Quantitative assessment of finger tapping characteristics in mild cognitive impairment, Alzheimer's disease, and Parkinson's disease.

BACKGROUND: Fine motor impairments are common in neurodegenerative disorders, yet standardized, quantitative measurements of motor abilities are uncommonly used in neurological practice. Thus, understanding and comparing fine motor abilities across disorders have been limited. OBJECTIVES: The current study compared differences in finger tapping, inter-tap interval, and variability in Alzheimer's disease (AD), Parkinson's disease (PD), mild cognitive impairment (MCI), and healthy older adults (HOA). METHODS: Finger tapping was measured using a highly sensitive light-diode finger tapper. Total number of finger taps, inter-tap interval, and intra-individual variability (IIV) of finger tapping was measured and compared in AD (n = 131), PD (n = 63), MCI (n = 46), and HOA (n = 62), controlling for age and sex. RESULTS: All patient groups had fine motor impairments relative to HOA. AD and MCI groups produced fewer taps with longer inter-tap interval and higher IIV compared to HOA. The PD group, however, produced more taps with shorter inter-tap interval and higher IIV compared to HOA. CONCLUSIONS: Disease-specific changes in fine motor function occur in the most common neurodegenerative diseases. The findings suggest that alterations in finger tapping patterns are common in AD, MCI, and PD. In addition, the present results underscore the importance of motor dysfunction even in neurodegenerative disorders without primary motor symptoms.

Clinical marker for Alzheimer disease pathology in logopenic primary progressive aphasia.

OBJECTIVE: To determine whether logopenic features of phonologic loop dysfunction reflect Alzheimer disease (AD) neuropathology in primary progressive aphasia (PPA). METHODS: We performed a retrospective case-control study of 34 patients with PPA with available autopsy tissue. We compared baseline and longitudinal clinical features in patients with primary AD neuropathology to those with primary non-AD pathologies. We analyzed regional neuroanatomic disease burden in pathology-defined groups using postmortem neuropathologic data. RESULTS: A total of 19/34 patients had primary AD pathology and 15/34 had non-AD pathology (13 frontotemporal lobar degeneration, 2 Lewy body disease). A total of 16/19 (84%) patients with AD had a logopenic spectrum phenotype; 5 met published criteria for the logopenic variant (lvPPA), 8 had additional grammatical or semantic deficits (lvPPA+), and 3 had relatively preserved sentence repetition (lvPPA-). Sentence repetition was impaired in 68% of patients with PPA with AD pathology; forward digit span (DF) was impaired in 90%, substantially higher than in non-AD PPA (33%, p < 0.01). Lexical retrieval difficulty was common in all patients with PPA and did not discriminate between groups. Compared to non-AD, PPA with AD pathology had elevated microscopic neurodegenerative pathology in the superior/midtemporal gyrus, angular gyrus, and midfrontal cortex (p < 0.01). Low DF scores correlated with high microscopic pathologic burden in superior/midtemporal and angular gyri (p ≤ 0.03). CONCLUSIONS: Phonologic loop dysfunction is a central feature of AD-associated PPA and specifically correlates with temporoparietal neurodegeneration. Quantitative measures of phonologic loop function, combined with modified clinical lvPPA criteria, may help discriminate AD-associated PPA.

The Penn Parkinson's Daily Activities Questionnaire-15: Psychometric properties of a brief assessment of cognitive instrumental activities of daily living in Parkinson's disease.

INTRODUCTION: To describe the psychometric properties of the Penn Parkinson's Daily Activities Questionnaire-15 (PDAQ-15), a 15-item measure of cognitive instrumental activities of daily living for Parkinson's disease (PD) patients derived from the original 50-item PDAQ. METHODS: PDAQ-15 items were chosen by expert consensus. Knowledgeable informants of PD participants (n = 161) completed the PDAQ-15. Knowledgeable informants were defined as an individual having regular contact with the PD participant. PD participants were assigned a diagnosis of normal cognition, mild cognitive impairment, or dementia based on expert consensus. RESULTS: PDAQ-15 scores correlated strongly with global cognition (Dementia Rating Scale-2, r = 0.71, p < 0.001) and a performance-based functional measure (Direct Assessment of Functional Status, r = 0.83; p < 0.001). PDAQ-15 scores accurately discriminated between non-demented PD participants (normal cognition/mild cognitive impairment) and PD with dementia (ROC curve area = 0.91), participants with and without any cognitive impairment (normal cognition versus mild cognitive impairment/dementia, ROC curve area = 0.85) and between participants with mild cognitive impairment and dementia (ROC curve area = 0.84). CONCLUSIONS: The PDAQ-15 shows good discriminant validity across cognitive stages, correlates highly with global cognitive performance, and appears suitable to assess daily cognitive functioning in PD.

Multisite assessment of NIA-AA guidelines for the neuropathologic evaluation of Alzheimer's disease.

INTRODUCTION: Neuropathologic assessment is the current "gold standard" for evaluating the Alzheimer's disease (AD), but there is no consensus on the methods used. METHODS: Fifteen unstained slides (8 brain regions) from each of the 14 cases were prepared and distributed to 10 different National Institute on Aging AD Centers for application of usual staining and evaluation following recently revised guidelines for AD neuropathologic change. RESULTS: Current practice used in the AD Centers Program achieved robustly excellent agreement for the severity score for AD neuropathologic change (average weighted κ = .88, 95% confidence interval: 0.77-0.95) and good-to-excellent agreement for the three supporting scores. Some improvement was observed with consensus evaluation but not with central staining of slides. Evaluation of glass slides and digitally prepared whole-slide images was comparable. DISCUSSION: AD neuropathologic evaluation as performed across AD Centers yields data that have high agreement with potential modifications for modest improvements.

Conversion between mini-mental state examination, montreal cognitive assessment, and dementia rating scale-2 scores in Parkinson's disease.

Cognitive impairment is one of the earliest, most common, and most disabling non-motor symptoms in Parkinson's disease (PD). Thus, routine screening of global cognitive abilities is important for the optimal management of PD patients. Few global cognitive screening instruments have been developed for or validated in PD patients. The Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Dementia Rating Scale-2 (DRS-2) have been used extensively for cognitive screening in both clinical and research settings. Determining how to convert the scores between instruments would facilitate the longitudinal assessment of cognition in clinical settings and the comparison and synthesis of cognitive data in multicenter and longitudinal cohort studies. The primary aim of this study was to apply a simple and reliable algorithm for the conversion of MoCA to MMSE scores in PD patients. A secondary aim was to apply this algorithm for the conversion of DRS-2 to both MMSE and MoCA scores. The cognitive performance of a convenience sample of 360 patients with idiopathic PD was assessed by at least two of these cognitive screening instruments. We then developed conversion scores between the MMSE, MoCA, and DRS-2 using equipercentile equating and log-linear smoothing. The conversion score tables reported here enable direct and easy comparison of three routinely used cognitive screening assessments in PD patients.

Neuropsychologic assessment in collaborative Parkinson's disease research: a proposal from the National Institute of Neurological Disorders and Stroke Morris K. Udall Centers of Excellence for Parkinson's Disease Research at the University of Pennsylvania and the University of Washington.

Cognitive impairment (CI) and behavioral disturbances can be the earliest symptoms of Parkinson's disease (PD), ultimately afflict the vast majority of PD patients, and increase caregiver burden. Our two Morris K. Udall Centers of Excellence for Parkinson's Disease Research were supported by the National Institute of Neurological Disorders and Stroke (NINDS) in an effort to recommend a comprehensive yet practical approach to cognitive and behavioral assessment to further collaborative research. We recommend a stepwise approach with two levels of standardized evaluation to establish a common battery, as well as an alternative testing recommendation for severely impaired subjects, and review supplemental tests that may be useful in specific research settings. Our flexible approach may be applied to studies with varying emphasis on cognition and behavior, does not place undue burden on participants or resources, and has a high degree of compatibility with existing test batteries to promote collaboration.

Advancing Alzheimer's disease diagnosis, treatment, and care: recommendations from the Ware Invitational Summit.

To address the pending public health crisis due to Alzheimer's disease (AD) and related neurodegenerative disorders, the Marian S. Ware Alzheimer Program at the University of Pennsylvania held a meeting entitled "State of the Science Conference on the Advancement of Alzheimer's Diagnosis, Treatment and Care," on June 21-22, 2012. The meeting comprised four workgroups focusing on Biomarkers; Clinical Care and Health Services Research; Drug Development; and Health Economics, Policy, and Ethics. The workgroups shared, discussed, and compiled an integrated set of priorities, recommendations, and action plans, which are presented in this article.

National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease.

A consensus panel from the United States and Europe was convened recently to update and revise the 1997 consensus guidelines for the neuropathologic evaluation of Alzheimer's disease (AD) and other diseases of brain that are common in the elderly. The new guidelines recognize the pre-clinical stage of AD, enhance the assessment of AD to include amyloid accumulation as well as neurofibrillary change and neuritic plaques, establish protocols for the neuropathologic assessment of Lewy body disease, vascular brain injury, hippocampal sclerosis, and TDP-43 inclusions, and recommend standard approaches for the workup of cases and their clinico-pathologic correlation.

National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease: a practical approach.

We present a practical guide for the implementation of recently revised National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease (AD). Major revisions from previous consensus criteria are: (1) recognition that AD neuropathologic changes may occur in the apparent absence of cognitive impairment, (2) an "ABC" score for AD neuropathologic change that incorporates histopathologic assessments of amyloid ß deposits (A), staging of neurofibrillary tangles (B), and scoring of neuritic plaques (C), and (3) more detailed approaches for assessing commonly co-morbid conditions such as Lewy body disease, vascular brain injury, hippocampal sclerosis, and TAR DNA binding protein (TDP)-43 immunoreactive inclusions. Recommendations also are made for the minimum sampling of brain, preferred staining methods with acceptable alternatives, reporting of results, and clinico-pathologic correlations.

Design of comprehensive Alzheimer's disease centers to address unmet national needs.

The problem of Alzheimer's disease (AD) exemplifies the challenges of dealing with a broad range of aging-related chronic disorders that require long-term, labor-intensive, and expensive care. As the baby boom generation ages and brain diseases become more prevalent, the need to confront the pending health care crisis is more urgent than ever before. Indeed, there is now a critical need to expand significantly the national effort to solve the problem of AD, with special focus on prevention. The Campaign to Prevent Alzheimer's Disease by 2020 (PAD2020) aims to create a new paradigm for planning and supporting the organization of worldwide cooperative research networks to develop new technologies for early detection and treatments of aging-related memory and motor impairments. PAD 2020 is developing an implementation plan to justify (1) increasing the federal budget for research, (2) developing novel national resources to discover new interventions for memory and motor disorders, and (3) creating innovative and streamlined decision-making processes for selecting and supporting new ideas. Since 1978 the National Institute on Aging or National Institute of Health (NIH) established an extensive national network of AD research facilities at academic institutions including AD Centers (ADCs), Consortium to Establish a Registry for AD, AD Cooperative Study (ADCS), AD Drug Discovery Program, National Alzheimer's Coordinating Center, National Cell Repository for AD, and AD Neuroimaging Initiative. However, despite the success of these programs and their critical contributions, they are no longer adequate to meet the challenges presented by AD. PAD 2020 is designed to address these changes by improving the efficiency and effectiveness of these programs. For example, the ADCs (P30s and P50s) can be enhanced by converting some into Comprehensive Alzheimer's Disease Centers (CADCs) to support not only research, but also by being demonstration projects on care/treatment, clinical trials, and education as well as by seamlessly integrating multisite collaborative studies (ADCS, AD Neuroimaging Initiative, Patient Registries, Clinical Data Banks, etc) into a cohesive structure that further enhances the original mission of the National Institute on Aging ADCs. Regional CADCs offer greater efficiency and cost savings while serving as coordinating hubs of existing ADCs, thereby offering greater economies of scale and programmatic integration. The CADCs also broaden the scope of ADC activities to include research on interventions, diagnosis, imaging, prevention trials, and other longitudinal studies that require long-term support. Thus, CADCs can address the urgent need to identify subjects at high risk of AD for prevention trials and very early in the course of AD for clinical trials of disease modification. The enhanced CADCs will allow more flexibility among ADCs by supporting collaborative linkages with other institutions and drawing on a wider expertise from different locations. This perspective article describes the University of Pennsylvania (Penn) CADC Model as an illustrative example of how an existing ADC can be converted into a CADC by better utilization of Penn academic resources to address the wide range of problems concerning AD. The intent of this position paper is to stimulate thinking and foster the development of other or alternative models for a systematic approach to the study of dementia and movement disorders.

A roadmap for the prevention of dementia II: Leon Thal Symposium 2008.

This document proposes an array of recommendations for a National Plan of Action to accelerate the discovery and development of therapies to delay or prevent the onset of disabling symptoms of Alzheimer's disease. A number of key scientific and public-policy needs identified in this document will be incorporated by the Alzheimer Study Group into a broader National Alzheimer's Strategic Plan, which will be presented to the 111th Congress and the Obama administration in March 2009. The Alzheimer's Strategic Plan is expected to include additional recommendations for governance, family support, healthcare, and delivery of social services.

Empiric refinement of the pathologic assessment of Lewy-related pathology in the dementia patient.

Lewy-related pathology (LRP) is a common pathologic finding at autopsy in dementia patients. Recently criteria for categorizing types of LRP in dementia patients were published, though these criteria have yet to be systematically applied to large dementia samples. We examined a large (n = 208) referral-based autopsy sample for LRP, and applied the published criteria for LRP categorization to these cases. We found almost half (49%) of LRP positive cases from this sample were not classifiable. However, modifying the published criteria by reducing the number of regions requiring examination, allowing more variability in LRP severity scores within specific brain regions, and adding an amygdala predominant category permitted classification of 97% of LRP positive cases from the referral-based sample. Application of the modified criteria to an unrelated community-based autopsy sample (n = 226) allowed classification of 96% of LRP positive cases. Modest modifications in the published criteria permit a significantly greater number of dementia cases with LRP to be classified. In addition, this modification allows for more limited sampling of brain regions for classification of LRP. We propose that these modified criteria for the categorization of LRP be utilized in patients with a history of dementia.

Living Longer and Paying the Price?

Over the past century, there have been tremendous increases in longevity in the United States and most other developed countries. If these trends continue, the costs of paying for public programs like Social Security, Medicare, and Medicaid will escalate at a startling rate with the aging of the "baby boomer" generation. A meeting titled "Living Longer and Paying the Price?" was organized to consider whether current trends in longevity will continue at the current pace, accelerate, or decelerate as a result of public health problems such as obesity and infectious diseases. Further, speakers presented their views on covering the costs of public and private programs for future generations of older adults.

Assessment of pathological tau proteins in frontotemporal dementias: qualitative and quantitative approaches.

A large group of clinically and neuropathologically heterogeneous frontotemporal dementias (FTDs) is distinguished by the accumulation of filamentous tau proteins in neuronal and non-neuronal cells, and these disorders are collectively designated as tauopathies. Recent advances in the development of new reagents and the utilization of new multidisciplinary approaches have made substantial progress in the extensive characterization of tau proteins in different tauopathies. Until recently, semi-quantitative assessment of specific pathological lesions in FTDs was limited to immunohistochemical methods. However, it has become increasingly evident that biochemical analyses of pathological tau proteins in diseased brains also play a significant role in establishing the diagnosis of specific FTD subtypes. In this review, the authors summarize recent findings of the unique biochemical tau signatures for a number of specific tauopathies. Moreover, the quantitative assessment of abnormal tau proteins described here reveals heterogeneity in the biochemical features of tau pathologies in FTDs. The identification of highly insoluble tau species that may be more prone to physiological clearance, other than those that form paired helical filaments, could provide additional insights into the role of tau in mechanisms of neurodegeneration in FTDs.