Specific Neurodegenerative Diseases Research Articles

Biochemical Evidence for a Pathological Variant of Progressive Supranuclear Palsy

AbstractBackgroundTau proteins aggregate into spatially and morphologically distinct lesions in primary and secondary tauopathies. These signature lesions result from deposition of tau proteins that are distinctly modified via missense mutation and/or post‐translational modification for each disease strain. Identifying the unique tau protein abnormalities that lead to specific neurodegenerative diseases is beneficial in their early diagnosis and treatment. This is especially true for Progressive Supranuclear Palsy a primary tauopathy with clinical symptoms mirroring Parkinsonian syndromes and frontotemporal dementias.MethodBiochemical analysis of tau aggregates from patients with a pathological diagnosis of Progressive Supranuclear Palsy (n = 60) demonstrate that the tau protein modifications observed in this disease result from tau that is specifically modified and thereby forms the basis of the distinct disease strains observed. Here data collected using the sarkosyl‐insoluble tau fractions from tissue samples of pathologically diagnosed patients with Progressive Supranuclear Palsy without comorbidities allows for the direct observation of the modifications. Most interesting is the variability of the tau proteins that actually accumulate for this disease opening up the possibility that tau strains may exist within any given tauopathy even as the clinical manifestations appear similar. This indicates that early and specific identification and detection of these strains is critical for the development of therapies for these diseases.ResultExtraction and examination of sarkosyl‐insoluble tau proteins from deceased patients pathologically diagnosed with Progressive Supranuclear Palsy indicate that multiple tau strains exist within this primary tauopathy. Western blotting of these extracts from patient tissues demonstrates a unique banding pattern of insoluble tau in a subset of the cases that exhibit extreme hyperphosphorylation as indicated by additional high molecular weight tau banding. These patients also had an earlier age of onset and age of death indicating a more aggressive disease strain. Additional data is presented comparing the structure and seeding capability of this insoluble tau and the distribution and burden of insoluble tau in these Progressive Supranuclear Palsy patients compared to those with typical onset and insoluble tau signature.ConclusionMultiple pathological tau strains exist in Progressive Supranuclear Palsy.

A multi-layered network model identifies Akt1 as a common modulator of neurodegeneration.

The accumulation of misfolded and aggregated proteins is a hallmark of neurodegenerative proteinopathies. Although multiple genetic loci have been associated with specific neurodegenerative diseases (NDs), molecular mechanisms that may have a broader relevance for most or all proteinopathies remain poorly resolved. In this study, we developed a multi-layered network expansion (MLnet) model to predict protein modifiers that are common to a group of diseases and, therefore, may have broader pathophysiological relevance for that group. When applied to the four NDs Alzheimer's disease (AD), Huntington's disease, and spinocerebellar ataxia types 1 and 3, we predicted multiple members of the insulin pathway, including PDK1, Akt1, InR, and sgg (GSK-3β), as common modifiers. We validated these modifiers with the help of four Drosophila ND models. Further evaluation of Akt1 in human cell-based ND models revealed that activation of Akt1 signaling by the small molecule SC79 increased cell viability in all models. Moreover, treatment of AD model mice with SC79 enhanced their long-term memory and ameliorated dysregulated anxiety levels, which are commonly affected in AD patients. These findings validate MLnet as a valuable tool to uncover molecular pathways and proteins involved in the pathophysiology of entire disease groups and identify potential therapeutic targets that have relevance across disease boundaries. MLnet can be used for any group of diseases and is available as a web tool at http://ssbio.cau.ac.kr/software/mlnet.

Blood-Based Transcriptomic Biomarkers Are Predictive of Neurodegeneration Rather Than Alzheimer's Disease.

Alzheimer's disease (AD) is a growing global health crisis affecting millions and incurring substantial economic costs. However, clinical diagnosis remains challenging, with misdiagnoses and underdiagnoses being prevalent. There is an increased focus on putative, blood-based biomarkers that may be useful for the diagnosis as well as early detection of AD. In the present study, we used an unbiased combination of machine learning and functional network analyses to identify blood gene biomarker candidates in AD. Using supervised machine learning, we also determined whether these candidates were indeed unique to AD or whether they were indicative of other neurodegenerative diseases, such as Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). Our analyses showed that genes involved in spliceosome assembly, RNA binding, transcription, protein synthesis, mitoribosomes, and NADH dehydrogenase were the best-performing genes for identifying AD patients relative to cognitively healthy controls. This transcriptomic signature, however, was not unique to AD, and subsequent machine learning showed that this signature could also predict PD and ALS relative to controls without neurodegenerative disease. Combined, our results suggest that mRNA from whole blood can indeed be used to screen for patients with neurodegeneration but may be less effective in diagnosing the specific neurodegenerative disease.

Antibiotics: Treatment for Alzheimer’s diseases

AbstractBackgroundAlzheimer’s is a specific neurodegenerative disease that accounts for 60‐80% of overall dementia cases. This is the most common type of dementia arises from the deposition of beta‐amyloid plaques and neurofibrillary tangles, in the hippocampal region and the entorhinal cortex tends to cause neuronal death. Currently, available drugs can provide symptomatic relief in patients associated with AD. Recently, it has been reported that antibiotics can exert a variety of biological actions that are independent of their anti‐microbial activity, including anti‐inflammatory, anti‐excitotoxic, anti‐apoptotic, and antioxidant activities.MethodA number of antibiotics are used in the preclinical and clinical studies of Alzheimer’s disease. Among all antibiotics β‐lactam antibiotics and tetracyclines are well reported to reach CSF concentration, targeting Alzheimer’s disease. These two classes well suggest their neuroprotective role in various neurodegenerative disorders. β‐lactam antibiotics (penicillins and cephalosporins) has been demonstrated as protectors against near excitotoxicity. Ceftriaxone posses good BBB penetration thus used for various neurodegenerative disorders and shows the improvement in learning and cognitive functions when studied in transgenic models of AD.ResultThe combination of two well known pharmacokinetically safer antibiotics to synergize their individual effects and develop a newer approach concerning the treatment of AD.ConclusionFurthermore, there is a need to develop the neuroprotective mechanisms in the treatment of Alzheimer’s disease.

Mechanism Exploration of Amyloid-β-42 Disaggregation by Single-Chain Variable Fragments of Alzheimer's Disease Therapeutic Antibodies.

Alzheimer's disease (AD) is a specific neurodegenerative disease. This study adopts single-chain variable fragments (scFvs) as a potential immunotherapeutic precursor for AD. According to the remarkable effects of monoclonal antibodies, such as the depolymerization or promotion of Aβ42 efflux by Crenezumab, Solanezumab, and 12B4, it is attractive to prepare corresponding scFvs targeting amyloid-β-42 protein (Aβ42) and investigate their biological activities. Crenezumab-like scFv (scFv-C), Solanezumab-like scFv (scFv-S), and 12B4-like scFv (scFv-12B4) were designed and constructed. The thermal stabilities and binding ability to Aβ42 of scFv-C, scFv-S, and scFv-12B4 were evaluated using unfolding profile and enzyme-linked immunosorbent assay. As the results indicated that scFv-C could recognize Aβ42 monomer/oligomer and promote the disaggregation of Aβ42 fiber as determined by the Thioflavin-T assay, the potential mechanism of its interaction with Aβ42 was investigated using molecular dynamics analysis. Interactions involving hydrogen bonds and salt bonds were predicted between scFv-C and Aβ42 pentamer, suggesting the possibility of inhibiting further aggregation of Aβ42. The successfully prepared scFvs, especially scFv-C, with favorable biological activity targeting Aβ42, might be developed for a potentially efficacious clinical application for AD.

New Perspectives in Nonintrusive Sleep Monitoring for Neurodegenerative Diseases—A Narrative Review

Good sleep quality is of primary importance in ensuring people’s health and well-being. In fact, sleep disorders have well-known adverse effects on quality of life, as they influence attention, memory, mood, and various physiological regulatory body functions. Sleep alterations are often strictly related to age and comorbidities. For example, in neurodegenerative diseases, symptoms may be aggravated by alterations in sleep cycles or, vice versa, may be the cause of sleep disruption. Polysomnography is the primary instrumental method to investigate sleep diseases; however, its use is limited to clinical practice. This review aims to provide a comprehensive overview of the available innovative technologies and methodologies proposed for less invasive sleep-disorder analysis, with a focus on neurodegenerative disorders. The paper intends to summarize the main studies, selected between 2010 and 2022, from different perspectives covering three relevant contexts, the use of wearable and non-wearable technologies, and application to specific neurodegenerative diseases. In addition, the review provides a qualitative summary for each selected article concerning the objectives, instrumentation, metrics, and impact of the results obtained, in order to facilitate the comparison among methodological approaches and overall findings.

Hallmarks of neurodegenerative diseases.

Decades of research have identified genetic factors and biochemical pathways involved in neurodegenerative diseases (NDDs). We present evidence for the following eight hallmarks of NDD: pathological protein aggregation, synaptic and neuronal network dysfunction, aberrant proteostasis, cytoskeletal abnormalities, altered energy homeostasis, DNA and RNA defects, inflammation, and neuronal cell death. We describe the hallmarks, their biomarkers, and their interactions as a framework to study NDDs using a holistic approach. The framework can serve as a basis for defining pathogenic mechanisms, categorizing different NDDs based on their primary hallmarks, stratifying patients within a specific NDD, and designing multi-targeted, personalized therapies to effectively halt NDDs.

Research Progress of Nanocarriers for the Treatment of Alzheimer's Disease.

Currently, many therapeutic drugs are difficult to cross the blood-brain barrier (BBB), making it difficult to reach the site of action and thus fail to achieve the desired efficacy. In recent years, researchers and drug designers have increasingly focused on nanotechnology to break through the difficulty of small molecule inhibitors to cross the blood-brain barrier (BBB) and improve the success rate of drug delivery to the central nervous system. Among the common central neurological diseases, such as encephalitis, Parkinson's, Alzheimer's disease, and epilepsy, Alzheimer's disease has attracted much attention from researchers. Alzheimer's disease is a specific neurodegenerative disease, which causes irreversible degeneration of neurons as well as synapses in the brain, resulting in memory and cognitive dysfunction, along with other psychiatric symptoms and behavioral disorders, which seriously affects people's everyday life. Moreover, nanotechnology has excellent potential for application in AD treatment. Studies have shown that nanocarriers can target the delivery of chemotherapeutic drugs, antioxidants, and other therapeutic substances to brain tissue using existing physiological mechanisms, thus effectively alleviating the disease progression of AD. Therefore, various nanoparticles and nanomedicine have been developed and constructed for diagnosing and treating AD in the past decades, such as nanoparticles, bionanoparticles, liposomes, nano-gel, dendrimers, and self-assembled nanoparticles. This study aims to review the applications and results of nanotechnology in the treatment of Alzheimer's disease in recent years and provide some ideas and clues for future research and development of more effective drug delivery systems.

Cultured dissociated primary dorsal root ganglion neurons from adult horses enable study of axonal transport.

Neurological disorders are prevalent in horses, but their study is challenging due to anatomic constraints and the large body size; very few host‐specific in vitro models have been established to study these types of diseases, particularly from adult donor tissue. Here we report the generation of primary neuronal dorsal root ganglia (DRG) cultures from adult horses: the mixed, dissociated cultures, containing neurons and glial cells, remained viable for at least 90 days. Similar to DRG neurons in vivo, cultured neurons varied in size, and they developed long neurites. The mitochondrial movement was detected in cultured cells and was significantly slower in glial cells compared to DRG‐derived neurons. In addition, mitochondria were more elongated in glial cells than those in neurons. Our culture model will be a useful tool to study the contribution of axonal transport defects to specific neurodegenerative diseases in horses as well as comparative studies aimed at evaluating species‐specific differences in axonal transport and survival.

Football and Dementia: Understanding the Link.

Football, also known as soccer or association football, is popular but has a potential link with dementia developing in retired players. The FA and soccer regulators in the USA have imposed guidelines limiting players exposure to heading, despite controversy whether this dementia is caused by heading the ball, a form of mild repetitive head injury (RHI), over many years. Substantial data exist showing that many ex-North American Football players develop a specific neurodegenerative disease: chronic traumatic encephalopathy (CTE), the neuropathological disorder of boxers. In the United Kingdom evidence for the neuropathological basis of footballers' dementia has been slow to emerge. A 2017 study revealed that in six ex-soccer players four had CTE with Alzheimer's disease (AD) and two had AD. A 2019 study showed that ex-footballers were 3.5 times more likely to die from dementia or other neuro-degenerative diseases than matched controls. We argue that in childhood and adolescence the brain is vulnerable to heading, predicated on its disproportionate size and developmental immaturity. RHI in young individuals is associated with early neuroinflammation, a potential trigger for promoting neurodegeneration in later life. Evidence is available to support the guidelines limiting heading for players of all ages, while professional and non-players should be included in prospective studies to investigate the link between soccer and dementia.

Perspective: cell death mechanisms and early diagnosis as precondition for disease modification in Parkinson’s disease: are we on the right track?

ABSTRACT Introduction Current research paradigms on biomarkers for chronic neurodegenerative diseases, such as Parkinson’s disease, focus on identification of reliable, easy-to-apply tools for diagnostic screening and progression assessment. Areas covered This perspective discusses possible misconceptions of biomarker research in chronic neurodegeneration from a clinician’s view based on a not systematic literature search. Multifactorial disease triggers, heterogeneity of symptom and their progression are main reasons for the still missing availability of biomarkers. Expert opinion Onset of chronic neurodegenerative disease entities may probably result from a decompensated endogenous repair machinery in the central nervous system, for example the neogenin receptor associated repulsive guidance molecule pathway. Future clinical research is warranted on these repair structures and aim to identify markers for the imbalance between damage and repair, which hypothetically contributes to generation of disease. An assignment to a specific chronic neurodegenerative disease entity probably appears to be secondary. Decryption of probable molecular signals of an impaired repair potential will enable an earlier diagnosis, better monitoring of disease progress and of treatment response. This concept will hopefully provide better preconditions for prevention, cure or therapeutic beneficial disease modification. These unmet therapeutic needs may be achieved for example via antagonism of repulsive guidance molecule A.

Neurodegenerative brain changes are associated with area deprivation in the United Kingdom: findings from the Brains for Dementia Research study

Socioeconomic disadvantage is associated with greater risk of dementia. This has been theorised to reflect inequalities in cognitive reserve, healthcare access, lifestyle, and other health factors which may contribute to the clinical manifestation of dementia. We aimed to assess whether area deprivation in the United Kingdom was associated with greater risk or severity of the specific neurodegenerative diseases which lead to dementia in a multi-centre cohort with autopsy assessment. Participants underwent clinical assessment prior to brain tissue donation post-mortem. Each then underwent detailed, standardised neuropathological assessment. National area deprivation statistics were derived for each participant’s neighbourhood, for use as a predictor in binary and ordinal logistic models assessing the respective presence and severity of staging of key neuropathological changes, adjusting for theorised confounders. Individuals from among the 20% most deprived neighbourhoods in the United Kingdom had significantly higher neurofibrillary tangle and neuritic plaque staging, and increased risk of cerebral amyloid angiopathy. These findings were not explained by a greater risk of diabetes or hypertension, APOE genotype, alcohol misuse or tobacco smoking, sex, or age differences. A sensitivity analysis conditioning on baseline cognitive impairment did not meaningfully change the observed association. Socioeconomic disadvantage may contribute to dementia incidence through a greater severity of specific neuropathological changes (neurofibrillary tangles, neuritic plaques, and cerebral amyloid angiopathy), independent of other indirect influences. Mechanisms through which deprivation is associated with these require further exploration.

Targeted Quantification of Detergent-Insoluble RNA-Binding Proteins in Human Brain Reveals Stage and Disease Specific Co-aggregation in Alzheimer's Disease.

Core spliceosome and related RNA-binding proteins aggregate in Alzheimer’s disease (AD) brain even in early asymptomatic stages (AsymAD) of disease. To assess the specificity of RNA-binding protein aggregation in AD, we developed a targeted mass spectrometry approach to quantify broad classes of RNA-binding proteins with other pathological proteins including tau and amyloid beta (Aβ) in detergent insoluble fractions from control, AsymAD, AD and Parkinson’s disease (PD) brain. Relative levels of specific insoluble RNA-binding proteins across different disease groups correlated with accumulation of Aβ and tau aggregates. RNA-binding proteins, including splicing factors with homology to the basic-acidic dipeptide repeats of U1-70K, preferentially aggregated in AsymAD and AD. In contrast, PD brain aggregates were relatively depleted of many RNA-binding proteins compared to AsymAD and AD groups. Correlation network analyses resolved 29 distinct modules of co-aggregating proteins including modules linked to spliceosome assembly, nuclear speckles and RNA splicing. Modules related to spliceosome assembly and nuclear speckles showed stage-specific enrichment of insoluble RBPs from AsymAD and AD brains, whereas the RNA splicing module was reduced specifically in PD. Collectively, this work identifies classes of RNA-binding proteins that distinctly co-aggregate in detergent-insoluble fractions across the specific neurodegenerative diseases we examined.

Human-Induced Pluripotent Stem Cell-Based Models for Studying Sex-Specific Differences in Neurodegenerative Diseases.

The prevalence of neurodegenerative diseases is steadily increasing worldwide, and epidemiological studies strongly suggest that many of the diseases are sex-biased. It has long been suggested that biological sex differences are crucial for neurodegenerative diseases; however, how biological sex affects disease initiation, progression, and severity is not well-understood. Sex is a critical biological variable that should be taken into account in basic research, and this review aims to highlight the utility of human-induced pluripotent stem cells (iPSC)-derived models for studying sex-specific differences in neurodegenerative diseases, with advantages and limitations. In vitro systems utilizing species-specific, renewable, and physiologically relevant cell sources can provide powerful platforms for mechanistic studies, toxicity testings, and drug discovery. Matched healthy, patient-derived, and gene-corrected human iPSCs, from both sexes, can be utilized to generate neuronal and glial cell types affected by specific neurodegenerative diseases to study sex-specific differences in two-dimensional (2D) and three-dimensional (3D) human culture systems. Such relatively simple and well-controlled systems can significantly contribute to the elucidation of molecular mechanisms underlying sex-specific differences, which can yield effective, and potentially sex-based strategies, against neurodegenerative diseases.

Extracellular Vesicles for the Diagnosis and Treatment of Parkinson's Disease.

Extracellular vesicles (EVs) shed by neurons and glia in the central nervous system carry a cargo of specific bioactive molecules, facilitating intercellular communication. However, in neurodegenerative disease conditions, EVs carry pathological miRNAs and/or proteins involved in spreading the disease. Such EVs are also found in the cerebrospinal fluid (CSF) or the circulating blood, the characterization of which could identify biomarkers linked to specific neurodegenerative diseases. Moreover, EVs secreted by various stem/progenitor cells carry therapeutic miRNAs and proteins, which have shown promise to alleviate symptoms and slow down the progression of neurodegenerative diseases. The ability of exogenously administered EVs to easily cross the blood-brain barrier with no risk for thrombosis and incorporate into neurons and glia has also opened up the possibility of using nano-sized EVs as carriers of therapeutic drugs or bioactive proteins. This review summarizes the role and function of EVs in alpha-synuclein-mediated neurodegeneration and the spread of alpha-synuclein from neurons to glia, leading to the activation of the inflammatory response in Parkinson’s disease (PD). Moreover, the promise of brain-derived EVs in the CSF and the circulating blood for biomarker discovery and the efficacy of stem/progenitor cell-derived EVs or EVs loaded with bioactive molecules such as dopamine, catalase, curcumin, and siRNAs, in alleviating Parkinsonian symptoms are discussed.

Benefits of nonlinear analysis indices of walking stride interval in the evaluation of neurodegenerative diseases.

Indices characterising the long-range temporal structure of walking stride interval (SI) variability such as Hurst exponent (H) and fractal dimension (D) may be used in addition to indices measuring the amount of variability like the coefficient of variation (CV). We assess the added value of the former indices in a clinical neurological context. Our aim is to demonstrate that they provide a clinical significance in aging and in frequent neurodegenerative diseases such as Parkinson's disease, Huntington, and amyotrophic lateral sclerosis. Indices assessing the temporal structure of variability are mainly dependent on SI time series length and algorithms used, making quantitative comparisons between different studies difficult or even impossible. Here, we recompute these indices from available SI time series, either from our lab or from online databases. More precisely, we recompute CV, H, and D in a unified way. The average SI is also added to the measured parameters. We confirm that variability indices are relevant indicators of aging process and neurodegenerative diseases. While CV is sensitive to aging process and pathology, it does not discriminate between specific neurodegenerative diseases. H, which measures predictability of SI, significantly decreases with age but increases in patients suffering from amyotrophic lateral sclerosis. D, catching complexity of SI, is correlated with total functional capacity in patients with Huntington's disease. We conclude that the computation of H complements the clinical diagnosis of walking in patients with neurodegenerative diseases and we recommend it as a relevant supplement to classical CV or averaged SI. Since H and D indices did not lead to the same observations, suggesting the multi-fractal nature of SI dynamics, we recommend to open clinical gait analysis to the evaluation of more parameters.

Medical cost and healthcare utilization of amyotrophic lateral sclerosis in China: A cohort study based on hospital data from 2015 to 2018.

Amyotrophic lateral sclerosis (ALS), a specific neurodegenerative disease, imposed increased economic and utilizations burden on the healthcare system, especially with the progress of the diseases severity. However, the economic burden on Chinese ALS patients remained unclear. This study therefore was aimed to investigate medical cost and healthcare utilization for Chinese ALS patients.Longitudinal health data of over 20 million individuals, including military personnel and civilians, was collected from all Chinese military hospitals. We identified 480 patients with a first major diagnosis for ALS from 2015 to 2018, while matched 400 controlled patients on age, gender, ethnic group, geographic region, length of stay, year of diagnosis and comorbidity. Their medical cost and healthcare utilizations were then measured 1 year before, and 1 year after ALS diagnosis.The median annual medical cost of ALS patients was about 2-fold higher, 17,087 CNY during the index year than 1 year before, 7859 CNY. The highest increase in utilizations may account for medical costs on ALS patients, which was represented by hospitalizations (Odd Ratio (OR) = 4.26, 95% confidence interval (CI) 3.52, 5.15), electromyography (OR = 4.14, 95% CI 2.37, 7.22), nerve conduction velocity (OR = 3.26, 95% CI 2.23, 4.77).This study is the first one reporting direct economic burden on Chinese ALS patients. Efforts should be made to develop cost-effective diagnostic tools in order that sources of medical cost were more effectively allocated, and this disease was detected earlier.

Brain Renin-Angiotensin System at the Intersect of Physical and Cognitive Frailty.

The renin–angiotensin system (RAS) was initially considered to be part of the endocrine system regulating water and electrolyte balance, systemic vascular resistance, blood pressure, and cardiovascular homeostasis. It was later discovered that intracrine and local forms of RAS exist in the brain apart from the endocrine RAS. This brain-specific RAS plays essential roles in brain homeostasis by acting mainly through four angiotensin receptor subtypes; AT1R, AT2R, MasR, and AT4R. These receptors have opposing effects; AT1R promotes vasoconstriction, proliferation, inflammation, and oxidative stress while AT2R and MasR counteract the effects of AT1R. AT4R is critical for dopamine and acetylcholine release and mediates learning and memory consolidation. Consequently, aging-associated dysregulation of the angiotensin receptor subtypes may lead to adverse clinical outcomes such as Alzheimer’s disease and frailty via excessive oxidative stress, neuroinflammation, endothelial dysfunction, microglial polarization, and alterations in neurotransmitter secretion. In this article, we review the brain RAS from this standpoint. After discussing the functions of individual brain RAS components and their intracellular and intracranial locations, we focus on the relationships among brain RAS, aging, frailty, and specific neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and vascular cognitive impairment, through oxidative stress, neuroinflammation, and vascular dysfunction. Finally, we discuss the effects of RAS-modulating drugs on the brain RAS and their use in novel treatment approaches.

Modelling neurodegenerative diseases with 3D brain organoids.

Neurodegenerative diseases are incurable and debilitating conditions characterized by the deterioration of brain function. Most brain disease models rely on human post-mortem brain tissue, non-human primate tissue, or in vitro two-dimensional (2D) experiments. Resource limitations and the complexity of the human brain are some of the reasons that make suitable human neurodegenerative disease models inaccessible. However, recently developed three-dimensional (3D) brain organoids derived from pluripotent stem cells (PSCs), including embryonic stem cells and induced PSCs, may provide suitable models for the study of the pathological features of neurodegenerative diseases. In this review, we provide an overview of existing 3D brain organoid models and discuss recent advances in organoid technology that have increased our understanding of brain development. Moreover, we explain how 3D organoid models recapitulate aspects of specific neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, and explore the utility of these models, for therapeutic applications.

Depressive Symptom Profiles Predict Specific Neurodegenerative Disease Syndromes in Early Stages.

Background: During early stages, patients with neurodegenerative diseases (NDG) often present with depressive symptoms. However, because depression is a heterogeneous disorder, more precise delineation of the specific depressive symptom profiles that arise early in distinct NDG syndromes is necessary to enhance patient diagnosis and care.Methods and Findings: Five-hundred and sixty four participants self-reported their depressive symptoms using the Geriatric Depression Scale (GDS), including 111 healthy older control subjects (NC) and 453 patients diagnosed with one of six NDGs who were at the mild stage of disease (CDR® Dementia Staging Instrument ≤ 1) [186 Alzheimer's disease (AD), 76 behavioral variant frontotemporal dementia (bvFTD), 52 semantic variant primary progressive aphasia (svPPA), 46 non-fluent variant PPA (nfvPPA), 49 progressive supranuclear palsy syndrome (PSPS), 44 corticobasal syndrome (CBS)]. The GDS was divided into subscales based on a previously published factor analysis, representing five symptoms (dysphoria, hopelessness, withdrawal, worry, and cognitive concerns). Mixed models were created to examine differences in depression subscale by group, and logistic regression analyses were performed to determine if patterns of depressive symptoms could predict a patient's NDG syndrome. PSPS patients presented with a hopeless, dysphoric, and withdrawn pattern, while patients with CBS presented with a similar but less severe pattern. Worry was a key symptom in the profile of patients with svPPA, while ADs only had abnormally elevated cognitive concerns. Depressive profile accurately predicted NDG diagnosis at a rate of between 70 and 84% accuracy.Conclusions: These results suggest that attention to specific depressive symptom profile can improve diagnostic sensitivity and can be used to provide more individualized patient care.