Molecular pathogenesis of spinocerebellar ataxia type 1 disease

Spinocerebellar ataxia type 1 (SCA1) is an autosomal-dominant neurodegenerative disorder characterized by ataxia and progressive motor deterioration. SCA1 is associated with an elongated polyglutamine tract in ataxin-1, the SCA1 gene product. As summarized in this review, recent studies have clarified the molecular mechanisms of SCA1 pathogenesis and provided direction for future therapeutic approaches. The nucleus is the subcellular site where misfolded mutant ataxin-1 acts to cause SCA1 disease in the cerebellum. The role of these nuclear aggregates is the subject of intensive study. Additional proteins have been identified, whose conformational alterations occurring through interactions with the polyglutamine tract itself or non-polyglutamine regions in ataxin-1 are the cause of SCA-1 cytotoxicity. Therapeutic hope comes from the observations concerning the reduction of nuclear aggregation and alleviation of the pathogenic phenotype by the application of potent inhibitors and RNA interference.     

Symmetric faces are a sign of successful cognitive aging

It has been proposed that a common cause underlies individual differences in bodily and cognitive decline in old age. No good marker for this common cause has been identified to date. Here, fluctuating asymmetry (FA), an indicator of developmental stability that relates to intelligence differences in young adults, was measured from facial photographs of 216 surviving members of the Lothian Birth Cohort 1921 at age 83 and related to their intelligence at ages 11, 79 and 83 years. FA at age 83 was unrelated to intelligence at ages 11 and 79 and to cognitive change between 11 and 79 years. It was, however, associated with intelligence and information processing efficiency at age 83 and with cognitive change between 79 and 83 years. Significant results were limited to men, a result predicted by sex differences in life history tradeoffs and life expectancy. Results were stronger when directional asymmetries were corrected in facial FA measures. Thus, FA is a candidate marker for the common cause of differential senescence.     

Assessment of risk factors for postoperative cognitive dysfunction after coronary artery bypass surgery: a single-center retrospective cohort study

Aim: To find out risk factors for postoperative cognitive dysfunction (POCD) after coronary artery bypass grafting (CABG), and to provide basis for clinical prevention of POCD. A total of 88 patients who underwent CABG were surveyed with Telephone Questionnaire (TICS-M) for their cognitive impairment after 3, 7, 21, 90, 180 days post-surgery. The occurrence of POCD was diagnosed by Neuropsychological Battery which included Vocabular Learning Test (VLT), Wisconsin Card Sorting Test (WCST), Trail Making Test (TMT) and Symbol Digit Modalities Test (SDMT). The preoperative, intraoperative and postoperative risk factors were assessed by the χ² or t test. Multivariate analysis was used to study the correlation between the risk factors and the occurrence of POCD. Age, aortic plaque, carotid artery stenosis, cerebrovascular disease, anesthesia time, the rate of decline in intraoperative hemoglobin concentration (ΔHb) and systemic inflammatory response syndrome (SIRS) score on postoperative day 2 had statistically significant (P<0.05) influence on the occurrence of POCD. Aortic plaque, carotid artery stenosis, anesthesia time and SIRS score (odds ratio (OR) value > 1, P<0.05) are the risk factors for POCD. The incidence of day-21 and -180 POCD was approximately 26.1 and 22.7%, respectively.     

Influence of manganese exposure on cognitive function,plasma APP and Aβ levels in older men

BackgroundElevated manganese (Mn) exposure impairs cognition in adults and children, but the association between Mn and cognitive function in elderly people is unclear. Previous studies have linked Mn neurotoxicity in AD to Aβ-dependent mechanisms. However, the association between Mn and plasma APP and Aβ in the general elderly population remains unknown. This study aimed to investigate the association between Mn exposure and cognitive function, plasma APP and plasma Aβ in older adults.MethodsCognitive abilities in 375 men aged 60 and older in Guangxi, China were assessed using the Mini-Mental State Examination (MMSE) and cognitive impairment were identified using education-stratified cut-off points of MMSE scores. Urinary Mn levels and plasma APP, and Aβ levels were measured using ICP-MS and ELISA, respectively.ResultsA total of 109 (29.07 %) older men were identified as having cognitive impairment. The median urinary Mn level was 0.22 μg/g creatinine. Urinary Mn levels were negatively correlated with MMSE scores (β = −1.35, 95 % CI: −2.65 to −0.06; p = 0.041). In addition, higher concentrations of urinary manganese were associated with a greater risk of cognitive impairment (OR = 2.03, 95 % CI: 1.14–3.59; comparing the highest and lowest manganese; p = 0.025). Moreover, plasma APP levels were inversely associated with urinary Mn levels (r = −0.123, p = 0.020), and positively associated with MMSE scores (r = 0.158, p = 0.002). Surprisingly, no correlations were observed between plasma Aβ42, Aβ40, Aβ40/Aβ42, or Aβ42/Aβ40 and urinary Mn levels and MMSE scores.ConclusionThese results suggested that Mn exposure is negatively associated with older men’s cognition and plasma APP levels, but not plasma Aβ levels.     

The role of abnormal mitochondrial dynamics in the pathogenesis of Alzheimer's disease

Mitochondria play critical roles in neuronal function and almost all aspects of mitochondrial function are altered in Alzheimer neurons. Emerging evidence shows that mitochondria are dynamic organelles that undergo continuous fission and fusion, the balance of which not only controls mitochondrial morphology and number, but also regulates mitochondrial function and distribution. In this review, after a brief overview of the basic mechanisms involved in the regulation of mitochondrial fission and fusion and how mitochondrial dynamics affects mitochondrial function, we will discuss in detail our and others' recent work demonstrating abnormal mitochondrial morphology and distribution in Alzheimer's disease (AD) models and how these abnormalities may contribute to mitochondrial and synaptic dysfunction in AD. We propose that abnormal mitochondrial dynamics plays a key role in causing the dysfunction of mitochondria that ultimately damage AD neurons.     

Three amino acids in the D2 dopamine receptor regulate selective ligand function and affinity

The D₂ dopamine receptor is an important therapeutic target for the treatment of psychotic, agitated, and abnormal behavioral states. To better understand the specific interactions of subtype‐selective ligands with dopamine receptor subtypes, seven ligands with high selectivity (>120‐fold) for the D₄ subtype of dopamine receptor were tested on wild‐type and mutant D₂ receptors. Five of the selective ligands were observed to have 21‐fold to 293‐fold increases in D₂ receptor affinity when three non‐conserved amino acids in TM2 and TM3 were mutated to the corresponding D₄ amino acids. The two ligands with the greatest improvement in affinity for the D₂ mutant receptor [i.e., 3‐{[4‐(4‐iodophenyl) piperazin‐1‐yl]methyl}‐1H‐pyrrolo[2,3‐b]pyridine (L‐750,667) and 1‐[4‐iodobenzyl]‐4‐[N‐(3‐isopropoxy‐2‐pyridinyl)‐N‐methyl]‐aminopiperidine (RBI‐257)] were investigated in functional assays. Consistent with their higher affinity for the mutant than for the wild‐type receptor, concentrations of L‐750,667 or RBI‐257 that produced large reductions in the potency of quinpirole’s functional response in the mutant did not significantly reduce quinpirole’s functional response in the wild‐type D₂ receptor. In contrast to RBI‐257 which is an antagonist at all receptors, L‐750,667 is a partial agonist at the wild‐type D₂ but an antagonist at both the mutant D₂ and wild‐type D₄ receptors. Our study demonstrates for the first time that the TM2/3 microdomain of the D₂ dopamine receptor not only regulates the selective affinity of ligands, but in selected cases can also regulate their function. Utilizing a new docking technique that incorporates receptor backbone flexibility, the three non‐conserved amino acids that encompass the TM2/3 microdomain were found to account in large part for the differences in intermolecular steric contacts between the ligands and receptors. Consistent with the experimental data, this model illustrates the interactions between a variety of subtype‐selective ligands and the wild‐type D₂, mutant D₂, or wild‐type D₄ receptors.     

Long-term persistence of vaccine-derived aluminum hydroxide is associated with chronic cognitive dysfunction

Macrophagic myofasciitis (MMF) is an emerging condition, characterized by specific muscle lesions assessing long-term persistence of aluminum hydroxide within macrophages at the site of previous immunization. Affected patients mainly complain of arthromyalgias, chronic fatigue, and cognitive difficulties. We designed a comprehensive battery of neuropsychological tests to prospectively delineate MMF-associated cognitive dysfunction (MACD). Compared to control patients with arthritis and chronic pain, MMF patients had pronounced and specific cognitive impairment. MACD mainly affected (i) both visual and verbal memory; (ii) executive functions, including attention, working memory, and planning; and (iii) left ear extinction at dichotic listening test. Cognitive deficits did not correlate with pain, fatigue, depression, or disease duration. Pathophysiological mechanisms underlying MACD remain to be determined. In conclusion, long-term persistence of vaccine-derived aluminum hydroxide within the body assessed by MMF is associated with cognitive dysfunction, not solely due to chronic pain, fatigue and depression.     

Mitochondrial DNA mutations and ageing

The mechanism by which we age has sparked a huge number of theories, and is an area of intense debate. As the elderly population rises, the importance of elucidating these mechanisms is becoming more apparent as age is the single biggest risk factor for a number of diseases such as cancer, diabetes and neurodegenerative disease. Mitochondrial DNA (MtDNA) mutations have been shown to accumulate in cells and tissues during the ageing process; however the question as to whether these mutations have a causal role in the ageing process remains an area of uncertainty. Here we review the current literature, and discuss the evidence for and against a causal role of mtDNA mutations in ageing and in the pathogenesis of age-related disease.