BACKGROUND: The sympathoadrenergic system and its major effector PKA (protein kinase A) are activated to maintain cardiac output coping with physiological or pathological stressors. If and how PKA plays a role in physiological cardiac hypertrophy (PhCH) and pathological CH (PaCH) are not clear. METHODS: Transgenic mouse models expressing the PKA inhibition domain (PKAi) of PKA inhibition peptide alpha (PKIalpha)-green fluorescence protein (GFP) fusion protein (PKAi-GFP) in a cardiac-specific and inducible manner (cPKAi) were used to determine the roles of PKA in physiological CH during postnatal growth or induced by swimming, and in PaCH induced by transaortic constriction (TAC) or augmented Ca 2+ influx. Kinase profiling was used to determine cPKAi specificity. Echocardiography was used to determine cardiac morphology and function. Western blotting and immunostaining were used to measure protein abundance and phosphorylation. Protein synthesis was assessed by puromycin incorporation and protein degradation by measuring protein ubiquitination and proteasome activity. Neonatal rat cardiomyocytes (NRCMs) infected with AdGFP (GFP adenovirus) or AdPKAi-GFP (PKAi-GFP adenovirus) were used to determine the effects and mechanisms of cPKAi on myocyte hypertrophy. rAAV9.PKAi-GFP was used to treat TAC mice. RESULTS: (1) cPKAi delayed postnatal cardiac growth and blunted exercise-induced PhCH; (2) PKA was activated in hearts after TAC due to activated sympathoadrenergic system, the loss of endogenous PKIα (PKA inhibition peptide α), and the stimulation by noncanonical PKA activators; (3) cPKAi ameliorated PaCH induced by TAC and increased Ca 2+ influxes and blunted neonatal rat cardiomyocyte hypertrophy by isoproterenol and phenylephrine; (4) cPKAi prevented TAC-induced protein synthesis by inhibiting mTOR (mammalian target of rapamycin) signaling through reducing Akt (protein kinase B) activity, but enhancing inhibitory GSK-3α (glycogen synthase kinase-3α) and GSK-3β signals; (5) cPKAi reduced protein degradation by the ubiquitin-proteasome system via decreasing RPN6 phosphorylation; (6) cPKAi increased the expression of antihypertrophic atrial natriuretic peptide (ANP); (7) cPKAi ameliorated established PaCH and improved animal survival. CONCLUSIONS: Cardiomyocyte PKA is a master regulator of PhCH and PaCH through regulating protein synthesis and degradation. cPKAi can be a novel approach to treat PaCH.

Rationale: Myocardial infarction (MI) leads to heart failure (HF) and premature death. The respective roles of myocyte death and depressed myocyte contractility in the induction of HF after MI have not been clearly defined and are the focus of this study. Objectives: We developed a mouse model in which we could prevent depressed myocyte contractility after MI and used it to test the idea that preventing depression of myocyte Ca 2+ -handling defects could avert post-MI cardiac pump dysfunction. Methods and Results: MI was produced in mice with inducible, cardiac-specific expression of the β2a subunit of the L-type Ca 2+ channel. Myocyte and cardiac function were compared in control and β2a animals before and after MI. β2a myocytes had increased Ca 2+ current; sarcoplasmic reticulum Ca 2+ load, contraction and Ca 2+ transients (versus controls), and β2a hearts had increased performance before MI. After MI, cardiac function decreased. However, ventricular dilation, myocyte hypertrophy and death, and depressed cardiac pump function were greater in β2a versus control hearts after MI. β2a animals also had poorer survival after MI. Myocytes isolated from β2a hearts after MI did not develop depressed Ca 2+ handling, and Ca 2+ current, contractions, and Ca 2+ transients were still above control levels (before MI). Conclusions: Maintaining myocyte contractility after MI, by increasing Ca 2+ influx, depresses rather than improves cardiac pump function after MI by reducing myocyte number.

Rationale: PKA (Protein Kinase A) is a major mediator of β-AR (β-adrenergic) regulation of cardiac function, but other mediators have also been suggested. Reduced PKA basal activity and activation are linked to cardiac diseases. However, how complete loss of PKA activity impacts on cardiac physiology and if it causes cardiac dysfunction have never been determined. Objectives: We set to determine how the heart adapts to the loss of cardiomyocyte PKA activity and if it elicits cardiac abnormalities. Methods and Results: (1) Cardiac PKA activity was almost completely inhibited by expressing a PKA inhibitor peptide in cardiomyocytes (cPKAi) in mice; (2) cPKAi reduced basal phosphorylation of 2 myofilament proteins (TnI [troponin I] and cardiac myosin binding protein C), and one longitudinal SR (sarcoplasmic reticulum) protein (PLB [phospholamban]) but not of the sarcolemmal proteins (Cav1.2 α1c and PLM [phospholemman]), dyadic protein RyR2, and nuclear protein CREB (cAMP response element binding protein) at their PKA phosphorylation sites; (3) cPKAi increased the expression of CaMKII (Ca 2+ /calmodulin-dependent kinase II), the Cav1.2 β subunits and current, but decreased CaMKII phosphorylation and CaMKII-mediated phosphorylation of PLB and RyR2; (4) These changes resulted in significantly enhanced myofilament Ca 2+ sensitivity, prolonged contraction, slowed relaxation but increased myocyte Ca 2+ transient and contraction amplitudes; (5) Isoproterenol-induced PKA and CaMKII activation and their phosphorylation of proteins were prevented by cPKAi; (6) cPKAi abolished the increases of heart rate, and cardiac and myocyte contractility by a β-AR agonist (isoproterenol), showing an important role of PKA and a minimal role of PKA-independent β-AR signaling in acute cardiac regulation; (7) cPKAi mice have partial exercise capability probably by enhancing vascular constriction and ventricular filling during β-AR stimulation; and (8) cPKAi mice did not show any cardiac functional or structural abnormalities during the 1-year study period. Conclusions: PKA activity suppression induces a unique Ca 2+ handling phenotype, eliminates β-AR regulation of heart rates and cardiac contractility but does not cause cardiac abnormalities.

Key points Cav3.1 T‐type Ca2+ channel current (ICa‐T) contributes to heart rate genesis but is not known to contribute to heart rate regulation by the sympathetic/β‐adrenergic system (SAS). We show that the loss of Cav3.1 makes the beating rates of the heart in vivo and perfused hearts ex vivo, as well as sinoatrial node cells, less sensitive to β‐adrenergic stimulation; it also renders less conduction acceleration through the atrioventricular node by β‐adrenergic stimulation. Increasing Cav3.1 in cardiomyocytes has the opposite effects. ICa‐T in sinoatrial nodal cells can be upregulated by β‐adrenergic stimulation. The results of the present study add a new contribution to heart rate regulation by the SAS system and provide potential new mechanisms for the dysregulation of heart rate and conduction by the SAS in the heart. T‐type Ca2+ channel can be a target for heart disease treatments that aim to slow down the heart rate AbstractCav3.1 (α1G) T‐type Ca2+ channel (TTCC) is expressed in mouse sinoatrial node cells (SANCs) and atrioventricular (AV) nodal cells and contributes to heart rate (HR) genesis and AV conduction. However, its role in HR regulation and AV conduction acceleration by the β‐adrenergic system (SAS) is unclear. In the present study, L‐ (ICa‐L) and T‐type (ICa‐T) Ca2+ currents were recorded in SANCs from Cav3.1 transgenic (TG) and knockout (KO), and control mice. ICa‐T was absent in KO SANCs but enhanced in TG SANCs. In anaesthetized animals, different doses of isoproterenol (ISO) were infused via the jugular vein and the HR was recorded. The EC50 of the HR response to ISO was lower in TG mice but higher in KO mice, and the maximal percentage of HR increase by ISO was greater in TG mice but less in KO mice. In Langendorff‐perfused hearts, ISO increased HR and shortened PR intervals to a greater extent in TG but to a less extent in KO hearts. KO SANCs had significantly slower spontaneous beating rates than control SANCs before and after ISO; TG SANCs had similar basal beating rates as control SANCs probably as a result of decreased ICa‐L but a greater response to ISO than control SANCs. ICa‐T in SANCs was significantly increased by ISO. ICa‐T upregulation by β‐adrenergic stimulation contributes to HR and conduction regulation by the SAS. TTCC can be a target for slowing the HR.

Protein Kinase A (PKA) is the major mediator of β-adrenergic (βAR) regulation of cardiac contractility but other mediators (e.g., EPAC) have also been suggested. Reduced PKA basal activity and activation are linked to cardiac diseases. However, the roles of PKA in cardiac physiology and pathology have not been clearly defined because it has been difficult to knockout all expressed PKA catalytic subunit genes in cardiomyocytes. We ablated PKA activity and activation in cardiomyocytes by expressing a PKA inhibitor peptide (PKAi-GFP) in cardiomyocytes in transgenic (TG) mice. We made novel discoveries that: (1) Basal PKA-mediated phosphorylation was reduced for proteins in myofilaments and longitudinal SR but not for proteins in subsarcolemmal and dyadic spaces in PKAi TG hearts, suggesting basal PKA activity is different in individual cellular compartments; (2) PKAi increased the expression of CaMKII, the L-type Ca 2+ channel β subunits and current, but decreased CaMKII phosphorylation; (3) These changes resulted in significantly enhanced myofilament Ca 2+ sensitivity with prolonged contraction and relaxation, decreased myocyte Ca 2+ transient decay rate but enhanced myocyte contractility. (4) PKA inhibition fully abolishes the increases of heart rate, and cardiac and myocyte contractility by a β-adrenergic agonist (isoproterenol, ISO), showing a surprising dominant role of PKA in heart rate regulation and a minimal role of PKA-independent βAR signaling in regulating cardiac function; (5) The increased phosphorylation of proteins mediated by PKA and CaMKII after ISO was prevented by PKAi because increased PKA and CaMKII activation by ISO was eliminated by PKAi in vivo and in vitro . (6) PKAi TG mice maintained partial exercise capability by enhancing basal cardiac function, vascular constriction and ventricular filling (i.e., preload) during βAR stimulation. These features resemble some of the characteristics of diseased hearts. However, PKAi TG mice did not show any cardiac functional or structural abnormalities during the 1-year study period. In conclusion, PKA is the essential mediator of acute βAR regulation of cardiac function and exercise capacity, but the loss of PKA basal activity and activation by βAR agonists do not cause cardiac disease.

Introduction: Elevated level of serum homocysteine (Hcy) has been identified as a risk factor for accelerating progression of cardiovascular disease. Nucleotide-binding oligomerization domain-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome activation by damaged mitochondria results in caspase-1 dependent inflammatory form of cell death. Methods and Results: AMI procedure was performed on hCBS/m cbs knockout mice at the age of 10weeks. Caspase-1 activity and myocardiocyte apoptosis were observed at the early stage of post-MI in severe HHcy mice (Hcy,120-220μM). Severe HHcy remarkably aggravated infarction size, cardiomyocyte area, and interstitial fibrosis 6 weeks after MI from 22.7 ± 4.3%, 340 ± 54μm 2 , 13.9 ± 1.9% in control mice (Hcy, 7-10μM) to 33.6 ± 6.5%, 485 ± 65μm 2 , 26 ± 4.5%, respectively, ( P =0.035, P = 0.041, P =0.002). In the meantime, HHcy significantly increased LV cavity dilatation and dysfunction as compared with control mice by echocardiography (5.9 ± 0.2 vs. 4.2 ± 0.4mm, P= 0.039; LV ejection fraction, 22.6 ± 3.9% vs. 36.8 ± 4.0%, P =0.011). Cultured neonatal mouse ventricular myocyte (NMVM) treated with the combination of DL-Hcy (500μM, 48h) and hypoxia (0.5% O2) showed that increased NLRP3 and caspase1 expression and activity, mitochondrial reactive oxygen species (mtROS) and mtDNA production, dissipation of mitochondrial membrane potential, and mitochondrial permeabilization. Moreover, synergetic effect of Hcy and hypoxia led to pronounced accumulation of damaged mitochondrial through suppressing mitophagy of damaged mitochondria. Caspase-1 activity and myocardiocyte death were lessened as NMVMs were administrated with mitochondria-targeted antioxidant Mito-temple and SOD2, whereas caspase-1 inhibition was not able to fully rescue damaged mitochondria. Conclusion: Acute myocardial infarction (AMI) initiates an intense inflammatory response in myocardium that promotes myocardiocyte death, ventricular remodeling, and cardiac dysfunction. Hcy accelerates cardiomyocyte death post-MI in part through mitochondrial-mediated NLRP3 inflammasome activation and inflammation, which contributes to adverse cardiac remodeling, ventricular dysfunction, and heart failure.

Introduction: Elevated level of serum homocysteine (Hcy) has been identified as a risk factor for accelerating progression of cardiovascular disease. The underlying mechanism by which NLRP3 inflamm...

Background: Determination of secular trends in cognitive aging is important for prioritization of resources, services, and research in aging populations. Prior studies have identified declining dementia incidence associated with changes in cardiovascular risk factors and increased educational attainment. However, few studies have examined these factors in multi-ethnic cohorts. Objective: To identify secular trends in the incidence rate of dementia in an elderly population. Methods: Participants in this study were drawn from the Washington Heights-Inwood Columbia Aging Project, a multiethnic cohort study of northern Manhattan residents aged 65 years and older. Cox proportional hazards models were used to examine differences in the incidence of dementia in cohorts recruited in 1992 and 1999, with age at dementia or age at last follow-up visit as the "time-to-event" variable. Results: Overall, there was a 41% reduction in the hazard ratio for dementia among participants in the 1999 cohort compared with those in the 1992 cohort, adjusting for age, sex, race, and baseline memory complaints (HR = 0.59). The reduction in incidence was greatest among non-Hispanic Whites and African-Americans and lowest among Hispanic participants (HRs = 0.60, 0.52 and 0.64, respectively), and was associated with increases in level of educational attainment, especially among African-Americans. Reduction in incidence of dementia was also greater among persons 75 years or older than among younger participants (HR = 0.52 versus HR = 0.69). Conclusions: Our results support previous findings that secular trends in dementia incidence are changing, including in aging minority populations.

Persistent elevation of Ca2+ influx due to prolongation of the action potential (AP), chronic activation of the β-adrenergic system and molecular remodeling occurs in stressed and diseased hearts. Increases in Ca2+ influx are usually linked to prolonged myocyte action potentials and arrhythmias. However, the contribution of chronic enhancement of Cav1.2 activity on cardiac electrical remodeling and arrhythmogenicity has not been completely defined and is the subject of this study. Chronically increased Cav1.2 activity was produced with a cardiac specific, inducible double transgenic (DTG) mouse system overexpressing the β2a subunit of Cav (Cavβ2a). DTG myocytes had increased L-type Ca2+ current (ICa-L), myocyte shortening, and Ca2+ transients. DTG mice had enhanced cardiac performance, but died suddenly and prematurely. Telemetric electrocardiograms revealed shortened QT intervals in DTG mice. The action potential duration (APD) was shortened in DTG myocytes due to significant increases of potassium currents and channel abundance. However, shortened AP in DTG myocytes did not fully limit excess Ca2+ influx and increased the peak and tail ICa-L. Enhanced ICa promoted sarcoplasmic reticulum (SR) Ca2+ overload, diastolic Ca2+ sparks and waves, and increased NCX activity, causing increased occurrence of early and delayed afterdepolarizations (EADs and DADs) that may contribute to premature ventricular beats and ventricular tachycardia. AV blocks that could be related to fibrosis of the AV node were also observed. Our study suggests that increasing ICa-L does not necessarily result in AP prolongation but causes SR Ca2+ overload and fibrosis of AV node and myocardium to induce cellular arrhythmogenicity, arrhythmias, and conduction abnormalities.

BACKGROUND:Depression has been associated with increased risk of death. However, there is lack of studies exploring such relationship in the context of dementia. Given the high prevalence of both depression and Alzheimer's Disease (AD), investigating their temporal association with mortality is of public health relevance. METHODS:Longitudinal data from the WHICAP study were analyzed (1958 individuals aged ≥65 years). Depressive symptoms were assessed with the 10-item Center for Epidemiologic Studies Depression Scale (CES-D). Respondents were identified as having AD if they satisfied the criteria of the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Cox regressions analyses were performed to determine the association between depressive symptoms and risk of all-cause mortality using the overall sample, and by AD status. RESULTS:Depressive symptoms were significantly associated with higher mortality risk after adjusting for all potential covariates in the overall sample (HR=1.22; 95% CI=1.02, 1.46) and in individuals with incident AD (HR=1.88; 95% CI=1.12, 3.18). LIMITATIONS:The CES-D does not measure clinical depression but depressive symptomatology. Since those who were exposed to known risk factors for mortality are likely to die prematurely, our results may have been skewed to the individuals with longer survival. CONCLUSIONS:Strategies focusing on prevention and early treatment of depression in the elderly may have a beneficial effect not only on patient quality of life and disability, but may also increase survival in the context of AD.

ObjectiveThis study aimed to examine the association between self‐reported sleep problems and cognitive decline in community‐dwelling older people. We hypothesized that daytime somnolence predicts subsequent cognitive decline.MethodsThis is a longitudinal study in a 3.2‐year follow‐up, with 18‐month intervals. The setting is the Washington Heights‐Inwood Community Aging Project. There were 1098 participants, who were over 65 years old and recruited from the community.Sleep problems were estimated using five sleep categories derived from the RAND Medical Outcome Study Sleep Scale: sleep disturbance, snoring, awaken short of breath/with a headache, sleep adequacy, and daytime somnolence. Four distinct cognitive composite scores were calculated: memory, language, speed of processing, and executive functioning. We used generalized estimating equations analyses with cognitive scores as the outcome, and time, sleep categories and their interactions as the main predictors. Models were initially unadjusted and then adjusted for age, gender, education, ethnicity, depression, and apolipoprotein E‐ε4 genotype.ResultsIncreased daytime somnolence (including feeling drowsy/sleepy, having trouble staying awake, and taking naps during the day) was linked to slower speed of processing both cross‐sectionally (B = −0.143, p = 0.047) and longitudinally (B = −0.003, p = 0.027). After excluding the demented participants at baseline, the results remained significant (B = −0.003, p = 0.021).ConclusionsOur findings suggest that daytime somnolence may be an early sign of cognitive decline in the older population. Copyright © 2015 John Wiley & Sons, Ltd.

Calcium channel plays an important role in smooth muscle contraction and relaxation and L-type calcium channel (Cav1.2) antagonist is widely used for treating hypertension. However, whether increasing Ca2+ influx into smooth muscle cells results in hypertension (through increasing smooth muscle cell contractility) or hypotension (through activating BKCa channels) is unclear. Aiming to answer this question, we established a transgenic (TG) mouse model with smooth muscle cell specific (SM22-α promoter driven) overexpression of a splicing variant of Cavβ2 subunit, Cavβ2a, tagged with GFP. Methods and Results: Immunostaining showed that Cavβ2a-GFP expressed in smooth muscle cells specifically and L-type Ca2+ current in smooth muscle cells from the 4 th branch of mesenteric arteries of transgenic mice was significantly increased (5.1±0.7pA/pF in TG, n=12 vs. 2.2±0.5pA/pF in control, n=10). Telemetric blood pressure measurement showed that 24h-averaged systolic pressure was significantly increased (135.2±9.8mmHg, n=25) compared to that of that of control c57bl/6 mice (110.2±7.8mmHg, n=16). The diastolic pressure was also significantly elevated in TG mice than in control mice. Maximum contractility of the 4 th branch mesenteric arteries measured with 40mM KCl was not different between control and TG groups. Sodium nitroprusside relaxed the phenylephrine-precontracted mesenteric artery in the same dose-dependent manner However, acetylcholine induced mesenteric artery relaxation was signficantly impaired in TG mesenteric arteries. Conclusions: Increasing Ca2+ influx through the L-type Ca2+ channel in smooth muscle cells causing hypertension via impairment of acetylcholine-dependent relaxation.

Introduction: The L-type Calcium channel (Cav1.2) plays an important role in smooth muscle contraction (via providing Ca2+ for contraction and inducing Ca2+ release from the sarcoplasmic reticulum)...

Introduction: Protein kinase inhibitor peptide α (PKIα) isoforms are abundantly expressed endogenous inhibitors of PKA in the heart. The physiological and pathophysiological relevance of PKIα has not been studied. Hypothesis: PKIα inhibits PKA activity in normal and stressed (post-myocardial infarction (MI)) hearts. Methods: PKIα knockout (KO) and c57bl/6 control (CTR) mice were used to test if PKIα affected cardiac β-adrenergic response and if played a role in post-MI hearts. Results: Protein abundance of PKIα was significantly increased in failing human and post-MI mouse ventricular tissue. The knockout of PKIα in mice did not affect the expression of the other two PKI isoforms. Nor did it change the expression of PKA regulatory and catalytic subunits. PKIα KO mice did not show alterations in basal cardiac morphology, function and life span of mice. Intra-LV hemodynamic measurements in response to different doses of isoproterenol showed that the loss of PKIα sensitizes the heart in response to isoproterenol (ISO) with a lower EC50 and the maximum response was increased more in KO mice than in control mice. ISO (10nM) increased myocyte contraction and Ca2+ transient amplitudes more in KO myocytes than control myocytes though 100nM ISO increased myocyte contraction and Ca2+ transients amplitude to the same. At the ISO concentration of 10nM, ISO increased more phosphorylation of the Ser16 site (PKA site) on phospholamban. In post-MI animals, the loss of PKIα enhances cardiac function at 1 week after MI but caused more myocardial infarction and functional depression at 8 weeks after MI. Conclusions: PKIα is an important regulator of cardiac β-adrenergic responses by antagonizing PKA. This mechanism could be protective to avoid β-adrenergic overstimulation, especially in post-MI patients and animal models.

OBJECTIVE:Estimates of the penetrance of LRRK2 G2019S vary widely (24%-100%), reflective of differences in ascertainment, age, sex, ethnic group, and genetic and environmental modifiers.METHODS:The kin-cohort method was used to predict penetrance in 2,270 relatives of 474 Ashkenazi Jewish (AJ) Parkinson disease (PD) probands in the Michael J. Fox LRRK2 AJ Consortium in New York and Tel Aviv, Israel. Patients with PD were genotyped for the LRRK2 G2019S mutation and at least 7 founder GBA mutations. GBA mutation carriers were excluded. A validated family history interview, including age at onset of PD and current age or age at death for each first-degree relative, was administered. Neurologic examination and LRRK2 genotype of relatives were included when available.RESULTS:Risk of PD in relatives predicted to carry an LRRK2 G2019S mutation was 0.26 (95% confidence interval [CI] 0.18-0.36) to age 80 years, and was almost 3-fold higher than in relatives predicted to be noncarriers (hazard ratio [HR] 2.89, 95% CI 1.73-4.55, p < 0.001). The risk among predicted G2019S carrier male relatives (0.22, 95% CI 0.10-0.37) was similar to predicted carrier female relatives (0.29, 95% CI 0.18-0.40; HR male to female: 0.74, 95% CI 0.27-1.63, p = 0.44). In contrast, predicted noncarrier male relatives had a higher risk (0.15, 95% CI 0.11-0.20) than predicted noncarrier female relatives (0.07, 95% CI 0.04-0.10; HR male to female: 2.40, 95% CI 1.50-4.15, p < 0.001).CONCLUSION:Penetrance of LRRK2 G2019S in AJ is only 26% and lower than reported in other ethnic groups. Further study of the genetic and environmental risk factors that influence G2019S penetrance is warranted.

Background/Aims: To examine the association between self-reported sleep problems and incidence of dementia in community-dwelling elderly people. Methods: 1,041 nondemented participants over 65 years old were examined longitudinally. Sleep problems were estimated using the RAND Medical Outcomes Study Sleep Scale examining sleep disturbance, snoring, sleep short of breath or with a headache, sleep adequacy, and sleep somnolence. Cox regression analysis was used to examine the association between sleep problems and risk for incident dementia. Age, gender, education, ethnicity, APOE-ε4, stroke, heart disease, hypertension, diabetes, and depression were included as covariates. Results: Over 3 years of follow-up, 966 (92.8%) participants remained nondemented, while 78 (7.2%) developed dementia. In unadjusted models, sleep inadequacy (‘Get the amount of sleep you need') at the initial visit was associated with increased risk of incident dementia (HR = 1.20; 95% CI 1.02-1.42; p = 0.027). Adjusting for all the covariates, increased risk of incident dementia was still associated with sleep inadequacy (HR = 1.20; 95% CI 1.01-1.42; p = 0.040), as well as with increased daytime sleepiness (‘Have trouble staying awake during the day') (HR = 1.24; 95% CI 1.00-1.54; p = 0.047). Conclusion: Our results suggest that sleep inadequacy and increased daytime sleepiness are risk factors for dementia in older adults, independent of demographic and clinical factors.

IMPORTANCE:Data on the long-term cognitive outcomes of patients with PARKIN-associated Parkinson disease (PD) are unknown but may be useful when counseling these patients. OBJECTIVE:Among patients with early-onset PD of long duration, we assessed cognitive and motor performances, comparing homozygotes and compound heterozygotes who carry 2 PARKIN mutations with noncarriers. DESIGN, SETTING, AND PARTICIPANTS:Cross-sectional study of 44 participants at 17 different movement disorder centers who were in the Consortium on Risk for Early-Onset PD study with a duration of PD greater than the median duration (>14 years): 4 homozygotes and 17 compound heterozygotes (hereafter referred to as carriers) and 23 noncarriers. MAIN OUTCOMES AND MEASURES:Unified Parkinson Disease Rating Scale Part III (UPDRS-III) and Clinical Dementia Rating scores and neuropsychological performance. Linear regression models were applied to assess the association between PARKIN mutation status and cognitive domain scores and UPDRS-III scores. Models were adjusted for age, education, disease duration, language, and levodopa equivalent daily dose. RESULTS:Carriers had an earlier age at onset of PD (P < .001) and were younger (P = .004) at time of examination than noncarriers. They performed better than noncarriers on the Mini-Mental State Examination (P = .010) and were more likely to receive lower scores on the Clinical Dementia Rating (P = .003). In multivariate analyses, carriers performed better than noncarriers on the UPDRS-III (P = .02) and on tests of attention (P = .03), memory (P = .03), and visuospatial (P = .02) cognitive domains. CONCLUSIONS AND RELEVANCE:In cross-sectional analyses, carriers demonstrated better cognitive and motor performance than did noncarriers with long disease duration, suggesting slower disease progression. A longitudinal follow-up study is required to confirm these findings.

Dietary factors have been found to play an important role in delay the onset of dementia. The mechanisms for dietary factors to be related with dementia was unclear but evidence suggests the involvement of antioxidative pathway. We examined whether dietary total antioxidant capacity, measured by the ferric-reducing antioxidant power (FRAP), was related with risks of dementia, AD, vascular dementia, as well as mild cognitive impairments (MCI), in a multi-ethnic elderly population. A total of 2891 non-demented elderly (aged ≥ 65 years) subjects in New York completed a semi-quantitative food-frequency questionnaire (SFFQ) and were prospectively evaluated for dementia and MCI development using the same standardized neurological and neuropsychological measures approximately every 1.5 years. Standardized FRAP values were applied to foods in the SFFQ and a total FRAP score for each study participant were calculated. Cox proportional hazard models were used to estimate risk of dementia and MCI outcomes associated with FRAP, adjusted for age, gender, ethnicity, education, APOE genotype, caloric intake, and cohort. During an average 5.25 years of follow-up, 467 dementia, 427 AD, and 13 vascular dementia cases, as well as 496 MCI, 235 amnestic MCI, and 219 non-amnestic MIC subjects were identified. FRAP score was positively correlated with several antioxidative vitamin intakes, including vitamin C, β-carotene, and vitamin E, with r=0.38, 0.13, and 0.13, respectively (p<0.0001 for all). In multivariable-adjusted models, dietary FRAP score was not associated with risk of all dementia [hazard ratio (HR) =1.02, 95%CI=0.99-1.05, p=0.23]; AD (HR=1.03, 95%CI=0.99-1.07, p=0.06); or vascular dementia (HR=0.86, 95%CI=0.66-1.13, p=0.29). Dietary FRAP was not associated with MCI (HR=0.98, 95%CI=0.95-1.01, p=0.20), amnestic MCI (HR=0.99, 95%CI=0.95-1.04, p=0.75), or non-amnestic MIC (HR=0.96, 95%CI=0.92-1.01, p=0.13). When Dietary FRAP was analyzed as quartiles, the trend was not significant for any of the associations. In line with other studies, our longitudinal study suggests that dietary total antioxidant capacity, measured by FRAP, is not associated with risks of developing dementia or MCI. Other mechanisms are worth exploration to understand the relationship between dietary factors and dementia.