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1.
Artigo em Inglês | MEDLINE | ID: mdl-33846084

RESUMO

OBJECTIVES: Anticholinergic burden has been associated with deleterious effects on cognition particularly in those with an underlying brain disorder. We developed a new assay based on cultured cells to measure serum anticholinergic activity (cSAA). We report on its relationships with established anticholinergic burden rating scales and cognitive assessments in older patients with mild cognitive impairment (MCI) or major depressive disorder (MDD) in remission or both. DESIGN: The study was cross sectional in nature. SETTING: This was a five-centre study conducted in Toronto, Canada. PARTICIPANTS: Serum samples were collected and cSAA levels were measured in 311 participants aged 60 years or older (154 with MCI, 57 with MDD, and 100 with MCI + MDD). MEASUREMENTS: The cSAA assay uses radio-ligand binding to cultured cells stably expressing the muscarinic M1 receptors, with an added procedure to remove potential confounds associated with serum proteins. Lists of medications were used to calculate Anticholinergic Burden and Anticholinergic Drug Scale total scores. Participants also completed a comprehensive cognitive battery. RESULTS: Higher cSAA levels were associated with higher anticholinergic burden and anticholinergic drug scale scores, and also with lower performance on executive function tests, after adjusting for age, gender, education, and diagnosis. CONCLUSIONS: These results support the use of the cSAA assay as a laboratory measure of anticholinergic burden.

2.
Int Psychogeriatr ; : 1-7, 2021 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-33775259

RESUMO

OBJECTIVES: To compare the prevalence of select cardiovascular risk factors (CVRFs) in patients with mild cognitive impairment (MCI) versus lifetime history of major depression disorder (MDD) and a normal comparison group using baseline data from the Prevention of Alzheimer's Dementia with Cognitive Remediation plus Transcranial Direct Current Stimulation (PACt-MD) study. DESIGN: Baseline data from a multi-centered intervention study of older adults with MCI, history of MDD, or combined MCI and history of MDD (PACt-MD) were analyzed. SETTING: Community-based multi-centered study based in Toronto across 5 academic sites. PARTICIPANTS: Older adults with MCI, history of MDD, or combined MCI and history of MDD and healthy controls. MEASUREMENTS: We examined the baseline distribution of smoking, hypertension and diabetes in three groups of participants aged 60+ years in the PACt-MD cohort study: MCI (n = 278), MDD (n = 95), and healthy older controls (n = 81). Generalized linear models were fitted to study the effect of CVRFs on MCI and MDD as well as neuropsychological composite scores. RESULTS: A higher odds of hypertension among the MCI cohort compared to healthy controls (p < .05) was noted in unadjusted analysis. Statistical significance level was lost on adjusting for age, sex and education (p > .05). A history of hypertension was associated with lower performance in composite executive function (p < .05) and overall composite neuropsychological test score (p < .05) among a pooled cohort with MCI or MDD. CONCLUSIONS: This study reinforces the importance of treating modifiable CVRFs, specifically hypertension, as a means of mitigating cognitive decline in patients with at-risk cognitive conditions.

3.
Alzheimers Res Ther ; 13(1): 43, 2021 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-33573702

RESUMO

BACKGROUND: The antihypertensive angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACE-Is) have similar indications and mechanisms of action, but prior work suggests divergence in their effects on cognition. METHODS: Participants in the National Alzheimer's Coordinating Center database with a clinical diagnosis of dementia due to Alzheimer's disease (AD) using an ACE-I or an ARB at any visit were selected. The primary outcome was delayed recall memory on the Wechsler Memory Scale Revised - Logical Memory IIA. Other cognitive domains were explored, including attention and psychomotor processing speed (Trail Making Test [TMT]-A and Digit Symbol Substitution Test [DSST]), executive function (TMT-B), and language and semantic verbal fluency (Animal Naming, Vegetable Naming, and Boston Naming Tests). Random slopes mixed-effects models with inverse probability of treatment weighting were used, yielding rate ratios (RR) or regression coefficients (B), as appropriate to the distribution of the data. Apolipoprotein (APOE) ε4 status and blood-brain barrier (BBB) penetrance were investigated as effect modifiers. RESULTS: Among 1689 participants with AD, ARB use (n = 578) was associated with 9.4% slower decline in delayed recall performance over a mean follow-up of 2.28 years compared with ACE-I use (n = 1111) [RR = 1.094, p = 0.0327]; specifically, users of BBB-crossing ARBs (RR = 1.25, p = 0.002), BBB-crossing ACE-Is (RR = 1.16, p = 0.010), and non-BBB-crossing ARBs (RR = 1.20, p = 0.005) had better delayed recall performance over time compared with non-BBB-crossing ACE-I users. An interaction with APOE ε4 status (drug × APOE × time RR = 1.196, p = 0.033) emerged; ARBs were associated with better delayed recall scores over time than ACE-Is in non-carriers (RR = 1.200, p = 0.003), but not in carriers (RR = 1.003, p = 0.957). ARB use was also associated with better performance over time on the TMT-A (B = 2.023 s, p = 0.0004) and the DSST (B = 0.573 symbols, p = 0.0485), and these differences were significant among APOE ε4 non-carriers (B = 4.066 s, p = 0.0004; and B = 0.982 symbols, p = 0.0230; respectively). Some differences were seen also in language and verbal fluency among APOE ε4 non-carriers. CONCLUSIONS: Among APOE ε4 non-carriers with AD, ARB use was associated with greater preservation of memory and attention/psychomotor processing speed, particularly compared to ACE-Is that do not cross the blood-brain-barrier.

4.
Psychoneuroendocrinology ; 126: 105149, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33503568

RESUMO

BACKGROUND: People with type 2 diabetes mellitus (T2DM) are at increased risk for depression. Both conditions are associated with disturbances in polyunsaturated fatty acids. Omega-3 and omega-6 fatty acids can be converted into bioactive epoxides by cytochrome P450s (CYP450), which play pro-resolving roles in the inflammatory response; however, soluble epoxide hydrolase (sEH) metabolizes epoxides into diols, which lack pro-resolving functions and can be cytotoxic. Here, we survey serum CYP450- and sEH-derived metabolite concentrations in people with T2DM with and without a major depressive episode. METHODS: Sunnybrook Type 2 Diabetes Study (NCT04455867) participants experiencing a major depressive episode (research version of the Structured Clinical Interview for DSM-5 criteria) were matched 1:1 for gender, glycosylated hemoglobin A1c and body mass index to participants without a current depressive episode. Depression severity was assessed using the Beck Depression Inventory 2nd Edition (BDI-II). From fasting morning blood, unesterified serum oxylipins were quantified by ultra-high-performance liquid chromatography tandem mass spectrometry following solid phase extraction, and interleukin-6 (IL-6) by enzyme-linked immunosorbent assay. RESULTS: Between 20 depressed and 20 non-depressed participants (mean age 58.9 ± 8.5 years, 65% women) with T2DM, several sEH-derived fatty acid diols, but not IL-6, were higher among those with a depressive episode (effect sizes up to d = 0.796 for 17,18-DiHETE, a metabolite of eicosapentaenoic acid [EPA]; t = 2.516, p = 0.016). Among people with a depressive episode, two epoxides were correlated with lower BDI-II scores: 12(13)-EpOME (ρ = -0.541, p = 0.014) and 10(11)-EpDPE (ρ = -0.444, p = 0.049), metabolites of linoleic acid and docosahexaenoic acid (DHA), respectively, while the ratio of 12,13-DiHOME/12(13)-EpOME was correlated with higher BDI-II scores (ρ = 0.513, p = 0.021). CONCLUSIONS: In people with T2DM, major depressive episodes and depressive symptom severity were associated with an oxylipin profile consistent with elimination of pro-resolving lipid mediators by sEH.

5.
J Alzheimers Dis ; 79(3): 1285-1296, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33427735

RESUMO

BACKGROUND: Coronary artery disease (CAD) increases risk for vascular cognitive impairment-no dementia (VCIND), a precursor to dementia, potentially through persistent oxidative stress. OBJECTIVE: This study assessed peripheral glutathione peroxidase activity (GPX), which is protective against oxidative stress, in VCIND versus cognitively normal CAD controls (CN). GPX activity was also evaluated as a biomarker of cognition, particularly verbal memory. METHODS: 120 CAD patients with VCIND (1SD below norms on executive function or verbal memory (VM)) or without (CN) participated in exercise rehabilitation for 24 weeks. Neurocognitive and cardiopulmonary fitness (VO2peak) assessments and plasma were collected at baseline and 24-weeks. RESULTS: GPX was higher in VCIND compared to CN (F1,119 = 3.996, p = 0.048). Higher GPX was associated with poorer baseline VM (ß= -0.182, p = 0.048), and longitudinally with VM decline controlling for sex, body mass index, VO2peak, and education (b[SE] = -0.02[0.01], p = 0.004). Only CN participants showed improved VM performance with increased fitness (b[SE] = 1.30[0.15], p < 0.005). CONCLUSION: GPX was elevated in VCIND consistent with a compensatory response to persistent oxidative stress. Increased GPX predicted poorer cognitive outcomes (verbal memory) in VCIND patients despite improved fitness.

6.
Neurobiol Aging ; 100: 22-31, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33461049

RESUMO

Some studies suggest that angiotensin II type 1 receptor blockers (ARBs) may protect against memory decline more than angiotensin-converting enzyme inhibitors (ACE-Is), but few have examined possible mechanisms. We assessed longitudinal differences between ARB versus ACE-I users in global and sub-regional amyloid-ß accumulation by 18F-florbetapir. In cognitively normal older adults (n= 142), propensity-weighted linear mixed-effects models showed that ARB versus ACE-I use was associated with slower amyloid-ß accumulation in the cortex, and specifically in the caudal anterior cingulate and precuneus, and in the precentral and postcentral gyri. In amyloid-positive participants with Alzheimer's disease dementia or mild cognitive impairment (n = 169), ARB versus ACE-I use was not associated with different rates of amyloid-ß accumulation. Apolipoprotein E ε4 carrier status explained some heterogeneity in the different rates of amyloid-ß accumulation between users of ARBs versus ACE-Is in the study. Replicative studies and clinical trials are warranted to confirm potential benefits of ARBs on rates of amyloid-ß accumulation in the contexts of Alzheimer's disease prevention and treatment.

7.
Artigo em Inglês | MEDLINE | ID: mdl-33455858

RESUMO

OBJECTIVE: Our understanding of why older adults with depression are at increased risk of Alzheimer's disease (AD) remains incomplete. Most adults living with AD are women, and women have a near twofold lifetime risk of depression. We examined the risk of depression upon incident AD, and how sex influences this risk. METHODS: Using the National Alzheimer's Coordinating Center database, older adults (age 50+) with normal cognition, who visited memory clinics across the United States between September 2005 and December 2019, were followed until first diagnosis of AD or loss to follow up. Multivariable survival analyses were performed to determine if recent and/or remote depression were independent risk factors for AD, if this depression-related risk exists for each sex or was moderated by sex. RESULTS: Six hundred and fifty-two of 10,739 enrolled participants developed AD over a median follow-up of 55.3 months. Recent depression (active within the last 2 years) was independently associated with increased risk of AD (hazard ratio [HR] = 2.0; 95%CI, 1.5-2.6) while a remote history of depression was not (HR = 1.0; 95%CI, 0.7-1.5). After stratification by sex, recent depression was an independent predictor in females (HR = 2.3; 95%CI, 1.7-3.1) but not in males (HR = 1.4; 95%CI, 0.8-2.6). No interaction between recent depression and sex was observed. CONCLUSION: Only a recent history of depression was associated with higher risk of AD. This association was significant among women only, but was not moderated by sex. Future analyses should determine if these findings extend to other populations and may be explained by variable distribution of neurobiological or other modifiable risk factors between the sexes.

8.
Stroke ; 51(12): 3531-3540, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33226916

RESUMO

BACKGROUND AND PURPOSE: Many patients with ischemic stroke present with multiple comorbidities that threaten survival and recovery. This study sought to determine the risks of adverse long-term stroke outcomes associated with multimorbid diabetes mellitus and depression. METHODS: Retrospective analysis of prospectively collected data on consecutive patients without premorbid dementia admitted from the community for a first-ever acute ischemic stroke to comprehensive stroke centers across Ontario, Canada (2003-2013). Premorbid histories of diabetes mellitus and depression were ascertained within 5 years before stroke admission. Adjusted hazard ratios (aHR [95% CI]) of admission to long-term care, incident dementia, readmission for stroke or transient ischemic attack and all-cause mortality, over time among those discharged back into the community poststroke. RESULTS: Among 23 579 stroke admissions, n=20 201 were discharged back into the community. Diabetes mellitus and depression were associated with synergistic hazards of admission to long-term care (X2=5.4; P=0.02) over a median follow-up of 5.6 years. This interaction was observed among women specifically; depression multimorbidity showed particularly high hazards of admission to long-term care (aHRDepression=1.57 [1.24-1.98]) and incident dementia (aHRDepression=1.85 [1.40-2.44]) among women with diabetes mellitus. In the whole cohort, diabetes mellitus and depression were associated individually with long-term care admission (aHRDiabetes=1.20 [1.12-1.29]; aHRDepression=1.19 [1.04-1.37]), incident dementia (aHRDiabetes=1.14 [1.06-1.23]; aHRDepression=1.27 [1.08-1.49]), stroke/transient ischemic attack readmission (aHRDiabetes=1.18 [1.10-1.26]; aHRDepression=1.24 [1.07-1.42]), and all-cause mortality (aHRDiabetes=1.29 [1.23-1.36]; aHRDepression=1.16 [1.05-1.29]). CONCLUSIONS: The risks of dementia and needing long-term care in the years after surviving a stroke were particularly elevated among women when premorbid diabetes mellitus and depression occurred together. Long-term stroke recovery strategies might target high-risk patients with mood and metabolic multimorbidity.

9.
Alzheimers Dement (N Y) ; 6(1): e12057, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33209972

RESUMO

Introduction: Earlier diagnosis of neurocognitive disorders and neurodegenerative disease is needed to implement preventative interventions, minimize harm, and reduce risk of exploitation in the context of undetected disease. Along the spectrum from subjective cognitive decline (SCD) to dementia, evidence continues to emerge with respect to detection, staging, and monitoring. Updates to previous guidelines are required for clinical practice. Methods: A subcommittee of the 5th Canadian Consensus Conference on Diagnosis and Treatment of Dementia (CCCDTD) reviewed emerging evidence to address the following: (1) Is there a role for screening at-risk patients without clinical concerns? In what context is assessment for dementia appropriate? (2) What tools can be used to evaluate patients in whom cognitive decline is suspected? (3) What important information can be gained from an informant, using which measures? (4) What instruments can be used to get more in-depth information to diagnose mild cognitive impairment (MCI) or dementia? (5) What is the approach to those with cognitive concerns but without objective changes (ie, SCD)? (6) How do we track response to treatment and change over time? The Grading of Recommendations Assessment, Development, and Evaluation system was used to rate quality of the evidence and strength of the recommendations. Results: We recommend instruments to assess and monitor cognition, behavior, and function across the cognitive spectrum, including reports from patient and informant. We recommend against screening asymptomatic older adults but recommend investigation for self- or informant reports of changes in cognition, emergence of behavioral or psychiatric symptoms, or decline in function or self-care. Standardized assessments should be used for cognitive and behavioral change that have sufficient validity for use in clinical practice. Discussion: The CCCDTD5 provides evidence-based recommendations for detection, assessment, and monitoring of neurocognitive disorders. Although these guidelines were developed for use in Canada, they may also be useful in other jurisdictions.

10.
Psychoneuroendocrinology ; 122: 104878, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33038647

RESUMO

BACKGROUND: Low serum osteocalcin is a risk factor for type 2 diabetes mellitus (T2DM), and osteocalcin release from bone is associated with an acute stress response in mice. Both diabetes and stress are associated with depression. Here, we assess relationships between serum osteocalcin, depression and subjective stress in people with T2DM. METHODS: Participants with T2DM (HbA1c above 6.4 %, impaired fasting glucose or impaired glucose tolerance) were assessed for a major depressive episode using the research version of the Structured Clinical Interview for DSM-5 depression criteria (SCID-5RV). Subjective stress over the past month was assessed using the Perceived Stress Scale (PSS). Serum carboxylated (cOCN) and fully decarboxylated (dcOCN) osteocalcin were assayed from fasting morning blood by commercial enzyme-linked immunosorbent assay. RESULTS: Among 95 participants (mean age 62.4 ± 9.9, 51 % women), 22 % were experiencing a depressive episode (9 men, 12 women). The presence of a depressive episode was not associated with dcOCN or cOCN concentrations; however, higher concentrations of cOCN were associated with higher PSS scores in participants with depression (r = 0.585, p = 0.005). In an analysis of covariance model controlling for age, sex, body mass index, glycemic control (glycosylated hemoglobin), insulin resistance (homeostatic model), depression, and antidepressant use, cOCN was associated with PSS scores (F=10.302, p = 0.002), and this relationship was stronger in those with depression (depression × cOCN interaction F=4.978, p = 0.028). Although associations between dcOCN concentrations and PSS scores did not reach significance, the same trend seen with cOCN concentrations was observed in participants with depression for dcOCN (r=0.365, p=0.10), and for a depression × dcOCN interaction associated with PSS scores in the whole group (F=2.165, p = 0.15). CONCLUSIONS: Osteocalcin is a neuroendocrine marker associated with perceived chronic stress among people with T2DM experiencing a depressive episode.

11.
Drugs Aging ; 37(11): 817-827, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32978758

RESUMO

BACKGROUND: In nursing homes, residents with dementia frequently receive potentially inappropriate medications that are associated with an increased risk of adverse events. Despite known sex differences in clinical presentation and sociodemographic characteristics among persons with dementia, few studies have examined sex differences in patterns and predictors of potentially inappropriate medication use. OBJECTIVES: The objectives of this study were to examine sex differences in the patterns of antipsychotic and benzodiazepine use in the 180 days following admission to a nursing home, estimate clinical and sociodemographic predictors of antipsychotic and benzodiazepine use in male and female residents, and explore the effects of modification by sex on the predictors of using these drug therapies. METHODS: We conducted a retrospective cohort study of 35,169 adults aged 66 years and older with dementia who were newly admitted to nursing homes in Ontario, Canada between 2011 and 2014. Health administrative databases were linked to detailed clinical assessment data collected using the Resident Assessment Instrument (RAI-MDS 2.0). Cox proportional hazards models were adjusted for clinical and sociodemographic covariates to estimate the rate of antipsychotic and benzodiazepine initiation and discontinuation in the 180 days following nursing home admission in the total sample and stratified by sex. Sex-covariate interaction terms were used to assess whether sex modified the association between covariates and the rate of drug therapy initiation or discontinuation following nursing home entry. RESULTS: Across 638 nursing homes, our analytical sample included 22,847 females and 12,322 males. At admission, male residents were more likely to be prevalent antipsychotic users than female residents (33.8% vs 28.3%; p < 0.001), and female residents were more likely to be prevalent benzodiazepine users than male residents (17.2% vs 15.3%, p < 0.001). In adjusted models, female residents were less likely to initiate an antipsychotic after admission (hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.73-0.86); however, no sex difference was observed in the rate of benzodiazepine initiation (HR 1.04, 95% CI 0.96-1.12). Female residents were less likely than males to discontinue antipsychotics (HR 0.89, 95% CI 0.81-0.98) and benzodiazepines (HR 0.82, 95% CI 0.75-0.89). Sex modified the association between some covariates and the rate of changes in drug use (e.g., widowed males exhibited an increased rate of antipsychotic discontinuation (p-interaction = 0.03) compared with married males), but these associations were not statistically significant among females. Sex did not modify the effect of frailty on the rates of initiation and discontinuation. CONCLUSIONS: Males and females with dementia differed in their exposure to antipsychotics and benzodiazepines at nursing home admission and their patterns of use following admission. A greater understanding of factors driving sex differences in potentially inappropriate medication use may help tailor interventions to reduce exposure in this vulnerable population.

12.
Alzheimers Dement ; 2020 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-32803865

RESUMO

INTRODUCTION: Few studies have examined memory decline among patients with type 2 diabetes using different oral hypoglycemic drugs. METHODS: Participants with normal cognition (NC) or Alzheimer's disease (AD) dementia using a hypoglycemic medication (2005 to 2019) were identified from the National Alzheimer's Coordinating Center database. Delayed memory was assessed using the Wechsler Memory Scale Revised-Logical Memory test. Associations between oral drug classes and memory over time were examined using mixed-effects models with inverse probability treatment weights. RESULTS: In NC (n = 1192), metformin use was associated with better memory performance over time, whereas in AD (n = 807), dipeptidyl peptidase-4 (DPP4) inhibitor use was associated with a slower rate of memory decline. Interaction effects suggested greater benefit associated with DPP4 inhibitor use among APOE ε4 carriers. DISCUSSION: Associations between different oral hypoglycemic drugs and memory change were not consistent between cognitively normal elderly and those with AD dementia. APOE ε4 genotype modified some relationships.

13.
J Clin Psychiatry ; 81(5)2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32841553

RESUMO

OBJECTIVE: Lithium is an important mood disorder treatment; however, the renal risks of its use in older adults are unclear. We wished to determine in older adults (1) whether lithium is associated with increased risk of renal decline compared to valproate and (2) whether this association differs with higher vs lower baseline serum lithium concentrations. METHOD: We conducted a population-based cohort study using linked health care databases (Ontario, Canada). The cohort consisted of older adults (mean age 71 years) accrued 2007-2015; 3,113 lithium users were propensity-score matched 1:1 to 3,113 valproate users. Users with higher (> 0.7 mmol/L) or lower concentration of serum lithium were further examined. The primary outcome was ≥ 30% loss in estimated glomerular filtration rate from baseline. RESULTS: Matched lithium users and valproate users demonstrated similar indicators of baseline health over a median (maximum) follow-up of 3.1 (8.3) years. Lithium was associated with increased risk of renal function loss compared to valproate (674/3,113 [21.7%] vs 584/3,113 [18.8%]; 6.5 vs 5.7 events per 100 person years; hazard ratio = 1.14 [95% CI = 1.02-1.27]). When baseline serum lithium concentrations were > 0.7 mmol/L, the risk of renal decline compared to valproate use was 1.26 (95% CI = 1.06-1.49); when baseline lithium concentrations were ≤ 0.7 mmol/L, the risk was 1.06 (95% CI = 0.92-1.22). CONCLUSION: In older adults, lithium use is associated with a statistically significant increased risk of renal decline compared to valproate use, although the decline is less than previously reported. Further studies should confirm whether this effect is primarily in patients with higher serum lithium concentrations.


Assuntos
Antimaníacos/uso terapêutico , Lítio/uso terapêutico , Insuficiência Renal/induzido quimicamente , Idoso , Antimaníacos/efeitos adversos , Antimaníacos/sangue , Humanos , Rim/efeitos dos fármacos , Rim/fisiopatologia , Lítio/efeitos adversos , Lítio/sangue , Estudos Longitudinais , Masculino , Pontuação de Propensão , Fatores de Risco , Ácido Valproico/efeitos adversos , Ácido Valproico/uso terapêutico
14.
Neuropsychopharmacology ; 45(12): 2038-2047, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32682324

RESUMO

Ordering of information is a critical component that underlies several cognitive functions. Prefrontal theta-gamma coupling (TGC) is a neurophysiologic measure associated with ordering of information during the performance of a working memory task (N-back). Little is known about the relationship between TGC and ordering during other cognitive tasks or whether the relationship between TGC and ordering of information is independent of clinical condition. This study aimed to determine whether the relationship between TGC and ordering of information exists independent of a task and its timing, and whether this relationship is the same in different clinical conditions. A total of 311 participants were assessed using a neuropsychological battery that included the N-back during which TGC was measured; two other tasks that also require ordering; and three tests that do not require ordering. All non-N-back tasks were completed several days separate from the N-back by a mean interval (SD) of 5.14 (8.03). Our three hypotheses were that TGC during the N-back task would be associated with performance on N-Back and other cognitive tasks that also require ordering, but not with performance on cognitive tasks that do not require ordering; and that these relationships will be independent of clinical diagnosis. Multivariate linear regression results show that TGC was associated with performance on the ordering tasks but not the non-ordering tasks. In addition, there was no interaction between TGC and diagnosis. Our study is the first to demonstrate that TGC is a neurophysiologic measure of ordering information across several cognitive tasks that require ordering, and this TGC-ordering relationship is stable over time even when several days separate the measurement of TGC and the performance of the ordering tasks. Our results also show that this relationship is independent of clinical diagnosis, supporting the brain-behavior nature of this relationship. These results highlight the importance of TGC in ordering-based cognition, and suggest that TGC could be a valid target for interventions that aim to enhance this function across cognitive tasks and clinical conditions.

15.
Ageing Res Rev ; 62: 101130, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32712109

RESUMO

Inflammation is involved in the pathophysiology of Alzheimer's disease (AD), with multiple inflammatory processes implicated in its risk and progression. This review included original peer-reviewed studies measuring the cerebrospinal fluid or peripheral blood concentrations of protein markers specifically related to neutrophil activity in healthy controls (HC) and in patients with AD or mild cognitive impairment (MCI). A total of 35 studies (NHC = 3095, NAD = 2596, NMCI = 1203) were included. Random-effects meta-analyses were used to estimate between-groups standardized mean differences (SMD) and 95 % confidence intervals. In blood, concentrations of myeloperoxidase (MPO; NAD/NHC = 271/209, SMD = 0.41 [0.20, 0.62]; I2 = 15.7 %) and neutrophil gelatinase associated lipocalin (NGAL; NAD/NHC = 273/185, SMD = 0.30 [0.11, 0.49]; I2 < 0.005 %) were significantly higher in AD relative to HC. Peripheral blood concentrations of NGAL were also higher in MCI compared to HC (NMCI/NHC = 489/145, SMD = 0.39 [0.11, 0.67]; I2 = 38.6 %). None of the protein markers exhibited a significant difference between HC, MCI, or AD groups in the cerebrospinal fluid. The evidence suggests that peripheral neutrophil activation, as indicated by blood concentrations of NGAL and MPO, may be a pathological feature of cognitive impairment due to AD, evident at stages of MCI and AD dementia.

16.
Alzheimers Dement ; 16(8): 1182-1195, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32725777

RESUMO

Since 1989, four Canadian Consensus Conferences on the Diagnosis and Treatment of Dementia (CCCDTD) have provided evidence-based dementia guidelines for Canadian clinicians and researchers. We present the results of the 5th CCCDTD, which convened in October 2019, to address topics chosen by the steering committee to reflect advances in the field, and build on previous guidelines. Topics included: (1) utility of the National Institute on Aging research framework for clinical Alzheimer's disease (AD) diagnosis; (2) updating diagnostic criteria for vascular cognitive impairment, and its management; (3) dementia case finding and detection; (4) neuroimaging and fluid biomarkers in diagnosis; (5) use of non-cognitive markers of dementia for better dementia detection; (6) risk reduction/prevention; (7) psychosocial and non-pharmacological interventions; and (8) deprescription of medications used to treat dementia. We hope the guidelines are useful for clinicians, researchers, policy makers, and the lay public, to inform a current and evidence-based approach to dementia.

17.
Bipolar Disord ; 2020 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-32621644

RESUMO

OBJECTIVE: Lithium remains an important treatment for mood disorders but is associated with kidney disease. Nephrogenic diabetes insipidus (NDI) is associated with up to 3-fold risk of incident chronic kidney disease among lithium users. There are limited randomized controlled trials (RCT) for treatments of lithium-induced NDI, and existing therapies can be poorly tolerated. Therefore, novel treatments are needed for lithium-induced NDI. METHOD: We conducted a 12-week double-blind pilot RCT to assess the feasibility and efficacy of 20 mg/d atorvastatin vs placebo in the treatment of NDI in chronic lithium users. Patients, recruited between September 2017 and October 2018, were aged 18 to 85, currently on a stable dose of lithium, and determined to have NDI. RESULTS: Urinary osmolality (UOsm) at 12 weeks adjusted for baseline was not statistically different between groups (+39.6 mOsm/kg [95% CI, -35.3, 114.5] in atorvastatin compared to placebo groups). Secondary outcomes of fluid intake and aquaporin-2 excretions at 12 weeks adjusted for baseline were -0.13 L [95% CI, -0.54, 0.28] and 98.68 [95% CI, -190.34, 387.70], respectively. A moderate effect size was observed for improvements in baseline UOsm by ≥100 mOsm/kg at 12 weeks in patients who received atorvastatin compared to placebo (38.45% (10/26) vs 22.58% (7/31); Cohen's d = 0.66). CONCLUSION: Among lithium users with NDI, atorvastatin 20 mg/d did not significantly improve urinary osmolality compared to placebo over a 12-week period. Larger confirmatory trials with longer follow-up periods may help to further assess the effects of statins on NDI, especially within patients with more severe NDI.

18.
J Alzheimers Dis ; 76(2): 601-611, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32538839

RESUMO

BACKGROUND: Patients with coronary artery disease have an increased risk for developing vascular cognitive impairment. Endothelial function is often diminished and has been associated with lower cognitive performance in these patients. The link between endothelial function and cognition in coronary artery disease is not fully understood. Angiogenesis may play a role in mediating the association between endothelial function and cognition since angiogenic processes rely heavily on the endothelium. OBJECTIVE: The aim of this study was to determine if markers of angiogenesis mediate the relationship between endothelial function and cognition in coronary artery disease patients. METHODS: In 50 participants with coronary artery disease, endothelial function was assessed using peripheral arterial tonometry. Vascular endothelial growth factor (pro-angiogenic) and endostatin (anti-angiogenic) were measured in peripheral serum samples. Cognition was assessed using the Montreal Cognitive Assessment. A mediation analysis, using a bias corrected inferential bootstrapping method with 10,000 permutations, was used to determine if vascular endothelial growth factor or endostatin mediated an association between peripheral arterial tonometry measures and cognitive performance on the Montreal Cognitive Assessment. RESULTS: Endostatin, but not vascular endothelial growth factor, mediated a relationship between endothelial function and cognitive performance when controlling for total years of education, body mass index, coronary artery bypass graft, stent, diabetes, and diuretic use. This analysis was also significant when delayed recall was substituted for the overall score on the Montreal Cognitive Assessment. CONCLUSION: These results suggest that endostatin mediates an association between endothelial function and cognitive performance in coronary artery disease.

19.
J Alzheimers Dis ; 76(2): 733-751, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32568198

RESUMO

BACKGROUND: By the time Alzheimer's disease and related disorders (ADRD) are diagnosed, efficacy of treatments is limited. Preventive interventions are urgently needed. OBJECTIVE: To design a randomized controlled trial to assess a novel intervention that aims to prevent ADRD in high-risk groups. METHODS: We report on the rationale and describe the design of a multisite randomized controlled trial that aims to prevent ADRD in older persons with: (1) mild cognitive impairment (MCI); (2) remitted major depressive disorder (MDD) without MCI; or (3) remitted MDD with MCI. RESULTS: PACt-MD (Prevention of Alzheimer's dementia with Cognitive remediation plus transcranial direct current stimulation in Mild cognitive impairment and Depression) is a trial that randomized 375 older participants with MCI, MDD, or MCI + MDD to cognitive remediation (CR) plus transcranial direct current stimulation (tDCS) or sham-CR + sham-tDCS for 5 days/week for 8 weeks followed by boosters for 5 days/week once every 6 months until participants progress to MCI or ADRD, or the end of the study. Between boosters, participants are asked to train on CR daily. At baseline, end of 8 weeks, and yearly from baseline, participants undergo clinical, cognitive, and functional assessments. The primary aims are to compare the efficacy of CR + tDCS versus sham + sham in preventing: 1) long-term cognitive decline; and 2) incidence of ADRD or MCI. The secondary aim is to assess for cognitive improvement after the 8-week course. We will also explore the moderating and mediating effects of several biomarkers collected from the participants. CONCLUSION: PACt-MD is unique in combining brain stimulation and a psychosocial intervention to prevent ADRD. PACt-MD is also a platform for studying multi-domain biomarkers that will advance our understanding of the relationships among MCI, MDD, and ADRD.

20.
Artigo em Inglês | MEDLINE | ID: mdl-32565008

RESUMO

BACKGROUND: Diagnostic criteria for apathy have been published but have yet to be evaluated in the context of clinical trials. The Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) operationalized the diagnostic criteria for apathy (DCA) into a clinician-rated questionnaire informed by interviews with the patient and caregiver. OBJECTIVE: The goal of the present study was to compare the classification of apathy using the DCA with that using the Neuropsychiatric Inventory-apathy (NPI-apathy) subscale in ADMET 2. Comparisons between NPI-Apathy and Dementia Apathy Interview Rating (DAIR) scale, and DCA and DAIR were also explored. METHODS: ADMET 2 is a randomized, double-blind, placebo-controlled phase III trial examining the effects of 20 mg/day methylphenidate on symptoms of apathy over 6 months in patients with mild to moderate Alzheimer's disease (AD). Participants scoring at least 4 on the NPI-Apathy were recruited. This analysis focuses on cross-sectional correlations between baseline apathy scale scores using cross-tabulation. RESULTS: Of 180 participants, the median age was 76.5 years and they were predominantly white (92.8%) and male (66.1%). The mean (±standard deviation) scores were 7.7 ± 2.4 on the NPI-apathy, and 1.9 ± 0.5 on the DAIR. Of those with NPI-defined apathy, 169 (93.9%, 95% confidence interval [CI] 89.3%-96.9%) met DCA diagnostic criteria. The DCA and DAIR overlapped on apathy diagnosis for 169 participants (93.9%, 95% CI 89.3%-96.9%). CONCLUSION: The measurements used for the assessment of apathy in patients with AD had a high degree of overlap with the DCA. The NPI-apathy cut-off used to determine apathy in ADMET 2 selects those likely to meet DCA criteria.

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