Rate Of Neurodegeneration Research Articles

Evaluation of Neuroprotective Effect of Gut Microbe in Parkinson's Disease: An In Silico and In Vivo Approach.

Parkinson's disease is a progressive neurodegenerative disorder marked by the death of dopaminergic neurons in the substantia nigra region of the brain. Aggregation of alpha-synuclein (α-synuclein) is a contributing factor to Parkinson's disease pathogenesis. The objective of this study is to investigate the neuroprotective effects of gut microbes on α-synuclein aggregation using both in silico and in vivo approaches. We focussed on the interaction between α-synuclein and metabolites released by gut bacteria that protect from PD. We employed three probiotic microbe strains against α-synuclein protein: Lactobacillus casei, Escherichia coli, and Bacillus subtilis, with their chosen PDB IDs being Dihydrofolate reductase (3DFR), methionine synthetase (6BM5), and tryptophanyl-tRNA synthetase (3PRH), respectively. Using HEX Dock 6.0 software, we examined the interactions between these proteins. Among the various metabolites, methionine synthetase produced by E. coli showed potential interactions with α-synuclein. To further evaluate the neuroprotective benefits of E. coli, an in vivo investigation was performed using a rotenone-induced Parkinsonian mouse model. The motor function of the animals was assessed through behavioural tests, and oxidative stress and neurotransmitter levels were also examined. The results demonstrated that, compared to the rotenone-induced PD mouse model, the rate of neurodegeneration was considerably reduced in mice treated with E. coli. Additionally, histopathological studies provided evidence of the neuroprotective effects of E. coli. In conclusion, this study lays the groundwork for future research, suggesting that gut bacteria may serve as potential therapeutic agents in the development of medications to treat Parkinson's disease. fig. 1.

Analysis and visualization of the effect of multiple sclerosis on biological brain age.

The rate of neurodegeneration in multiple sclerosis (MS) is an important biomarker for disease progression but can be challenging to quantify. The brain age gap, which quantifies the difference between a patient's chronological and their estimated biological brain age, might be a valuable biomarker of neurodegeneration in patients with MS. Thus, the aim of this study was to investigate the value of an image-based prediction of the brain age gap using a deep learning model and compare brain age gap values between healthy individuals and patients with MS. A multi-center dataset consisting of 5,294 T1-weighted magnetic resonance images of the brain from healthy individuals aged between 19 and 89 years was used to train a convolutional neural network (CNN) for biological brain age prediction. The trained model was then used to calculate the brain age gap in 195 patients with relapsing remitting MS (20-60 years). Additionally, saliency maps were generated for healthy subjects and patients with MS to identify brain regions that were deemed important for the brain age prediction task by the CNN. Overall, the application of the CNN revealed accelerated brain aging with a larger brain age gap for patients with MS with a mean of 6.98 ± 7.18 years in comparison to healthy test set subjects (0.23 ± 4.64 years). The brain age gap for MS patients was weakly to moderately correlated with age at disease onset (ρ = -0.299, p < 0.0001), EDSS score (ρ = 0.206, p = 0.004), disease duration (ρ = 0.162, p = 0.024), lesion volume (ρ = 0.630, p < 0.0001), and brain parenchymal fraction (ρ = -0.718, p < 0.0001). The saliency maps indicated significant differences in the lateral ventricle (p < 0.0001), insula (p < 0.0001), third ventricle (p < 0.0001), and fourth ventricle (p = 0.0001) in the right hemisphere. In the left hemisphere, the inferior lateral ventricle (p < 0.0001) and the third ventricle (p < 0.0001) showed significant differences. Furthermore, the Dice similarity coefficient showed the highest overlap of salient regions between the MS patients and the oldest healthy subjects, indicating that neurodegeneration is accelerated in this patient cohort. In conclusion, the results of this study show that the brain age gap is a valuable surrogate biomarker to measure disease progression in patients with multiple sclerosis.

Plasma glial fibrillary acidic protein in autosomal dominant Alzheimer's disease: Associations with Aβ-PET, neurodegeneration, and cognition.

Glial fibrillary acidic protein (GFAP) is a promising candidate blood-based biomarker for Alzheimer's disease (AD) diagnosis and prognostication. The timing of its disease-associated changes, its clinical correlates, and biofluid-type dependency will influence its clinical utility. We evaluated plasma, serum, and cerebrospinal fluid (CSF) GFAP in families with autosomal dominant AD (ADAD), leveraging the predictable age at symptom onset to determine changes by stage of disease. Plasma GFAP elevations appear a decade before expected symptom onset, after amyloid beta (Aβ) accumulation and prior to neurodegeneration and cognitive decline. Plasma GFAP distinguished Aβ-positive from Aβ-negative ADAD participants and showed a stronger relationship with Aβ load in asymptomatic than symptomatic ADAD. Higher plasma GFAP was associated with the degree and rate of neurodegeneration and cognitive impairment. Serum GFAP showed similar relationships, but these were less pronounced for CSF GFAP. Our findings support a role for plasma GFAP as a clinical biomarker of Aβ-related astrocyte reactivity that is associated with cognitive decline and neurodegeneration. Plasma glial fibrillary acidic protein (GFAP) elevations appear a decade before expected symptom onset in autosomal dominant Alzheimer's disease (ADAD). Plasma GFAP was associated to amyloid positivity in asymptomatic ADAD. Plasma GFAP increased with clinical severity and predicted disease progression. Plasma and serum GFAP carried similar information in ADAD, while cerebrospinal fluid GFAP did not.

Associations of Neprilysin Activity in CSF with Biomarkers for Alzheimer’s Disease

Background: Neprilysin (NEP) cleaves amyloid-β 1–42 (Aβ₄₂) in the brain. Hence, we aimed to elucidate the effect of NEP on Aβ₄₂ in cerebrospinal fluid (CSF) and on in vivo brain amyloid load using amyloid positron emission tomography (PET) with [¹¹C]PiB (Pittsburgh compound B). In addition, associations with the biomarkers for neuronal injury, CSF-tau and FDG-PET, were investigated. Methods: Associations were calculated using global and voxel-based (SPM8) linear regression analyses in the same cohort of 23 highly characterized Alzheimer’s disease patients. Results: CSF-NEP was significantly inversely associated with CSF-Aβ₄₂ and positively with the extent of neuronal injury as measured by CSF-tau and FDG-PET. Conclusions: Our results on CSF-NEP are compatible with the assumption that local degradation, amongst other mechanisms of amyloid clearance, plays a role in the development of Alzheimer’s pathology. In addition, CSF-NEP is associated with the extent and the rate of neurodegeneration.

P 1 Effect of ocrelizumab on magnetic resonance imaging markers of neurodegeneration in patients with relapsing multiple sclerosis – analysis of the phase III, double-blind, double-dummy, interferon beta-1a- controlled OPERA I and OPERA II studies

Background Ocrelizumab (OCR) is a humanised monoclonal antibody that selectively targets CD20+B cells. The pathogenesis of multiple sclerosis (MS), including neurodegeneration, is thought to be influenced by B cells. Volumetric magnetic resonance imaging (MRI) measurements can be used to assess neurodegeneration. Objective To evaluate the effect of OCR vs interferon beta-1a (IFN β -1a) on brain MRI markers of neurodegeneration in patients with relapsing MS enrolled in two identical Phase III, randomised, double-blind, double-dummy trials (OPERA I and OPERA II). Methods In OPERA I and OPERA II, patients were randomised (1:1) to receive OCR 600 mg via intravenous infusion every 24 weeks or subcutaneous IFN β -1a 44 μ g three-times weekly over 96 weeks. MRI endpoints thought to be related to neurodegeneration included the change in whole brain volume, change in cortical grey matter volume and change in cerebral white matter volume. Results Compared with IFN β -1a, OCR reduced the rate of whole brain volume loss from baseline to Week 96 by 23.5% ( p p = 0.0001), and from Week 24 to Week 96 by 22.8% ( p = 0.0042) and 14.9% ( p = 0.0900) in OPERA I and OPERA II, respectively. OCR-treated patients showed a smaller mean percentage of cortical grey matter volume loss compared with IFN β -1a from baseline to Week 96, with a mean difference of 0.273% ( p = 0.0005) in OPERA I and 0.516% ( p β -1a from baseline to Week 96, with a mean difference of 0.261% ( p = 0.0024); in OPERA II, there was no difference ( p = 0.2748) in cerebral white matter volume loss in patients treated with OCR compared with IFN β -1a from baseline to Week 96. Conclusion The rate of neurodegeneration as measured by whole brain, cortical grey and cerebral white matter volume loss on MRI was reduced by OCR compared with IFN β -1a in patients with relapsing MS over 96 weeks. This study is sponsored by F. Hoffmann-La Roche Ltd.

382 - Ablation of Gpx4 in Forebrain Neurons Leads to Ferroptotic Cell Death and Cognitive Impairment

Synaptic loss and neuron death are the underlying drivers of neurodegenerative diseases such as Alzheimer’s disease (AD); however, the modalities of cell death remain unclear. Although apoptosis has long been considered the major mechanism of neurodegeneration in AD, inconclusive results of clinical trials and pathological data indicate that non-apoptotic cell-death mechanisms may also be involved. Ferroptosis is a newly identified oxidative cell-death pathway regulated by lipid peroxidation that promotes inflammation. Recently, our lab found that motor neurons are particularly susceptible to ferroptosis in vivo . Here, we investigated whether neurons in forebrain regions that are severely afflicted in AD patients (cerebral cortex and hippocampus) might also be vulnerable to ferroptosis. To this end, we deleted the ferroptosis regulator Gpx4 exclusively in fore B rain neurons of 3 month old mice using a novel tamoxifen- I nducible K nock O ut model ( Gpx4 BiKO). At 12 weeks post Gpx4 knockout, the mice exhibited significant deficits in spatial learning and memory versus control mice as determined by Morris water maze task. Hippocampal tissues from Gpx4 BiKO mice also showed reduced levels of neural marker proteins NeuN, Synaptophysin, and SNAP25 indicating the occurrence of neurodegeneration. Interestingly, classical markers of apoptosis such as activation of caspase-3 were absent while several markers associated with ferroptosis were pronounced in both hippocampus and cortex of Gpx4 BiKO mice. These features, which included elevated lipid peroxidation (4-HNE adducts), elevated gliosis (GFAP, Iba1), increased pro-inflammatory cytokine production, and increased ERK1/2 phosphorylation strongly suggested that neurodegeneration in Gpx4 BiKO mice occurred via ferroptosis. Knowing that vitamin-E has anti-ferroptotic properties, we next examined the effects of vitamin-E deficiency on the rate of neurodegeneration in Gpx4 BiKO mice. As expected, Gpx4 BiKO on VED exhibited a noticeably expedited rate of hippocampal neurodegeneration appearing at 2 weeks post Gpx4 ablation. Taken together, our results indicate that forebrain neurons are indeed susceptible to ferroptosis and that ferroptosis may be an important degenerative mechanism of neurons in AD.

Cerebrospinal fluid markers including trefoil factor 3 are associated with neurodegeneration in amyloid-positive individuals.

We aimed to identify cerebrospinal fluid (CSF) biomarkers associated with neurodegeneration in individuals with and without CSF evidence of Alzheimer pathology. We investigated 287 Alzheimer's Disease Neuroimaging Initiative (ADNI) subjects (age=74.9±6.9; 22/48/30% with Alzheimer's disease/mild cognitive impairment/controls) with CSF multiplex analyte data and serial volumetric MRI. We calculated brain and hippocampal atrophy rates, ventricular expansion and Mini Mental State Examination decline. We used false discovery rate corrected regression analyses to assess associations between CSF variables and atrophy rates in individuals with and without amyloid pathology, adjusting in stages for tau, baseline volume, p-tau, age, sex, ApoE4 status and diagnosis. Analytes showing statistically significant independent relationships were entered into reverse stepwise analyses. Adjusting for tau, baseline volume, p-tau, age, sex and ApoE4, 4/83 analytes were significantly independently associated with brain atrophy rate, 1/83 with ventricular expansion and 2/83 with hippocampal atrophy. The strongest CSF predictor for the three atrophy measures was low trefoil factor 3 (TFF3). High cystatin C (CysC) was associated with higher whole brain atrophy and hippocampal atrophy rates. Lower levels of vascular endothelial growth factor and chromogranin A (CrA) were associated with higher whole brain atrophy. In exploratory reverse stepwise analyses, lower TFF3 was associated with higher rates of whole brain, hippocampal atrophy and ventricular expansion. Lower levels of CrA were associated with higher whole brain atrophy rate. The relationship between low TFF3 and increased hippocampal atrophy rate remained after adjustment for diagnosis. We identified a series of CSF markers that are independently associated with rate of neurodegeneration in amyloid-positive individuals. TFF3, a substrate for NOTCH processing may be an important biomarker of neurodegeneration across the Alzheimer spectrum.

Rate of Neurodegeneration in the Mouse Controlled Cortical Impact Model Is Influenced by Impactor Tip Shape: Implications for Mechanistic and Therapeutic Studies

Controlled cortical impact (CCI), one of the most common models of traumatic brain injury, is being increasingly used with mice for exploration of cell injury mechanisms and pre-clinical evaluation of therapeutic strategies. Although CCI brain injury was originally effected using an impactor with a rounded tip, the majority of studies with mouse CCI use a flat or beveled tip. Recent finite element modeling analyses demonstrate that tip geometry is a significant determinant of predicted cortical tissue strains in rat CCI, and that cell death is proportional to predicted tissue strains. In the current study, a three-dimensional finite element model of a C57BL/6J mouse brain predicted higher maximum principal strains during a simulated 1.0-mm, 3.5-m/s CCI injury with a flat tip when compared to a rounded tip. Consistent with this prediction, experimental CCI with a flat-tip impactor resulted in greater acute cortical hemorrhage and neuron loss in adult male C57BL/6J mice. The amount of neocortical tissue damage was equivalent for the two tip geometries at 9 days following injury, but the rate of neocortical neurodegeneration was markedly slower following CCI with a rounded-tip impactor, with damage reaching a plateau after 24?h as opposed to after 4?h for the flat tip. The flat-tip impactor was associated in general with more regional hippocampal neurodegeneration, especially at early time points such as 4?h. Impactor tip geometry did not have a notable effect on blood?brain barrier breakdown, traumatic axonal injury, or motor and cognitive dysfunction. Execution of CCI injury with a rounded-tip impactor is posited to provide a substantially enhanced temporal window for the study of cellular injury mechanisms and therapeutic intervention while maintaining critical aspects of the pathophysiological response to contusion brain injury.

Serial PIB and MRI in normal, mild cognitive impairment and Alzheimer's disease: implications for sequence of pathological events in Alzheimer's disease

The purpose of this study was to use serial imaging to gain insight into the sequence of pathologic events in Alzheimer's disease, and the clinical features associated with this sequence. We measured change in amyloid deposition over time using serial 11C Pittsburgh compound B (PIB) positron emission tomography and progression of neurodegeneration using serial structural magnetic resonance imaging. We studied 21 healthy cognitively normal subjects, 32 with amnestic mild cognitive impairment and 8 with Alzheimer's disease. Subjects were drawn from two sources—ongoing longitudinal registries at Mayo Clinic, and the Alzheimer's disease Neuroimaging Initiative (ADNI). All subjects underwent clinical assessments, MRI and PIB studies at two time points, approximately one year apart. PIB retention was quantified in global cortical to cerebellar ratio units and brain atrophy in units of cm3 by measuring ventricular expansion. The annual change in global PIB retention did not differ by clinical group (P = 0.90), and although small (median 0.042 ratio units/year overall) was greater than zero among all subjects (P < 0.001). Ventricular expansion rates differed by clinical group (P < 0.001) and increased in the following order: cognitively normal (1.3 cm3/year) < amnestic mild cognitive impairment (2.5 cm3/year) < Alzheimer's disease (7.7 cm3/year). Among all subjects there was no correlation between PIB change and concurrent change on CDR-SB (r = −0.01, P = 0.97) but some evidence of a weak correlation with MMSE (r =−0.22, P = 0.09). In contrast, greater rates of ventricular expansion were clearly correlated with worsening concurrent change on CDR-SB (r = 0.42, P < 0.01) and MMSE (r =−0.52, P < 0.01). Our data are consistent with a model of typical late onset Alzheimer's disease that has two main features: (i) dissociation between the rate of amyloid deposition and the rate of neurodegeneration late in life, with amyloid deposition proceeding at a constant slow rate while neurodegeneration accelerates and (ii) clinical symptoms are coupled to neurodegeneration not amyloid deposition. Significant plaque deposition occurs prior to clinical decline. The presence of brain amyloidosis alone is not sufficient to produce cognitive decline, rather, the neurodegenerative component of Alzheimer's disease pathology is the direct substrate of cognitive impairment and the rate of cognitive decline is driven by the rate of neurodegeneration. Neurodegeneration (atrophy on MRI) both precedes and parallels cognitive decline. This model implies a complimentary role for MRI and PIB imaging in Alzheimer's disease, with each reflecting one of the major pathologies, amyloid dysmetabolism and neurodegeneration.

Magnetic Resonance Imaging of Dementia

When magnetic resonance imaging (MRI) was first developed for medical imaging, most physicians and investigators focused on brain disorders which could not be easily be diagnosed with x-ray computed tomography (CT) scanning. Multiple sclerosis was an obvious example because x-ray CT did not provide sufficient soft tissue contrast to identify lesions in the white matter, whereas T2-weighted MRI highlighted these areas. The ability of MRI to identify brain tumors and stroke rapidly became apparent, and like x-ray CT, MRI has been extensively used to characterize diseases of the brain and other organs, which have identifiable lesions. Until recently, there has been comparatively little interest in using MRI for the study of neurodegenerative diseases, including Alzheimer disease, other causes of dementia such as frontotemporal dementia and Lewy body disease, Parkinson disease, amyotropic lateral sclerosis, etc. There are several reasons for this. First, the lack of interest on the part of the MRI community has reflected the relative lack of interest on the part of the medical community at large. Second, the lack of interest was due to the fact that no treatments were available for neurodegenerative disease, thus, fostering the attitude if you can’t treat it, why diagnose it? Third, for the most past, neurodegenerative diseases are not characterized by lesions, although various types of lesions, especially in white matter, often occur in these conditions. Fourth, neurodegenerative diseases do produce brain atrophy, due to loss of neuronal cell bodies and axons. However, the wide range of normal prevents diagnosis of Alzheimer and other neurodegenerative diseases, until the disease is very advanced, and the atrophy becomes extreme. During the last decade, interest in MRI of neurodegenerative diseases has been rapidly rising. Much of this increased interest is due to the increase in the incidence and prevalence of these diseases, caused by the increase in the numbers of elders in the populations of the United States, Europe, and Japan. In addition, the imaging techniques have become more refined, especially due to the development of computer-assisted image processing tools with quantification of the volumes of brain structures. Finally, improved knowledge concerning the pathophysiological mechanisms of neurodegenerative diseases, especially Alzheimer disease, has led to the development of putative treatments which are entering clinical trials. The pharmaceutical companies have recognized that imaging techniques especially MRI and positron emission tomography provide surrogate information concerning the pattern and rate of neurodegeneration, which can be used to monitor the effects of treatments which slow the progression of neurodegeneration. All of these factors have led to an explosion of interest in imaging of neurodegenerative diseases, culminating in the funding of the Alzheimer’s Disease Neuroimaging Initiative which is a very large multisite study using MRI, positron emission tomography, and biomarkers, together with clincian measures, to monitor disease progression (further information at http://www.ADNI-info.org). In this special issue of Topics in Magnetic Resonance Imaging, we present invited review papers dealing with several important topics in this area. The paper Magnetic Resonance Approaches to Brain Aging–Associated Neuropathology by Anderson and Kaye provides an overview of the topic. Dr DeCarli reviews an important topic in his paper Measurement and Impact of Concurrent Cerebrovascular Brain Injury in Alzheimer Disease. Drs Whitehall and Jack also deal with the issue of differential diagnosis in their paper Comparisons Between Alzheimer Disease, Frontotemporal Lobar Degeneration, and Normal Aging With Brain Mapping, and finally, Dr Wahlund presents An Evidence-based Evaluation of Magnetic Resonance Imaging as a Diagnostic Tool. Finally, this observer of the scene predicts that the importance of this entire field will increase several orders of magnitude as soon as a treatment which slows the progression of Alzheimer disease is identified and announced. Several clinical treatment trials are coming to a close (results not yet announced), and many more are being planned; thus, we could read such an announcement of a successful treatment trial in our morning newspapers as early as next year or within the next few years. The implications then become obvious and huge. How do we assist the family physician in making the diagnosis of Alzheimer disease and distinguishing it from other dementias? What is the role of the neuroradiologist in diagnosing disorders not characterized by lesions? How do we use automated segmentation and registration programs for improved diagnosis? And finally, how do we identify those individuals who are currently cognitively healthy but who are at high risk for the future development of Alzheimer disease, and what is the role of MRI in early detection? We, in this field, will have the opportunity to take advantage of all of the rapidly improving technologies of MRI acquisition (structural, perfusion, diffusion tensor, susceptibility-weighted MRI and magnetic resonance spectroscopic imaging), reconstruction (Fourier and Bayesian methods), and image processing (segmentation and registration) techniques to address these fascinating and very high-impact medical questions.