Advances in Deep Neuropathological Phenotyping of Alzheimer Disease: Past, Present, and Future.

Alzheimer disease (AD) is a neurodegenerative disorder characterized pathologically by the presence of neurofibrillary tangles and amyloid beta (Aß) plaques in the brain. The disease was first described in 1906 by Alois Alzheimer, and since then, there have been many advancements in technologies that have aided in unlocking the secrets of this devastating disease. Such advancements include improving microscopy and staining techniques, refining diagnostic criteria for the disease, and increased appreciation for disease heterogeneity both in neuroanatomic location of abnormalities as well as overlap with other brain diseases; for example, Lewy body disease and vascular dementia. Despite numerous advancements, there is still much to achieve as there is not a cure for AD and postmortem histological analyses is still the gold standard for appreciating AD neuropathologic changes. Recent technological advances such as in-vivo biomarkers and machine learning algorithms permit great strides in disease understanding, and pave the way for potential new therapies and precision medicine approaches. Here, we review the history of human AD neuropathology research to include the notable advancements in understanding common co-pathologies in the setting of AD, and microscopy and staining methods. We also discuss future approaches with a specific focus on deep phenotyping using machine learning.

COllaborative Neuropathology NEtwork Characterizing ouTcomes of TBI (CONNECT-TBI).

Efforts to characterize the late effects of traumatic brain injury (TBI) have been in progress for some time. In recent years much of this activity has been directed towards reporting of chronic traumatic encephalopathy (CTE) in former contact sports athletes and others exposed to repetitive head impacts. However, the association between TBI and dementia risk has long been acknowledged outside of contact sports. Further, growing experience suggests a complex of neurodegenerative pathologies in those surviving TBI, which extends beyond CTE. Nevertheless, despite extensive research, we have scant knowledge of the mechanisms underlying TBI-related neurodegeneration (TReND) and its link to dementia. In part, this is due to the limited number of human brain samples linked to robust demographic and clinical information available for research. Here we detail a National Institutes for Neurological Disease and Stroke Center Without Walls project, the COllaborative Neuropathology NEtwork Characterizing ouTcomes of TBI (CONNECT-TBI), designed to address current limitations in tissue and research access and to advance understanding of the neuropathologies of TReND. As an international, multidisciplinary collaboration CONNECT-TBI brings together multiple experts across 13 institutions. In so doing, CONNECT-TBI unites the existing, comprehensive clinical and neuropathological datasets of multiple established research brain archives in TBI, with survivals ranging minutes to many decades and spanning diverse injury exposures. These existing tissue specimens will be supplemented by prospective brain banking and contribute to a centralized route of access to human tissue for research for investigators. Importantly, each new case will be subject to consensus neuropathology review by the CONNECT-TBI Expert Pathology Group. Herein we set out the CONNECT-TBI program structure and aims and, by way of an illustrative case, the approach to consensus evaluation of new case donations.

A half century of change in diagnostic neuropathology: from the giants of yore to current brain tumor classification.

The first issue of Human Pathology contains a laudatory review of one of the most treasured books in the history of neuropathology: Neurological Clinicopathological Conferences of the Massachusetts General Hospital, a collection of neurological cases that appeared first in the New England Journal of Medicine in the 1940s, 1950s, and 1960s. Each patient history is discussed by well-known neurologists, neurosurgeons, and neuropathologists. Review of these cases provides a framework to explore diagnostic shifts that have occurred over the past half century. Importantly, while the discussants of these cases were great diagnosticians, they were somewhat limited by the methods available to them at the time; subsequent novel technologies provided opportunities for new insights that were made by the next generation of experts. Today's pathologists (whether neuropathologists or any other pathology subspecialists) are similarly skilled at diagnosis, although their diagnoses are now more often made on biopsies (rather than autopsies) and informed by pre-operative imaging studies as well as post-operative molecular analyses. In turn, one would conclude that, even in the face of future technological changes brought about by disruptive innovations like artificial intelligence and deep molecular analyses, a need will continue for the expertise of pathologists and other clinical diagnosticians.

Temporal changes in the likelihood of dementia and MCI over 18 years in a population sample.

OBJECTIVE: To examine the temporal changes in the likelihood of dementia and mild cognitive impairment (MCI) between 1993 and 2012 using a short battery of cognitive tests. METHODS: A cohort of 10,342 participants underwent a short battery of cognitive tests collected during triennial in-home interviews with 2,794 of those evaluated for the clinical diagnosis of dementia and MCI. We used a generalized logit regression model to estimate the likelihood of dementia and MCI, and a quasibinomial regression model to examine the temporal changes in those likelihood scores. RESULTS: A short battery of cognitive tests-delayed story recall test, Symbol Digit Modalities Test, and the Mini-Mental State Examination-were associated with the clinical diagnosis of dementia and MCI. The classification accuracy of likelihood scores was 0.92 for dementia and 0.85 for MCI. After adjusting for age, race/ethnicity, and education, the likelihood of dementia in the population decreased from 21.6% (95% confidence interval [CI] 20.9%-22.3%) to 18.9% (95% CI 18.1%-19.7%) between 1993-1996 and 2000-2002 and showed no significant decline between 2000-2002 and 2009-2012 (-0.2%, 95% CI -1.1% to 0.7%). The estimated likelihood of MCI remained similar between 1993-1996 and 2009-2012 (29.0%, 95% CI 27.9%-30.1%), but showed a nonsignificant decrease in 2000-2002. CONCLUSION: The likelihood scores based on a short battery of cognitive tests can serve as a measure of dementia and MCI in epidemiologic studies. The decline in the likelihood of dementia and MCI over earlier years was not sustained in later years.

Advances in the Differentiation of Retinal Ganglion Cells from Human Pluripotent Stem Cells.

Human pluripotent stem cell (hPSC) technology has revolutionized the field of biology through the unprecedented ability to study the differentiation of human cells in vitro. In the past decade, hPSCs have been applied to study development, model disease, develop drugs, and devise cell replacement therapies for numerous biological systems. Of particular interest is the application of this technology to study and treat optic neuropathies such as glaucoma. Retinal ganglion cells (RGCs) are the primary cell type affected in these diseases, and once lost, they are unable to regenerate in adulthood. This necessitates the development of strategies to study the mechanisms of degeneration as well as develop translational therapeutic approaches to treat early- and late-stage disease progression. Numerous protocols have been established to derive RGCs from hPSCs, with the ability to generate large populations of human RGCs for translational applications. In this review, the key applications of hPSCs within the retinal field are described, including the use of these cells as developmental models, disease models, drug development, and finally, cell replacement therapies. In greater detail, the current report focuses on the differentiation of hPSC-derived RGCs and the many unique characteristics associated with these cells in vitro including their genetic identifiers, their electrophysiological activity, and their morphological maturation. Also described is the current progress in the use of patient-specific hPSCs to study optic neuropathies affecting RGCs, with emphasis on the use of these RGCs for studying disease mechanisms and pathogenesis, drug screening, and cell replacement therapies in future studies.

World Health Organization 2016 Classification of Central Nervous System Tumors.

The recent update of the World Health Organization (WHO) classification of tumors of the central nervous system represents a paradigm shift. Previous iterations of the classification relied on morphologic features for classification. In the 2016 update, the definitions of specific neoplastic entities tumors now include precise molecularly defined entities. This article discusses this paradigm shift, and focuses on the refinements in classification criteria, relations to previous editions, and their implication to neuropathology and neuro-oncology practice. The authors distinguish the criteria that were used to determine why molecular changes were included.

Connectomics and other novel methods for examining neural systems.

Novel approaches for studying the brain and relating its activities to mental phenomena have come into use during the past decade (Bargmann, 2015). These include both new laboratory methods - involving, among others, generation of isolated cells which retain neuronal characteristics in vivo; the selective stimulation of neurons by light in vivo; and direct electrical stimulation of specific brain regions to restore a system's balance of excitation and inhibition - and a new organizing principle, "connectomics", which recognizes that networks, and not simply a key nucleus or region, underlie most brain functions and malfunctions. Its application has already improved our comprehension of how the brain normally functions and our ability to help patients with such poorly treated neurologic and psychiatric diseases as Alzheimer's disease.

The future of psychiatry: brain devices.

Recent advances in deep brain stimulators and brain-machine interfaces have greatly expanded the possibilities of neuroprosthetics and neuromodulation. Together with advances in neuroengineering, nanotechnology, molecular biology and material sciences, it is now possible to address fundamental questions in neuroscience in new, more powerful ways. It is now possible to apply these new technologies in ways that range from augmenting and restoring function to neuromodulation modalities that treat neuropsychiatric disorders. Recent developments in neuromodulation methods offer significant advantages and potential clinical benefits for a variety of disorders. Here we describe the current state of the art in neuromodulation methods, and some advances in brain-machine interfaces, describing the advantages and limitations of the clinical applications of each method. The future applications of these new methods and how they will shape the future of psychiatry and medicine, along with safety and ethical implications, are also discussed.

Neurosurgery of the future: Deep brain stimulations and manipulations.

Important advances are afoot in the field of neurosurgery-particularly in the realms of deep brain stimulation (DBS), deep brain manipulation (DBM), and the newly introduced refinement "closed-loop" deep brain stimulation (CLDBS). Use of closed-loop technology will make both DBS and DBM more precise as procedures and will broaden their indications. CLDBS utilizes as feedback a variety of sources of electrophysiological and neurochemical afferent information about the function of the brain structures to be treated or studied. The efferent actions will be either electric, i.e. the classic excitatory or inhibitory ones, or micro-injection of such things as neural proteins and transmitters, neural grafts, implants of pluripotent stem cells or mesenchymal stem cells, and some variants of gene therapy. The pathologies to be treated, beside Parkinson's disease and movement disorders, include repair of neural tissues, neurodegenerative pathologies, psychiatric and behavioral dysfunctions, i.e. schizophrenia in its various guises, bipolar disorders, obesity, anorexia, drug addiction, and alcoholism. The possibility of using these new modalities to treat a number of cognitive dysfunctions is also under consideration. Because the DBS-CLDBS technology brings about a cross-fertilization between scientific investigation and surgical practice, it will also contribute to an enhanced understanding of brain function.

Chronic Traumatic Encephalopathy-Like Abnormalities in a Routine Neuropathology Service.

Chronic traumatic encephalopathy (CTE) has been described mainly in professional athletes and military personnel and is characterized by deposition of hyperphosphorylated tau at the depths of cortical sulci and around blood vessels. To assess CTE-like changes in a routine neuropathology service, we prospectively examined 111 brains (age 18-60 years). The presence of tau-immunoreactive deposits was staged using guidelines described by others and was correlated with the medical history. 72/111 cases were negative for CTE-like changes; 34/111 were CTE stage <1; 3/111 were CTE stage 1; and 2/111 were CTE stage 2. The combined history of head injury and alcohol and/or drug abuse was a significant predictor of any CTE-like changes. Age was also a significant predictor; most with any CTE-like changes were >40 years old. CTE-like changes were not identified at sites of contusion. Among a separate group studied retrospectively, we identified 4 cases that met full criteria for CTE. We conclude that CTE-like findings are not confined to professional athletes; the risk factors of head injury and substance abuse are similar in the routine population. However, the significance of very small hyperphosphorylated tau deposits remains to be determined. In addition, the absence of typical CTE-like deposits near contusion sites keeps open the question of pathogenesis.