Objectives: To develop a 10-minute cognitive screening tool (Montreal Cognitive Assessment, MoCA) to assist first-line physicians in detection of mild cognitive impairment (MCI), a clinical state that often progresses to dementia.

Design: Validation study.

Setting: A community clinic and an academic center.

Participants: Ninety-four patients meeting MCI clinical criteria supported by psychometric measures, 93 patients with mild Alzheimer's disease (AD) (Mini-Mental State Examination (MMSE) score≥17), and 90 healthy elderly controls (NC).

Measurements: The MoCA and MMSE were administered to all participants, and sensitivity and specificity of both measures were assessed for detection of MCI and mild AD.

Results: Using a cutoff score 26, the MMSE had a sensitivity of 18% to detect MCI, whereas the MoCA detected 90% of MCI subjects. In the mild AD group, the MMSE had a sensitivity of 78%, whereas the MoCA detected 100%. Specificity was excellent for both MMSE and MoCA (100% and 87%, respectively).

Conclusion: MCI as an entity is evolving and somewhat controversial. The MoCA is a brief cognitive screening tool with high sensitivity and specificity for detecting MCI as currently conceptualized in patients performing in the normal range on the MMSE.

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The Montreal Cognitive Assessment, MoCA: A Brief Screening Tool For Mild Cognitive Impairment

The National Institute on Aging and the Alzheimer's Association charged a workgroup with the task of revising the 1984 criteria for Alzheimer's disease (AD) dementia. The workgroup sought to ensure that the revised criteria would be flexible enough to be used by both general healthcare providers without access to neuropsychological testing, advanced imaging, and cerebrospinal fluid measures, and specialized investigators involved in research or in clinical trial studies who would have these tools available. We present criteria for all-cause dementia and for AD dementia. We retained the general framework of probable AD dementia from the 1984 criteria. On the basis of the past 27 years of experience, we made several changes in the clinical criteria for the diagnosis. We also retained the term possible AD dementia, but redefined it in a manner more focused than before. Biomarker evidence was also integrated into the diagnostic formulations for probable and possible AD dementia for use in research settings. The core clinical criteria for AD dementia will continue to be the cornerstone of the diagnosis in clinical practice, but biomarker evidence is expected to enhance the pathophysiological specificity of the diagnosis of AD dementia. Much work lies ahead for validating the biomarker diagnosis of AD dementia.

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The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer's disease

Eighty-three brains obtained at autopsy from nondemented and demented individuals were examined for extracellular amyloid deposits and intraneuronal neurofibrillary changes. The distribution pattern and packing density of amyloid deposits turned out to be of limited significance for differentiation of neuropathological stages. Neurofibrillary changes occurred in the form of neuritic plaques, neurofibrillary tangles and neuropil threads. The distribution of neuritic plaques varied widely not only within architectonic units but also from one individual to another. Neurofibrillary tangles and neuropil threads, in contrast, exhibited a characteristic distribution pattern permitting the differentiation of six stages. The first two stages were characterized by an either mild or severe alteration of the transentorhinal layer Pre-alpha (transentorhinal stages I-II). The two forms of limbic stages (stages III-IV) were marked by a conspicuous affection of layer Pre-alpha in both transentorhinal region and proper entorhinal cortex. In addition, there was mild involvement of the first Ammon's horn sector. The hallmark of the two isocortical stages (stages V-VI) was the destruction of virtually all isocortical association areas. The investigation showed that recognition of the six stages required qualitative evaluation of only a few key preparations.

Neuropathological stageing of Alzheimer-related changes.

Background Subjects with a mild cognitive impairment (MCI) have a memory impairment beyond that expected for age and education yet are not demented. These subjects are becoming the focus of many prediction studies and early intervention trials. Objective To characterize clinically subjects with MCI cross-sectionally and longitudinally. Design A prospective, longitudinal inception cohort. Setting General community clinic. Participants A sample of 76 consecutively evaluated subjects with MCI were compared with 234 healthy control subjects and 106 patients with mild Alzheimer disease (AD), all from a community setting as part of the Mayo Clinic Alzheimer's Disease Center/Alzheimer's Disease Patient Registry, Rochester, Minn. Main Outcome Measures The 3 groups of individuals were compared on demographic factors and measures of cognitive function including the Mini-Mental State Examination, Wechsler Adult Intelligence Scale–Revised, Wechsler Memory Scale–Revised, Dementia Rating Scale, Free and Cued Selective Reminding Test, and Auditory Verbal Learning Test. Clinical classifications of dementia and AD were determined according to the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition and the National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer's Disease and Related Disorders Association criteria, respectively. Results The primary distinction between control subjects and subjects with MCI was in the area of memory, while other cognitive functions were comparable. However, when the subjects with MCI were compared with the patients with very mild AD, memory performance was similar, but patients with AD were more impaired in other cognitive domains as well. Longitudinal performance demonstrated that the subjects with MCI declined at a rate greater than that of the controls but less rapidly than the patients with mild AD. Conclusions Patients who meet the criteria for MCI can be differentiated from healthy control subjects and those with very mild AD. They appear to constitute a clinical entity that can be characterized for treatment interventions.

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Mild Cognitive Impairment: Clinical Characterization and Outcome

I have developed "tennis elbow" from lugging this book around the past four weeks, but it is worth the pain, the effort, and the aspirin. It is also worth the (relatively speaking) bargain price. Including appendixes, this book contains 894 pages of text. The entire panorama of the neural sciences is surveyed and examined, and it is comprehensive in its scope, from genomes to social behaviors. The editors explicitly state that the book is designed as "an introductory text for students of biology, behavior, and medicine," but it is hard to imagine any audience, interested in any fragment of neuroscience at any level of sophistication, that would not enjoy this book. The editors have done a masterful job of weaving together the biologic, the behavioral, and the clinical sciences into a single tapestry in which everyone from the molecular biologist to the practicing psychiatrist can find and appreciate his or

Principles of Neural Science

Animal models provide unique opportunities to analyze mechanisms of βamyloid protein (Aβ) amyloidogenesis One set of studies in control animals was designed to identify the neural cells that express the amyloid precursor protein (APP) and to characterize the transport and processing of APP in vivo APP is synthesized by neurons and transported by fast axonal transport to terminals, where it may play a role in cell-cell and synaptic interactions A second group of investigations focused on amyloidogenesis in aged nonhuman primates In late middle life, monkeys develop age-associated impairments in performance on cognitive/memory tasks and begin to show brain abnormalities, including deposits of Aβ and formation of neurites Amyloid is readily demonstrable in proximity to APP-enriched swollen axonal terminals and dendrites, suggesting that neurons may be one source of Aβ However, in ways not yet clear, astrocytes, microglia, and vascular cells may also contribute to the formation of Aβ In the neuropil of brain, alterations in the normal biology of APP may lead not only to the formation of amyloid fibrils but may also impair synaptic interactions, resulting in synaptic disjunction and disconnection More recently, in a third set of experiments, we have begun to examine transgenic mice, generated by the yeast artificial chromosome (YAC)-embryonic stem (ES) cell technique These animals express the entire human APP gene and transgene expression that approximates levels of endogenous APP These mice, trisomic for APP, may develop Alzheimer’s disease (AD)-type pathology, as occurs in individuals with Down’s syndrome (trisomy 21) Finally, recent research is designed to produce transgenic mice with AD-linked APP mutations; these studies are essential for determining some of the genetic/molecular/biochemical mechanisms that cause AD-type brain lesions in familial AD (FAD) The strategies that have proved valuable in aged monkeys will be very helpful in studies of these mice Both nonhuman primate and transgenic models will permit the testing of therapeutic approaches designed to ameliorate some of the abnormalities that occur in humans with AD In conclusion, this review summarizes briefly the features of AD relevant to these studies and outlines some of our research focusing on the biology of APP in neural tissues and animal models, including aged nonhuman primates and transgenic mice

Amyloid in Alzheimer’s Disease and Animal Models

Genetically engineered models of neurodegenerative diseases

Because neurons possess the most complex geometries of any cell type, intracellular transport systems are essential to deliver critical proteins to specific anatomical and functional sites (e.g., dendrites, axons, and synaptic terminals) where relatively few proteins are synthesized. Although increasing evidence suggests that some proteins are synthesized locally within dendrites and spines and even within axons/terminals, the principal sites of neuronal protein synthesis are the cell bodies; axons and nerve terminals, in particular, depend primarily on this source for a continued supply of certain proteins to perform normal functions. The axonal transport systems, which evolved to deliver essential materials to the most distal parts of nerve cells, participate in the delivery of proteins and prepackaged cargo to specific destinations. These systems were initially distinguished based on velocity (fast, intermediate, or slow) and direction of movement (anterograde and retrograde). The identification of anterograde and retrograde transport motors and delineation of transport vesicles and cargo are critical players in this evolving story of discovery. Because axonal transport is a critical process within nerve cells, it is not surprising that axonal transport is involved in regeneration and that impairments in transport are associated with a variety of disorders of the peripheral and central nervous systems. In this article, we describe these transport systems and discuss how axonal transport functions in regeneration and repair and how malfunctions of transport processes are implicated in both experimental models and in human disorders.

Axonal Transport Disorders

Characterization of intracytoplasmic abnormalities in low expressor sod1 transgenic mice with motor neuron disease

Investigations of processes that lead to cell death in the central (CNS) and peripheral (PNS) nervous systems are exciting areas of research in neuropathology. Programmed death of neurons has long been recognized as a critical process in shaping the developing nervous system, and neuronal degeneration plays a central role in many pathological processes associated with diseases of the CNS and PNS. Current research focuses on mechanisms that lead to cell death in different settings (i.e. development, ischemia, genetic and toxic diseases, and degenerative disorders); recent studies have implicated genetic factors, loss of trophic support, excitotoxicity, perturbations of the cytoskeleton, etc. in the pathogenesis of death of nerve cells in both animal models and their human counterparts. The symposium will focus on in vim and in vivo investigations of these processes as illustrated in selected model systems. Dr. Price will introduce the symposium with an overview of recent advances in the biology of cell death and the relevance of some of this work for human neurological disorders. Dr. Driscoll will review genetic mechanisms that lead to the death of nerve cells, as illustrated in molecular studies of these processes in the developing nematode Caetiorhabditis elegans. In this species, two types of cell death have been identified: programmed cell death, which occurs during normal development; and pathological cell death, which results from genetic mutations. For example, two genes, ced3 and ceti4 are critical for programmed cell death; ced3 has been shown to be the nematode homologue of interleukin-lp-coverting enzyme, whereas ced4, may be a calcium binding protein. Investigations of mutated genes involved in abnormal cell death have defined the degenerins, a novel gene family that encodes putative membrane proteins; dominant alleles of two of these species, mec-4 and deg-I, cause neurodegeneration. Subsequently, Dr. Johnson will discuss how cultures of sympathetic neurons deprived of nerve growth factor have been used to study RNA and protein synthesisdependent programmed cell death. This process, termed apoptosis, has been hypothesized to be a consequence of conflicting growth signals leading to the inappropriate activation of cell cycle genes. Dr. Johnson and colleagues have shown that cyclin D1 appears to be selectively induced in dying postmitotic neurons. Amyotrophic lateral sclerosis (ALS), one of the classical neurodegenerative diseases, is characterized by cytoskeletal pathology and death of motor neurons. Some cases of the familial form of this disease are linked to mutations in the superoxide dismutase 1 (SODl) gene. Several groups, including investigators at Johns Hopkins, have used transgenic technologies to introduce SODl mutations into the mouse genome. Transgenic animals with the G37R mutation exhibit a remarkable clinical phenotype. These animals show extraordinary pathology of lower motor neurons including swollen axons and death of motor neurons. Similar -transgenic strategies in which wild-type or mutant neurofilament genes have been over-expressed also reproduce aspects of the neurofibrillary pathology that occurs in ALS. SODl mutation transgenic mice, in particular, provide an opportunity to clarify the mechanisms of motor neuron dysfunction / death and to test novel therapies. Finally, Dr. Koliatsos will outline the ways in which trophic factors affect specific populations of cells. He will review the biology of trophic factors and neural cytokines and their recepors and will discuss the phenotypes of mice whose neurotrophic factor/ receptor gene have been ablated by gene targeting strategies. Subsequently, he will review the utility of neurotrophins neural cytokines in simple model paradigms and will close with a discussion of the implications of these studies for designing new therapies for human disorders.

Donald L. Price

Papers

Amyloid in Alzheimer’s Disease and Animal Models

Genetically engineered models of neurodegenerative diseases

Axonal Transport Disorders

Characterization of intracytoplasmic abnormalities in low expressor sod1 transgenic mice with motor neuron disease

Symposium 4: Neuronal Cell Death in the Nervous System