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.

/pdf/the-diagnosis-of-dementia-due-to-alzheimer-s-disease-w5k0egjbz5.pdf

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

Alzheimer's disease (AD) and Parkinson's disease (PD), the two most common types of adult-onset chronic degenerative disorders of the CNS l,z are characterized by degeneration of certain populations of neurons with relative sparing of other groups of nerve cells 3,4. Dysfunction of at-risk neurons is associated with several types of cytoskeletal pathology. As these nerve cells degenerate alterations occur in neurotransmitter markers. Dysfunction~death of neurons in these systems result in the clinical syndromes of AD and PD. The bradykinesia and rigidity of PD are associated with lesions in the nigrostriatal dopaminergic system, whereas the dementia of AD is attributed to abnormalities of nerve cells in monoaminergic brainstem nuclei, in the basal forebrain cholinergic system, and in neuronal populations within the amygdala, hippocampus, and neocortex. On the basis of clinical and histopathological criteria, AD and PD are distinguished from other adult-onset degenerative neurological disorders, including Pick's disease, progressive supranuclear palsy, the Guamanian parkinsonism--dementia complex, etc. The present review describes the current status of our understanding of cellular abnormalities occurring in at-risk neuronal populations in AD and PD. Along with amyotrophic lateral sclerosis, Alzbeimer's disease (AD) and Parkinson's disease (PD) are prototypes of human neurological disorders characterized by occurrences of cytoskeletal pathology in specific populations of nerve cells 5. In AD and PD, at-risk neurons may exhibit several types of cytoskeletal abnormali- ties, including neurofibrillary tangles (NFF), Hirano bodies, Lewy bodies, and enlarged neurites in senile plaques. In addition, recent preliminary studies suggest that granulovacuolar degenera- tion, occurring particularly in hippo- campal pyramidal neurons of indi- viduals with AD, may also represent a form of cytoskeletal disorganization. Each of these forms of structural pathology can be found in low frequen- cies in the brains of aged individuals who, overtly, are not impaired neuro- logically; however, in classical AD and PD, these types of structural abnormal- ities are abundant, and their presence serve as diagnostic criteria. Because cytoskeletal elements are important in the maintenance of neuronal size and shape, in intracellular transport proces- ses, and in the organization of both cytoplasmic elements and membrane constituents, nerve cells exhibiting these abnormalities may not be able to carry out normal functions. In addition to these structural alterations in the neuronal cytoskeleton, patients with AD and, much less commonly, some demented individuals with PD have deposits of amyloid in the neural parenchyma (senile plaques) and in cerebral vessels (congophilic angiopathy). The nature, components, and distributions of these different structural pathologies are discussed below. Cytoskeletal pathology in Alzheimer's disease Neurofibrillary tangles. Demonstra- ted by silver impregnation methods, histocbemical stains (thioflavin-T), and immunocytochemical techniques, NFT occur in perikarya of neurons a variety of brain regions, including the locus coeruleus, dorsal raphe, basal forebrain cholinergic system, amyg- dala, hippocampus, and neocortex 6. The major component of NFT are 10 nm paired helical filaments (PHF) 7 which may be admixed with 10 nm neurofilaments and 15 nm straight filaments. These different types of filaments may be related, with structu- ral differences between filaments re- flecting heterogeneity of composition, different modifications of component proteins, and/or stages in the evolution of filamentous pathology. PHF, the most characteristic filamentous patho- logy, are highly insoluble crosslinked polymers s which may be, in part, composed of neurofilament proteins 9-11. Recent studies indicate that NFT- bearing neurons show perikaryal im- munoreactivities of several phosphory- lated epitopes of the 200 kDa neuro- filament protein, which are not norm- ally present within perikarya 12, and these inappropriately phosphorylated proteins may represent an early stage in the formation of abnormal filaments. In addition, non-neurofilament pro- teins, including microtubule-associated protein-2, also appear to be implicated in the formation of PHF 11,13. The composition of PHF and 15 nm straight filaments and their relationship to other elements should be clarified as progress is made in purifying these abnormal filamentous organelles and in solubilizing and sequencing their constituents for comparisons with other neuronal proteins, including those of neurofilaments. Eventually, NFT-containing neurons die, leaving behind extracellular PHF-rich NFT. The number of NFT in cortex corre- lates with the presence of dementia and with reductions in the activity of cortical choline acetylransferase 14. Senile plaques. These complex struc- tural abnormalities are composed of enlarged argentophilic axons/synaptic terminals (neurites), abnormal den- dritic processes, extracellular amyloid (see below), and variable numbers of astroglia and microglia. Neurites in plaques are filled with accumulations of straight filaments and PHF resembling components of NFT, but it is not known whether these abnormal fila- ments in neurites are transported from NFF-bearing perikarya or are formed locally within distal axons. Many enlarged neurites appear to be de- generating axons/terminals, but some neurites may represent regenerating neuronal processes. Plaques are most common in the amygdala, hippocam- pus, and neocortex but also occur, much less commonly, in the basal forebrain and certain brainstem nuclei. Plaques, which are believed to repre- sent loci of altered synaptic interac- tions, are thought to play an important role in the expression of the dementia of AD; correlations exist between the presence of plaques and two other parameters - the presence of dementia and reductions in cortical choline acetyltransferase activity is. Hirano bodies. These rod-shaped eosinophilic intra-cytoplasmic inclu- sions are common in the pyramidal cell layer and the stratum lacunosum of hippocampi in patients with AD. Hirano bodies are enriched in actin and appear, by EM, to be made up of 6- 10 nm filaments16; freeze-fracture/ deep-etch techniques demonstrate that Hirano bodies are composed of para- crystalline arrays of actin (Heuser, J. and Price, D. L., unpublished observa- tions). Granulovacuolar degeneration. These cytoplasmic inclusions, which con- sist of an electron-dense granule surrounded by a membrane-bound vacuole, are present in pyramidal

https://www.cell.com/trends/neurosciences/pdf/0166-2236(86)90011-1.pdf

Cellular pathology in Alzhelmer's and Parkinson's diseases

Response : Neural Transport of Tetanus Toxin

Senile plaques are composed of neurites (enlarged axons, nerve terminals, and, possibly, dendrites) associated with focal deposits of amyloid. Plaques are present in small numbers in the amygdala, hippocampus, and neocortex in elderly primates and are abundant in these regions in individuals with Alzheimer’s disease. Aged macaques provide a model for investigations of plaques. One of the earliest abnormalities identified in these older animals is multifocal enlargement of individual axons within the cortex. Later, enlarged neurites appear in clusters (neurite plaques); in mixed plaques, neurites are associated with amyloid. In the oldest animals, many plaques show relatively greater proportions of amyloid. These observations are interpreted to indicate that axonal pathology is an early event and that plaques evolve from the neurite type to the amyloid type. Using antibody probes, we have identified abnormal axons and neurites derived from cholinergic, monoaminergic, and peptidergic systems. These axons and neurites also show accumulations of cytoskeletal antigens, including neurofilament peptides. Similarly, in human tissues, these approaches have identified abnormalities of the cytoskeleton and demonstrated a variety of transmitter-specific antigens in plaques.

Neurobiological Probes for Specific Constituents of Senile Plaques in Aging and Alzheimer’s Disease

The mechanisms that lead to the selective degeneration of motor neurons in familial and sporadic amyotrophic lateral sclerosis (FALS and ALS) are not clearly understood. A subset of FALS cases are caused by mutations in Cu/Zn superoxide dismutase 1 (SOD1) (Deng et al., 1993; Rosen et al., 1993), but the mechanism by which mutant SOD1 injure motor neurons is unclear. We have suggested that abnormalities in Cu+ + metabolism may play a role in disease (Wong et al., 1995). This speculation derives from a number of observations: Cu++ can catalyze the formation of toxic radical species (Olanow, 1993; Brown, 1995); SOD1 is abundant in nervous tissues (Pardo et al., 1995; Tsuda et al., 1994); and the metal binding domains of the enzyme generally lack mutations (Brown, 1995; Wong and Borchelt, 1995). Moreover, several investigations have demonstrated that FALS-linked mutations do not necessarily compromise free radical scavenging activity (Borchelt et al., 1994; Fujii et al., 1995; Rabizadeh et al., 1995), and transgenic mice expressing mutant SOD1 develop motor neuron disease (MND) despite elevated or unchanged levels of superoxide scavenging activity (Gurney et al., 1994; Ripps et al., 1995; Wong et al., 1995). Although these data suggest that abnormal Cu++ metabolism could play a role in the disease, it is not clear whether mutations in SOD1 alter the levels of free Cu++ by diminishing the functions of an abundant Cu++-binding protein or whether mutations alter SOD1 structure to allow enzyme-bound Cu++ to catalyze deleterious reactions, such as protein nitration (Beck-man et al., 1993) or peroxidation (Stadtman, 1990; Yim et al., 1990; Stadtman and Oliver, 1991; Yim et al., 1993; Wiedau-Pazos et al., 1996).

Perspectives on the Mechanisms of Familial Amyotrophic Lateral Sclerosis Caused by Mutations in Superoxide Dismutase 1

La presente invention concerne des animaux non humains transgeniques, notamment, par exemple des rongeurs transgeniques et des cellules mammaliennes non humaines transgeniques abritant un transgene qui elimine l'expression de la β-secretase, BACE1. En outre, cette invention a trait a des anticorps specifiques de BACE1, a des methodes de diagnostic d'une maladie neurodegenerative, y compris la maladie d'Alzheimer, et a des methodes d'identification d'agents modulant ou traitant la maladie d'Alzheimer et la pathologie afferente.

Donald L. Price

Papers

Cellular pathology in Alzhelmer's and Parkinson's diseases

Response : Neural Transport of Tetanus Toxin

Neurobiological Probes for Specific Constituents of Senile Plaques in Aging and Alzheimer’s Disease

Perspectives on the Mechanisms of Familial Amyotrophic Lateral Sclerosis Caused by Mutations in Superoxide Dismutase 1

Organismes transgeniques de la beta-secretase, anticorps anti-beta-secretase, et methodes d'utilisation correspondantes