Cognitive impairment in Parkinson's disease: impact on quality of life of carers

Background

The quality of life (QoL) of informal caregivers of people with Parkinson's disease (PD) (PwP) can be affected by the caring role. Because of cognitive symptoms and diminished activities of daily living, in addition to the management of motor symptoms, carers of PwP and cognitive impairment may experience increased levels of burden and poorer QoL compared with carers of PwP without cognitive impairment. This study aimed to investigate the impact of cognitive impairment in PD upon QoL of carers.

Methods

Approximately 36 months after diagnosis, 66 dyadic couples of PwP and carers completed assessments. PwP completed a schedule of neuropsychological assessments and QoL measures; carers of PwP completed demographic questionnaires and assessments of QoL. Factor scores of attention, memory/executive function and global cognition, as derived by principal component analysis, were used to evaluate cognitive domains.

Results

Hierarchical regression analysis found lower Montreal Cognitive Assessment was a significant independent predictor of poorer carer QoL, in addition to number of hours spent caregiving, carer depression and PD motor severity. Attentional deficits accounted for the largest proportion of variance of carer QoL. Carers of PwP and dementia (n = 9) had significantly poorer QoL scores compared with PwP and mild cognitive impairment (n = 18) or normal cognition (n = 39) carers (p < 0.01).

Conclusions

Attentional deficits were the strongest predictor of carer QoL compared with other cognitive predictors. Carers for those with PD dementia reported the poorest QoL. Interventions such as respite or cognitive behavioural therapy to improve mood and self‐efficacy in carers may improve carer QoL. © 2016 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons, Ltd.     

Small CGG repeat expansion alleles of FMR1 gene are associated with parkinsonism

Fragile X-associated tremor/ataxia syndrome (FXTAS) affects older males carrying premutation, that is, expansions of the CGG repeat (in the 55–200 range), in the FMR1 gene. The neurological changes are linked to the excessive FMR1 messenger RNA (mRNA), becoming toxic through a 'gain-of-function'. Because elevated levels of this mRNA are also found in carriers of the smaller expansion (grey zone) alleles, ranging from 40 to 54 CGGs, we tested for a possible role of these alleles in the origin of movement disorders associated with tremor.
We screened 228 Australian males affected with idiopathic Parkinson's disease and other causes of parkinsonism recruited from Victoria and Tasmania for premutation and grey zone alleles. The frequencies of either of these alleles were compared with the frequencies in a population-based sample of 578 Guthrie spots from consecutive Tasmanian male newborns (controls). There was a significant excess of premutation carriers (Fisher's exact test p = 0.006). There was also a more than twofold increase in grey zone carriers in the combined sample of the Victorian and Tasmanian cases, with odds ratio (OR ) = 2.36, and 95% confidence intervals (CI): 1.20–4.63, as well as in Tasmanian cases only (OR = 2.33, 95% CI: 1.06–5.13), compared with controls. The results suggest that the FMR1 grey zone alleles, as well as premutation alleles, might contribute to the aetiology of disorders associated with parkinsonism.     

Quality of routine spirometry tests in Dutch general practices

Background

Spirometry is an indispensable tool for diagnosis and monitoring of chronic airways disease in primary care.

Aim

To establish the quality of routine spirometry tests in general practice, and explore associations between test quality and patient characteristics.

Design of study

Analysis of routine spirometry test records.

Setting

Fifteen general practices which had a working agreement with a local hospital pulmonary function laboratory for spirometry assessment regarding test quality and interpretation.

Method

Spirometry tests were judged by a pulmonary function technician and a chest physician. Proportions of test adequacy were analysed using markers for manoeuvre acceptability and test reproducibility derived from the 1994 American Thoracic Society spirometry guideline. Associations between quality markers and age, sex, and severity of obstruction were examined using logistic regression.

Results

Practices performed a mean of four (standard deviation = 2) spirometry tests per week; 1271 tests from 1091 adult patients were analysed; 96.4% (95% confidence interval [CI] = 95.6 to 97.2) of all tests consisted of ≥3 blows. With 60.6% of tests, forced expiratory time was the marker with the lowest acceptability rate. An overall 38.8% (95% CI = 36.0 to 41.6) of the tests met the acceptability as well as reproducibility criteria. Age, sex, and severity of obstruction were associated with test quality markers.

Conclusion

The quality of routine spirometry tests was better than in previous reports from primary care research settings, but there is still substantial room for improvement. Sufficient duration of forced expiratory time is the quality marker with the highest rate of inadequacy. Primary care professionals should be aware of patient characteristics that may diminish the quality of their spirometry tests. Further research is needed to establish to what extent spirometry tests that are inadequate, according to stringent international expert criteria, result in incorrect clinical interpretations in general practice.     

Distinct molecular requirements for activation or stabilization of soluble guanylyl cyclase upon haem oxidation-induced degradation

Background and purpose:

In endothelial dysfunction, signalling by nitric oxide (NO) is impaired because of the oxidation and subsequent loss of the soluble guanylyl cyclase (sGC) haem. The sGC activator 4-[((4-carboxybutyl){2-[(4-phenethylbenzyl)oxy]phenethyl}amino)methyl[benzoic]acid (BAY 58-2667) is a haem-mimetic able to bind with high affinity to sGC when the native haem (the NO binding site) is removed and it also protects sGC from ubiquitin-triggered degradation. Here we investigate whether this protection is a unique feature of BAY 58-2667 or a general characteristic of haem-site ligands such as the haem-independent sGC activator 5-chloro-2-(5-chloro-thiophene-2-sulphonylamino-N-(4-(morpholine-4-sulphonyl)-phenyl)-benzamide sodium salt (HMR 1766), the haem-mimetic Zn-protoporphyrin IX (Zn-PPIX) or the haem-dependent sGC stimulator 5-cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-pyrimidin-4-ylamine (BAY 41-2272).

Experimental approach:

The sGC inhibitor 1H-(1,2,4)-oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) was used to induce oxidation-induced degradation of sGC. Activity and protein levels of sGC were measured in a Chinese hamster ovary cell line as well as in primary porcine endothelial cells. Cells expressing mutant sGC were used to elucidate the molecular mechanism underlying the effects observed.

Key results:

Oxidation-induced sGC degradation was prevented by BAY 58-2667 and Zn-PPIX in both cell types. In contrast, the structurally unrelated sGC activator, HMR 1766, and the sGC stimulator, BAY 41-2272, did not protect. Similarly, the constitutively haem-free sGC mutant β₁H105F was stabilized by BAY 58-2667 and Zn-PPIX.

Conclusions:

The ability of BAY 58-2667 not only to activate but also to stabilize oxidized/haem-free sGC represents a unique example of bimodal target interaction and distinguishes this structural class from non-stabilizing sGC activators and sGC stimulators such as HMR 1766 and BAY 41-2272, respectively.     

The negative inotropic action of canrenone is mediated by L-type calcium current blockade and reduced intracellular calcium transients

Background and purpose:

Adding spironolactone to standard therapy in heart failure reduces morbidity and mortality, but the underlying mechanisms are not fully understood. We analysed the effect of canrenone, the major active metabolite of spironolactone, on myocardial contractility and intracellular calcium homeostasis.

Experimental approach:

Left ventricular papillary muscles and cardiomyocytes were isolated from male Wistar rats. Contractility of papillary muscles was assessed with force transducers, Ca²⁺ transients by fluorescence and Ca²⁺ fluxes by electrophysiological techniques.

Key results:

Canrenone (300–600 µmol·L⁻¹) reduced developed tension, maximum rate of tension increase and maximum rate of tension decay of papillary muscles. In cardiomyocytes, canrenone (50 µmol·L⁻¹) reduced cell shortening and L-type Ca²⁺ channel current, whereas steady-state activation and inactivation, and reactivation curves were unchanged. Canrenone also decreased the Ca²⁺ content of the sarcoplasmic reticulum, intracellular Ca²⁺ transient amplitude and intracellular diastolic Ca²⁺ concentration. However, the time course of [Ca²⁺]_i decline during transients evoked by caffeine was not affected by canrenone.

Conclusion and implications:

Canrenone reduced L-type Ca²⁺ channel current, amplitude of intracellular Ca²⁺ transients and Ca²⁺ content of sarcoplasmic reticulum in cardiomyocytes. These changes are likely to underlie the negative inotropic effect of canrenone.     

Nonenzymatic role of acetylcholinesterase in neuritic sprouting: Regional changes in acetylcholinesterase and choline acetyltransferase after neonatal 6-hydroxydopamine lesions

Acetylcholinesterase (AChE) is postulated to play a nonenzymatic role in the development of neuritic projections. We gave the specific neurotoxin, 6-OHDA to rats on postnatal day (PN) 1, a treatment that destroys noradrenergic nerve terminals in the forebrain while producing reactive sprouting in the brainstem. AChE showed profound decreases in the forebrain that persisted in males over the entire phase of major synaptogenesis, from PN4 through PN21; in the brainstem, AChE was increased. Parallel examinations of choline acetyltransferase, an enzymatic marker for cholinergic nerve terminals, showed a different pattern of 6-OHDA-induced alterations, with initial decreases in both forebrain and brainstem in males and regression toward normal by PN21; females were far less affected. The sex differences are in accord with the greater plasticity of the female brain and its more rapid recovery from neurotoxic injury; our findings indicate that these differences are present well before puberty. These results support the view that AChE is involved in neurite formation, unrelated to its enzymatic role in cholinergic neurotransmission. Further, the results for choline acetyltransferase indicate that early depletion of norepinephrine compromises development of acetylcholine systems, consistent with a trophic role for this neurotransmitter.     

Modulation of Allergic Airway Inflammation by the Oral Pathogen Porphyromonas gingivalis

Accumulating evidence suggests that bacteria associated with periodontal disease may exert systemic immunomodulatory effects. Although the improvement in oral hygiene practices in recent decades correlates with the increased incidence of asthma in developed nations, it is not known whether diseases of the respiratory system might be influenced by the presence of oral pathogens. The present study sought to determine whether subcutaneous infection with the anaerobic oral pathogen Porphyromonas gingivalis exerts a regulatory effect on allergic airway inflammation. BALB/c mice sensitized and subsequently challenged with ovalbumin exhibited airway hyperresponsiveness to methacholine aerosol and increased airway inflammatory cell influx and Th2 cytokine (interleukin-4 [IL-4], IL-5, and IL-13) content relative to those in nonallergic controls. Airway inflammatory cell and cytokine contents were significantly reduced by establishment of a subcutaneous infection with P. gingivalis prior to allergen sensitization, whereas serum levels of ovalbumin-specific IgE and airway responsiveness were not altered. Conversely, subcutaneous infection initiated after allergen sensitization did not alter inflammatory end points but did reduce airway responsiveness in spite of increased serum IgE levels. These data provide the first direct evidence of a regulatory effect of an oral pathogen on allergic airway inflammation and responsiveness. Furthermore, a temporal importance of the establishment of infection relative to allergen sensitization is demonstrated for allergic outcomes.A causative relationship between decreased microbial exposure and infection in recent decades and the concurrent increase in asthma prevalence in developed countries has been suggested and is thought to be attributable, at least in part, to a phenomenon known as the hygiene hypothesis (30). Originally put forth by Strachan (32), the hypothesis proposes that increased cleanliness of modern industrialized societies has resulted in decreased exposure to bacterial, viral, and other immunomodulatory organisms and their products, particularly in early life, and that this has in turn resulted in a loss of potentially protective effects of these exposures on the development of allergic diseases. Accumulating clinical and experimental evidence largely supports the hygiene hypothesis as it relates to asthma, although a consensus has not been reached. As reviewed recently (31), a variety of infections of a viral, bacterial, and parasitic nature influence the host immune response, such that regulation of the Th1-Th2 balance is modified to promote Th1 responses and impede Th2 responses, thereby reducing Th2-mediated allergic outcomes. However, this is likely a simplistic view of the effects of infections on immune system development and responses, and other factors, including host genetic makeup and timing of exposures to the infective agent relative to allergen exposure, undoubtedly contribute to the overall allergic phenotype.In addition to the influence of environmental exposure to microbes, the potential regulation of allergic diseases by the microflora of the host is receiving increased attention. Evidence suggests that the composition of the gastrointestinal microflora differs between individuals with and without allergy (reviewed in reference 25), and disruption of the normal gut microflora by antibiotic administration leads to allergic airway responses following allergen challenge in mice not previously sensitized to the allergen (24). Moreover, although similar benefits have not yet been demonstrated in humans, the oral administration of probiotic bacteria was recently shown to decrease allergic airway inflammation in mice (8, 9).As in the gut, the microenvironment of the oral cavity is complex and comprises hundreds of bacterial species. Porphyromonas gingivalis, a Gram-negative opportunistic periodontal pathogen, can initiate periodontal lesions in nonhuman primates when introduced into the periodontal microbiota (15) and is a major etiological agent in severe forms of periodontal disease such as chronic periodontitis (21). Interest in chronic oral infections and their potential role in adverse systemic health effects has been heightened by observations of positive associations between serum concentrations of antibodies to oral pathogens such as P. gingivalis and the incidence of cardiovascular diseases and renal dysfunction (3, 19, 28, 29). Recently, however, an inverse relationship between serum concentrations of antibodies to P. gingivalis and the prevalence of asthma, wheeze, and hay fever was observed in a representative sample of the population of the United States (2). Furthermore, a significant inverse association between periodontitis and the incidences of hay fever and allergy to house dust mites was reported for a northeast German population, with a borderline significant inverse association between periodontitis and asthma also observed (10). While limitations of these observational studies include potential recall bias pertaining to asthma symptoms and the inability to directly assess cause and effect, these findings nonetheless suggest a potential protective effect of infection with oral pathogens such as P. gingivalis on asthma pathogenesis.In order to examine the influence of oral pathogens on the development of allergic airway disease under controlled experimental conditions, the present study sought to determine whether infection with P. gingivalis modified allergic outcomes in a murine model of asthma. To accomplish this, a subcutaneous chamber model was employed wherein mice were subjected to a local infection with live P. gingivalis either before or after sensitization to allergen, and the effects of this infection on subsequent responses to allergen challenge were assessed. The results indicate that P. gingivalis infection exerts a modulatory effect on allergic airway responses and that this effect is dependent on the timing of infection relative to allergic sensitization.     

ACUTE ENCEPHALOPATHY DUE TO COEXISTENT NICOTINIC ACID AND THIAMINE DEFICIENCY

SUMMARY We report the case of an alcoholic woman with confusion, catatonia and extrapyramidal signs, who developed features of the Wernicke-Korsakoff syndrome after treatment with intravenous high potency vitamins. We emphasise that this should arouse the suspicion of nicotinic acid deficiency even in the absence of gastrointestinal symptoms or skin lesions.