A graph theoretic approach to neurodegeneration: five data-driven neuropsychological subtypes in mild cognitive impairment.

Mild cognitive Impairment (MCI) is notoriously heterogenous in terms of clinical presentation, neuroimaging correlates, and subsequent progression. Predicting who will progress to dementia, which type of dementia, and over what timeframe is challenging. Previous work has attempted to identify MCI subtypes using neuropsychological measures in an effort to address this challenge; however, there is no consensus on approach, which may account for some of the variability. Using a hierarchical community detection approach, we examined cognitive subtypes within an MCI sample (from the Alzheimer's Disease Neuroimaging Initiative [ADNI] study). We then examined whether these subtypes were related to biomarkers (e.g., cortical volumes, fluorodeoxyglucose (FDG)-positron emission tomography (PET) hypometabolism) or clinical progression. We identified five communities (i.e., cognitive subtypes) within the MCI sample: 1) predominantly memory impairment, 2) predominantly language impairment, 3) cognitively normal, 4) multidomain, with notable executive dysfunction, 5) multidomain, with notable processing speed impairment. Community membership was significantly associated with 1) cortical volume in the hippocampus, entorhinal cortex, and fusiform cortex; 2) FDG PET hypometabolism in the posterior cingulate, angular gyrus, and inferior/middle temporal gyrus; and 3) conversion to dementia at follow up. Overall, community detection as an approach appears a viable method for identifying unique cognitive subtypes in a neurodegenerative sample that were linked to several meaningful biomarkers and modestly with progression at one year follow up.

Relationship between cognitive reserve, brain volume, and neuropsychological performance in amnestic and nonamnestic MCI.

Cognitive Reserve (CR) is a theoretical construct that influences the onset and course of cognitive and structural changes that occur with aging and mild cognitive impairment (MCI). There is a paucity of research that examines the relationship of CR and brain volumes in amnestic (aMCI) and nonamnestic (naMCI) separately. This study is a retrospective chart review of MCI patients who underwent neuropsychological evaluation and brain MRI with NeuroReader™ (NR). NR is an FDA-cleared software that standardizes MRI volumes to a control sample. Classifications of aMCI and naMCI were based on Petersen criteria. CR was measured as education, occupation, and word reading. Data analysis included bivariate correlations between CR, neuropsychological test scores, and NR-brain volumes by MCI subtype. The Benjamini-Hochberg method corrected for multiple comparisons. The sample included 91 participants with aMCI and 41 with naMCI. Within naMCI, positive correlations were observed between CR and whole brain volume, total gray matter, bifrontal, left parietal, left occipital, and bilateral cerebellum. Within aMCI, no significant correlations were observed between CR and brain volumes. Positive correlations with CR were observed in language, attention, and visual learning in both aMCI and naMCI groups. The current study adds to the minimal literature on CR and naMCI. Results revealed that CR is associated with volumetrics in naMCI only, though cognitive findings were similar in both MCI groups. Possible explanations include heterogeneous disease pathologies, disease stage, or a differential influence of CR on volumetrics in MCI. Additional longitudinal and biomarker studies will better elucidate this relationship.

Knowledge transfer, policymaking and community empowerment: a consensus model approach for providing public mental health and substance abuse services.

An important problem in creating new programs and policies is how to encourage the transfer of knowledge in non-hierarchical ways so that new, relevant and specific knowledge is co-created by all interested parties. In this paper, we suggest that a consensus model of policymaking is one response and identify four key structural elements thought necessary for creating such a consensus infrastructure. These are a) a leadership and facilitating capacity for initiating and promoting such an endeavor, b) a network or consortium of key researchers, practitioners, consumers, and policymakers to empower community ownership of the endeavor, c) a process for consensus building and strategic problem-solving for such a consortium, and d) the continued creation of a multi-directional dialogue through information dissemination. We examine these elements in action by describing a particular problem solving and consensus building model for developing and implementing a program, resolving group differences, and evaluating the group's process and products.

Spin-lock magnetic resonance imaging of muscle in patients with autosomal recessive limb girdle muscular dystrophy.

Spin-lock imaging is a new magnetic resonance imaging (MRI) technique used to reflect the microstructural integrity of muscle. The purpose of this study was to characterize spin-lock contrast (SLC) of calf muscles in limb girdle muscular dystrophy (LGMD). The calf muscles of 5 patients with LGMD and 10 healthy volunteers were imaged with an off-resonance magnetic resonance (MR) spin-lock suppression pulse. Spin-lock suppression ratios were calculated for anterior tibialis, posterior tibialis, soleus, and gastrocnemius muscles. Clinical assessments of muscle strength were compared to the spin-lock suppression ratios in the LGMD group. Strong SLC was observed in healthy muscles, with mean (+/- SD) suppression ratios ranging from 51.2% (+/- 3.6%) to 56.3% (+/- 1.3%). In diseased muscle, spin-lock signal suppression was reduced by 8%-70%, demonstrating an inverse correlation between symptom duration and suppression ratios. Spin-lock contrast in the patients with LGMD, as a reflection of tissue integrity, was best preserved in posterior tibialis, anterior tibialis, soleus, and gastrocnemius muscles in descending order. Clinical assessments did a poorer job of differentiating than SLC did and were in poor agreement with spin-lock suppression ratios. Spin-lock MRI can quantify microstructural changes in LGMD and appears to provide information not obtainable from clinical evaluations. This suggests that this noninvasive technique may be useful in evaluating the extent, progression, and response to therapy of LGMD.

Magnetization transfer imaging of skeletal muscle in autosomal recessive limb girdle muscular dystrophy.

PURPOSE: The purpose of this work was to characterize magnetization transfer (MT) contrast of skeletal muscles in limb girdle muscular dystrophy (LGMD). METHOD: The calf muscles of five LGMD patients and 10 normal volunteers were imaged with an off-resonance MT suppression pulse applied to T1-weighted images. MT suppression ratios were calculated for anterior tibialis, posterior tibialis, soleus, and gastrocnemius muscles in the LGMD and control groups. The relationship between MT of individual muscles and the duration of LGMD symptoms was determined. RESULTS: Strong MT contrast was observed in normal calf muscles, with mean (+/-SD) suppression ratios ranging from 37.9% (+/-3.0) to 41.1% (+/-2.1). In diseased muscle, MT signal suppression ranged from 11 to 38%, demonstrating an inverse relationship between symptom duration and suppression ratios. MT contrast in the LGMD patients, as a reflection of muscle tissue integrity, was preserved in posterior or anterior tibialis, soleus, and gastrocnemius muscles, respectively. Suppression ratios were dramatically reduced in muscles with gross fatty infiltration but also were reduced in muscle tissues without visual evidence of fatty infiltration. CONCLUSION: MT imaging provides a quantitative measure of pathologic changes occurring within the skeletal muscles of patients with LGMD relative to normal and may be useful in evaluating disease extent, progression, and response to new therapies as they become available.

Effects of a cotton bract extract on guinea pig isolated airway smooth muscle.

The effects of a water extract of cotton bracts (CBE) on guinea pig isolated trachealis smooth muscle was studied. The ability of CBE to evoke tension responses, to modify tissue reactivity to excitatory and inhibitory agents, and to modify electric field stimulation-induced neurogenic responses was evaluated. CBE caused contraction in low concentrations, which were not mediated by histamine H1-, muscarinic, or 5-hydroxytryptamine (5-HT) receptors, and caused relaxation in high concentrations. In the presence of CBE, the maximum contractile response to 5-HT and the sensitivity to KCl were reduced. The maximum relaxation responses and sensitivities to adenosine and ATP were increased by CBE. In contrast, contractile responses to histamine and methacholine and relaxation responses to isoproterenol were unaffected. Neurogenic cholinergic excitatory responses and neurogenic adrenergic responses did not appear to be affected by CBE. However, the relaxant effect of nonadrenergic inhibitory nerve stimulation was increased in the presence of CBE. These findings differ from previous ones observed in our laboratory for dog isolated trachealis smooth muscle preparations, which indicates that the effects of CBE in isolated airways is species-dependent. Virtually all of the contractile activity of CBE was dialyzable (molecular weight less than 14,000) and retained in ashed samples. Inorganic constituents may contribute to the spasmogenic activity of CBE.

Interactions of a water extract of cotton bract with dog isolated airway smooth muscle.

The inhalation of cotton dust by cotton-mill workers causes byssinosis, a disease characterized by chest tightness and other symptoms indicative of bronchoconstriction. In the present study the dog isolated trachealis smooth muscle preparation was employed to examine the ability of a crude, water extract of cotton bracts (CBE) to (1) cause contractile responses mediated by receptors, (2) modify responses of the tissue to a number of excitatory and inhibitory agents, and (3) alter responsiveness of the preparations to electrical field stimulation mediated by intrinsic cholinergic, excitatory nerves and adrenergic, inhibitory nerves. CBE evoked contraction of the tissues by an action that did not involve muscarinic, histamine, or 5-hydroxytryptamine receptors. The maximum tissue responses to exogenous histamine, 5-hydroxytryptamine, and isoproterenol were enhanced significantly in the presence of CBE, while those to KCl and methacholine were unaffected. The sensitivities (EC50 values) of the tissues to these agents were not, however, altered by CBE. Contractions induced by cholinergic nerve stimulation were increased in the presence of CBE, via a mechanism that appears, at present, to result from a prejunctional facilitation of acetycholine release. Relaxations to adrenergic nerve stimulation were not affected by CBE. Results suggest that, in addition to its direct, contractile activity, CBE can alter indirectly the responsiveness of the tissue to a number of endogenous mediator substances. Intrinsic, cholinergic excitatory nerves may be a target for the acute action of CBE as well.

Effects of a two-year inhalation exposure of rats to coal dust and/or diesel exhaust on tension responses of isolated airway smooth muscle.

This study was performed to determine whether chronic inhalation exposure of rats to levels of coal dust (CD) and/or diesel exhaust (DE) similar to those experienced by underground miners affects the pharmacologic characteristics of the animal's airway smooth muscle. Animals were exposed for 2 yr to CD alone (2 mg/m3 of respirable particulates), DE alone (2 mg/m3 of respirable particulates), or CD and DE (CD + DE) in combination (1 mg/m3 CD plus 1 mg/m3 DE). Concentration-response relationships for tension changes induced with acetylcholine, 5-hydroxytryptamine, potassium chloride, and isoproterenol were assessed in vitro on isolated preparations of rat airway smooth muscle (trachealis). Compared with control animals, the maximal contractile responses to acetylcholine of tissues from CD-, DE-, and CD + DE-exposed animals were significantly increased; the effects of CD and DE exposure were additive. The CD + DE exposure, but not the individual treatments, resulted in a significant increase in the maximal relaxation response elicited by isoproterenol; this interaction may have resulted from the addition of, or the synergism between, the nonsignificant effects of CD and DE alone. No treatment altered the sensitivity (EC50 values) of the muscles to the agonists used. The results indicate that chronic exposure to CD, DE, and CD + DE produces differential modifications in the behavior of rat airway smooth muscle. These findings may have some bearing on humans exposed to these substances.