Molecular Mechanisms of Synaptotoxicity and Neuroinflammation in Alzheimer’s Disease

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

Sub-classification based specific movement control exercises are superior to general exercise in sub-acute low back pain when both are combined with manual therapy: A randomized controlled trial

Background: Clinical guidelines recommend research on sub-groups of patients with low back pain (LBP) but, to date, only few studies have been published. One sub-group of LBP is movement control impairment (MCI) and clinical tests to identify this sub-group have been developed. Also, exercises appear to be beneficial for the management of chronic LBP (CLBP), but very little is known about the management of sub-acute LBP. Methods: A randomized controlled trial (RCT) was conducted to compare the effects of general exercise versus specific movement control exercise (SMCE) on disability and function in patients with MCI within the recurrent sub-acute LBP group. Participants having a MCI attended five treatment sessions of either specific or general exercises. In both groups a short application of manual therapy was applied. The primary outcome was disability, assessed by the Roland-Morris Disability Questionnaire (RMDQ). The measurements were taken at baseline, immediately after the three months intervention and at twelve-month follow-up. Results: Seventy patients met the inclusion criteria and were eligible for the trial. Measurements of 61 patients (SMCE n = 30 and general exercise n = 31) were completed at twelve months. (Drop-out rate 12.9 %). Patients in both groups reported significantly less disability (RMDQ) at twelve months follow-up. However, the mean Change on the RMDQ between baseline and the twelve-month measurement showed statistically significantly superior improvement for the SMCE group -1.9 points (-3.9 to -0.5) 95 % (CI). The result did not reach the clinically significant three point difference. There was no statistical difference between the groups measured with Oswestry Disability Index (ODI). Conclusion: For subjects with non-specific recurrent sub-acute LBP and MCI an intervention consisting of SMCE and manual therapy combined may be superior to general exercise combined with manual therapy. Trial registration: The study protocol registration number is ISRCTN48684087. It was registered retrospectively 18th Jan 2012

Surgery for degenerative cervical spine disease in Finland, 1999-2015

Background The incidence of surgery for degenerative cervical spine disease (DCSD) has risen by almost 150% in the USA in the last three decades and stabilized at slightly over 70 operations/100,000 people. There has been significant regional variation in the operation incidences. We aim to assess the diagnosis-based, age-adjusted trends in the operation incidences and the regional variation in Finland between 1999 and 2015. Methods Data from the Finnish Hospital Discharge Register (FHDR), the Cause of Death Register, and the registers of the Social Insurance Institution were combined to analyze all the primary operations for DCSD or rheumatoid atlanto-axial subluxation (rAAS). Combinations of the operative and the diagnosis codes were used to classify the patients into five diagnostic groups. Results A total of 19,701 primary operations were included. The age-adjusted operation incidence rose from 21.0 to 36.5/100,000 people between 1999 and 2013 and plateaued thereafter. The incidence of surgery for radiculopathy increased from 13.1 to 23.3 operations/100,000 people, and the incidence of surgery for DCM increased from 5.8 to 7.0 operations/100,000 people. The rise was especially pronounced in surgery for foraminal stenosis, which increased from 5.3 to 12.4 operations/100,000 people. Of the five diagnostic groups, only operations for rAAS declined. Operations increased especially in the 40- to 65-year-old age group. The overall operation incidences varied from 18.3 to 43.1 operations/100,000 people between the university hospitals. Conclusions The age-adjusted incidence of surgery for DCSD has risen in Finland by 76%, but the rise has plateaued. Surgery for radiculopathy, especially for foraminal stenosis, increased more steeply than surgery for degenerative medullopathy, with vast regional differences in the operation incidences.Peer reviewe

Engine preheating under real-world subfreezing conditions provides less than expected benefits to vehicle fuel economy and emission reduction for light-duty vehicles

Six light-duty vehicles, both gasoline- and diesel-fueled, were driven a prescribed 13.8 km route in a real-world low-traffic environment under Finnish subfreezing winter conditions (−28. −10 °C). Cold starts, hot starts, and starts with different preheating strategies were used. Fuel consumption and emissions of particles and nitrogen oxides (NOx) were examined by a chasing method with a mobile laboratory. Both electric preheaters (0.3–1.2 kW) and fuel-operated auxiliary heaters (5 kW) were used in the experiments where a cold engine was preheated before starting. While most vehicles showed potential for reducing fuel consumption and emissions of particles (PM), black carbon (BC), and NOx during hot starts compared to subfreezing-cold starts, the benefits of preheating were relatively small and limited to only a few vehicles. The fuel consumption for the 13.8 km drive decreased less than 4% with one gasoline vehicle and one diesel vehicle by preheating. These two vehicles are both equipped with a fuel-operated auxiliary heater, and taking the fuel consumption of the heater during preheating into account leads to about 30% higher total fuel consumption, canceling the preheating benefit out. These two vehicles also showed the largest reductions in PM, BC, and NOx emissions achieved with preheating, e.g., the PM emission reductions being 72% (the gasoline vehicle) and 24% (the diesel vehicle). Whereas the NOx emission reduction for this gasoline vehicle was 41% when considering only the drive, it decreases to 15% when the NOx emissions from the auxiliary heater during preheating are also taken into account. High particle number (PN) emissions from all vehicles and NOx emissions from the diesel vehicles were detected. The PN emissions of particles larger than 23 nm were up to 2 orders of magnitude higher and the NOx emissions up to a factor of 21 higher than the corresponding limits in the European regulations for type-approval of new vehicles. The PN emissions did not depend on the start types; thus, no benefits to reduce them with preheating were detected. The limit-exceeding PN emissions are partially explained with the used measurement method for PN taking both nonvolatile and semivolatile particles into account, whereas the regulations take only the nonvolatile particles into account. The PM emissions were also observed to consist mostly of semivolatile material in most of the cases, organics being the main component of the semivolatile material.Peer reviewe

Kaularangan luisen juuriaukkoahtauman kirurginen hoito

Kaularangan kuluma on normaaliin ikääntymiseen liittyvä ilmiö. Kulumaan liittyvä juuriaukkoahtauma voi aiheuttaa puutumista ja pistelyä, säteilykipua ja voimaheikkoutta, jotka liittyvät hermojuuren puristumiseen ja reaktiivisiin muutoksiin. Kipu voi tuntua myös ainoastaan niskassa, hartioissa tai yläselässä. Oire on tavallisin 50-60-vuotiailla sekä miehillä. Diagnoosi pohjautuu magneettikuvaukseen ja kliinisiin tutkimuslöydöksiin, joissa esiintyy kuitenkin huomattavaa vaihtelua jopa lähes 50 \%:lla potilaista. Hermo-lihassähkötutkimuksella (ENMG) ei voida sulkea pois hermojuurikompressiota. Oireiden pitkittyessä tai ollessa hankalia kannattaa harkita kirurgista hoitoa. Leikkaushoidon tulokset ovat hyviä ja vaikeat komplikaatiot harvinaisia. Myös niskakipu helpottaa suurella osalla potilaista. Uusintaleikkausriski on kuitenkin merkittävä erityisesti niillä, joilla ahtaumaa on useammassa tasossa

Upper limb dysfunction and activities in daily living in idiopathic normal pressure hydrocephalus

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.Peer reviewe

Cerebrospinal Fluid Biomarkers in Idiopathic Normal Pressure Hydrocephalus

The diagnosis of idiopathic normal pressure hydrocephalus (iNPH) is still challenging. Alzheimer's disease (AD), along with vascular dementia, the most important differential diagnosis for iNPH, has several potential cerebrospinal fluid (CSF) biomarkers which might help in the selection of patients for shunt treatment. The aim of this study was to compare a battery of CSF biomarkers including well-known AD-related proteins with CSF from patients with suspected iNPH collected from the external lumbar drainage test (ELD). A total of 35 patients with suspected iNPH patients were evaluated with ELD. CSF was collected in the beginning of the test, and the concentrations of total tau, ptau181, Aβ42, NFL, TNF-α, TGFβ1, and VEGF were analysed by ELISA. Twenty-six patients had a positive ELD result—that is, their gait symptoms improved; 9 patients had negative ELD. The levels of all analyzed CSF biomarkers were similar between the groups and none of them predicted the ELD result in these patients. Contrary to expectations lumbar CSF TNF-α concentration was low in iNPH patients