Indicator Of Neurodegeneration Research Articles

Evaluation of cervical spinal cord atrophy using a modified SIENA approach

Spinal cord (SC) atrophy obtained from structural magnetic resonance imaging has gained relevance as an indicator of neurodegeneration in various neurological disorders. The common method to assess SC atrophy is by comparing numerical differences of the cross-sectional spinal cord area (CSA) between time points. However, this indirect approach leads to considerable variability in the obtained results. Studies showed that this limitation can be overcome by using a registration-based technique.The present study introduces the Structural Image Evaluation using Normalization of Atrophy on the Spinal Cord (SIENA-SC), which is an adapted version of the original SIENA method, designed to directly calculate the percentage of SC volume change over time from clinical brain MRI acquired with an extended field of view to cover the superior part of the cervical SC.In this work, we compared SIENA-SC with the Generalized Boundary Shift Integral (GBSI) and the CSA change. On a scan-rescan dataset, SIENA-SC was shown to have the lowest measurement error than the other two methods. When comparing a group of 190 Healthy Controls with a group of 65 Multiple Sclerosis patients, SIENA-SC provided significantly higher yearly rates of atrophy in patients than in controls and a lower sample size when measured for treatment effect sizes of 50%, 30% and 10%.Our findings indicate that SIENA-SC is a robust, reproducible, and sensitive approach for assessing longitudinal changes in spinal cord volume, providing neuroscientists with an accessible and automated tool able to reduce the need for manual intervention and minimize variability in measurements.

Changes in cortical thickness along the Alzheimer disease continuum in people with Down syndrome

AbstractBackgroundTriplication of the APP allele in Down syndrome (DS) leads to excess amyloid production and Alzheimer’s disease (AD) related cognitive decline. Key biomarkers (amyloid, tau, neurodegeneration) can identify pathological processes that occur before clinical symptoms and more precisely stage adults with DS along the AD continuum. Previous research has used changes in cortical thickness (CT) as an indicator of neurodegeneration in autosomal‐dominant AD1, but not DS‐related AD. It is unclear when and where cortical thinning occurs along the AD continuum in DS and if these differences are associated with increasing AD pathology.MethodCross‐sectional analysis compared DS participants from the Alzheimer Biomarkers Consortium‐Down Syndrome (106 amyloid‐/cognitively unimpaired, nonclinical, 20% reserved for receiver‐operating characteristic, ROC, analyses; 45 amyloid+/cognitively unimpaired, preclinical; 27 amyloid+/cognitively impaired, clinical) who had amyloid positron emission tomography and magnetic resonance imaging (MRI). Amyloid positivity was defined using standardized uptake value ratio (partial volume corrected) cortical mean values (1.42/1.19 for PIB/AV452) and impairment was based on consensus diagnosis. CT differences between nonclinical and clinical groups were calculated in FreeSurfer v5.3 for multiple thresholds (p<.05/.01/.005/.001/.0005/.0001) using a cluster‐wise false discovery rate of .001, corrected across hemispheres, after controlling for age and sex. CT values were extracted for each threshold and used in ROC analyses (nonclinical reserved participants compared against preclinical and preclinical compared against clinical) to identify key cortical regions that best discriminated amyloid positivity and between unimpaired and impaired.ResultSignificant decreases in parietal and inferior temporal CT were observed between nonclinical and clinical (Figures 1 and 2). ROC analyses identified regions in the left (threshold .05) and right (threshold .005) hemispheres that best differentiated nonclinical from preclinical. Observed area under the curves (AUCs) of .772 and .830 exceeded those previously reported for autosomal‐dominant AD (.547/.540)1. Analyses differentiating preclinical from clinical observed AUCs of .786 for left (threshold .0005) and .770 for right (threshold .0005) hemispheres.ConclusionCT differences primarily within posterior cortical regions differentiated adults with DS by amyloid status and cognitive impairment. CT differences were more diffuse for amyloid positivity but more focal for impairment.1. Dincer (2020). NeuroImage: Clinical, 28, 102491.2. Su (2019). Alzheimer’s Dement, 11, 180‐190.

Plasma NfL is associated with the APOE ε4 allele, brain imaging measurements of neurodegeneration, and lower recall memory scores in cognitively unimpaired late-middle-aged and older adults

BackgroundPlasma neurofilament light (NfL) is an indicator of neurodegeneration and/or neuroaxonal injury in persons with Alzheimer’s disease (AD) and a wide range of other neurological disorders. Here, we characterized and compared plasma NfL concentrations in cognitively unimpaired (CU) late-middle-aged and older adults with two, one, or no copies of the APOE ε4 allele, the major genetic risk factor for AD. We then assessed plasma NfL associations with brain imaging measurements of AD-related neurodegeneration (hippocampal atrophy and a hypometabolic convergence index [HCI]), brain imaging measurements of amyloid-β plaque burden, tau tangle burden and white matter hyperintensity volume (WMHV), and delayed and total recall memory scores.MethodsPlasma NfL concentrations were measured in 543 CU 69 ± 9 year-old participants in the Arizona APOE Cohort Study, including 66 APOE ε4 homozygotes (HM), 165 heterozygotes (HT), and 312 non-carriers (NC). Robust regression models were used to characterize plasma NfL associations with APOE ε4 allelic dose before and after adjustment for age, sex, and education. They were also used to characterize plasma NfL associations with MRI-based hippocampal volume and WMHV measurements, an FDG PET-based HCI, mean cortical PiB PET measurements of amyloid-β plaque burden and meta-region-of-interest (meta-ROI) flortaucipir PET measurements of tau tangle burden, and Auditory Verbal Learning Test (AVLT) Delayed and Total Recall Memory scores.ResultsAfter the adjustments noted above, plasma NfL levels were significantly greater in APOE ε4 homozygotes and heterozygotes than non-carriers and significantly associated with smaller hippocampal volumes (r = − 0.43), greater tangle burden in the entorhinal cortex and inferior temporal lobes (r = 0.49, r = 0.52, respectively), and lower delayed (r = − 0.27), and total (r = − 0.27) recall memory scores (p < 0.001). NfL levels were not significantly associated with PET measurements of amyloid-β plaque or total tangle burden.ConclusionsPlasma NfL concentrations are associated with the APOE ε4 allele, brain imaging biomarkers of neurodegeneration, and less good recall memory in CU late-middle-aged and older adults, supporting its value as an indicator of neurodegeneration in the preclinical study of AD.

Tau pathology mediates the effects of amyloid on cerebral blood flow and propagation of tau

AbstractBackgroundAmyloid is associated with greater tau pathology and is thought to facilitate the spread of tau from the medial temporal lobe (MTL) to the neocortex. The extent to which amyloid versus MTL tau is involved in propagating tau remains unclear. Given the potential role of cortical tau in early neurodegeneration, understanding the contributors to its spread might inform preventative strategies.MethodWe acquired 18F‐flortaucipir (FTP) PET scans to measure tau pathology in 113 non‐demented Baltimore Longitudinal Study of Aging participants. To assess if amyloid facilitates the spread of tau from the MTL to the neocortex, we investigated whether amyloid moderates the association between tau in the entorhinal cortex (EC) and the inferior temporal gyrus (ITG). To quantify the involvement of amyloid versus MTL tau in propagating tau, we investigated whether EC tau mediates the association between amyloid and ITG tau. Finally, we investigated the local relationship between ITG tau and cerebral blood flow (CBF), an indicator of neurodegeneration, quantified as the relative radiotracer delivery parameter R1 computed from dynamic Pittsburgh compound B (PiB) PET scans. We used robust linear regression for all statistical models to mitigate the influence of the few outlying tau data points on the estimates, and included age, sex, race, and education as covariates.ResultAmyloid positive (A+) participants had higher FTP‐SUVR in the EC and ITG. Higher FTP‐SUVR in the EC was associated with higher FTP‐SUVR in the ITG. This association was steeper among A+ individuals (amyloid and EC FTP‐SUVR interaction β=0.269, p=0.023). EC FTP‐SUVR mediated the association between amyloid and ITG FTP‐SUVR (indirect effect=0.136, p=0.043).Higher ITG FTP‐SUVR was associated with lower PiB‐R1 (β=‐0.277, p=0.039). The direct association between amyloid and PiB‐R1 was not statistically significant (direct effect=‐0.366, p=0.192), but there was an indirect effect via ITG FTP‐SUVR (indirect effect=‐0.14, p=0.015).ConclusionOur findings suggest that both amyloid and MTL tau pathology are involved in the spread of tau into the neocortex. Tau accounted for 28% of the amyloid‐CBF relationship, indicating its role in early neuronal hypoactivity. Therapeutics may need to target both amyloid and tau early to prevent neocortical involvement.

The significance of reticulon4A as a potential indicator of neurodegeneration

AbstractBackgroundNeurodegeneration characterizes by dysfunction, progressive atrophy and loss of neurons, which is presented in both neurodegenerative as well as demyelinating disorders. Both groups of diseases share common pathological hallmarks: neuroinflammation and gradual loss of neurons and axons, which lead to the central nervous system (CNS) damage and the development of these disorders. Mounting evidence has supported the reticulon4A (RTN4A) role in the pathogenesis of some neurodegenerative and demyelinating disorders, including MS. RTN4A also known as Nogo‐A protein, contributes to neuroinflammation and demyelination. Moreover, this protein acts as a relevant inhibitor of neurite outgrowth and axonal regeneration. Therefore, the objectives of the present study were evaluation of Nogo‐A and Tau levels in the cerebrospinal fluid (CSF) of MS patients and subjects from the control group, as well as the assessment of a relationships between concentrations of immunoglobulins, albumin, immunoglobulins and albumin quotients, as well as oligoclonal bands.MethodThe concentrations of Nogo‐A and Tau proteins were measured in the CSF of 15 MS patients and 16 subjects from control group by means of quantitative technique ELISA. CSF and serum concentrations of albumin and immunoglobulins were measured by using nephelometer. To evaluate the integrity of the blood‐CSF barrier and intrathecal immunoglobulins production, albumin and immunoglobulins quotients were calculated. Furthermore, the oligioclonal bands were assessed by using isoelectofocusing method.ResultThe CSF concentrations of Nogo‐A was significantly higher in MS group in comparison with controls. The increased CSF level of the protein was observed significantly correlate with the concentration of Tau protein in MS patients. Furthermore, we revealed associations between Nogo‐A protein and CSF levels of albumin, Tau and QIgG in the whole study group.ConclusionOur preliminary results indicate a potential role of Nogo‐A protein in the neurodegenerative pathology of MS. Moreover, it seems that reticuon4A is a promising candidate biomarker for demyelinating disorders, including MS, but these investigations need to be further clarified using a larger study group. The study was conducted with the use of equipment purchased by Medical University of Białystok as part of the RPOWP 2007‐2013 funding, Priority I, Axis 1.1, contract No. UDA‐RPPD.01.01.00‐20‐001/15‐00 dated 26.06.2015.

Assessment of neurodegeneration by optical coherence tomography and mini–mental test in Parkinson's disease

Background:Parkinson's disease is a neurodegenerative disease. Cognitive disorders and retinal degeneration may occur during the early stages of the disease. Retinal degeneration and cognitive findings can be assessed easily with optical coherence tomography and mini–mental test, respectively.Materials and Methods:Twenty-two patients who are being followed-up with Parkinson's disease and 22 healthy controls have been included in the study. The Unified Parkinson's Disease Rating Scale (UPDRS) and Hoehn–Yahr staging of the patients have been conducted at the time of admission. Retinal nerve fiber layer analysis and ganglion cell thickness (ganglion cell complexes [GCCs]) were evaluated through optical coherence tomography (OCT). And at the same time, we aimed to compare the stage of the disease, the UPDRS score and the duration of the disease with OCT and cognitive functions by mini–mental test.Results:Mini–mental test total score value (P = 0.025) and language value (P = 0.021) were lower in the patient group compared to the control group. In patients, there is a reverse significant correlation between UPDRS-T and GCC-left-superior (r = −0.495; P = 0.026), GCC-left-inferior (r = −0.517; P = 0.019), and GCC-left-to (r = −0.508; P = 0.022). There is a significant parallel relation between recall and RFNL-right-mean (r = 0.626; P = 0.039).Conclusion:Our findings indicate that the neurodegeneration continues multisystemically and neurodegeneration increases simultaneously with the disease. OCT, which is a noninvasive method, can be used as an indicator of neurodegeneration in patients with Parkinson's disease.

Synthesis and Biological Evaluation of Thiophene-Based Cannabinoid Receptor Type 2 Radiotracers for PET Imaging

Over the past two decades, our understanding of the endocannabinoid system has greatly improved due to the wealth of results obtained from exploratory studies. Currently, two cannabinoid receptor subtypes have been well-characterized. The cannabinoid receptor type 1 (CB1) is widely expressed in the central nervous system, while the levels of the cannabinoid receptor type 2 (CB2) in the brain and spinal cord of healthy individuals are relatively low. However, recent studies demonstrated a CB2 upregulation on activated microglia upon neuroinflammation, an indicator of neurodegeneration. Our research group aims to develop a suitable positron emission tomography (PET) tracer to visualize the CB2 receptor in patients suffering from neurodegenerative diseases. Herein we report two novel thiophene-based 11C-labeled PET ligands designated [11C]AAT-015 and [11C]AAT-778. The reference compounds were synthesized using Gewald reaction conditions to obtain the aminothiophene intermediates, followed by amide formation. Saponification of the esters provided their corresponding precursors. Binding affinity studies revealed Ki-values of 3.3 ± 0.5 nM (CB2) and 1.0 ± 0.2 μM (CB1) for AAT-015. AAT-778 showed similar Ki-values of 4.3 ± 0.7 nM (CB2) and 1.1 ± 0.1 μM (CB1). Radiosynthesis was carried out under basic conditions using [11C]iodomethane as methylating agent. After semi-preparative HPLC purification both radiolabeled compounds were obtained in 99% radiochemical purity and the radiochemical yields ranged from 12 to 37%. Specific activity was between 96 and 449 GBq/μmol for both tracers. In order to demonstrate CB2 specificity of [11C]AAT-015 and [11C]AAT-778, we carried out autoradiography studies using CB2-positive mouse/rat spleen tissues. The obtained results revealed unspecific binding in spleen tissue that was not blocked by an excess of CB2-specific ligand GW402833. For in vivo analysis, [11C]AAT-015 was administered to healthy rats via tail-vein injection. Evaluation of the CB2-positive spleen, however, showed no accumulation of the radiotracer. Despite the promising in vitro binding affinities, specific binding of [11C]AAT-015, and [11C]AAT-778 could not be demonstrated.

Evaluation of the neurotoxical effect of aluminum on the Wistar rat

Our previous investigations on an animal model of neurotoxicity show that increased power in the delta range is connected with the neurotoxic effect of aluminum exposure. In this study we used several aluminum-treated animals as a reliable model for the evaluation of the neurotoxic effects of aluminum on neurons, and compared it with a control group. We conclude that spectral analysis and the ratio between the delta and theta ranges might be reliable for a qualitative description of the neurotoxic effect of aluminum, and that the t test might be used to evaluate the change in brain activity between the treated and control groups of animals. The animal model under anesthesia was used to describe the state of brain activity with neurotoxicity with suppressed functional connectivity in the brain structure. We also performed fractal analysis to quantitatively describe neurotoxic effect in different pathophysiological states of animals treated with different doses of aluminum. A decrease in the fractal dimension is an indicator of neurodegeneration in the state of stress. This animal model is suitable for evaluation of the neurodegenerative processes in Alzheimer's dementia and Parkinson's disease. .

Myelin-containing corpora amylacea in vestibular root entry zone.

The vestibular nerve of patients with Meniere's disease and vascular cross-compression syndrome of the root entry zone due to the antero-inferior cerebellar artery was studied. All patients underwent vestibular neurectomy using the retrosigmoid approach, which permits the removal of a long nerve segment. CA were found in the cytoplasm of astrocytes that had not shown signs of degeneration at the central portion of the vestibular root entry zone. No membrane intervened between CA and the surrounding cytoplasm, which was rich in filaments, in particular near the CA, and poorly equipped with other organelles. CA were round or oval inclusions measuring 10-12 microns in diameter. The matrix of the CA was composed of low-density amorphous material, with irregular masses displaying a medium density. A network of randomly oriented filaments and bilaminar, osmiophilic lipid fragments with the same structure and thickness of myelin layers were embedded in the matrix. The CA rich in bilaminar fragments were recognizable also at low magnification for their high electron density. In the astrocytic cytoplasm, near the CA, round or ovalshaped, electron-dense bodies with a multilamellar structure were often visible. These results confirm the hypothesis that CA may contain degenerating myelin embedded in a microenvironment rich in glucose polymers and that CA could be an indicator of neurodegeneration.

Corpora amylacea could be an indicator of neurodegeneration

We describe an investigation of corpora amylacea (CA) in the brain tissue of Alzheimer's disease (AD) cases and normal ageing controls, using both light (LM) and electron (EM) microscopic techniques. CA populations were shown by routine histological staining of LR White resin sections with methenamine silver and PAS, and were compared with those shown by immunocytochemistry using antibodies to tau, GFAP, tubulin, ubiquitin, beta-amyloid and serum amyloid P component in serial sections. All CA were immunoreactive with anti-tau and all were unreactive with anti-beta-amyloid. Most were immunoreactive with anti-serum amyloid P component, although this was often weak in AD. CA from normal ageing brain were immunoreactive for proteins that are associated with the neuronal cytoskeleton and cell injury. CA from AD brain shared some of these but differed from those in normal ageing brain by being in much larger number and more variable in their immunoreactivity. In all CA, X-ray microanalysis illustrated the presence of the metallic elements Ca, Fe and Cu. Aluminium, often associated with AD, was not present, even in CA from AD brain. Phosphorus and sulphur, probably from phosphorylated proteins associated with degenerating cytoskeleton elements, were usually detected. In AD brain, the greater numbers of CA and their variable biochemical and elemental composition, when compared with CA in the normal ageing brain, suggests that they may derive from a number of sources both neuronal and glial as a result of the neurodegenerative disease.