Among the major impediments to the design of clinical trials for the prevention of Alzheimer's disease (AD), the most critical is the lack of validated biomarkers, assessment tools, and algorithms that would facilitate identification of asymptomatic individuals with elevated risk who might be recruited as study volunteers. Thus, the Leon Thal Symposium 2009 (LTS'09), on October 27-28, 2009 in Las Vegas, Nevada, was convened to explore strategies to surmount the barriers in designing a multisite, comparative study to evaluate and validate various approaches for detecting and selecting asymptomatic people at risk for cognitive disorders/dementia. The deliberations of LTS'09 included presentations and reviews of different approaches (algorithms, biomarkers, or measures) for identifying asymptomatic individuals at elevated risk for AD who would be candidates for longitudinal or prevention studies. The key nested recommendations of LTS'09 included: (1) establishment of a National Database for Longitudinal Studies as a shared research core resource; (2) launch of a large collaborative study that will compare multiple screening approaches and biomarkers to determine the best method for identifying asymptomatic people at risk for AD; (3) initiation of a Global Database that extends the concept of the National Database for Longitudinal Studies for longitudinal studies beyond the United States; and (4) development of an educational campaign that will address public misconceptions about AD and promote healthy brain aging.
Counts of total neuron number per section and of neurons per microscopic field of inferior olivary principal nuclei were made on sections from 10 patients with Down syndrome (DS) aged 0.36 to 28 months and seven control (C) patients aged 1 to 29 months. After stereologic and appropriate shrinkage corrections of the count data, the ratios of values for DS/C were calculated. For mean principal olivary nucleus neuron number, DS/C = 0.64; for mean number of neurons per field, DS/C = 0.84; for mean volume of olivary neuronal band per section, DS/C = 0.79; and for mean volume of neuronal band per neuron, DS/C =1.27. The data are in accord with other data suggesting that (1) numbers of cells in various cell populations, including various areas of the cerebrum, in DS approximate two-thirds normal (DS/C ≈ 0.67); (2) for the volumes of such cell populations, DS/C ≈ 0.82 normal; and (3) for volumes of individual cells, DS/C ≈ 1.22 normal. The data of the present study suggest that the inferior olivary nuclei in DS are affected in the same way and to a similar degree as other brain areas, with the age distribution and histologic features of the specimens studied suggesting that the reduced olivary principal nucleus number in early Down syndrome results from reduced initial neuron production rather than postnatal neuron loss.
The Memory Performance Index (MPI) is a quantitative measure of the performance profile of CERAD wordlist test (CWL). It translates the pattern onto a 0–100 scale, and classifies the score into normal, borderline and impaired. To characterize the MPI's measurement characteristics for normal aging and dementia, aggregate data analyses were performed. Community Sample A: 38,817 independently living subjects 18–100 years old were assessed with the CWL, and classified as cognitively impaired or normal. The MPI and CWL immediate, delayed and total free recall scores were each regressed against age, gender and education. Clinical Sample B: As part of a comprehensive battery, the CWL plus the Functional Assessment Staging Test (FAST) was administered to 441 normal-to-moderately severely demented patients (FAST stages 1–6. Their median MPI scores were tested for significant differences across FAST stages. A total of 31,583 Sample A subjects were classified as normal. Age explained 4.7% and 3.0% of CWL immediate and delayed free recall score variance, and 43.7% of MPI score variance. Gender and education only slightly increased the variance explained. For Sample B, median MPI scores progressively declined across all FAST stages (p < 0.00013) except stages 2 and 3 (p=0.15). In cognitively normal subjects, age, gender and education poorly predicted the numbers of words recalled during immediate or delayed recall, but predicted the pattern of recalled and non-recalled words (MPI scores) very well. Pattern of memory performance is a much better measure of normal, age-related change than number of words recalled. Also, the correlation between declining function (FAST) and MPI score from normal aging to moderately severe dementia makes the MPI useful for longitudinal monitoring of cognitively impaired and demented patients.
Alzheimer's disease (AD) patients show lower dipolarity (goodness-of-fit) for dipole localizations of alpha or other dominant electroencephalography (EEG) frequency components in the occipital cortex. In the present study, we performed computer simulations to discover which of distributions of dipole activity lower dipolarity in a manner similar to that seen in severe AD. Dipolarity was estimated from simulations of various electric dipole generator configurations within the occipital cortex under conditions of widened cortical sulci (a severely demented AD case) or no sulcal widening (a normal subject). The cortical and scalp surfaces, derived from the subjects' MRI's, were assumed to be uniformly electrically conducting. Randomly placed, nonoverlapping lesions ranging from 1 to 4 mm2 per lesion were used in both the normal and AD models to simulate the electrical effect of neuropathological AD lesions. In both models, dipolarity decreased as total lesion size increased. However, the AD model showed lower dipolarity than the normal model for both individual lesion sizes and for larger total lesion sizes. The larger decline in dipolarity in the AD model appears to be due to sulcal widening which unmasks the effect of lesions buried within sulci. These simulations identify a possible mechanism explaining why sulcally-located neuropathological changes plus progressive cortical atrophy in AD brains (and presumably other cortical disorders producing atrophy) alter EEG patterns and dipolarity differently from normal cortex damaged by similar lesions.
DYNAMIC MR imaging has revealed dramatic fluctuations in the appearance of CSF in the cortical sulci and cortical subarachnoid spaces in aging individuals and patients with hydrocephalus, dementia and Down syndrome in contrast to young healthy volunteers. The changes have been interpreted as volume fluctuations that represent undamped CSF hydrodynamics and have implications with respect to the origin of CSF in the cortical regions and with respect to the similarity between aging and dementia and edematous states of the brain.
Intravenous immunoglobulin (IVIG) therapy has shown treatment efficacy in patients with mild to moderate Alzheimer's disease (AD). IVIG binds to abnormally folded proteins, such as oligomeric beta amyloid and alpha synuclein, thought to be involved in both AD and Lewy Body disease (LBD) pathogenesis. Therefore, IVIG therapy may be useful in AD and LBD. In this study, we evaluated longitudinal treatment efficacy of IVIG therapy in patients with AD and LBD in mild cognitive impairment to moderately severe stages. Patient with AD (n=13) and with LBD (n=4) received IVIG therapy for average of 18 (stdev=14.5) and 14 (stdev=14) months. Dementia severity was determined using the Functional Assessment Staging Test (FAST). Pre-IVIG monitoring of AD and LBD patients using MCI Screen (a modification of the CERAD Wordlist) and FAST staging tests averaged 21 (σ=12) and 36 (σ=16) months respectively. Cognitive, functional and behavioral testing at baseline and during IVIG therapy consisted of ADAS-Cog, MMSE, MCI Screen, NPI, ADCS-ADL, DAD, FAST, and CGIC tests. Baseline and endpoint CSF Tau and Ab42 levels were obtained when possible. IVIG therapy either stabilized or significantly slowed cognitive and functional decline in most of the AD and LBD patients. Disease delaying effects appeared more significant in patients with AD. Of the AD and LBD patients who discontinued IVIG treatment_primarily due to cost_they declined more rapidly within months after stopping IVIG than while they were on it. CSF studies suggested that IVIG reduces either beta amyloid 1-42 levels, or phosphorylated tau levels, or both. When patients serve as their own control in an off-on or off-on-off design, disease delaying treatment effects can be more easily detected. In this study using such a design, both functional and cognitive improvement (or reduced rate of decline) was demonstrable in LBD and AD patients receiving IVIG therapy. Since both AD and LBD pathologies involve abnormal protein folding, it may be that other neurologic diseases with abnormal protein folding will respond to IVIG therapy. Some examples include Huntington's disease and certain forms of Frontal Temporal Lobe Dementia. More rigorous clinical trials are needed, particularly in LBD.
