Evolving concepts of chronic traumatic encephalopathy as a neuropathological entity

Chronic traumatic encephalopathy (CTE) is a long‐term neurodegenerative consequence of repetitive head impacts which can only be definitively diagnosed in post‐mortem. Recently, the consensus neuropathological criteria for the diagnosis of CTE was published requiring the presence of the accumulation of abnormal tau in neurons and astroglia distributed around small blood vessels at the depths of cortical sulci in an irregular pattern as the mandatory features. The clinical diagnosis and antemortem prediction of CTE pathology remain challenging if not impossible due to the common co‐existing underlying neurodegenerative pathologies and the lack of specific clinical pointers and reliable biomarkers. This review summarizes the historical evolution of CTE as a neuropathological entity and highlights the latest advances and future directions of research studies on the topic of CTE.     

Proposed neuropathological criteria for the post mortem diagnosis of multiple system atrophy

This report summarizes the recommendations of the multiple system atrophy (MSA) Working Group on Diagnostic Neuropathology Criteria for MSA that was part of an international MSA Workshop held on 26 and 27 April 2007 in Boston, MA. The workshop was supported by a grant from the National Institute of Neurological Disorders and Stroke that was intended to convene a group of international experts to revise and update criteria for the clinical and neuropathological diagnosis of MSA. The MSA Workshop recognized the glial cytoplasmic inclusions (GCIs) composed of filamentous alpha-synuclein as a defining morphological feature of MSA, and it recommends that widespread GCIs should be a criterion for the definite neuropathological diagnosis of MSA. The deliberations and recommendations of the Working Group on Diagnostic Neuropathology Criteria for MSA are summarized in this report.     

Prospective validation of consensus criteria for the diagnosis of dementia with Lewy bodies

OBJECTIVE: To determine the validity of a clinical diagnosis of probable or possible dementia with Lewy bodies (DLB) made using International Consensus criteria. BACKGROUND: Validation studies based on retrospective chart reviews of autopsy-confirmed cases have suggested that diagnostic specificity for DLB is acceptable but case detection rates as low as 0.22 have been suggested. METHODS: We evaluated the first 50 cases reaching neuropathologic autopsy in a cohort to which Consensus clinical diagnostic criteria for DLB, National Institute for Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria for AD, and National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche et l'Enseignement en Neurosciences criteria for vascular dementia (VaD) had been prospectively applied. RESULTS: Twenty-six clinical diagnoses of DLB, 19 of AD, and 5 of VaD were made. At autopsy, 29 DLB cases, 15 AD, 5 VaD, and 1 progressive supranuclear palsy were identified. The sensitivity and specificity of a clinical diagnosis of probable DLB in this sample were 0.83 and 0.95. Of the five cases receiving a false-negative diagnosis of DLB, significant fluctuation was present in four but visual hallucinations and spontaneous motor features of parkinsonism were generally absent. Thirty-one percent of the DLB cases had additional vascular pathology and in two cases this contributed to a misdiagnosis of VaD. No correlations were found between the distribution of Lewy bodies and clinical features. CONCLUSION: The Consensus criteria for DLB performed as well in this prospective study as those for AD and VaD, with a diagnostic sensitivity substantially higher than that reported by previous retrospective studies. DLB occurs in the absence of extrapyramidal features and in the presence of comorbid cerebrovascular disease. Fluctuation is an important diagnostic indicator, reliable measures of which need to be developed further.     

Operational criteria for the classification of chronic alcoholics: identification of Wernicke's encephalopathy.

OBJECTIVES: To establish better operational criteria for the diagnosis of Wernicke''s encephalopathy. Current criteria for diagnosing Wernicke''s encephalopathy require the presence of three clinical signs (oculomotor abnormalities, cerebellar dysfunction, and an altered mental state), although it has often been reported that most patients do not fulfil all these criteria. METHODS: The clinical histories of 28 alcoholics with neurological and neuropsychological assessments and definitive neuropathological diagnoses were examined to determine clinical signs for use in a screening schedule. Operational criteria were then proposed for differentiating patients with Wernicke''s encephalopathy alone or in combination with Korsakoff''s psychosis or hepatic encephalopathy. The new criteria for Wernicke''s encephalopathy require two of the following four signs; (1) dietary deficiencies, (2) oculomotor abnormalities, (3) cerebellar dysfunction, and (4) either an altered mental state or mild memory impairment. Reproducibility and validity testing of these criteria were performed on 106 alcoholics screened from a large necropsy sample. RESULTS: Despite rater variability with regard to specific symptoms, within and between rater reliability for diagnostic classification using the criteria retrospectively on patient records was 100% for three independent raters. Validity testing showed that Wernicke''s encephalopathy was underrecognized only when occurring with hepatic encephalopathy (50% sensitivity). CONCLUSIONS: By contrast with current criteria, the proposed operational criteria show that the antemortem identification of Wernicke''s encephalopathy can be achieved with a high degree of specificity.     

Use of p62/SQSTM1 antibodies for neuropathological diagnosis

The demonstration of proteinaceous inclusions in the brain is the key step in the pathological diagnosis of degenerative dementias. The diversity of these diseases has necessitated the use of a panel of (immuno)stains to visualize all suspect pathologies, elevating diagnostic costs. Immunodetection of p62 (sequestosome 1), an abundant constituent in diverse pathological inclusions, holds the potential for a broad-specificity, high-contrast inclusion label. In the brain, pathological p62-positive aggregates comprise both cytoplasmic and nuclear types in neurones and glia, with abnormal tau, alpha-synuclein, TAR DNA-binding protein 43 or polyglutamine proteins as primary components. We therefore set out to evaluate the performance of p62 antibodies for diagnostic immunohistochemistry. We optimized the application conditions and compared the staining profiles of eight commercial p62 antibodies with each other and with reference immunostains, using 2-mm tissue multiarrays representing the major tauo- and synucleinopathies and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). The lesions were best visualized using monoclonal antibodies, displaying most types of hallmark inclusions with excellent contrast. Expanding the list of p62-containing aggregates, we demonstrated p62 in tufted astrocytes, coiled bodies, astrocytic plaques, and variform neocortical inclusions and pathological processes in FTLD-U. Polyclonal antibodies exhibited lower sensitivities with variable background levels. We also noted more subtle p62-immunoreactive features lacking overt disease associations. Emphasizing the importance of proper antibody and epitope unmasking methods for maximum sensitivity, we recommend p62 immunodetection as a screening stain for diagnostic practice.     

Application of the National Institute on Aging (NIA)-Reagan Institute criteria for the neuropathological diagnosis of Alzheimer disease

The Khachaturian criteria and the Consortium to Establish a Registry for Alzheimer Disease (CERAD) criteria for the neuropathological assessment of Alzheimer disease (AD) emphasize senile or neuritic plaques, age, and clinical history. A new scheme stressing topographic staging of neurofibrillary changes in addition to neuritic plaques has been proposed by the National Institute on Aging (NIA)-Reagan Institute Consensus Conference. This scheme assigns cases to high, intermediate, or low likelihood categories that the dementia is due to AD. We applied this method to 84 brains from subjects with clinical and neuropathological diagnoses of AD (n = 33), non-AD dementing illnesses (n = 34), including dementia with Lewy bodies (DLB) and progressive supranuclear palsy (PSP), and no neurological disease (n = 17). We also used Khachaturian and CERAD criteria. Neurofibrillary tangle and neuropil thread densities were assessed on 6-micrometer-thick modified Bielschowsky-stained paraffin sections from entorhinal-perirhinal cortex, CA1 of hippocampus, and neocortex including inferior temporal, visual association, and primary visual cortices. Each case was assigned a Braak and Braak stage. Using the NIA-Reagan criteria, we found excellent agreement between clinical history of AD dementia and brains assigned to the high likelihood category that dementia was due to AD. Among brains diagnosed neuropathologically with other degenerative diseases, NIA-Reagan criteria were more conservative than previous criteria, and these cases were likely to be categorized as intermediate or low likelihood that dementia was due to AD. All brains from nondemented subjects were assigned to the low (81%) or intermediate (19%) categories. In summary, we found good correlation between the NIA-Reagan criteria and clinical dementia, and there was generally good agreement between these criteria and existing neuropathological methods, Khachaturian and CERAD, in diagnosing AD. In studying several other neurodegenerative diseases, such as DLB, which shows neuropathological and clinical overlap with AD, the staging of neurofibrillary changes offered potential diagnostic refinement.     

Provisional diagnostic criteria for depression in Parkinson's disease: report of an NINDS/NIMH Work Group.

Mood disorders are the most common psychiatric problem associated with Parkinson's disease (PD), and have a negative impact on disability and quality of life. Accurate diagnosis of depressive disturbances in PD is critical and will facilitate the testing and use of new interventions; however, there are no clear diagnostic criteria for depressive disorders in PD. In their current form, strict Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria are difficult to use in PD and require attribution of specific symptoms to PD itself or the depressive syndrome. Additionally, DSM criteria for major depression and dysthymia exclude perhaps half of PD patients with comorbid clinically significant depression. This review summarizes an NIH-sponsored workshop and describes recommended changes to DSM diagnostic criteria for depression for use in PD. Participants also recommended: (1) an inclusive approach to symptom assessment to enhance reliability of ratings in PD and avoid the need to attribute symptoms to a particular cause; (2) the inclusion of subsyndromal depression in clinical research studies of depression of PD; (3) the specification of timing of assessments for PD patients with motor fluctuations; and (4) the use of informants for cognitively impaired patients. The proposed diagnostic criteria are provisional and intended to be defined further and validated but provide a common starting point for clinical research in PD-associated depression.     

Consensus neuropathological diagnosis of common dementia syndromes: testing and standardising the use of multiple diagnostic criteria

The aim of this study was to assess the variation between neuropathologists in the diagnosis of common dementia syndromes when multiple published protocols are applied. Fourteen out of 18 Australian neuropathologists participated in diagnosing 20 cases (16 cases of dementia, 4 age-matched controls) using consensus diagnostic methods. Diagnostic criteria, clinical synopses and slides from multiple brain regions were sent to participants who were asked for case diagnoses. Diagnostic sensitivity, specificity, predictive value, accuracy and variability were determined using percentage agreement and kappa statistics. Using CERAD criteria, there was a high inter-rater agreement for cases with probable and definite Alzheimer's disease but low agreement for cases with possible Alzheimer's disease. Braak staging and the application of criteria for dementia with Lewy bodies also resulted in high inter-rater agreement. There was poor agreement for the diagnosis of frontotemporal dementia and for identifying small vessel disease. Participants rarely diagnosed more than one disease in any case. To improve efficiency when applying multiple diagnostic criteria, several simplifications were proposed and tested on 5 of the original 20 cases. Inter-rater reliability for the diagnosis of Alzheimer's disease and dementia with Lewy bodies significantly improved. Further development of simple and accurate methods to identify small vessel lesions and diagnose frontotemporal dementia is warranted.     

Positron emission tomography imaging for the assessment of mild traumatic brain injury and chronic traumatic encephalopathy: recent advances in radiotracers

A chronic phase following repetitive mild traumatic brain injury can present as chronic traumatic encephalopathy in some cases,which requires a neuropathological examination to make a definitive diagnosis.Positron emission tomography(PET)is a molecular imaging modality that has high sensitivity for detecting even very small molecular changes,and can be used to quantitatively measure a range of molecular biological processes in the brain using different radioactive tracers.Functional changes have also been reported in patients with different forms of traumatic brain injury,especially mild traumatic brain injury and subsequent chronic traumatic encephalopathy.Thus,PET provides a novel approach for the further evaluation of mild traumatic brain injury at molecular levels.In this review,we discuss the recent advances in PET imaging with different radiotracers,including radioligands for PET imaging of glucose metabolism,tau,amyloid-beta,γ-aminobutyric acid type A receptors,and neuroinflammation,in the identification of altered neurological function.These novel radiolabeled ligands are likely to have widespread clinical application,and may be helpful for the treatment of mild traumatic brain injury.Moreover,PET functional imaging with different ligands can be used in the future to perform largescale and sequential studies exploring the time-dependent changes that occur in mild traumatic brain injury.     

抗tau蛋白抗体基因疗法对慢性颅脑创伤的治疗作用研究

目的探究抗tau蛋白（pTau）基因腺病毒相关病毒（AAV）载体中枢神经系统（CNS）直接干预对慢性颅脑创伤（CTE）的治疗效果。 方法随机选取24只C57小鼠按随机数字表法分为3组，正常对照组（sham组）、CTE 4周组和CTE 12周组，每组8只，采用皮质撞击法建立CTE小鼠动物模型，并在实验开始的第4、12周时取脑组织Western blot检测pTau蛋白相对水平评估该模型；将余56只小鼠按随机数字表法分为7组：sham组、noAAV组、AAVrh.10Null组和编码2B6、CisTau、IPN007、PHF1基因载体组，每组8只，除sham组外，各组小鼠通过皮质撞击法构建CTE模型。第3周时sham组与noAAV组注射等量人工脑脊液，其余各组小鼠分别在海马区注射对应基因编码的表达载体，第4周时所有小鼠安乐死，取脑组织进行免疫荧光和Western blot法评估抗pTau抗体表达，并评估对CTE小鼠的治疗效果。 结果CTE小鼠模型4和12周组脑组织pTau明显高于sham组，差异均具有统计学意义（P<0.05）；AAVrh.10 PHF1与AAVrh.10 IPN治疗组显著降低了小鼠脑组织中pTau的水平，且AAVrh.10 PHF1组优于AAVrh.10 IPN组（P=0.032）。 结论抗pTau抗体基因的AAVrh.10病毒载体CNS直接治疗CTE有效，为治疗提供了新的方向。     

The neuropathological basis to the functional role of microglia/macrophages in gliomas

Neurological Sciences - The paper wants to be a tracking shot of the main recent acquisitions on the function and significance of microglia/macrophages in gliomas. The observations have been...