Deep Brain Stimulation in Non-motor Symptoms of Neurodegenerative Diseases

Deep brain stimulation (DBS) is a functional neuromodulatory technique that involves the use of a neurostimulator to deliver electrical impulses to the brain. It primarily alleviates the motor symptoms in neurodegenerative diseases; however, it has been found beneficial in a multitude of neurological and psychiatric diseases, such as dystonia, essential tremor, Tourette syndrome, intractable pain, epilepsy, treatment-resistant depression, and obsessive-compulsive disorder. Nonmotor symptoms, such as neurobehavioral disorders, autonomic dysfunction, sleep dysfunction, and somatosensory dysfunction, play an important role in neurodegenerative diseases and have a significant impact on the quality of life. The effects of deep brain stimulation on these symptoms are not yet apparent, although early results are promising and warrant future investigations. The main problem in interpretation is the lack of studies in this field, as most have methodological issues or small sample sizes, which limit the strength of the evidence. However, it is clear that DBS has a promising future in the treatment of neurodegenerative diseases in general and will have a vital role in personalized medicine as functional neuroimaging and our understanding of brain physiology improve

Reduced Sympathetic Response to Head-Up Tilt in Subjects with Mild Cognitive Impairment or Mild Alzheimer's Dementia

Background: Hemodynamic control was compared in patients with mild cognitive impairment (MCI) or mild Alzheimer's dementia (AD) as well as in healthy elderly subjects. Methods: Noninvasive, continuous hemodynamic recordings were obtained from 14 patients and 48 controls during supine rest (tilt of 30 and 70°). Cardiac output, end-diastolic volume, total peripheral resistance, heart rate variability (HRV), systolic blood pressure variability (SBPV), and baroreceptor sensitivity were calculated. Results: At 70° tilt, the HRV indices differed significantly, with higher high-frequency (HF) variability as well as lower low-frequency (LF) variability and LF/HF ratios in the patients. The patients had significantly lower SBPV in the LF range at 30° tilt. Conclusions: The results indicate a poorer sympathetic response to orthostatic stress in MCI and mild AD

Diagnostic accuracy and clinical applicability of the Swedish version of the 4AT assessment test for delirium detection, in a mixed patient population and setting

Background: Delirium is common in older hospitalized patients. It has serious consequences e.g., poor health outcomes, mortality and increased costs. Despite that, many cases are undetected. Early detection of delirium is important in improving outcomes and use of assessment tools improves detection rates. The 4AT is a brief screening tool for delirium detection, which has not previously been translated into Swedish. The study aim was to evaluate diagnostic accuracy and clinical applicability of a Swedish version of the screening tool 4AT for delirium detection. Method: This diagnostic test accuracy study used a quantitative and a qualitative approach and evaluated the patients’ and the health care professionals’ experiences of the tool. Study included 200 patients ≥65 years from a university hospital and a county hospital in two Swedish regions. Medical specialties were geriatric stroke/neurology, geriatric multimorbidity, severe cognitive impairment, orthopaedic, and urology. The translated 4AT was tested against the reference standard DSM-IV-TR criteria, based on the Organic Brain Syndrome scale and patient records. The 4AT was assessed simultaneously and independently by two assessors. Additionally, data was collected through patient record reviews, and questions about applicability to the patients (n = 200) and the assessors (n = 37). Statistical analyses, and qualitative content analyses were conducted. Results: By reference standard 18% had delirium, and by 4AT 19%. The overall percent agreement was 88%, AUROC 0.808, sensitivity 0.70 (95% CI 0.51–0.84) and specificity 0.92 (95% CI 0.87–0.96). In the ward for severe cognitive impairment (n = 63) the 4AT was less sensitive and less specific. In the other wards (n = 132) sensitivity was 0.77 (95% CI 0.50–0.93), specificity 0.93 (95% CI 0.87–0.97), and AUROC 0.848. Interrater reliability (Kappa) was 0.918, p = \u3c 0.001 (n = 144). The 4AT was well tolerated by patients, easy to use for health care professionals, and took a few minutes to conduct. Conclusion: The Swedish version of 4AT is an accurate and applicable tool to use in clinical practice for detecting delirium in hospitalized patients across different medical specialities, and to use by different professionals and levels of seniority. To improve patient outcomes, we recommend the 4AT to be incorporated in clinical practice in health care settings in Sweden

Mixed Brain Pathologies in Dementia: The BrainNet Europe Consortium Experience

Background: Dementia results from heterogeneous diseases of the brain. Mixed disease forms are increasingly recognized. Methods: We performed a survey within brain banks of BrainNet Europe to estimate the proportion of mixed disease forms underlying dementia and age- and gender-specific influences. Results: Data collected in 9 centres from 3,303 individuals were analysed. The proportion of patients with mixed diagnoses among all cases with Alzheimer disease (AD), vascular pathology (VP), argyrophilic grain dementia (AGD), and synucleinopathies, such as Lewy body dementia (LBD), Parkinson disease (PD) and synuclein pathology only in the amygdala, was 53.3%. Mixed pathology was more frequently reported with LBD, PD, AGD, and VP than with AD. The percentage of mixed diagnoses for AGD and VP significantly differed between centres. In patients younger than 75 years, synucleinopathies, and pure forms of AD, VP, and AGD were more frequent in men. Above 75 years of age, more women had pure AD and pure AGD. Conclusions: The most obvious neuropathological alteration should not terminate the diagnostic procedure since copathology is likely to be found. Neuropathological interpretation of AGD and VP has not been sufficiently established in a consensus. Pure forms of synucleinopathies are unlikely sole substrates for dementia. Copyright (C) 2008 S. Karger AG, Base

USE OF INTERNAL REFLECTION SPECTROSCOPY FOR MAIZE (Zea mays L.) GRAIN DIAGNOSIS

Инфракрасная (ИК) спектроскопия и спектроскопия комбинационного рассеяния (КР) — современные методы, на основе которых успешно формируются биотехнологические подходы, поз-воляющие проводить генетический и функциональный анализ отдельных органов и тканей растений на молекулярном уровне. В представленной работе с помощью спектроскопии поверхностного внут-реннего отражения (ПВО), которая представляет собой модификацию ИК-спектроскопии, впервые зарегистрированы и выявлены различия в содержании и конформации биомолекул в гомогенатах целого зерна гибридов кукурузы ZP 735 и его компонентов (эндосперм, перикарп, зародыш). Нашей целью была разработка методологии спектроскопии поверхностного внутреннего отражения для идентификации органических молекул, их содержания и конформации в семени кукурузы и его тканях. Объектом исследования служили зерна гибрида кукурузы (Zea mays L.) ZP 735 (оригина-тор — Maize Research Institute, Zemun Polje, г. Белград, Сербия). Методом случайной выборки было отобрано 30 зерен. Для получения ПВО-спектров образцы целых зерен и их частей (эндо-сперма, перикарпа и зародыша) измельчали, гомогенизировали и помещали в специальную ячейку прибора. Для регистрации ПВО-спектров использовали спектрометр (Nicolet™ iS20 FTIR Spectro-meter, «Thermo Scientific», США) с алмазом (diamond ATR crystal, «Thermo Scientific», США), для анализа спектров — пакет программ («Thermo Scientific», США). ПВО-спектры сопоставляли в библиотеке данных программы Advanced ATR correction Algorithm. Метод ПВО-спектроскопии ос-нован на отражении пучка света на границе раздела двух фаз: фазы кристалла с высоким показа-телем преломления, входящего в состав прибора ПВО, и фазы исследуемого образца с более низ-ким показателем преломления. В процессе измерения луч света проникает на небольшую глубину в фазу образца, где частично поглощается. При последующих облучениях образца это явление повторяется, и в результате регистрируется ПВО-спектр. Доказано, что в диапазоне от 400 см1 до 4000 см1 ПВО-спектры целого зерна, эндосперма, перикарпа и зародыша гибрида ZP 735 были аналогичны полученным ранее ИК-спектрам зерна, что свидетельствует о возможности использо-вания нового метода для технологий молекулярной селекции. Расположение полос ПВО-спектра характеризует различные формы колебаний валентных связей функциональных групп органических молекул семени, что позволяет идентифицировать не только наличие определенных молекул, но и их конформацию. Доказано, что с помощью анализа амплитуды полос ПВО-спектра (максималь-ная амплитуда интенсивности и высокая амплитуда интенсивности) в тканях семени можно кон-тролировать изменение содержания ряда органических соединений: протеинов, липидов, сахаров, сложных эфиров, амидов, кетонов, альдегидов, карбоновых кислот, простых эфиров, фенолов, спиртов, ароматических углеводородов, ациклических соединений, алкенов, алканов и алкинов. Полученные результаты важны для тестирования наличия в зерне необходимых органических со-единений или изменения их конформации в процессе селекции. К важным преимуществам метода ПВО-пектроскопии по сравнению с ИК-спектроскопией относятся, с одной стороны, сохранение нативности объекта (возможность проведения исследования без фиксации или окрашивания) и простая пробоподготовка, с другой — эффективная оценка содержания и конформации молекул с высокой чувствительностью (разрешение порядка 1,0 см1). Реализация разработанной методики для формирования технологии молекулярной селекции повысит рентабельность культивирования и эффективность селекции не только кукурузы, но и других сельскохозяйственных растений.Infrared (IR) spectroscopy and Raman spectroscopy (RS) are modern methods on the basis of which biotechnological approaches are being successfully developed that allow genetic and func-tional analysis of individual plant organs and tissues at the molecular level. In the present work, using surface internal reflection spectroscopy (SIR), which is a modification of IR spectroscopy, differences in the content and conformation of biomolecules in grain homogenates and its components (endo-sperm, pericarp, germ) of ZP 735 maize hybrids were first recorded and revealed. Our goal was to develop a methodology for surface SIR for the identification of organic molecules, their content and conformation in corn seed and its tissues. The grains of the corn hybrid (Zea mays L.) ZP 735 (origi-nator Maize Research Institute, Zemun Polje, Belgrade, Serbia) served as the object of the study. Thirty grains were selected by random sampling. To obtain SIR spectra, samples of grains and their parts (endosperm, pericarp, and embryo) were crushed, homogenized, and placed in a special cell of the device. A spectrometer (FT-IR spectrophotometer, Thermo Scientific, USA) with diamond (dia-mond ATR crystal, Thermo Scientific, USA) was used to record the SIR spectra, and a software package (Thermo Scientific™ ) was used to analyze the spectra. The SIR spectra were compared in the data library of the Advanced ATR correction Algorithm program. The SIR spectroscopy method is based on the reflection of a light beam at the interface between two phases: the phase of a crystal with a high refractive index, which is part of the SIR device, and the phase of the sample under study with a lower refractive index. During the measurement, the light beam penetrates to a small depth into the phase of the sample, where it is partially absorbed. During subsequent irradiation of the sample, this phenomenon is repeated, and as a result, the SIR spectrum is recorded. It has been proven that in the range from 400 cm-1 to 4000 cm-1 ATR spectra of whole grain, endosperm, pericarp and embryo of the ZP 735 hybrid are similar to the previously obtained IR spectra of grain, which indicates the possibility of using a new method for molecular breeding technologies. The location of the bands of the SIR spectrum characterizes various forms of vibrations of the valence bonds of the functional groups of the organic molecules of the seed, which makes it possible to identify not only the presence of certain molecules, but also their conformation. It has been proved that by analyzing the amplitude of the SIR spectrum bands (maximum intensity amplitude and high intensity amplitude), it is possible to control changes in the content of a number of organic compounds in seed tissues: proteins, lipids, sugars, esters, amides, ketones, aldehydes, carboxylic acids, simple ethers, phenols, alcohols, aromatic hydrocarbons, acyclic compounds, alkenes, alkanes and alkynes. The obtained results are important for testing the presence of the necessary organic compounds in the grain or changes in their confor-mation during the selection process. The important advantages of SIR spectroscopy compared to IR spectroscopy include, on the one hand, the preservation of the nativeness of the object (the possibility of conducting research without fixing or staining the object) and simple sample preparation, on the other hand, an effective assessment of the content and conformation of molecules with high sensitivity (resolution about 1.0 cm-1). The implementation of the developed methodology for the formation of molecular breeding technology will increase the profitability of cultivation and the efficiency of breed-ing not only corn, but also other agricultural plants

Alzheimer's disease biomarker profiling in a memory clinic cohort without common comorbidities

Alzheimer's disease is a multifactorial disorder with large heterogeneity. Comorbidities such as hypertension, hypercholesterolaemia and diabetes are known contributors to disease progression. However, less is known about their mechanistic contribution to Alzheimer's pathology and neurodegeneration. The aim of this study was to investigate the relationship of several biomarkers related to risk mechanisms in Alzheimer's disease with the well-established Alzheimer's disease markers in a memory clinic population without common comorbidities. We investigated 13 molecular markers representing key mechanisms underlying Alzheimer's disease pathogenesis in CSF from memory clinic patients without diagnosed hypertension, hypercholesterolaemia or diabetes nor other neurodegenerative disorders. An analysis of covariance was used to compare biomarker levels between clinical groups. Associations were analysed by linear regression. Two-step cluster analysis was used to determine patient clusters. Two key markers were analysed by immunofluorescence staining in the hippocampus of non-demented control and Alzheimer's disease individuals. CSF samples from a total of 90 participants were included in this study: 30 from patients with subjective cognitive decline (age 62.4 ± 4.38, female 60%), 30 with mild cognitive impairment (age 65.6 ± 7.48, female 50%) and 30 with Alzheimer's disease (age 68.2 ± 7.86, female 50%). Angiotensinogen, thioredoxin-1 and interleukin-15 had the most prominent associations with Alzheimer's disease pathology, synaptic and axonal damage markers. Synaptosomal-associated protein 25 kDa and neurofilament light chain were increased in mild cognitive impairment and Alzheimer's disease patients. Grouping biomarkers by biological function showed that inflammatory and survival components were associated with Alzheimer's disease pathology, synaptic dysfunction and axonal damage. Moreover, a vascular/metabolic component was associated with synaptic dysfunction. In the data-driven analysis, two patient clusters were identified: Cluster 1 had increased CSF markers of oxidative stress, vascular pathology and neuroinflammation and was characterized by elevated synaptic and axonal damage, compared with Cluster 2. Clinical groups were evenly distributed between the clusters. An analysis of post-mortem hippocampal tissue showed that compared with non-demented controls, angiotensinogen staining was higher in Alzheimer's disease and co-localized with phosphorylated-tau. The identification of biomarker-driven endophenotypes in cognitive disorder patients further highlights the biological heterogeneity of Alzheimer's disease and the importance of tailored prevention and treatment strategies

Insulin-Independent and Dependent Glucose Transporters in Brain Mural Cells in CADASIL

Typical cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by mutations in the human NOTCH3 gene. Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy is characterized by subcortical ischemic strokes due to severe arteriopathy and fibrotic thickening of small vessels. Blood regulating vascular smooth muscle cells (VSMCs) appear as the key target in CADASIL but the pathogenic mechanisms remain unclear. With the hypothesis that brain glucose metabolism is disrupted in VSMCs in CADASIL, we investigated post-mortem tissues and VSMCs derived from CADASIL patients to explore gene expression and protein immunoreactivity of glucose transporters (GLUTs), particularly GLUT4 and GLUT2 using quantitative RT-PCR and immunohistochemical techniques.In vitrocell model analysis indicated that both GLUT4 and -2 gene expression levels were down-regulated in VSMCs derived from CADASIL patients, compared to controls.In vitrostudies further indicated that the down regulation of GLUT4 coincided with impaired glucose uptake in VSMCs, which could be partially rescued by insulin treatment. Our observations on reduction in GLUTs in VSMCs are consistent with previous findings of decreased cerebral blood flow and glucose uptake in CADASIL patients. That impaired ability of glucose uptake is rescued by insulin is also consistent with previously reported lower proliferation rates of VSMCs derived from CADASIL subjects. Overall, these observations are consistent with the development of severe cerebral arteriopathy in CADASIL, in which VSMCs are replaced by widespread fibrosis

Staging of Neurofibrillary Pathology in Alzheimer's Disease: A Study of the BrainNet Europe Consortium

It has been recognized that molecular classifications will form the basis for neuropathological diagnostic work in the future. Consequently, in order to reach a diagnosis of Alzheimer's disease (AD), the presence of hyperphosphorylated tau (HP-tau) and β-amyloid protein in brain tissue must be unequivocal. In addition, the stepwise progression of pathology needs to be assessed. This paper deals exclusively with the regional assessment of AD-related HP-tau pathology. The objective was to provide straightforward instructions to aid in the assessment of AD-related immunohistochemically (IHC) detected HP-tau pathology and to test the concordance of assessments made by 25 independent evaluators. The assessment of progression in 7-µm-thick sections was based on assessment of IHC labeled HP-tau immunoreactive neuropil threads (NTs). Our results indicate that good agreement can be reached when the lesions are substantial, i.e., the lesions have reached isocortical structures (stage V–VI absolute agreement 91%), whereas when only mild subtle lesions were present the agreement was poorer (I–II absolute agreement 50%). Thus, in a research setting when the extent of lesions is mild, it is strongly recommended that the assessment of lesions should be carried out by at least two independent observers

Meta-analysis of Alzheimer’s disease on 9,751 samples from Norway and IGAP study identifies four risk loci

Source at https://doi.org/10.1038/s41598-018-36429-6.A large fraction of genetic risk factors for Alzheimer’s Disease (AD) is still not identified, limiting the understanding of AD pathology and study of therapeutic targets. We conducted a genome-wide association study (GWAS) of AD cases and controls of European descent from the multi-center DemGene network across Norway and two independent European cohorts. In a two-stage process, we first performed a meta-analysis using GWAS results from 2,893 AD cases and 6,858 cognitively normal controls from Norway and 25,580 cases and 48,466 controls from the International Genomics of Alzheimer’s Project (IGAP), denoted the discovery sample. Second, we selected the top hits (p −6) from the discovery analysis for replication in an Icelandic cohort consisting of 5,341 cases and 110,008 controls. We identified a novel genomic region with genome-wide significant association with AD on chromosome 4 (combined analysis OR = 1.07, p = 2.48 x 10-8). This finding implicated HS3ST1, a gene expressed throughout the brain particularly in the cerebellar cortex. In addition, we identified IGHV1-68 in the discovery sample, previously not associated with AD. We also associated >i>USP6NL/ECHDC3 and BZRAP1-AS1 to AD, confirming findings from a follow-up transethnic study. These new gene loci provide further evidence for AD as a polygenic disorder, and suggest new mechanistic pathways that warrant further investigation