CONCUSSION, ALS, TAU BLOOD TEST, GENETIC MISFOLDING PROTEIN PATHOLOGY

Genetics Quickview in Amyotrophic lateral sclerosis (ALS) and Frontotemporal Dementia (FTD), Alzheimer’s Disease, Dystonia, other Brain Misfolding and Aggregation Proteinopathies:
• Now >100 genes are known to contribute to ALS/FTD, with a few major contributors that are reviewed below
• ALS, is a sporadic disease with genetic and environmental contributions,
• Tau Protein, was the first genetic association in FTD,
• non-coding GGGGCC expansions in C9orf72 were identified as the most common mutations in inherited forms of ALS (40%) and FTD (25%),
• and in a significant number of sporadic ALS (5%–20%) and FTD (6%) (figure 1).3 ,4,
• both LOF and GOF have been proposed to mediate TDP-43 pathogenesis.
• FUS was identified as a component of neuronal inclusions that were SOD1 and TDP-43 negative and ubiquitin positive in patients with ALS, leading to the identification of mutations in FUS in familial ALS (figure 1).64 ,65
• Small number of genes also play a significant role in inherited forms of ALS/FTD.
• VCP is a highly abundant class II AAA (ATP-associated with diverse cellular activities) protein that targets a variety of substrates for degradation by the ubiquitin-proteasome pathway
• Thus, C9orf72 increases the risk of developing ALS/FTD and the second mutation determines the pathology.
• Combinations of TDP-43, FUS and SOD1 with minor genes have been described due to the high incidence of double mutants in sporadic ALS.
• A review of the major ALS/FTD genes suggests that they mainly perturb two cellular processes: aberrant RNA processing and protein degradation (fig 2)

“Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating neurological conditions with midlife onset and no cure. ALS and FTD where initially described in the mid-to-late 1800s as pure movement and cognitive disorders, respectively, a distinction that has continued until recently.

“ALS is a common neurodegenerative condition affecting motor neurons with rapid progression.1 FTD is the most common form of dementia after Alzheimer’s disease (AD) and is characterised by progressive degeneration of the frontal and temporal cortex.2 The ALS and FTD clinical entities remained separated from their original descriptions, although a few studies recognised heterogeneous phenotypes in ALS that included cognitive impairment overlapping FTD. These studies were sidelined for decades in favour of a more homogenous diagnosis for classic ALS that placed the complex cases into subcategories, exceptions and dual diagnoses.

“This view of ALS and FTD as independent clinical entities has changed dramatically in the last few years due to exciting advances in genetics. With the completion of the human genome in 2000, sequencing technologies have continued to improve in accuracy, speed and cost, enabling the analysis of larger populations.

“The identification of hexarepeat expansions in chromosome 9 open reading frame 72 (C9orf72) as the cause of the most common inherited form of ALS in 2011 explained most of the unknown genetic risk in ALS and uncovered a strong connection with FTD.3 ,4 Mutant C9orf72 accounts for 30%–50% of familial ALS, around 25% of familial FTD and a small fraction of sporadic ALS and FTD (∼5% each),5 ,6 indicating that C9orf72 is the major genetic factor in both conditions.

“Once this strong genetic connection between ALS and FTD was uncovered, the careful re-evaluation of clinical descriptions recognised the existence of mixed ALS/FTD pathologies that could account for a disease spectrum.7 ,8 Other genes as well as protein pathology further connect ALS and FTD, including TAR DNA-binding protein-43 (TDP-43), fused in sarcoma (FUS) and sequestrome-1 (SQSTM1), among others. Although these genes with autosomal dominant effect have received the most attention in the last few years, a significant portion of sporadic ALS can be explained by a polygenic genetic contribution. Genome-wide association studies have revealed around 100 genetic loci that predispose to ALS with low penetrance and minor contribution to disease for each individual gene.2 ,9

“Advances in genome sequencing have brought radical changes into our understanding of ALS/FTD from two separate clinical entities to a complex disease spectrum. At a pathological level, the SOD1 and tau pathologies fit perfectly in distinct motor neuron and cognitive disorders, but the shared TDP-43 pathology was puzzling. The discovery of C9orf72 hexarepeat expansions in familial forms of ALS and FTD forced the revision of previous clinical and pathological reports for a connection between these two diseases. The common TDP-43 pathology makes more sense in the context of overlapping clinical phenotypes. Together with the genetics of C9orf72, all data available contribute to describe a complex neurodegenerative condition with extremes representing pure ALS and FTD, and the rest represented by different degrees of combined phenotypes.

“Despite the clarity provided by the recognition of an ALS/FTD spectrum, the complex genetics and pathology of these conditions still need further clarification. Over a hundred genes contribute to the risk of ALS/FTD, but only a few are major genes with high penetrance. Most genes have minor contributions to the disease, supporting an oligogenic model where contributions from two or more genes trigger the disease. This is supported by many reports of individuals carrying two mutations, where the low penetrant C9orf72 mutations have been found together with mutations in several other ALS/FTD genes. In these cases, the second hit can explain how the extreme pure phenotypes arise. It is also clear that environmental factors contribute to ALS, suggesting that low penetrance mutations together with external triggers can result in motor neuron disease.

“Much work is still needed to understand the complexity of ALS/FTD, including the contribution of most minor genes and the molecular mechanisms of ALS/FTD pathologies. But the field has already taken giant steps towards integrating the pathologies, leading to new hypotheses that should launch research to a higher level of mechanistic understanding. Only when the molecular targets are clearly identified will be possible to develop therapeutic strategies with disease-modifying potential, including therapies against several targets combined with improved symptomatic therapies.[Genetics insight into the amyotrophic lateral sclerosis/frontotemporal dementia spectrum, Ai-Ling Ji1, Xia Zhang2,3,4,5, Wei-Wei Chen2,3,4,5, Wen-Juan Huang2,3,4,5, British Medical Journal, Volume 54, Issue 3]
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Abnormal deposition of misprocessed and aggregated proteins is a common final pathway of most neurodegenerative diseases, including Alzheimer’s disease (AD). AD is characterized by the extraneuronal deposition of the amyloid β (Aβ) protein in the form of plaques and the intraneuronal aggregation of the microtubule-associated protein tau in the form of filaments. Based on the biochemically diverse range of pathological tau proteins, a number of approaches have been proposed to develop new potential therapeutics. Here we discuss some of the most promising ones: inhibition of tau phosphorylation, proteolysis and aggregation, promotion of intra- and extracellular tau clearance, and stabilization of microtubules. We also emphasize the need to achieve a full understanding of the biological roles and post-translational modifications of normal tau, as well as the molecular events responsible for selective neuronal vulnerability to tau pathology and its propagation. It is concluded that answering key questions on the relationship between Aβ and tau pathology should lead to a better understanding of the nature of secondary tauopathies, especially AD, and open new therapeutic targets and strategies.

Keywords: Alzheimer’s disease, amyloid β, neurofibrillary degeneration, microtubules, neuropathology, phosphorylation, protein aggregation, protein oligomerization, tauopathies, tau protein [Šimić G, Babić Leko M, Wray S, et al. Tau Protein Hyperphosphorylation and Aggregation in Alzheimer’s Disease and Other Tauopathies, and Possible Neuroprotective Strategies. Bähler J, ed. Biomolecules. 2016;6(1):6,]
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“Athletes who show higher levels of the brain TAU protein 6 hours after a sports-related concussion tend to face a longer period of recovery and delayed return to play, according to a new study published in the journal Neurology.

“The findings suggest that TAU, a protein that can be measured in the blood, may be a biomarker to help physicians determine an athlete’s readiness to resume play. TAU is known to play a role in the development of chronic traumatic encephalopathy (CTE), frontotemporal dementia and Alzheimer’s disease.

“This study suggests that TAU may be a useful biomarker (blood test for TAU Protein) for identifying athletes who may take longer to recover after a concussion,” said Jeffrey Bazarian, M.D., M.P.H. of the University of Rochester Medical Center (URMC), professor of Emergency Medicine and Physical Medicine & Rehabilitation who treats patients at the UR Medicine Sports Concussion Clinic.
[Pedersen, T. (2017). Brain Protein May Predict Length of Concussion Recovery. Psych Central. Retrieved on June 8, 2017, from https://psychcentral.com/news/2017/01/09/brain-protein-may-predict-length-of-concussion-recovery/114893.html][Acute plasma TAU relates to prolonged return to play after concussion Jessica Gill, RN, PhD, Kian Merchant-Borna, MPH, Andreas Jeromin, PhD, Whitney Livingston, BA and Jeffrey Bazarian, MD, MPH January 6, 2017, Neurology February 7, 2017 vol. 88 no. 6 595-602]

“When someone bangs his or her head, rotational forces can damage long-projecting axons, the fibers that extend from neurons. That can cause proteins to leak out of brain cells, and the tests currently being developed are based on detecting tiny increases in the concentration of these proteins in blood samples.”

“Zetterberg using Quanterix Lexington, Mass technology to measure TAU protein 2013 reported Olympic boxers have elevated blood plasma levels and more recently shown TAU levels are closely correlated with the duration of concussion symptoms in professional hockey players.

“The latest study, by National Institutes of Health, measured TAU protein concentrations in 46 college athletes and 37 healthy controls, and showed that players with elevated TAU levels within six hours of a sports-related concussion experienced symptoms longer.

“Together, these results suggest blood tests could not only detect concussion more accurately but may also be used to predict a player’s recovery time, to ensure that they do not return to play prematurely.”

“Neurologist Beth McQuiston, medical director at global health care company Abbott With funding from the U.S. Department of Defense, McQuiston and her colleagues are busy developing a blood test for two other concussion markers, UCH-L1, a neuron enzyme, and GFAP, structural protein released from damaged neuron-supporting cells called astrocytes, using an existing hand-held blood analysis device called the i-STAT.

“Both of these protein-based markers are substantially increased in patients with traumatic brain injury, even those with a normal brain scan, so they could indicate undetected microscopic injuries.
[Simple Blood Tests for Rapid Concussion Diagnosis, by Mo Costandi, March 9, 2017, Scientific American]

A recent study found characteristic patterns of protein deposits in brains of retired NFL players who suffered concussions. “Previous brain autopsy studies have shown that amyloid plaques are present in less than 45% of retired football players, most typically in those with advanced Chronic Traumatic Encephalopathy (CTE). Most of the retired players in the new study did not have advanced CTE, which suggests that their FDDNP signal represents mostly TAU deposits in the brain.”

“The latest study also shows that the brain imaging pattern of people who have suffered concussions is markedly different from the scans of healthy people and from those with Alzheimer’s disease. Researchers say the findings could help lead to better identification of brain disorders in athletes and would allow doctors and scientists to test treatments that might help delay the progression of the disease before significant brain damage and symptoms emerge. The study appears in the April 6 online edition of the Proceedings of the National Academy of Science.

“The scans of people with the highest levels of FDDNP binding in areas where TAU accumulates in CTE, also show binding in areas of the brain affected by amyloid plaques, which is consistent with autopsy findings indicating that this abnormal protein also plays a role in more serious cases of CTE. [New test may lead to better identification of brain disorders like CTE Rachel Champeau | April 06, 2015]

“Traumatic brain injury (TBI) due to contact sports may cause chronic behavioral, mood, and cognitive disturbances associated with pathological deposition of TAU protein found at brain autopsy,” particularly Pro Football Players. Scientists used positron emission tomography (PET) scans after intravenous injections of FDDNP that revealed deposition of TAU in the brain where the brain lit-up. In the past, only autopsy was indicative. This may offer a means for identification prior to death of neurodegeneration in contact-sports athletes. [Gary W. Small, M.D., et al Am J Geriatr Psychiatry 21:2, February 2013]

“Objective: Mild traumatic brain injury due to contact sports may cause chronic behavioral, mood, and cognitive disturbances associated with pathological deposition of TAU protein found at brain autopsy. To explore whether brain TAU deposits can be detected in living retired players, we used positron emission tomography (PET) scans after intravenous injections of 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]- 2-naphthyl}ethylidene)malononitrile (FDDNP). Conclusions: If future research confirms these initial findings, FDDNP-PET may offer a means for premorbid identification of neurodegeneration in contact-sports athletes. The small sample size and lack of autopsy confirmation warrant larger, more definitive studies. (Am J Geriatr Psychiatry 2013; 21:138e144)

“According to recent CDC estimates, 1.6-3.8 million sports-related traumatic brain injuries (TBIs) occur each year, including those never reported to healthcare professionals.1 Most are minor concussions; many are repeated injuries and subconcussive blows.1

Researchers “examined recent population-based data from the National Health Interview Survey, Consumer Product Safety Commission, and state-based traumatic brain injury (TBI) surveillance programs that provide estimates of the overall incidence of sports-related TBI in the United States.

“Available data indicate that sports-related TBI is an important public health problem because of the large number of people who incur these injuries each year, the generally young age of patients at the time of injury (with possible long-term disability), and the potential cumulative effects of repeated injuries. The importance of this problem indicates the need for more effective prevention measures. The public health approach can guide efforts in injury prevention and control. The steps in this approach are (1) identifying the problem, (2) identifying risk factors, (3) developing and testing interventions, and (4) implementing programs and evaluating outcomes. [The epidemiology of sports-related traumatic brain injuries in the United States: recent developments.Thurman DJ, Branche CM, Sniezek JE.J Head Trauma Rehabil. 1998 Apr;13(2):1-8.]

“Repetitive mild TBI due to contact sports may lead to chronic mood, behavioral, and cognitive changes.2 Studies of retired contact-sport athletes, such as National Football League (NFL) players, show a higher rate of personality, behavioral, and mood disturbances (e.g., depression, irritability, impulsiveness), mild cognitive impairment (MCI, a risk state for dementia), and dementia compared with controls.

“Professional athletes exposed to repetitive mild TBIs are prone to develop chronic impairment, and available evidence suggests a possible dose response.3 Retired NFL players with three or more reported concussions during their career were three times more likely to be diagnosed with depression and five times more likely to be diagnosed with MCI.3,4

“Several investigators have described chronic traumatic encephalopathy (CTE), a clinicopathological entity that includes mood, personality, cognitive, and behavioral changes (e.g., suicidality), and motor symptoms (e.g., abnormal gait, tremor) associated with a range of autopsy findings, particularly widespread accumulation of phosphorylated TAU protein as neurofibrillary tangles (similar to those observed in Alzheimer disease), astrocytic tangles, neurites, diffuse axonal injury, white matter abnormalities, inflammation, and immune proinflammatory cytokine responses in traumatized brain regions.5

“Immunoreactive deposits are found in neocortical, subcortical (e.g., thalamus, caudate, putamen, midbrain, and cerebellar white matter), and medial temporal (hippocampus, entorhinal cortex, and amygdala) regions, where neuronal loss may be observed.5 TDP-43 proteinopathy may accompany Tauopathy in CTE cases and is more prominent in motor neuron disease cases.6 Amyloid deposition has been reported in approximately 40% of CTE cases and generally consists of diffuse plaques with relatively few cortical neuritic plaques.5

“Currently, CTE in former football players is only diagnosed at autopsy. Our group invented 2-(1-{6-[(2-[F-18]fluoroethyl) (methyl)amino]-2 naphthyl}ethylidene)malononitrile (FDDNP)-positron emission tomography (PET) for measuring both TAU tangle and amyloid plaque deposition in living brains.7 FDDNP signals differentiate

“Alzheimer disease from MCI and normal aging and predict future cognitive decline in nondemented subjects.8,9 Although other TAU tracers have been tested in human brain tissue sections and animal models,10,11 FDDNP is the only PET probe of TAU that has been studied in vivo in human imaging trials. FDDNP is not specific for Tauopathies, but previous autopsy follow-up studies indicate regional specificity in patients with Alzheimer disease, wherein FDDNP-PET shows high signals in medial temporal regions where autopsy studies indicate a preponderance of TAU tangles, as well as high signal in lateral temporal regions, where amyloid plaques
are highly concentrated.8

“Despite the devastating consequences of TBIs due to contact sports and the large number of people at risk, no method for early detection of brain pathology has
yet been established. To address this issue, we performed PET scans after intravenous injections of FDDNPto explore whether brain TAU deposits could be detected in a small group of retired NFL players with cognitive and mood symptoms and compared them with a group of male controls of comparable age, educational achievement, and bodymass index (BMI).”

“References”
1.Centers for Disease Control and Prevention: National Center for Injury Prevention and Control. Nonfatal traumatic brain injuries from sports and recreation activities—United States, 2001e2005. MMWR Weekly 2007; 56(29):733e737
2. Wall SE, Williams WH, Cartwright-Hatton S, et al: Neuropsychological
dysfunction following repeat concussions in jockeys. J Neurol Neurosurg Psychiatry 2006; 77:518e520
3. Guskiewicz KM, Marshall SW, Bailes JE: Association between recurrent concussion and late-life cognitive impairment in retired professional football players. Neurosurgery 2005; 57: 719e726
4. Guskiewicz KM, Marshall SW, Bailes JE, et al: Recurrent concussion and risk of depression in retired professional football players. Med Sci Sports Exerc 2007; 39:903e909
5. McKee AC, Cantu RC, Nowinski CJ, et al: Chronic traumatic encephalopathy in athletes: progressive Tauopathy following repetitive head injury. J Neuropathol Exp Neurol 2009; 68: 709e735
6. McKee AC, Gavett BE, Stern RA, et al: TDP-43 proteinopathy and motor neuron disease in chronic traumatic encephalopathy. J Neuropathol Exp Neurol 2010; 69:918e929
7. Shoghi-Jadid K, Small GW, Agdeppa ED, et al: Localization of neurofibrillary tangles and beta-amyloid plaques in the brains of living patients with Alzheimer’s disease. Am J Geriatr Psychiatry 2002; 10:24e35
8. Small GW, Kepe V, Ercoli LM, et al: PET of brain amyloid and TAU in mild cognitive impairment. N Engl J Med 2006; 355: 2652e2663
9. Small GW, Siddarth P, Kepe V, et al: PET of brain amyloid and TAU predicts and tracks cognitive decline in people without dementia. Arch Neurol 2012; 69:215e222
10. Fodero-Tavoletti MT, Okamura N, Furumoto S, et al: 18F-THK523: a novel in vivo TAU imaging ligand for Alzheimer’s disease. Brain 2011; 134:1089e1100
11. Zhang W, Arteaga J, Cashion DK, et al: A highly selective and specific PET tracer for imaging of TAU pathologies. J Alzheimers Dis 2012; 31:601e612
12. RosenbaumPR,RubinDB:The central role of the propensity score in observational studies for causal effects. Biometrika 1983; 70:41e55
13. Omalu B, Bailes J, Hamilton RL, et al: Emerging histomorphologic phenotypes of chronic traumatic encephalopathy in American athletes. Neurosurgery 2011; 69:173e183
14. Lavretsky H, Siddarth P, Kepe V, et al: Depression and anxiety symptoms are associated with cerebral FDDNP-PET binding in middle-aged and older adults. Am J Geriatr Psychiatry 2009; 17: 493e502
15. Kumar A, Kepe V, Barrio JR, et al: Protein binding in patients with late-life depression detected using [18F]FDDNP positron emission tomography. Arch Gen Psychiatry 2011; 68:1143e1150
16. Silverman DH, Gambhir SS, Huang HW, et al: Evaluating early dementia with and without assessment of regional cerebral metabolism by PET: a comparison of predicted costs and benefits. J Nucl Med 2002; 43:253e266
17. Finkelstein E, Corso P, Miller T, et al: The Incidence and Economic Burden of Injuries in the United States. New York, Oxford University Press, 2006

[Gary W. Small, M.D., Vladimir Kepe, Ph.D., Prabha Siddarth, Ph.D., Linda M. Ercoli, Ph.D., David A. Merrill, M.D., Ph.D., Natacha Donoghue, B.A., Susan Y. Bookheimer, Ph.D., Jacqueline Martinez, M.S., Bennet Omalu, M.D., Julian Bailes, M.D., Jorge R. Barrio, Ph.D. From the Department of Psychiatry and Biobehavioral Sciences and Semel Institute for Neuroscience and Human Behavior (GWS, PS, LME, DAM, ND, SYB, JM), Department of Molecular and Medical Pharmacology (VK, JRB), the Center for Cognitive Neurosciences (SYB), and the UCLA Longevity Center (GWS, PS, LME, DAM) et al at the David Geffen School of Medicine, Department of Psychology (SYB), the University of California, Los Angeles, Los Angeles, CA; the Department of Pathology, University of California, Davis, CA (BO); and the Department of Neurosurgery, NorthShore University Health System, Chicago, IL (JB). Send correspondence and reprint requests to Dr. Gary Small, Semel Institute, 760 Westwood Plaza, Los Angeles, CA 90024. e-mail: gsmall@ucla.edu Am J Geriatr Psychiatry 21:2, February 2013]
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Dementia Disorders and Movement Disorders have revealed common intracellular molecular misfolding proteins within Brain Neurons present during neuropathological autopsy studies.

Chronic Traumatic Encephalopathy from repeated Concussion-like Football injuries is one such disorder under investigation. Increased Awareness and concern have improved Sports, Recreation and Exercise activity preventative measures during play and diagnostic and potential therapeutic developments in the laboratory by dedicated scientists and investigators.
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Neurodegeneration: The Molecular Pathology of Dementia and Movement Disorders by Dennis Dickson, Roy O. Weller

“In contrast, this book looks to the future and uses a classification based upon molecular mechanisms, rather than clinical or anatomical boundaries. Major advances in molecular genetics and the application of biochemical and immunocytochemical techniques to neurodegenerative disorders have generated this new approach. Throughout most of the current volume, diseases are clustered according to the proteins that accumulate within cells (e.g. tau, α-synuclein and TDP-43) and in the extracellular compartments (e.g. β-amyloid and prion proteins) or according to a shared pathogenetic mechanism, such as trinucleotide repeats, that are a feature of specific genetic disorders.

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“The worldwide increasing age of populations brought the neurodegenerative diseases into the focus of interest. A number of the diverse human neurodegenerative diseases are now recognized as conformational diseases frequently caused by aggregations of unfolded or misfolded proteins.

“Knowledge on the intrinsically unstructured proteins, a new family of gene products as well as on the misfolded proteins produced by genetic mutation or environmental effects has been extensively accumulated in the past years. These proteins frequently cause proteolytic stress and/ or enter into aberrant, non-physiological protein-protein interactions leading to sequestration of protein aggregates which are assemblies of many not-yet-identified components in addition to the deposition of well-characterized misfolded peptides and proteins such as b-amyloid, tau, a-synuclein and polyglutamine containing proteins. These protein assemblies display diverse ultrastructures such aggresomes, fibers, oligomers or amorphous structures, however, the nature of these species concerning their cytoprotective or cytotoxic effects has not been clarified yet.

“The main focus of this volume is to review the molecular events initiated by unfolded or misfolded proteins leading to conformational human diseases, with special emphasis on the macromolecular homo- and heteroassociations of the malfolded proteins into characteristic ultrastructures found primarily in Parkinson’s and Alzheimer’s diseases. This book reviews the structural knowledge accumulated for well-studied and for newly discovered proteins involved in paradigmatic conformational disorders with the aim to broaden our understanding of the pathomechanisms of neurodegeneration, which is crucial for finding effective therapeutic interventions that could prevent or circumvent the development of neurodegenerative disorders in humans.
[Protein folding and misfolding: neurodegenerative diseases Focus on Structural Biology, Vol. 7 Ovádi, Judit; Orosz, Ferenc (Eds.) 2009, XIV, 278 p.]

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Abstract
“Neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, Prion disease, Huntington’s disease, and amyotrophic lateral sclerosis (ALS, Lou Gerhigs Disease) are increasingly being realized to have common cellular and molecular mechanisms including protein aggregation and inclusion body formation in selected brain regions. The aggregates usually consist of insoluble fibrillar aggregates containing misfolded protein with β-sheet conformation. The most probable explanation is that inclusions and the aggregates symbolize an end stage of a molecular cascade of several events, and that earlier event in the cascade may be more directly tied up to pathogenesis than the inclusions themselves. Small intermediates termed as ‘soluble oligomers’ in the aggregation process might influence synaptic dysfunction, whereas large, insoluble deposits might function as reservoir of the bioactive oligomers. Compelling evidence suggests the role of misfolded proteins in the form of oligomers might lead to synaptic dysfunction, neuronal apoptosis and brain damage. However, the mechanism by which oligomers trigger neurodegeneration still remains mysterious. The aim of this article is to review the literature around the molecular mechanism and role of oligomers in neurodegeneration and leading approaches toward rational therapeutics.
[J Alzheimers Dis. 2011;24 Suppl 2:223-32. Targeting oligomers in neurodegenerative disorders: lessons from α-synuclein, tau, and amyloid-β peptide. Gadad BS, Britton GB, Rao KS., Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas, TX 75390-9070, USA. b4utsw@gmail.com]
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Neurons require long-distance microtubule-based transport systems to ferry vital cellular cargoes and signals between cell bodies and axonal or dendritic terminals. Considerable progress has been made on developing a molecular understanding of these processes and how they are integrated into normal neuronal functions. Recent work also suggests that these transport systems may fail early in the pathogenesis of a number of neurodegenerative diseases. [Do Disorders of Movement Cause Movement Disorders and Dementia? Lawrence S.B Goldstein, Neuron, Volume 40, Issue 2, 415-425, 9 October 2003, Howard Hughes Medical Institute, Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093 USA]
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What is Chronic Traumatic Encephalopathy (CTE)?
“Chronic Traumatic Encephalopathy (CTE) is a progressive degenerative disease of the brain found in athletes (and others) with a history of repetitive brain trauma, including symptomatic concussions as well as asymptomatic subconcussive hits to the head.

“CTE has been known to affect boxers since the 1920s. However, recent reports have been published of neuropathologically confirmed CTE in retired professional football players and other athletes who have a history of repetitive brain trauma.

“This trauma triggers progressive degeneration of the brain tissue, including the build-up of an abnormal protein called TAU.

“These changes in the brain can begin months, years, or even decades after the last brain trauma or end of active athletic involvement. The brain degeneration is associated with memory loss, confusion, impaired judgment, impulse control problems, aggression, depression, and, eventually, progressive dementia. [Center for the Study of Traumatic Encephalopathy, Boston University]
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“CTE was diagnosed in Mike Borich, a Snow College and Western Illinois University player in the 1980s, by neuropathologist Ann McKee, MD, co-director of the CSTE. Borich went on to become an award-winning division I college football coach, and was named the Offensive Coordinator of the Year in 2001, while coaching at Brigham Young University under head coach Gary Crowton. Borich also coached for the NFL’s Chicago Bears in 1999-2000. He left coaching in 2003 struggling with overwhelming drug and alcohol addictions, ultimately dying from a drug overdose in February 2009. Other CTE sufferers, such as Tom McHale of the Tampa Bay Buccaneers, died with similar late-onset drug and alcohol problems. Borich was known to have approximately 10 concussions during his college football career with no subsequent concussions or head injuries since that time.

“Robert Cantu, MD, a leading sports concussion expert and BUSM CSTE co-director and clinical professor of neurosurgery at BUSM said, “CTE is the only fully preventable cause of dementia. It is our hope that this evidence helps draw the focus of the CTE discussion to amateur athletes, where it belongs. Young men and women are voluntarily exposing themselves to repetitive brain trauma without full knowledge of the potential consequences, and the rules of the games are designed without an appreciation for the risks carried by the players.”

“The disease is characterized by the build-up of a toxic protein called tau in the form of neurofibrillary tangles (NFTs) and neuropil threads (NTs) throughout the brain. The abnormal protein initially impairs the normal functioning of the brain and eventually kills brain cells. Early on, CTE sufferers may display clinical symptoms such as memory impairment, emotional instability, erratic behavior, depression and problems with impulse control. However, CTE eventually progresses to full-blown dementia. Although similar to Alzheimer’s disease, CTE is an entirely distinct disease.

[Source: Gina DiGravio Boston University Medical Center Chronic Traumatic Encephalopathy Diagnosed In Deceased Former College Football PlayerMain Category: Neurology / Neuroscience Also Included In: Sports Medicine / Fitness; Alzheimer’s / Dementia Article Date: 24 Oct 2009]
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Abstract
“DYT1 dystonia is a severe form of young-onset dystonia caused by a mutation in the gene that encodes for the protein torsinA, which is thought to play a role in protein transport and degradation. We describe, for the first time to our knowledge, perinuclear inclusion bodies in the midbrain reticular formation and periaqueductal gray in four clinically documented and genetically confirmed DYT1 patients but not in controls. The inclusions were located within cholinergic and other neurons in the pedunculopontine nucleus, cuneiform nucleus, and griseum centrale mesencephali and stained positively for ubiquitin, torsinA, and the nuclear envelope protein lamin A/C. No evidence of inclusion body formation was detected in the substantia nigra pars compacta, striatum, hippocampus, or selected regions of the cerebral cortex. We also noted tau/ubiquitin-immunoreactive aggregates in pigmented neurons of the substantia nigra pars compacta and locus coeruleus in all four DYT1 dystonia cases, but not in controls. This study supports the notion that DYT1 dystonia is associated with impaired protein handling and the nuclear envelope. The role of the pedunculopontine and cuneiform nuclei, and related brainstem brainstem structures, in mediating motor activity and controlling muscle tone suggests that alterations in these structures could underlie the pathophysiology of DYT1 dystonia
[Ann Neurol. 2004 Oct;56(4):540-7. Brainstem pathology in DYT1 primary torsion dystonia. McNaught KS, Kapustin A, Jackson T, Jengelley TA, Jnobaptiste R, Shashidharan P, Perl DP, Pasik P, Olanow CW., Department of Neurology, Neuropathology Division, Mount Sinai School of Medicine, New York, NY 10029, USA. kevin.mcnaught@mssm.edu]
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‘Neurons are cells with a very complex morphology that develop two types of cytoplasmic extensions, axons and dendrites. Neural transmission occurs through these processes, and therefore, any changes in neuronal morphology
may affect their behavior and even produce pathological events. Indeed, it should be born in mind that the morphological differentiation of a neuron involves the extensive rearrangement of the cytoskeleton, which is responsible for maintaining the cell’s shape.

“The cytoskeleton is composed of three main components: the microtubules, the microfilaments, and the intermediate filaments. Microtubules are very dynamic structures, and in proliferating cells such as neuroblasts (neuron precursors), their probability of assembly is the same as that of depolymerization in all directions. This equilibrium results in the cell maintaining a spherelike morphology. However, during the differentiation of a neuroblast into a neuron (209), the microtubules become stabilized in specific directions, thereby generating the cytoplasmic extensions that will become the axon and the dendrites (209).

“It has been suggested that specific proteins may serve to stabilize microtubules and such proteins including the microtubule-associated proteins (or MAPs) MAP1A, MAP1B, MAP2, and tau (Fig. 1B). In support of this hypothesis, an asymmetric distribution of MAPs (205) is seen in mature neurons (52), and tau is preferentially localized in axons (24). Indeed, as well as being present mainly in the axon of a neuron, tau function and dysfunction
have been related to axonal microtubule function, both alone and in synergy with other MAPs (101). Furthermore, in pathological situations, tau has additionally been shown to be capable of forming aberrant fibrillar polymers (Fig. 1C).

“Tau protein was discovered almost simultaneously in the United States and Europe as a protein that lowered the concentration at which tubulin polymerizes into microtubules in the brain (45, 46, 74, 291). At the same time, other high-molecular-weight MAPs were also found to influence the cycles of microtubule assembly and disassembly in vitro (255). As a result, the question rose as to whether tau was simply a degradation product of the high-molecular-weight MAPs. The groups of Kirschner (45) and Nun˜ ez (74) rapidly showed that tau was indeed an independent protein.

“Several good reviews dealing with specific features of tau have been published recently (32, 147, 160, 182, 254). Thus here we intend to cover the more general aspects of this protein, to discuss recent developments, and to highlight what we believe may be the future for the study of tau. [Role of Tau Protein in Both Physiological and Pathological Conditions JESU´ S AVILA, JOSE´ J. LUCAS, MAR PE´ REZ, AND FE´ LIX HERNA´ NDEZ Centro de Biologı´a Molecular “Severo Ochoa” (CSIC-UAM), Facultad de Ciencias, Campus de Cantoblanco, Madrid, Spain, Physiol Rev 84: 361–384, 2004; 10.1152/physrev.00024.2003]
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Abstract: “The microtubule-associated protein Tau (MAPT) is a major component of the pathogenesis of a wide variety of brain-damaging disorders, known as tauopathies. These include Alzheimer’s disease (AD), denoted as secondary tauopathy because of the obligatory combination with amyloid pathology.

“In all tauopathies, protein Tau becomes aberrantly phosphorylated, adopts abnormal conformations, and aggregates into fibrils that eventually accumulate as threads in neuropil and as tangles in soma. The argyrophilic neurofibrillary threads and tangles, together denoted as NFT, provide the postmortem pathological diagnosis for all tauopathies.

“In AD, neurofibrillary threads and tangles (NFTs) are codiagnostic with amyloid depositions but their separated and combined contributions to clinical symptoms remain elusive. Importantly, NFTs are now considered a late event and not directly responsible for early synaptic dysfunctions. Conversely, the biochemical and pathological timeline is not exactly known in human tauopathy, but experimental models point to smaller Tau-aggregates, termed oligomers or multimers, as synaptotoxic in early stages. The challenge is to molecularly define these Tau-isoforms that cause early cognitive and synaptic impairments. Here, we discuss relevant studies and data obtained in our mono- and bigenic validated preclinical models, with the perspective of Tau as a therapeutic target.[ International Journal of Alzheimer’s DiseaseVolume 2012 (2012), Article ID 251426, 13 pagesdoi:10.1155/2012/251426, Review Article, Protein Tau: Prime Cause of Synaptic and Neuronal Degeneration in Alzheimer’s Disease, Natalia Crespo-Biel, Clara Theunis, and Fred Van Leuven, Experimental Genetics Group (LEGTEGG), Department of Human Genetics, KU Leuven, Campus Gasthuisberg ON1-06.602, Herestraat 49, 3000 Leuven, Belgium, Received 14 February 2012; Accepted 16 March 2012]
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“Local field potentials were recorded from the subthalamic nucleus (STN) in a patient with dystonia to further elucidate disease-specific aspects of basal ganglia oscillatory activity.

“Conclusions: Dystonia is associated with pathological activity in the theta range present throughout the cortical-basal ganglia network. This activity differs from that in Parkinson’s disease, suggesting that different movement disorders may involve distinct oscillatory circuit disturbances. [Author: Wolf-Julian Neumann and colleaguesScript for MDS Journal Podcast Volume 27, Issue 8HOST: On behalf of the Movement Disorder Society, welcome to our monthly series ofreports on movement disorders research. In this podcast you will hear a reading of theabstracts from the July 2012 issue of the Movement Disorders Journal.]
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Introduction
“Movement disorders are a group of neurological conditions consisting of abnormal control of voluntary and automatic movements.1 According to whether they imply excessive or diminished speed, range and/or accuracy of movements, they can be classified as hyperkinesia or hypokinesia. Chorea and parkinsonism are, respectively, the paradigmatic syndromes of these two categories. Table 1 provides a summary of hyperkinetic and hypokinetic disorders. Movement disorders, taken together, constitute frequent neurological disorders. In particular, Parkinson’s disease and essential tremor, whose prevalence range from 1.7% and 4% among adults, are the two most frequent movement disorders, with the former being the second most frequent neurodegenerative disease, after Alzheimer’s disease. Other types of movement disorders, most importantly dystonia, are much rarer, but still clinically and socially relevant due to the disability they imply.1

“From an anatomo-functional point of view, movement disorders are generally
viewed as a disturbance of the basal ganglia or their connections with other brain structures. Classically, a misbalance between two key basal ganglia neurotransmitters, namely dopamine and acetylcholine, has been used as a model to understand the dichotomy between hypokinesia (lack of dopamine, excess of acetylcholine) and hyperkinesia (the opposite),2 although nowadays many other neurotransmitters, neuropeptides, and proteins have been implicated.

“Table 1 Hypo- and hyperkinesias

Hypokinesias

Parkinsonism
(bradykinesia, akinesia)
Chorea, dystonia, ballism
Freezing Myoclonus, myokymia, myorhythmia
Rigidity Tics
Stiffness Tremor
Apraxia Ataxia (dysmetria)
Cataplexy Akathisia
Catatonia, obsessional slowness Stereotypy

Hyperkinesias

Chorea,
dystonia,
ballism
Myoclonus,
myokymia,
myorhythmia
Tics
Tremor
Ataxia (dysmetria)
Akathisia
Stereotypy
[Identifying the genetic components underlying the pathophysiology of movement disorders, Mario Ezquerra Yaroslau Compta
Maria J Marti Parkinson’s Disease and Movement Disorders Unit, Service of Neurology, Institute of Clinical Neurosciences, Hospital Clinic of Barcelona, IDIBAPS, CIBERNED, Spain, The Application of Clinical Genetics 2011:4, Dove Press Journal 21 June 2011]

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