Characteristics of Hoarding in Older Adults

Objective: This study determined the clinical characteristics of late-life hoarding disorder (HD). Methods: Older adults (age 60 and older) with HD (n = 55) and without psychiatric diagnoses (n = 39) were compared on psychiatric, functional, cognitive, and health-related measures. Associations between age and clinical characteristics in a large sample of mixed age (n = 210; age range: 20-78) participants with HD were also determined. Results: Individuals with late-life HD were characterized by substantial impairments in psychiatric, functional, cognitive, and medical status. Health risks (e.g., risks of falls and fire) were also common. However, older age was generally not associated with increased severity of hoarding or other clinical correlates (with the exception of one global clinician-rated measure of severity). Conclusions: Late-life HD is characterized by considerable morbidity and health risks, and these characteristics may be consistent across the lifespan in cross-sectional mixed-age samples of individuals with HD

Rational mutagenesis to support structure-based drug design: MAPKAP kinase 2 as a case study

<p>Abstract</p> <p>Background</p> <p>Structure-based drug design (SBDD) can provide valuable guidance to drug discovery programs. Robust construct design and expression, protein purification and characterization, protein crystallization, and high-resolution diffraction are all needed for rapid, iterative inhibitor design. We describe here robust methods to support SBDD on an oral anti-cytokine drug target, human MAPKAP kinase 2 (MK2). Our goal was to obtain useful diffraction data with a large number of chemically diverse lead compounds. Although MK2 structures and structural methods have been reported previously, reproducibility was low and improved methods were needed.</p> <p>Results</p> <p>Our construct design strategy had four tactics: <it>N</it>- and <it>C</it>-terminal variations; entropy-reducing surface mutations; activation loop deletions; and pseudoactivation mutations. Generic, high-throughput methods for cloning and expression were coupled with automated liquid dispensing for the rapid testing of crystallization conditions with minimal sample requirements. Initial results led to development of a novel, customized robotic crystallization screen that yielded MK2/inhibitor complex crystals under many conditions in seven crystal forms. In all, 44 MK2 constructs were generated, ~500 crystals were tested for diffraction, and ~30 structures were determined, delivering high-impact structural data to support our MK2 drug design effort.</p> <p>Conclusion</p> <p>Key lessons included setting reasonable criteria for construct performance and prioritization, a willingness to design and use customized crystallization screens, and, crucially, initiation of high-throughput construct exploration very early in the drug discovery process.</p

Metabolic shift underlies recovery in reversible infantile respiratory chain deficiency.

Reversible infantile respiratory chain deficiency (RIRCD) is a rare mitochondrial myopathy leading to severe metabolic disturbances in infants, which recover spontaneously after 6-months of age. RIRCD is associated with the homoplasmic m.14674T>C mitochondrial DNA mutation; however, only ~ 1/100 carriers develop the disease. We studied 27 affected and 15 unaffected individuals from 19 families and found additional heterozygous mutations in nuclear genes interacting with mt-tRNAGlu including EARS2 and TRMU in the majority of affected individuals, but not in healthy carriers of m.14674T>C, supporting a digenic inheritance. Our transcriptomic and proteomic analysis of patient muscle suggests a stepwise mechanism where first, the integrated stress response associated with increased FGF21 and GDF15 expression enhances the metabolism modulated by serine biosynthesis, one carbon metabolism, TCA lipid oxidation and amino acid availability, while in the second step mTOR activation leads to increased mitochondrial biogenesis. Our data suggest that the spontaneous recovery in infants with digenic mutations may be modulated by the above described changes. Similar mechanisms may explain the variable penetrance and tissue specificity of other mtDNA mutations and highlight the potential role of amino acids in improving mitochondrial disease

Do People with Hoarding Disorder Under-Report Their Symptoms?

Previous research indicates that people with hoarding sometimes under- or over-report the severity of their symptoms. This article examines the results of two separate studies that evaluate severity ratings made by participants with hoarding disorder (HD) in comparison to ratings by family members or independent evaluators. In Study 1, HD participants\u27 ratings of the severity of the clutter in their home and their hoarding behaviors were less severe than those made by their friends or family members. This result may be accounted for by family members\u27 rejecting attitudes towards the participant. In Study 2, HD participants appeared to under-report specific hoarding symptoms while over-reporting their overall global impression of hoarding severity. A three-pronged assessment approach is recommended in which ratings of hoarding severity are made by the HD participant, their family member, and an independent observer or clinician. Such an approach would better inform future research, and also clinical treatment

The relationship between self-reported and objective neuropsychological impairments in patients with hoarding disorder

Although hoarding disorder (HD) is characterized by self- and clinician-reported difficulties with cognitive functioning, studies of neuropsychological performance have yielded little evidence of consistent, clinical-level cognitive impairments. The aim of this study was to quantify this inconsistency and to examine whether this pattern is unique to HD. Fifty-three adults (20 with HD, 19 with obsessive compulsive disorder (OCD) and minimal hoarding symptoms, and 14 with OCD and a high degree of hoarding symptoms (OCD-H)) completed self-report and objective neuropsychological tests of inhibition, attention, and memory. The three groups differed significantly on self-reported attention and memory deficits, with the HD group reporting greater difficulties. However, the groups performed comparably on objective neuropsychological tests of inhibition, attention, immediate and delayed nonverbal memory, and immediate verbal memory. The OCD-H group demonstrated a greater rate of impairment on a test of delayed verbal memory. The HD group was characterized by lower concordance rates between self-report and objective memory impairment. The groups did not differ significantly in concordance rates for self-report and objective measures of attention and inhibition. Understanding the discrepancy between self-report and objective neuropsychological measures may help to better characterize the role of cognitive processes in HD

Mitochondrial dysfunction in mut methylmalonic acidemia

Methylmalonic acidemia is an autosomal recessive inborn error of metabolism caused by defective activity of methylmalonyl-CoA mutase (MUT) that exhibits multiorgan system pathology. To examine whether mitochondrial dysfunction is a feature of this organic acidemia, a background-modified Mut-knockout mouse model was constructed and used to examine mitochondrial ultrastructure and respiratory chain function in the tissues that manifest pathology in humans. In parallel, the liver from a patient with mut methylmalonic acidemia was studied in a similar fashion. Megamitochondria formed early in life in the hepatocytes of the Mut−/− animals and progressively enlarged. Liver extracts prepared from the mutants at multiple time points displayed respiratory chain dysfunction, with diminished cytochrome c oxidase activity and reduced intracellular glutathione compared to control littermates. Over time, the exocrine pancreas and proximal tubules of the kidney also exhibited megamitochondria, and older mutant mice eventually developed tubulointerstitial renal disease. The patient liver displayed similar morphological and enzymatic findings as observed in the murine tissues. These murine and human studies establish that megamitochondria formation with respiratory chain dysfunction occur in a tissue-specific fashion in methylmalonic acidemia and suggest treatment approaches based on improving mitochondrial function and ameliorating the effects of oxidative stress.—Chandler, R. J., Zerfas, P. M., Shanske, S., Sloan, J., Hoffmann, V., DiMauro, S., Venditti, C. P. Mitochondrial dysfunction in mut methylmalonic acidemia