Neurodegenerative Syndrome Research Articles

PET Imaging of Neurodegeneration With [18F]AV-1451 PET After Repetitive Traumatic Brain Injury

Abstract INTRODUCTION TBI (traumatic brain injury) is associated with an increased risk of late neurodegeneration in chronic TBI survivors. The underlying pathophysiology of trauma-related neurodegeneration is hypothesized to involve a tauopathy, with p-tau deposited in beta-pleated sheets. Current research focuses on identifying strategies to detect trauma-related neurodegeneration in-Vivo. [F-18]AV-1451, a tau-specific PET radiotracer, may detect hyper-phosphorylated tau deposits in living patients. METHODS Participants with a history of TBI >6 mo prior with concern for cognitive decline with age-matched controls were recruited. Subjects were classified into three groups: few (=3 TBI exposures), intermediate (4–10 exposures), and numerous (>10 exposures). Participants underwent PET imaging with [F-18]AV-1451, and qualitative and semi-quantitative (SUVR) analyses of radiotracer retention were performed. Visual classification of tau positivity (+/−) was performed with absence of established positivity thresholds for [F-18]AV-1451 SUVR values. All subjects underwent neuropsychological evaluation, including measures of processing speed, executive function, and memory. RESULTS Twenty-seven TBI subjects and 7 controls were enrolled. A total of 9 participants were categorized as few, 2 as intermediate, 7 as numerous. All TBI subjects demonstrated impairment on at least one neurocognitive measure, while control subjects had normal neuropsychological test results. Analysis of [F-18]AV-1451 uptake patterns demonstrated evidence of tauopathy in 3 subjects, based on visual reads. Significantly increased [F-18]AV-1451 retention was noted in occipital gray matter, posterior cingulate gyrus, and parietal cortex in these 3 tau (+) TBI subjects compared to 24 TBI subjects visually classified as tau (−) and also normal controls. CONCLUSION Evidence of tauopathy, indicative of trauma-related neurodegeneration, was noted in 3 chronic TBI subjects, all of whom were categorized as numerous (>10) TBI exposures and cognitive deficits on neuropsychological testing. No tau PET [F-18]AV-1451 uptake was noted in control participants or in participants categorized as few or intermediate. The data represent a possible [F-18]AV-1451 PET uptake pattern associated with a clinical neurodegeneration syndrome in repetitive TBI.

Comparison of the Short Test of Mental Status and the Montreal Cognitive Assessment Across the Cognitive Spectrum

ObjectiveTo compare the Short Test of Mental Status (STMS) with the Montreal Cognitive Assessment (MoCA) for predicting and detecting mild cognitive impairment (MCI). Participants and MethodsParticipants from the community-based Mayo Clinic Study of Aging (MCSA) (November 24, 2010, through May 19, 2012) and an academic referral Alzheimer’s Disease Research Center (ADRC) (March 16, 2015, through September 5, 2018) were analyzed. All participants were evaluated using a standardized neuropsychological battery, and a multidisciplinary consensus diagnosis was assigned. The MCSA and ADRC samples included 313 and 106 stable cognitively normal (CN) participants, 72 and 8 CN participants at baseline who developed incident MCI or dementia, 114 and 96 participants with prevalent MCI, and 25 and 132 participants with dementia, respectively. ResultsThere were no statistically significant differences between the 2 tests in 6 of 7 diagnostic comparisons across academic referral and community populations. The STMS had a better area under the curve (0.90; 95% CI, 0.87-0.93) for differentiating prevalent MCI from CN participants in the MCSA cohort compared with the MoCA cohort (0.85; 95% CI, 0.81-0.89; P=.01). In addition, 53% of the stable CN participants (222 of 419) scored less than 26 on the MoCA, with specificity of 47% for diagnosing prevalent MCI. ConclusionWe provide evidence that the STMS performs similarly to the MoCA in a variety of settings and neurodegenerative syndromes. These results suggest that the current recommended MoCA cutoff score may be overly sensitive, consistent with previous studies. We also provide a conversion table for comparing the 2 cognitive tests.

Lathyrus sativus Originating from Different Geographical Regions Reveals Striking Differences in Kunitz and Bowman-Birk Inhibitor Activities.

Grass pea (Lathyrus sativus L.) is an important legume commonly grown in arid and semi-arid regions. This protein-rich legume performs well even under harsh environmental conditions and is considered to be a strategic famine food in developing countries. Unfortunately, its potential usage is greatly limited as a result of the presence of antinutritional factors, including the neuroexcitatory amino acid β-N-oxalyl-l-α,β-diaminopropionic acid (β-ODAP) and protease inhibitors. β-ODAP is responsible for a neurodegenerative syndrome that results in the paralysis of lower limbs, while protease inhibitors affect protein digestibility, resulting in reduced growth. Concerted research efforts have led to development of grass pea cultivars with reduced β-ODAP content. In contrast, very little information is available on the protease inhibitors of L. sativus. In this study, we have conducted biochemical characterization of 51 L. sativus accessions originating from different geographical regions. Sodium dodecyl sulfate polyacrylamide gel electrophoresis analyses of seed globulins and prolamins revealed striking similarity in their protein profile, although geographic-specific variations in profiles was also evident. Measurement of Bowman-Birk chymotrypsin inhibitor (BBi) and Kunitz trypsin inhibitor (KTi) activities in accessions revealed striking differences among them. Amino acid sequence alignment of grass pea BBi and KTi revealed significant homology to protease inhibitors from several legumes. Real-time polymerase chain reaction analysis demonstrated high-level expression of BBi and KTi in dry seeds and weak expression in other organs. Our study demonstrates substantial variation in BBi and KTi among grass pea accessions that could be exploited in breeding programs for the development of grass pea lines that are devoid of these antinutritional factors.

Factors that predict diagnostic stability in neurodegenerative dementia.

To determine the frequency and characteristics of clinical diagnostic change in frontotemporal dementia (FTD)-spectrum syndromes and Alzheimer's disease (AD)-type dementia. We reviewed records and categorized diagnostic changes in patients seen ≥ 2 times with behavioral variant FTD (bvFTD, n = 99), nonfluent and semantic variant primary progressive aphasia (nfvPPA, n = 32; svPPA, n = 59), corticobasal syndrome (CBS, n = 40), progressive supranuclear palsy-Richardson syndrome (PSP-RS, n = 34), and AD-type dementia (n = 49). For bvFTD, we compared patients with and without diagnostic change, and assessed predictors of diagnostic change by logistic regression. Initial diagnoses changed infrequently at subsequent visits in svPPA (6.8%), PSP-RS (8.8%), and nfvPPA (12.5%), with rare changes largely involving clinicopathological overlap or diagnostic ambiguity. Changes in AD-type dementia (30.6%) and CBS (37.5%) were more common, but reflected greater specificity, predicted co-pathology, or overlapping syndromes. Diagnostic change in bvFTD was also common (32.3%), but more diverse, including motor neuron disease development, alternative neurodegenerative syndromes, and non-neurodegenerative diseases. Diagnostic change occurred more often in those who met possible rather than probable bvFTD criteria (70.6% vs 15.3%, p < 0.001). Patients with stable diagnoses showed greater overall impairment, bvFTD behavioral severity, and atrophy in core right-hemisphere bvFTD regions. Patients with diagnostic change had more severe depression (p < 0.05) and more frequent contributing, secondary diagnoses (p = 0.01), such as cerebrovascular disease. By logistic regression, the accuracy of predicting stable bvFTD diagnoses using first-visit data was 80%. bvFTD displays more diverse diagnostic change than other neurodegenerative syndromes. First-visit bvFTD diagnoses may waver if based on meeting possible criteria only.

Amelioration of Dystonic Opisthotonus in Pantothenate Kinase-Associated Neurodegeneration Syndrome with Absent "Eye-of-the-Tiger" Sign Following Bilateral Pallidal Deep Brain Stimulation.

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Cerebrolysin – mechanism of action and application in psychiatry and neurology

Cerebrolysin is a medication, which has been used in psychiatry and neurology for over 50 years. The aim of this paper is to present the current state of knowledge on cerebrolysin. It is a non-lipid mixture of free L-amino acids and neuropeptides of low molecular weight that are purified via enzymatic proteolysis from brains of young pigs. It also contains magnesium, phosphorus, potassium and selenium. Cerebrolysin passes the blood-brain barrier. It was proved that it supports endogenous regeneration processes, mimics the behaviour of neurotrophic factors and modifies their level, affects the Sonic Hedgehog protein’s signalling pathway, protects from the pathological events and cascades which stem from an injury or a neurodegenerative disease, reduces amounts of free radicals as well as pro-apoptotic enzymes, modulates inflammatory response and also affects neuroplasticity and neurogenesis. Because of these characteristics, cerebrolysin is used in treatment of patients suffering from strokes, traumatic brain injuries, patients with cognitive disorders, including Alzheimer’s dementia and vascular dementia. The standard route of administration is via injections; however, some research was conducted on oral administration as well. The commonly reported adverse effects of cerebrolysin are transient and of mild severity. Results of research on the effectiveness and safety of cerebrolysin seem to be encouraging. They confirm high safety level and theoretical legitimacy of its use. The treatment of patients with organic, metabolic and neurodegenerative syndromes is difficult and often ineffective. Therefore, every available method of treatment needs to be taken under consideration.

Looking for a partner: ceruloplasmin in protein-protein interactions.

Ceruloplasmin (CP) is a mammalian blood plasma ferroxidase. More than 95% of the copper found in plasma is carried by this protein, which is a member of the multicopper oxidase family. Proteins from this group are able to oxidize substrates through the transfer of four electrons to oxygen. The essential role of CP in iron metabolism in humans is particularly evident in the case of loss-of-function mutations in the CP gene resulting in a neurodegenerative syndrome known as aceruloplasminaemia. However, the functions of CP are not limited to the oxidation of ferrous iron to ferric iron, which allows loading of the ferric iron into transferrin and prevents the deleterious reactions of Fenton chemistry. In recent years, a number of novel CP functions have been reported, and many of these functions depend on the ability of CP to form stable complexes with a number of proteins.

PREVALENCE OF NEUROPSYCHIATRIC SYMPTOMS ACROSS THE COGNITIVE SPECTRUM AND THEIR IMPACT ON FUTURE COGNITIVE DECLINE: Session 203

In the recently published National Institute on Aging and Alzheimer's Association (NIA-AA)’s Research Framework, the definition of Alzheimer's disease (AD) shifts from a syndromal to a biological entity, defined by underlying pathology as evidenced by the presence of AD biomarkers in vivo or on post-mortem examination (Jack et al., 2018, Alzheimers Dement. 2018 Apr;14(4):535-562). The new NIA-AA framework also describes syndromal staging of cognitive continuum to define research cohorts, independent of biomarker profile. With respect to mild cognitive impairment (MCI), the current framework differs from the 2011 NIA-AA definition in its reference to “neurobehavioral” symptoms, defined as symptoms attributable to mood or behavioral disorders, such as anxiety, depression, and apathy, which “commonly coexist and may be a prominent part of the presentation” (Table 3, Jack et al., 2018). We argue that neurobehavioural or neuropsychiatric symptoms (NPS) across the spectrum of AD disease should not be conceptualized as simply co-existing alongside cognitive impairment or attributable to mood or behavioural disorders. Rather, NPS are core features of neurodegenerative cognitive syndromes that may serve as prognostic indicators of outcome. This symposium will review the prevalence of NPS across the cognitive spectrum; namely in subjective cognitive decline (SCD), mild cognitive impairment (MCI), and Alzheimer's disease (AD), and highlight their association with AD biomarkers and contribution to future cognitive decline or disease progression in AD. Dr. Linda Mah will review the prevalence of neurobehavioural symptoms and their association with AD biomarkers and future cognitive decline in older adults who are cognitively unimpaired (CU) or who present with SCD, drawing from the extant literature and new data from an ongoing study of SCD. Dr. Krista L. Lanctôt will review the prevalence of NPS in mild neurocognitive disorder (NCD) and impact on progression. In addition, emerging evidence linking specific NPS with biomarkers of major NCD and the efficacy of interventions including pharmacologic, nonpharmacologic and neuromodulatory during this phase will be highlighted, with emphasis on recent findings. Dr. Corinne E. Fischer will review the prevalence and trajectory, clinical features and treatment approach to neuropsychiatric symptoms (NPS) in patients with established Alzheimer's disease. Particular emphasis will be placed on studies demonstrating the link between disease biomarkers and NPS disease burden, highlighting specific NPS such as apathy, aberrant sleep behavior, psychosis and depression.

Biochemistry of Autoinflammatory Diseases: Catalyzing Monogenic Disease.

Monogenic autoinflammatory disorders are a group of conditions defined by systemic or localized inflammation without identifiable causes, such as infection. In contrast to classical primary immunodeficiencies that manifest with impaired immune responses, these disorders are due to defects in genes that regulate innate immunity leading to constitutive activation of pro-inflammatory signaling. Through studying patients with rare autoinflammatory conditions, novel mechanisms of inflammation have been identified that bare on our understanding not only of basic signaling in inflammatory cells, but also of the pathogenesis of more common inflammatory diseases and have guided treatment modalities. Autoinflammation has further been implicated as an important component of cardiovascular, neurodegenerative, and metabolic syndromes. In this review, we will focus on a subset of inherited enzymatic deficiencies that lead to constitutive inflammation, and how these rare diseases have provided insights into diverse areas of cell biology not restricted to immune cells. In this way, Mendelian disorders of the innate immune system, and in particular loss of catalytic activity of enzymes in distinct pathways, have expanded our understanding of the interplay between many seemingly disparate cellular processes. We also explore the overlap between autoinflammation, autoimmunity, and immunodeficiency, which has been increasingly recognized in patients with dysregulated immune responses.

DNA damage and transcriptional regulation in iPSC-derived neurons from Ataxia Telangiectasia patients

Ataxia Telangiectasia (A-T) is neurodegenerative syndrome caused by inherited mutations inactivating the ATM kinase, a master regulator of the DNA damage response (DDR). What makes neurons vulnerable to ATM loss remains unclear. In this study we assessed on human iPSC-derived neurons whether the abnormal accumulation of DNA-Topoisomerase 1 adducts (Top1ccs) found in A-T impairs transcription elongation, thus favoring neurodegeneration. Furthermore, whether neuronal activity-induced immediate early genes (IEGs), a process involving the formation of DNA breaks, is affected by ATM deficiency. We found that Top1cc trapping by CPT induces an ATM-dependent DDR as well as an ATM-independent induction of IEGs and repression especially of long genes. As revealed by nascent RNA sequencing, transcriptional elongation and recovery were found to proceed with the same rate, irrespective of gene length and ATM status. Neuronal activity induced by glutamate receptors stimulation, or membrane depolarization with KCl, triggered a DDR and expression of IEGs, the latter independent of ATM. In unperturbed A-T neurons a set of genes (FN1, DCN, RASGRF1, FZD1, EOMES, SHH, NR2E1) implicated in the development, maintenance and physiology of central nervous system was specifically downregulated, underscoring their potential involvement in the neurodegenerative process in A-T patients.

Neuroimmunological phenomena involved in chronic traumatic brain injury

AbstractCurrently, chronic traumatic encephalopathy (CTE) is widely recognized as a neurodegenerative syndrome caused by constant exposure to events of acceleration and deceleration. CTE produces a myriad of neurological alterations in both the short‐ and long term; some of these alterations disturb the homeostasis of the central nervous system, and trigger several behavioral and cognitive deficits. The pathology of CTE resembles that of Alzheimer's, Parkinson's and Huntington's disease (among many others), which are characterized by the important role of the immune response in the development of the disease and the deposition of proteins, such as amyloid beta and tau. In the present article, we review the succession of events that develop after exposure to acceleration/deceleration events, and how such events affect the distinct cellular types in the central nervous system and their role in the activation of the immune system. We also review how the activation of the immune system affects mechanisms, such as neurogenesis and neurodegeneration, and how this in turn could generate the behavioral and cognitive deficits associated with this pathology.

S.05.04 RNA processing impairments in neurodegeneration syndromes

There is an increasing interest in the putative role of glucagon-like peptide 1 receptor (GLP-1R) agonists as novel therapeutic agents for mental disorders. Herein, we investigated the expressions of GLP-1R and GLP-2R genes, and its relationship with body mass index (BMI), in the post-mortem brain tissue of patients with mood (MD) and psychotic disorders. Brain samples were localized to the dorsolateral prefrontal cortex (dlPFC) (n = 459) and hippocampus (n = 378). After adjustment for age, sex, ethnicity, post-mortem interval (PMI) and BMI, we observed significant differences, between healthy controls and MD subjects, in GLP-1R and GLP-2R gene expression in the dlPFC (β = 1.504, p = 0.004; and β = 1.305, p = 0.011, respectively); whereas in the hippocampus, only GLP-1R expression was significantly associated with MD (β = −1.28, p = 0.029). No significant differences were found in relation to schizophrenia. In addition, we observed a moderating effect of MD diagnosis on the associations between BMI, GLP-1R and GLP-2R expression values in the dlPFC (β = −0.05, p = 0.003; and β = −0.04, p = 0.004, respectively). There was a similar moderating effect for GLP-1R in the hippocampus (β = 0.043, 95% CI 0.003; 0.08 p = 0.03), but in an opposite direction than observed in the dlPFC. This is the first evidence of abnormal gene expression of GLP-1R and GLP-2R in postmortem brain of individuals with MD, providing a rationale for further inquiry and proof of principle interventional studies.

Quantifying the Differentiated Trajectory of the Wernicke’s-like Presentation of Logopenic Variant Primary Progressive Aphasia (lvPPA)

Quantifying the Differentiated Trajectory of the Wernicke’s-like Presentation of Logopenic Variant Primary Progressive Aphasia (lvPPA)

Phenotypic assays in yeast and zebrafish reveal drugs that rescue ATP13A2 deficiency.

Mutations in ATP13A2 (PARK9) are causally linked to the rare neurodegenerative disorders Kufor-Rakeb syndrome, hereditary spastic paraplegia and neuronal ceroid lipofuscinosis. This suggests that ATP13A2, a lysosomal cation-transporting ATPase, plays a crucial role in neuronal cells. The heterogeneity of the clinical spectrum of ATP13A2-associated disorders is not yet well understood and currently, these diseases remain without effective treatment. Interestingly, ATP13A2 is widely conserved among eukaryotes, and the yeast model for ATP13A2 deficiency was the first to indicate a role in heavy metal homeostasis, which was later confirmed in human cells. In this study, we show that the deletion of YPK9 (the yeast orthologue of ATP13A2) in Saccharomyces cerevisiae leads to growth impairment in the presence of Zn2+, Mn2+, Co2+ and Ni2+, with the strongest phenotype being observed in the presence of zinc. Using the ypk9Δ mutant, we developed a high-throughput growth rescue screen based on the Zn2+ sensitivity phenotype. Screening of two libraries of Food and Drug Administration-approved drugs identified 11 compounds that rescued growth. Subsequently, we generated a zebrafish model for ATP13A2 deficiency and found that both partial and complete loss of atp13a2 function led to increased sensitivity to Mn2+. Based on this phenotype, we confirmed two of the drugs found in the yeast screen to also exert a rescue effect in zebrafish—N-acetylcysteine, a potent antioxidant, and furaltadone, a nitrofuran antibiotic. This study further supports that combining the high-throughput screening capacity of yeast with rapid in vivo drug testing in zebrafish can represent an efficient drug repurposing strategy in the context of rare inherited disorders involving conserved genes. This work also deepens the understanding of the role of ATP13A2 in heavy metal detoxification and provides a new in vivo model for investigating ATP13A2 deficiency.

Electrical stimulation of the left IFG improves category fluency in primary progressive aphasia: far-transfer effects and their neural mechanisms

Electrical stimulation of the left IFG improves category fluency in primary progressive aphasia: far-transfer effects and their neural mechanisms

Chapter 28 - Clinical neurophysiology of multiple system atrophy

Multiple system atrophy (MSA) is an adult-onset, rapidly progressive neurodegenerative syndrome. The diagnosis of MSA is primarily clinical. Neurophysiologic studies can provide important clues to the diagnosis of MSA and differentiate it from other neurodegenerative diseases especially when the clinical picture is unclear. This chapter reviews common and less common neurophysiological studies useful in the diagnosis of MSA.

Enfermedad CLN8 congénita de lipofuscinosis neuronal ceroidea: un nuevo fenotipo

CLN8 disease is one of the thirteen recognized genetic types of neuronal ceroid lipofuscinosis, a group of neurodegenerative lysosomal storage disorders, most frequent in childhood. A putative 286 amino acids transmembrane CLN8 protein with unknown function is affected. Pathological variants in the CLN8 gene were associated with two different phenotypes: variant late-infantile in individuals from many countries worldwide, and epilepsy progressive with mental retardation, appearing in Finnish and Turkish subjects. The girl showed psychomotor delay and dementia since birth, tonic-clonic seizures, myoclonus, ataxia with cerebellar atrophy, and early death at 12 years old. Electron microscopy of the skin showed mixed GROD, curvilinear, fingerprint cytosomes and mitochondrial hypertrophy. Two pathological DNA variants in the CLN8 gene (exon 2 c.1A>G; p.?/ exon 3 c.792C>G; p.Asn264Lys) were found confirming a compound heterozygous genotype. This case is the Latin American index for a new congenital phenotype of the CLN8 disease. The congenital phenotype has to be added to the clinical spectrum of the CLN8 disease. The suspicion of CLN8 disease should be genetically sustained in challenging cases of a neurodegenerative syndrome with psychomotor delay since birth, speech difficulty and seizures. The course includes ataxia, cerebellar atrophy, and early death.

Genetic analysis of neurodegenerative diseases in a pathology cohort

Molecular genetic research provides unprecedented opportunities to examine genotype-phenotype correlations underlying complex syndromes. To investigate pathogenic mutations and genotype-phenotype relationships in diverse neurodegenerative conditions, we performed a rare variant analysis of damaging mutations in autopsy-confirmed neurodegenerative cases from the Johns Hopkins Brain Resource Center (n = 1243 patients). We used NeuroChip genotyping and C9orf72 hexanucleotide repeat analysis to rapidly screen our cohort for disease-causing mutations. In total, we identified 42 individuals who carried a pathogenic mutation in LRRK2, GBA, APP, PSEN1, MAPT, GRN, C9orf72, SETX, SPAST, or CSF1R, and we provide a comprehensive description of the diverse clinicopathological features of these well-characterized cases. Our study highlights the utility of high-throughput genetic screening arrays to establish a molecular diagnosis in individuals with complex neurodegenerative syndromes, to broaden disease phenotypes and to provide insights into unexpected disease associations.

Frontotemporal dementia spectrum: first genetic screen in a Greek cohort

Frontotemporal dementia (FTD) is a heterogeneous group of neurodegenerative syndromes associated with several causative and susceptibility genes. Herein, we aimed to determine the incidence of the most common causative dementia genes in a cohort of 118 unrelated Greek FTD spectrum patients. We also screened for novel possible disease-associated variants in additional 21 genes associated with FTD or amyotrophic lateral sclerosis. Pathogenic or likely pathogenic variants were identified in 16 cases (13.6%). These included repeat expansions in C9orf72 and loss-of-function GRN variants, and likely pathogenic variants in TARDBP, MAPT, and PSEN1. We also identified 14 variants of unknown significance in other rarer FTD or amyotrophic lateral sclerosis genes that require further segregation and functional analysis. Our genetic screen revealed a high genetic burden in familial Greek FTD cases (30.4%), whereas only two of the sporadic cases (3.5%) carried a likely pathogenic variant. A substantial number of familial cases still remain without an obvious causal variant, suggesting the existence of other FTD genetic causes besides those currently screened in clinical routine.

Therapeutic trial design for frontotemporal dementia and related disorders

The frontotemporal dementia (FTD) spectrum is a heterogeneous group of neurodegenerative syndromes with overlapping clinical, molecular and pathological features, all of which challenge the design of clinical trials in these...