Med.
Alzheimer's disease (AD) is the most common neurodegenerative disorder, which is clinically associated with a global cognitive decline and progressive loss of memory and reasoning. According to the ...prevailing amyloid cascade hypothesis of AD, increased soluble amyloid-β (Aβ) oligomer levels impair the synaptic functions and augment calcium dyshomeostasis, neuroinflammation, oxidative stress as well as the formation of neurofibrillary tangles at specific brain regions. Emerging new findings related to synaptic dysfunction and initial steps of neuroinflammation in AD have been able to delineate the underlying molecular mechanisms, thus reinforcing the development of new treatment strategies and biomarkers for AD beyond the conventional Aβ- and tau-targeted approaches. Particularly, the identification and further characterization of disease-associated microglia and their RNA signatures, AD-associated novel risk genes, neurotoxic astrocytes, and in the involvement of complement-dependent pathway in synaptic pruning and loss in AD have set the outstanding basis for further preclinical and clinical studies. Here, we discuss the recent development and the key findings related to the novel molecular mechanisms and targets underlying the synaptotoxicity and neuroinflammation in AD.
The amyloid β-peptide (Aβ) has been suggested to exert its toxicity intracellularly. Mitochondrial functions can be negatively affected by Aβ and accumulation of Aβ has been detected in mitochondria. ...Because Aβ is not likely to be produced locally in mitochondria, we decided to investigate the mechanisms for mitochondrial Aβ uptake. Our results from rat mitochondria show that Aβ is transported into mitochondria via the translocase of the outer membrane (TOM) machinery. The import was insensitive to valinomycin, indicating that it is independent of the mitochondrial membrane potential. Subfractionation studies following the import experiments revealed Aβ association with the inner membrane fraction, and immunoelectron microscopy after import showed localization of Aβ to mitochondrial cristae. A similar distribution pattern of Aβ in mitochondria was shown by immunoelectron microscopy in human cortical brain biopsies obtained from living subjects with normal pressure hydrocephalus. Thus, we present a unique import mechanism for Aβ in mitochondria and demonstrate both in vitro and in vivo that Aβ is located to the mitochondrial cristae. Importantly, we also show that extracellulary applied Aβ can be internalized by human neuroblastoma cells and can colocalize with mitochondrial markers. Together, these results provide further insight into the mitochondrial uptake of Aβ, a peptide considered to be of major significance in Alzheimer's disease.
Noninvasive, affordable circulating biomarkers for difficult-to-diagnose mild traumatic brain injury (mTBI) are an unmet medical need. Although blood microRNA (miRNA) levels are reportedly altered ...after traumatic brain injury (TBI), their diagnostic potential for mTBI remains inconclusive. We hypothesized that acutely altered plasma miRNAs could serve as diagnostic biomarkers both in the lateral fluid percussion injury (FPI) model and clinical mTBI. We performed plasma small RNA-sequencing from adult male Sprague-Dawley rats (
= 31) at 2 days post-TBI, followed by polymerase chain reaction (PCR)-based validation of selected candidates. miR-9a-3p, miR-136-3p, and miR-434-3p were identified as the most promising candidates at 2 days after lateral FPI. Digital droplet PCR (ddPCR) revealed 4.2-, 2.8-, and 4.6-fold elevations in miR-9a-3p, miR-136-3p, and miR-434-3p levels (
< 0.01 for all), respectively, distinguishing rats with mTBI from naïve rats with 100% sensitivity and specificity. DdPCR further identified a subpopulation of mTBI patients with plasma miR-9-3p (
= 7/15) and miR-136-3p (
= 5/15) levels higher than one standard deviation above the control mean at <2 days postinjury. In sTBI patients, plasma miR-9-3p levels were 6.5- and 9.2-fold in comparison to the mTBI and control groups, respectively. Thus, plasma miR-9-3p and miR-136-3p were identified as promising biomarker candidates for mTBI requiring further evaluation in a larger patient population.
Central Sensitization (CS) involves dysfunction in neurophysiological mechanisms that increase neuronal responses to both noxious and non-noxious stimuli in the central nervous system. The Central ...Sensitization Inventory (CSI) is considered the leading patient-reported outcome measure for assessing CS-related symptoms. The aim of this study was to translate and cross-culturally adapt the CSI into Finnish (CSI-FI) and to evaluate its psychometric properties.
Translation and cross-cultural validation of the CSI was conducted according to established guidelines. The validation sample was 229 subjects, including 42 pain free controls and 187 subjects with chronic musculoskeletal pain. The CSI-FI was evaluated for internal consistency, test-retest reliability, exploratory factor analysis with maximum likelihood extraction, relationship with subject-reported outcome measures Tampa scale of kinesiophobia (TSK), the Depression scale (DEPS), 5-level EQ-5D version (EQ-5 L-5D), Roland-Morris Disability Questionnaire (RMDQ), and Pain and Sleep Questionnaire Three-Item Index (PSQ-3), pain history, subjective symptoms of dizziness, and CS-related diagnoses on CSI part B. Furthermore, we studied the ability of the CSI-FI to distinguish pain free controls, subjects with chronic pain in a single body area, and subjects with multisite chronic pain. In addition, we studied the relationship of CSI-FI scores with postural control on a force plate.
The CSI-FI demonstrated good internal consistency (0.884) and excellent test-retest reliability (0.933) with a 7 ± 1 day gap between test administrations. Exploratory factor analysis with maximum likelihood extraction yielded a one factor solution. Fair to good correlations were found between the CSI-FI and the TSK, DEPS, EQ-5 L-5D, RMDQ, and PSQ-3. Subjective symptoms of dizziness correlated better with CSI-FI scores than any of the CS-related diagnoses on CSI part B. Total CSI-FI scores successfully distinguished between pain free controls, subjects with chronic pain in a single body area, and subjects with multisite chronic pain. The multisite pain group reported significantly more dizziness symptoms than the other two groups. Force plate measurements showed no relationship between postural control and CSI-FI scores.
The CSI-FI translation was successfully cross-culturally adapted and validated into Finnish. CSI-FI psychometric properties and scores were all in acceptable levels and in line with previous CSI validations. The CSI-FI appears to be a valid and reliable instrument for assessing CS-related symptomology in Finnish-speaking populations.
No single-omic approach completely elucidates the multitude of alterations taking place in Alzheimer's disease (AD). Here, we coupled transcriptomic and phosphoproteomic approaches to determine the ...temporal sequence of changes in mRNA, protein, and phosphopeptide expression levels from human temporal cortical samples, with varying degree of AD-related pathology. This approach highlighted fluctuation in synaptic and mitochondrial function as the earliest pathological events in brain samples with AD-related pathology. Subsequently, increased expression of inflammation and extracellular matrix-associated gene products was observed. Interaction network assembly for the associated gene products, emphasized the complex interplay between these processes and the role of addressing post-translational modifications in the identification of key regulators. Additionally, we evaluate the use of decision trees and random forests in identifying potential biomarkers differentiating individuals with different degree of AD-related pathology. This multiomic and temporal sequence-based approach provides a better understanding of the sequence of events leading to AD.
•Multiomic assessment of human brain with varying degree of AD-related pathology.•Expression profiles associated with specific cell types and AD-related pathology.•Phosphopeptide analysis to determine the AD-related kinome.•Identification of key gene product expression changes differentiating Braak stages.
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. Fibroblasts from C9-HRE carriers were found to produce RNA foci, but no dipeptide repeat proteins, and they showed unchanged levels of
C9orf72
mRNA transcripts. The main protein degradation pathways, the ubiquitin–proteasome system and autophagy, did not show alterations between the fibroblasts from C9-HRE-carrying and non-carrying FTLD patients and compared to healthy controls. An increase in the number and size of p62-positive puncta was evident in fibroblasts from both C9-HRE carriers and non-carriers. In addition, several parameters of mitochondrial function, namely, basal and maximal respiration and respiration linked to ATP production, were significantly reduced in the FTLD patient–derived fibroblasts from both C9-HRE carriers and non-carriers. Our findings suggest that FTLD patient–derived fibroblasts, regardless of whether they carry the C9-HRE expansion, show unchanged proteasomal and autophagic function, but significantly impaired mitochondrial function and increased accumulation of p62 when compared to control fibroblasts. These findings suggest the possibility of utilizing FTLD patient–derived fibroblasts as a platform for biomarker discovery and testing of drugs targeted to specific cellular functions, such as mitochondrial respiration.
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