Clinico-pathologic studies in dementia: nondemented subjects with pathologically confirmed Alzheimer's disease.

Department of Neurology, Albert Einstein College of Medicine, Bronx, NY 10461.
Neurology (Impact Factor: 8.3). 12/1988; 38(11):1682-7. DOI: 10.1212/WNL.38.11.1682
Source: PubMed

ABSTRACT We compared neuropsychological findings in 28 longitudinally evaluated elderly subjects with their postmortem neuropathology, including senile plaque and neurofibrillary tangle counts from standardized sections. Nine of the subjects were not demented when evaluated just prior to their death. Numerous cortical senile plaques and other changes of Alzheimer's disease (AD) occurred in six of nine nondemented old-old subjects. Five of these six subjects had shown decline on yearly neuropsychological tests but their cognitive impairment was too mild to meet clinical criteria for dementia. Whereas cortical senile plaque count did not distinguish well between demented and nondemented subjects, every subject with numerous cortical neurofibrillary tangles was demented. The nondemented subjects with Alzheimer pathology may have had "preclinical" AD, or numerous cortical plaques may occur in some elderly subjects who would never develop clinical dementia.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The conventional fMRI image analysis approach to associating stimuli to brain activation is performed by carrying out a massive number of parallel univariate regression analyses. fMRI blood-oxygen-level dependent (BOLD) signal, the basis of these analyses, is known for its low signal-noise-ratio and high spatial and temporal signal correlation. In order to ensure accurate localization of brain activity, stimulus administration in an fMRI session is often lengthy and repetitive. Real-time fMRI BOLD signal analysis is carried out as the signal is observed. This method allows for dynamic, real-time adjustment of stimuli through sequential experimental designs. We have developed a voxel-wise sequential probability ratio test (SPRT) approach for dynamically determining localization, as well as decision rules for stopping stimulus administration. SPRT methods and general linear model (GLM) approaches are combined to identify brain regions that are activated by specific elements of stimuli. Stimulus administration is dynamically stopped when sufficient statistical evidence is collected to determine activation status across regions of interest, following predetermined statistical error thresholds. Simulation experiments and an example based on real fMRI data show that scan volumes can be substantially reduced when compared with pre-determined, fixed designs while achieving similar or better accuracy in detecting activated voxels. Moreover, the proposed approach is also able to accurately detect differentially activated areas, and other comparisons between task-related GLM parameters that can be formulated in a hypothesis-testing framework. Finally, we give a demonstration of SPRT being employed in conjunction with a halving algorithm to dynamically adjust stimuli.
    PLoS ONE 01/2015; 10(3):e0117942. DOI:10.1371/journal.pone.0117942 · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The mechanisms of neuronal death in protein misfolding neurodegenerative diseases such as Alzheimer's, Parkinson's and prion diseases are poorly understood. We used a highly toxic misfolded prion protein (TPrP) model to understand neurotoxicity induced by prion protein misfolding. We show that abnormal autophagy activation and neuronal demise is due to severe, neuron-specific, nicotinamide adenine dinucleotide (NAD(+)) depletion. Toxic prion protein-exposed neuronal cells exhibit dramatic reductions of intracellular NAD(+) followed by decreased ATP production, and are completely rescued by treatment with NAD(+) or its precursor nicotinamide because of restoration of physiological NAD(+) levels. Toxic prion protein-induced NAD(+) depletion results from PARP1-independent excessive protein ADP-ribosylations. In vivo, toxic prion protein-induced degeneration of hippocampal neurons is prevented dose-dependently by intracerebral injection of NAD(+). Intranasal NAD(+) treatment of prion-infected sick mice significantly improves activity and delays motor impairment. Our study reveals NAD(+) starvation as a novel mechanism of autophagy activation and neurodegeneration induced by a misfolded amyloidogenic protein. We propose the development of NAD(+) replenishment strategies for neuroprotection in prion diseases and possibly other protein misfolding neurodegenerative diseases. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email:
    Brain 02/2015; DOI:10.1093/brain/awv002 · 10.23 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: We previously showed that activity of the large conductance calcium-activated potassium (Big-K; BK) channels is suppressed in 3xTg Alzheimer disease (AD) model mice. However, its behavioral significance is not known. In the present report, ventricular injection of the BK channel activator isopimaric acid (ISO) was conducted to examine whether BK channel activation ameliorates cognition in 3xTg mice. The novel object recognition (NOR) test revealed that chronic injection of ISO improved non-spatial memory in 3xTg mice. In the Morris water maze, the probe test demonstrated an improved spatial memory after ISO injection. Electrophysiological underpinnings of the ISO effect were then examined in slices obtained from the mice after behavior. At hippocampal CA1 synapses, the basic synaptic transmission was abnormally elevated and long-term potentiation (LTP) was partially suppressed in 3xTg mice. These were both recovered by ISO treatment. We then confirmed suppressed BK channel activity in 3xTg mice by measuring the half-width of evoked action potentials. This was also recovered by ISO treatment. We previously showed that the recovery of BK channel activity accompanies reduction of neuronal excitability in pyramidal cells. Here again, pyramidal cell excitability, as assessed by calculating the frequency of evoked spikes, was elevated in the 3xTg mouse and was normalized by ISO. ELISA experiments demonstrated an ISO-induced reduction of Aβ1-42 content in hippocampal tissue in 3xTg mice. The present study thus suggests a potential therapeutic utility of BK channel blockers for AD. Copyright © 2015. Published by Elsevier Ltd.
    Neuropharmacology 01/2015; 92. DOI:10.1016/j.neuropharm.2014.12.033 · 4.82 Impact Factor