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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.

Background Idiopathic Normal Pressure Hydrocephalus (iNPH) is a chronic condition affecting the elderly. It is characterized by a triad of symptoms and radiological findings. Glaucoma is the leading cause of irreversible blindness worldwide. Earlier studies have proposed that the rate of glaucoma is higher in iNPH patients, and of a possible link between ventriculoperitoneal shunt (VP) treatment and the development of glaucoma. Objectives This study aimed to determine the prevalence of glaucoma among iNPH patients and assess the impact of VPs on glaucoma prevalence. Methods A cohort study was conducted at Kuopio University Hospital (KUH), including 262 patients with a ventriculoperitoneal shunt. Clinical data were obtained from the Kuopio NPH Registry and medical records. Patients were grouped by iNPH status: iNPH (+) – probable/possible iNPH ( n  = 192), and iNPH (-) – other causes of hydrocephalus (congenital, secondary, obstructive) ( n  = 70). We conducted statistical analysis using the Independent Samples T-test, Fisher’s exact test, and Pearson Chi-Square. We compared demographics, glaucoma prevalence, brain biopsies positive for Amyloid-β (Aβ) and hyperphosphorylated tau (HPτ) as well as comorbidities for hypertension and diabetes medication. Age stratification assessed glaucoma prevalence in the full cohort. Results Both iNPH (+) and iNPH (-) groups had comparable demographic and comorbidity profiles. The prevalence of glaucoma in the iNPH (+) group was 11.5% ( n  = 22) and 11.4% ( n  = 8) in the iNPH (-) group without a statistically significant difference ( p  = 1.000). Brain biopsies positive for Amyloid-β (Aβ) and hyperphosphorylated tau (HPτ) were similar. Conclusions Neither shunted iNPH patients nor those with a comorbid condition other than iNPH showed a markedly higher prevalence of glaucoma. Instead, both groups exhibited age-related increases in glaucoma prevalence, similar to the trends observed in population-based studies. Our data does not suggest a correlation between VP shunts and an elevated rate of glaucoma.

Background Normal pressure hydrocephalus (NPH) is a memory and movement disorder covering up to 5% of all dementia. Familial aggregation in up to 20% of NPH is a strong indicator of notable genetic component in the pathobiological process. Number of genetic variants and disease associated loci have been identified in NPH. These findings seem to be independent from neurodegenerative diseases but are linked with blood brain borders, brain ventricle volume and CSF biomarker levels. The most important differential diagnosis and comorbidity is Alzheimer's disease (AD). Method Kuopio NPH cohort include over 1200 patients with possible or probable NPH, frontal cortical brain biopsy and life‐long follow‐up since 1993 till date. Biopsies have systematically immunohistochemically stained against amyloid β (Aβ) and tau. Currently, the fresh biopsy is shortly after extraction sliced also for immediate electrophysiology and frozen for transcriptomic analysis. Result Half of the patients have various degree of Aβ pathology, around 10% have both Aβ and tau pathology and up to 5% have tau pathology without Aβ. CSF biomarkers of AD (Aβ1‐42, p‐Tau181 and T‐Tau) are generally decreased in NPH but correlate well with brain biopsy AD‐related pathologies. Since Aβ pathology occur early in frontal cortex, the biopsy is sensitive for Aβ pathology and subsequent clinical AD. On the other hand, the biopsy is not so sensitive for tau since cortical tau occur later but when positive indicate already an advanced pathology (Braak stage V‐VI). Conclusion Amyloid plaques even in tiny frontal (or parietal) brain biopsy taken during shunt surgery can indicate high risk of comorbid clinical AD and together with tau, neuropathologically verified biological AD or rarely seen tau pathology alone, a primary tauopathy like frontotemporal dementia (FTD). Furthermore, obtainment of living human brain samples, are valuable for omics techniques and imaging at single cell level to uncover individual cell level disease mechanisms related with NPH and AD as well as other neurodegenerative diseases seen in NPH patients and hampering their prognosis.

Normal pressure hydrocephalus (NPH) is a memory and movement disorder covering up to 5% of all dementia. Familial aggregation in up to 20% of NPH is a strong indicator of notable genetic component in the pathobiological process. Number of genetic variants and disease associated loci have been identified in NPH. These findings seem to be independent from neurodegenerative diseases but are linked with blood brain borders, brain ventricle volume and CSF biomarker levels. The most important differential diagnosis and comorbidity is Alzheimer's disease (AD). Kuopio NPH cohort include over 1200 patients with possible or probable NPH, frontal cortical brain biopsy and life-long follow-up since 1993 till date. Biopsies have systematically immunohistochemically stained against amyloid β (Aβ) and tau. Currently, the fresh biopsy is shortly after extraction sliced also for immediate electrophysiology and frozen for transcriptomic analysis. Half of the patients have various degree of Aβ pathology, around 10% have both Aβ and tau pathology and up to 5% have tau pathology without Aβ. CSF biomarkers of AD (Aβ1-42, p-Tau181 and T-Tau) are generally decreased in NPH but correlate well with brain biopsy AD-related pathologies. Since Aβ pathology occur early in frontal cortex, the biopsy is sensitive for Aβ pathology and subsequent clinical AD. On the other hand, the biopsy is not so sensitive for tau since cortical tau occur later but when positive indicate already an advanced pathology (Braak stage V-VI). Amyloid plaques even in tiny frontal (or parietal) brain biopsy taken during shunt surgery can indicate high risk of comorbid clinical AD and together with tau, neuropathologically verified biological AD or rarely seen tau pathology alone, a primary tauopathy like frontotemporal dementia (FTD). Furthermore, obtainment of living human brain samples, are valuable for omics techniques and imaging at single cell level to uncover individual cell level disease mechanisms related with NPH and AD as well as other neurodegenerative diseases seen in NPH patients and hampering their prognosis.

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. Graphical Abstract 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.

Background Idiopathic normal pressure hydrocephalus (iNPH) is a neurodegenerative disease with a characteristic symptom triad of gait disturbance, cognitive decline, and incontinence. Recently, also dysfunctions in upper limbs have been described in iNPH and reported to improve after shunt surgery. We aim to describe the role of upper limb motor function in the clinical assessment of iNPH patients and its influence on activities of daily living (ADL). Methods Seventy-five consecutive patients with probable iNPH were studied pre-operatively and at 3 and 12 months after shunt surgery. The pre-operative evaluation included lumbar drainage of cerebrospinal fluid (tap test). Motor functions were assessed in upper and lower limbs with Grooved Pegboard Test (GPT), Box & Block Test (BBT), Total Score of Gait (TSG), and balance test. ADL was assessed with Barthel’s index and cognition in accordance with the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Results Patients showed improvement in all motor tests and ADL at 3 months after shunt surgery. The improvement remained stable during the 12-month post-operative follow-up. The motor function tests correlated with each other and with ADL. Conclusions A 3-month follow-up period after shunt surgery is adequate to show improvement in motor tasks, and a positive outcome will last for at least 12 months. A shunt-responsive dysfunction of upper limb motor performance plays a major role in ADL of iNPH patients. Therefore, we suggest an evaluation of upper limb motor performance to be included in routine evaluation of iNPH patients.

Background 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. Aims and objectives 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. Design A parallel randomised analyst-blinded feasibility trial with two-month follow-up. Outcome measures 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. Methods 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. Discussion 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.

Background There is a limited understanding of how older patients perceive the potential of using wearables for remote monitoring (RM) at home. Exploring patients' perspectives prior to the implementation of wearables in healthcare can offer valuable insights into what may enhance the effectiveness and outcomes of RM. Objectives The objective of this study was to explore the expectations of older patients with a susceptible chronic illness towards prospective use of the Oura Ring for health monitoring at home. Unlike previous research, which primarily addresses patients' experiences during or after RM has taken place, we explored their perspective before the use. Methods Healthcare professionals identified the 10 study participants among those who were undergoing a diagnostic procedure for the chronic neurological disease iNPH at the Kuopio University Hospital in Finland. All invited patients consented to participate. Qualitative interview data were analysed using reflexive thematic analysis by Braun and Clarke. Findings Patients expected Oura to support both health and broader well‐being through self‐tracking and proactive health management, presenting themselves as active contributors to their care. Being monitored by healthcare professionals or caregivers was viewed as reassuring, mirroring the increasing digitalisation of healthcare and a reduction in in‐person contact. Conclusion The findings highlight the relevance of approaching older patients with chronic conditions to gauge interest in home‐based RM. This emphasises involving the patient perspective early on in RM processes, including decisions about the specific solutions to be used. Patient or Public Contribution The second author is a trained patient expert by experience who ensured that the analysis and the findings were grounded in authentic patient perspectives. The findings were shared with the study participants in the form of an information leaflet, the quality of which was ensured by the expert by experience.