Early Detection Of Neurodegenerative Disorders Research Articles

Considering Biomarkers of Neurodegeneration in Alzheimer’s Disease: The Potential of Circulating Cell-Free DNA in Precision Neurology

Neurodegenerative diseases, such as Alzheimer’s disease (AD), are a growing public health crisis, exacerbated by an aging global population and the lack of effective early disease-modifying therapies. Early detection of neurodegenerative disorders is critical to delaying symptom onset and mitigating disease progression, but current diagnostic tools often rely on detecting pathology once clinical symptoms have emerged and significant neuronal damage has already occurred. While disease-specific biomarkers, such as amyloid-beta and tau in AD, offer precise insights, they are too limited in scope for broader neurodegeneration screening for these conditions. Conversely, general biomarkers like neurofilament light chain (NfL) provide valuable staging information but lack targeted insights. Circulating cell-free DNA (cfDNA), released during cell death, is emerging as a promising biomarker for early detection. Derived from dying cells, cfDNA can capture both general neurodegenerative signals and disease-specific insights, offering multi-layered genomic and epigenomic information. Though its clinical potential remains under investigation, advances in cfDNA detection sensitivity, standardized protocols, and reference ranges could establish cfDNA as a valuable tool for early screening. cfDNA methylation signatures, in particular, show great promise for identifying tissue-of-origin and disease-specific changes, offering a minimally invasive biomarker that could transform precision neurology. However, further research is required to address technological challenges and validate cfDNA’s utility in clinical settings. Here, we review recent work assessing cfDNA as a potential early biomarker in AD. With continued advances, cfDNA could play a pivotal role in shifting care from reactive to proactive, improving diagnostic timelines and patient outcomes.

Plasma neurofilament light chain associated with impaired regional cerebral blood flow in healthy individuals.

Background: Recent findings suggest that the plasma axonal structural protein, neurofilament light (NFL) chain, may serve as a potential blood biomarker for early signs of neurodegenerative diseases, such as Alzheimer's disease (AD). Given the need for early detection of neurodegenerative disorders, the current study investigated the associations between regional cerebral blood flow (rCBF) in brain regions associated with neurodegenerative disorders and memory function with plasma NFL in AD, mild cognitive impairment (MCI), and healthy controls (HCs). Methods: We recruited 29 AD, 76 MCI, and 39 HCs from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database in the current cross-sectional study. We used Pearson's correlation models adjusted for the effect of age, sex, and APOE genotype to investigate the association between plasma NFL and rCBF. Results: We found non-significant differences in age (F(2, 141) = 1.304; P = 0.275) and years of education (F(2, 141) = 0.013; P = 0.987). Additionally, we found significant differences between groups in terms of MMSE scores (F(2, 141) = 100.953; P < 0.001). Despite the observation of significantly reduced rCBF in AD and MCI groups versus HCs, we did not detect significant differences in plasma NFL between these groups. We found significant negative associations between plasma NFL and rCBF in various AD-related regions, these findings were only observed after analyses in all participants, and were observed in HCs alone and no significant associations were observed in the AD or MCI groups. Conclusion: These outcomes add to our current understanding surrounding the use of rCBF and plasma NFL biomarkers as tools for early detection and diagnosis of neurodegenerative diseases. A conclusion might be that the association between NFL and impaired rCBF exists before the clinical symptoms appear. Further longitudinal studies with a large sample size should be performed to examine the correlation between plasma NFL and rCBF in order to understand these complex relationships.

Artificial intelligence-powered analysis of medical images for early detection of neurodegenerative diseases

Neurodegenerative diseases including Alzheimer's, Parkinson's, and Huntington's offer serious health issues to people all over the world, due to their progressive nature and lack of effective therapies. In order to improve patient outcomes and allow for prompt action to limit the progression of the disease, early identification is essential. With a focus on deep learning methods, this study investigates the use of AI-powered analysis of medical images for the early detection of neurodegenerative disorders. The use of several medical imaging modalities, such as PET, CT, and MRI, in identifying disease biomarkers at an early stage is investigated. The usefulness of deep learning techniques to automate feature extraction, categorize illness states, and track disease progression is highlighted. These techniques include convolutional neural networks [CNNs], recurrent neural networks [RNNs], and generative adversarial networks [GANs]. The study also discusses the difficulties in using AI implementation, including data quality, image variability, and the interpretability of AI models. Furthermore, the study explores possible regulatory and ethical considerations in clinical adoption. It also examines AI's growing role in clinical settings and its ability to work with personalized medicine which present promising opportunities for improving the diagnosis and management neurodegenerative disease. The final section of this paper outlines important future directions for increasing the use of AI in clinical care, including multi-modal fusion and transfer learning.

Plasma neurofilament light chain associated with Impaired regional cerebral blood flow in healthy individuals (P10-6.007)

<h3>Objective:</h3> Given the need for early detection of neurodegenerative disorders, the current study investigated the associations between rCBF in brain regions associated with neurodegenerative disorders and memory function with plasma NFL in AD, mild cognitive impairment (MCI), and healthy controls (HCs). <h3>Background:</h3> Recent findings suggest the plasma axonal structural protein, neurofilament light chain (NFL), may serve as a potential blood biomarker for early signs of neurodegenerative diseases, such as Alzheimer’s disease (AD). <h3>Design/Methods:</h3> We recruited 29 AD, 76 MCI, and 39 HCs from Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. <h3>Results:</h3> Despite the observation of significantly reduced rCBF in AD and MCI versus HCs, we did not detect significant differences in plasma NFL between these groups. We found significant negative associations between plasma NFL and rCBF in various AD-related regions, these findings were only observed after analyses in all participants, and HCs alone, while there were no significant associations in the AD or MCI groups. <h3>Conclusions:</h3> These outcomes add to our current understanding surrounding the use of rCBF and plasma NFL biomarkers as tools for early detection and diagnosis of neurodegenerative diseases. A conclusion might be that the association between NFL and impaired rCBF exists before the clinical symptoms appear. Further longitudinal studies with a large sample size should be performed to examine the correlation between plasma NFL and rCBF to needed to understand these complex relationships. <b>Disclosure:</b> Mr. Nabizadeh has nothing to disclose.

Ultra-sensitive techniques for detecting neurological biomarkers: Prospects for early diagnosis

Identifying reliable biomarkers and ultra-sensitive techniques are crucial for the early detection of neurodegenerative disorders (NDDs) to improve the clinical diagnosis and development of effective disease-modifying treatments. Here, we discussed recent technological advancements that enabled scientists to monitor brain health by detecting biological molecules even at lower levels. These technologies enabled the detection of neurological biomarkers in blood, revolutionizing the diagnosis and prognosis of NDDs. Moreover, it provided a better understanding of disease pathology's long-term effects, resulting in fewer invasive tests, early diagnosis, faster drug development, and possibly more effective therapies as possible outcomes.

Disposable Stochastic Sensors for the Simultaneous Assay of Acetylcholine and Dopamine in Whole Blood Samples

ABSTRACTAcetylcholine and dopamine are neurotransmitters important for aging and brain pathology. Their assay in whole blood is essential for fast and early detection of neurodegenerative disorders. Therefore, polymeric textile covered with a thin layer of Ag was used to provide stochastic sensors modified with maltodextrins presenting different dextrose equivalence: Maltodextrin I (dextrose equivalence 13.0–17.0), and Maltodextrin II (dextrose equivalence 16.5–19.5). These stochastic sensors were used reliable for both qualitative and quantitative analysis of acetylcholine and dopamine in whole blood samples. Their sensitivity and selectivity were high, and they were reliable for the assay of dopamine and acetylcholine in whole blood samples, with recoveries higher than 98.00%, and relative standard deviations (%) values lower than 1.00%.

Cognitive Variability during Middle-Age: Possible Association with Neurodegeneration and Cognitive Reserve.

Objective: Increased variability in cognition with age has been argued as an indication of pathological processes. Focusing on early detection of neurodegenerative disorders, we investigated variability in cognition in healthy middle-aged adults. In order to understand possible determinants of this variability, we also investigated associations with cognitive reserve, neuroimaging markers, subjective memory complaints, depressive symptomatology, and gender.Method: Thirty-one 50 ± 2 years old individuals were investigated as target group and deviation was studied in comparison to a reference younger group of 30 individuals 40 ± 2 years old. Comprehensive neuropsychological and structural imaging protocols were collected. Brain regional volumes and cortical thickness were calculated with FreeSurfer, white matter hyperintensities with CASCADE, and mean diffusivity with FSL.Results: Across-individuals variability showed greater dispersion in lexical access, processing speed, executive functions, and memory. Variability in global cognition correlated with, reduced cortical thickness in the right parietal-temporal-occipital association cortex, and increased mean diffusivity in the cingulum bundle and right inferior fronto-occipital fasciculus. A trend was also observed for the correlation between global cognition and hippocampal volume and female gender. All these associations were influenced by cognitive reserve. No correlations were found with subjective memory complaints, white matter hyperintensities and depressive symptomatology. Across-domains and across-tasks variability was greater in several executive components and cognitive processing speed.Conclusion: Variability in cognition during middle-age is associated with neurodegeneration in the parietal–temporal–occipital association cortex and white matter tracts connecting this to the prefrontal dorsolateral cortex and the hippocampus. Moreover, this effect is influenced by cognitive reserve. Studying variability offers valuable information showing that differences do not occur in the same magnitude and direction across individuals, cognitive domains and tasks. These findings may have important implications for early detection of subtle cognitive impairment and clinical interpretation of deviation from normality.

Gait Is Associated with Cognitive Flexibility: A Dual-Tasking Study in Healthy Older People.

Objectives: To analyze which gait parameters are primarily influenced by cognitive flexibility, and whether such an effect depends on the walking condition used.Design: Cross-sectional analysis.Setting: Tübingen evaluation of Risk factors for Early detection of Neurodegenerative Disorders.Participants: A total of 661 non-demented individuals (49–80 years).Measurements: A gait assessment with four conditions was performed: a 20 m walk at convenient speed (C), at fast speed (F), at fast speed while checking boxes (FB), and while subtracting serial 7s (FS). Seven gait parameters from a wearable sensor-unit (McRoberts, Netherlands) were compared with delta Trail-Making-Test (dTMT) values, which is a measure of cognitive flexibility. Walking strategies of good and poor dTMT performers were compared by evaluating the patterns of gait parameters across conditions.Results: Five parameters correlated significantly with the dTMT in the FS condition, two parameters in the F and FB condition, and none in the C condition. Overall correlations were relatively weak. Gait speed was the gait parameter that most strongly correlated with the dTMT (r2 = 7.4%). In good, but not poor, dTMT performers differences between FB and FS were significantly different in variability-associated gait parameters.Conclusion: Older individuals need cognitive flexibility to perform difficult walking conditions. This association is best seen in gait speed. New and particularly relevant for recognition and training of deficits is that older individuals with poor cognitive flexibility have obviously fewer resources to adapt to challenging walking conditions. Our findings partially explain gait deficits in older adults with poor cognitive flexibility.

Evidence for a Selectively Regulated Prioritization Shift Depending on Walking Situations in Older Adults.

Background: Older adults have increased risks of balance issues and falls when walking and performing turns in daily situations. Changes of prioritization during different walking situations associated with dual tasking may contribute to these deficits. The objective of this study was therefore to investigate whether older adults demonstrate changes of prioritization during different walking paths.Methods: In total, 1,054 subjects with an age range from 50 to 83 years were selected from the first follow-up visit of the TREND (Tuebinger evaluation of Risk factors for Early detection of Neurodegenerative Disorders) study. They were classified according to their performance on the Trail Making Test (TMT) into good and poor TMT performers (based on recent results showing that cognitive flexibility affects prioritization strategies during straight walking). Absolute dual-task performance and relative dual-task costs (DTC, relative performance under dual-task conditions compared with single-task conditions) were assessed in two paradigms: walking while subtracting serial 7 s and walking while checking boxes on a clipboard. Both tasks were performed on straight and curved paths.Results: Overall, the poor TMT performers group performed worse in all single and dual tasks. Interestingly, the relative change in performance measured by dual-task costs differed in the groups between the two walking paths. On straight paths, poor TMT performers had a similar DTC of walking to that of good performers (p = 0.10) but had a significantly lower DTC of subtracting (p = 0.02). On curved paths, poor performers had a similar DTC of subtracting (p = 0.10), but their DTC of walking was significantly higher (p < 0.0001).Conclusion: Given that walking on curved paths is considered more difficult than that on straight paths and that the serial subtracting dual task is more difficult than the box checking dual task, this study in older adults provides evidence for the existence of a (walking) situation-dependent change of prioritization. If confirmed in other studies, situation-dependent change of prioritization should be included as a potential factor contributing to gait and balance impairments, and increased fall risk in older adults.

Poor Trail Making Test Performance Is Directly Associated with Altered Dual Task Prioritization in the Elderly – Baseline Results from the TREND Study

BackgroundDeterioration of executive functions in the elderly has been associated with impairments in walking performance. This may be caused by limited cognitive flexibility and working memory, but could also be caused by altered prioritization of simultaneously performed tasks. To disentangle these options we investigated the associations between Trail Making Test performance—which specifically measures cognitive flexibility and working memory—and dual task costs, a measure of prioritization.Methodology and Principal FindingsOut of the TREND study (Tuebinger evaluation of Risk factors for Early detection of Neurodegenerative Disorders), 686 neurodegeneratively healthy, non-demented elderly aged 50 to 80 years were classified according to their Trail Making Test performance (delta TMT; TMT-B minus TMT-A). The subjects performed 20 m walks with habitual and maximum speed. Dual tasking performance was tested with walking at maximum speed, in combination with checking boxes on a clipboard, and subtracting serial 7 s at maximum speeds. As expected, the poor TMT group performed worse when subtracting serial 7 s under single and dual task conditions, and they walked more slowly when simultaneously subtracting serial 7 s, compared to the good TMT performers. In the walking when subtracting serial 7 s condition but not in the other 3 conditions, dual task costs were higher in the poor TMT performers (median 20%; range −6 to 58%) compared to the good performers (17%; −16 to 43%; p<0.001). To the contrary, the proportion of the poor TMT performance group that made calculation errors under the dual tasking situation was lower than under the single task situation, but higher in the good TMT performance group (poor performers, −1.6%; good performers, +3%; p = 0.035).ConclusionUnder most challenging conditions, the elderly with poor TMT performance prioritize the cognitive task at the expense of walking velocity. This indicates that poor cognitive flexibility and working memory are directly associated with altered prioritization.

Looking backward to move forward: early detection of neurodegenerative disorders.

Early detection of neurodegenerative disorders would provide clues to the underlying pathobiology of these diseases and would enable more effective diagnosis and treatment of patients. Recent advances in molecular neuroscience have begun to provide the tools to detect diseases like Alzheimer's disease, Parkinson's disease, and others early in their course and potentially even before the development of clinical manifestations of disease. These genetic, imaging, clinical, and biochemical tools are being validated in a number of studies. Early detection of these slowly progressive diseases offers the promise of presymptomatic diagnosis and, ultimately, of disease-modifying medications for use early in disease and during the presymptomatic period.

Problems and Progress

### Contents #### News In Sickness or in Health? Future Brightening for Depression Treatments #### Reviews and Viewpoints Games Played by Rogue Proteins in Prion Disorders and Alzheimer's Disease A. Aguzzi and C. Haass Molecular Pathways of Neurodegeneration in Parkinson's Disease T. M. Dawson and V. L. Dawson The Genetics of Common Adult-Onset Neuropsychiatric Disease: Complexities and Conundra? J. L. Kennedy et al. Postnatal Neurodevelopmental Disorders: Meeting at the Synapse? H. Y. Zoghbi Looking Backward to Move Forward: Early Detection of Neurodegenerative Disorders S. T. DeKosky and K. Marek Immunotherapeutic Approaches to Alzheimer's Disease A. Monsonego and H. L. Weiner Related Science's SAGEKE and STKE material; related Brevia article by Singleton et al., related Reports by Mallucci et al., W.G. Chen et al., and Martinowich et al.; and related special Web supplement T his special issue of Science focuses on a wide range of brain diseases. The past years have seen tremendous progress in the battle against these diseases. Most promising in the long run, our understanding of the basic mechanisms underlying many of these diseases has grown. There have also been improvements in diagnostics and important additions to our arsenal of treatments and interventions. Our contributors describe some of the most exciting recent developments in the field and give a sense of the prospects for future prevention and therapy. Aguzzi and Haass (p. [814][1]) review the common features and the differences in the pathogenesis of Alzheimer's disease and prion disorders, both of which involve the accumulation of misfolded proteins. Dawson and Dawson (p. [819][2]) overview the present state of our knowledge of Parkinson's disease. Their main focus is on recent progress in the unraveling of the molecular pathways that cause neurodegeneration in this disease. Kennedy et al . (p. [822][3]) look at the complexities of the genetics underlying many neurodegenerative and neuropsychiatric disorders, such as schizophrenia or frontotemporal dementia. Zoghbi (p. 826) reviews recent developments in our understanding of autism and Rett syndrome, a developmental disorder in young children, and proposes a new model to explain the relation between these two diseases. DeKosky and Marek (p. 830) review the different imaging, biochemical, and clinical measures presently available for early detection of neurodegenerative disorders. This may trigger interventions, some of which slow the course of disease, before a large part of the damage has been done. Monsonego and Weiner (p. [834][4]) describe the promising concept of immunotherapeutic approaches to treat Alzheimer's disease. The News section focuses on mental illness. Psychiatrists are contemplating a major overhaul of the manual they use to define brain diseases (Helmuth, p. 808). One of the most problematic diagnoses is depression. While researchers explore possible causes of depression and associated brain dysfunction, several treatment options are wending their way through clinical trials (Holden, p. [810][5]). At Science 's Signal Transduction Knowledge Environment (STKE, ), Manji et al . discuss a possible role of the phosphatase calcineurin in schizophrenia; Robinson reviews contributions of neurotransmitter transporters in psychiatric disorders; and MacDonald examines evidence for the signaling functions of huntingtin, a protein altered in Huntington's disease. In the Science of Aging Knowledge Environment (SAGE KE, ), Groves et al . present the case of a 48-year-old man who suffered from Huntington's disease. The case study includes pathology slides and a movie of the patient's neurological testing. An updated introduction to Alzheimer's disease by Helmuth covers diagnosis, pathology, prevention, and treatment. [1]: /lookup/doi/10.1126/science.1087348 [2]: /lookup/doi/10.1126/science.1087753 [3]: /lookup/doi/10.1126/science.1092132 [4]: /lookup/doi/10.1126/science.1088469 [5]: /lookup/doi/10.1126/science.302.5646.810