Neurofilament Light Chain as a Biomarker of Global Cognition in Individuals With Possible Vascular Mild Cognitive Impairment.

BACKGROUND: Neurofilament Light Chain (NfL) is a biomarker of axonal injury elevated in mild cognitive impairment (MCI) and Alzheimer's disease dementia. Blood NfL also inversely correlates with cognitive performance in those conditions. However, few studies have assessed NfL as a biomarker of global cognition in individuals demonstrating mild cognitive deficits who are at risk for vascular-related cognitive decline. OBJECTIVE: To assess the relationship between blood NfL and global cognition in individuals with possible vascular MCI (vMCI) throughout cardiac rehabilitation (CR). Additionally, NfL levels were compared to age/sex-matched cognitively unimpaired (CU) controls. METHOD: Participants with coronary artery disease (vMCI or CU) were recruited at entry to a 24-week CR program. Global cognition was measured using the Montreal Cognitive Assessment (MoCA) and plasma NfL level (pg/ml) was quantified using a highly sensitive enzyme-linked immunosorbent assay. RESULTS: Higher plasma NfL was correlated with worse MoCA scores at baseline (ß = -.352, P = .029) in 43 individuals with vMCI after adjusting for age, sex, and education. An increase in NfL was associated with worse global cognition (b[SE] = -4.81[2.06], P = .023) over time, however baseline NfL did not predict a decline in global cognition. NfL levels did not differ between the vMCI (n = 39) and CU (n = 39) groups (F(1, 76) = 1.37, P = .245). CONCLUSION: Plasma NfL correlates with global cognition at baseline in individuals with vMCI, and is associated with decline in global cognition during CR. Our findings increase understanding of NfL and neurobiological mechanisms associated with cognitive decline in vMCI.

Modifiable Risk Factors Associated With Cognitive Decline in Late Life Depression: Findings From the Canadian Longitudinal Study on Aging: Facteurs de risque modifiables associés au déclin cognitif dans la dépression en fin de vie : constatations de l'Étude longitudinale canadienne sur le vieillissement.

OBJECTIVE: Depression in later life is associated with a two-fold increased risk of dementia. It is not clear to what extent potentially modifiable risk factors account for this association. METHOD: Older adults (age 50 + ) with objective health measures (n = 14,014) from the Canadian Longitudinal Study on Aging were followed for a mean duration of 35 months. Linear regression analyses were used to determine if clinically significant depression (Centre for Epidemiologic Studies Depression scale score (CESD) ≥ 10) was associated with global cognitive decline, assessed with a neuropsychological battery during follow-up, and if modifiable risk factors mediated this association. RESULTS: Depression was associated with an excess of risk factors for cognitive decline including: vascular disease, hypertension, diabetes, apnoea during sleep, higher body mass index, smoking, physical inactivity and lack of social participation. In regression analyses depression remained independently associated with cognitive decline over time (beta -0.060, P = 0.038) as did cerebrovascular disease (beta -0.197, P < 0.001), HbA1C (beta -0.059, P < 0.001), visual impairment (beta -0.070, P = 0.007), hearing impairment (beta -0.098, P < 0.001) and physical inactivity (beta -0.075, P = 0.014). In mediation analyses, we found that cerebrovascular disease (z = -3.525, P < 0.001), HbA1C (z = -4.976, P < 0.001) and physical inactivity (z = -3.998, P < 0.001) partially mediated the association between depression and cognitive decline. CONCLUSIONS: In this large sample of Canadian older adults incorporating several objective health measures, older adults with depression were at increased risk of cognitive decline and had an excess of potentially modifiable risk factors. Clinicians should pay particular attention to control of diabetes, physical inactivity and risk factors for cerebrovascular disease in older adults presenting with depression as they can contribute to accelerated cognitive decline and may be addressed during routine clinical care.

Lipopolysaccharide, Immune Biomarkers and Cerebral Amyloid-Beta Deposition in Older Adults With Mild Cognitive Impairment & Major Depressive Disorder.

OBJECTIVE: Inflammatory activation and increased immune response to lipopolysaccharide occur in both depression and cognitive decline and may link these two conditions. We investigated whether lipopolysaccharide (LPS), LPS binding protein (LBP) and peripheral biomarkers of immune response were associated with increased cerebral deposition of amyloid-beta (Abeta) in older adults with mild cognitive impairment (MCI) and remitted major depressive disorder (rMDD). DESIGN: Cross-sectional analysis. SETTING: Five academic health centers in Toronto. PARTICIPANTS: Older adults with MCI with/without rMDD. MEASUREMENTS: We investigated the associations among serum LPS, LBP, biomarkers of inflammatory activation - Interleukin-6 (IL-6), C-reactive protein (CRP), monocyte chemoattractant protein-1 (MCP-1), and cerebral Abeta deposition quantified by positron emission tomography. RESULTS: Among 133 study participants (82 with MCI and 51 with MCI+rMDD) there was no association between LPS (beta - 0.17, p = 0.8) or LBP (beta - 0.11, p = 0.12) and global deposition of Abeta following adjustment for age, gender, and APOE genotype in multivariable regression analyses. LBP was positively correlated with CRP (r = 0.5, p <0.001) and IL-6 (r = 0.2, p = 0.02) but no inflammatory biomarker was associated with Abeta deposition; rMDD was not associated with deposition of Abeta (beta -0.09, p = 0.22). CONCLUSION: In this cross-sectional analysis, we did not find an association among LPS/LBP, immune biomarkers or rMDD and global deposition of Abeta. Future analyses should assess the longitudinal relationships between peripheral and central biomarkers of immune activation, depression and cerebral Abeta deposition.

Association between depression, gender and Alzheimer's neuropathology in older adults without dementia.

OBJECTIVES: Previous studies regarding the relationship between depression and Alzheimer's neuropathology in older adults without dementia have reported conflicting findings. This study examined whether depression is associated with Alzheimer's neuropathology and whether sex moderates these relationships. METHODS: This is a cross-sectional study of older adults without dementia (normal cognition or mild cognitive impairment, age 50+; CDR ≤ 0.5) who had autopsy within 1 year of their last clinic visit in the National Alzheimer's Coordinating Center database (2005-2020). Logistic regression models were fitted to determine if a recent or remote history of depression was associated with amyloid spread beyond the neocortex measured by modified Thal phase score, density of amyloid plaques measured by CERAD score or tau neuropathology measured by modified Braak score. A moderator analysis was performed to determine if any of these associations were moderated by sex. RESULTS: This study included 407 participants (96 Thal, 405 Braak, and 406 CERAD). Those who had recently active depression (within previous 2 years) but not remote depression only were more likely to have higher Thal phase score compared to those without a history of depression (OR = 3.74; 95% CI, 1.15-12.17; p = 0.028). Sex did not moderate this association. No significant associations between recent depression and Braak or CERAD scores were observed. CONCLUSION: Our findings indicate that the association between late life depression and Alzheimer's neuropathology is associated with spread of amyloid pathology beyond the neocortex to include allocortical and subcortical regions critical for regulation of mood and motivated behavior.

Comparing cardiovascular risk factors in older persons with mild cognitive impairment and lifetime history of major depressive disorder.

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.

Mild behavioral impairment is associated with progression to Alzheimer's disease: A clinicopathological study.

INTRODUCTION: Mild behavioral impairment (MBI) is characterized by later-life emergence of neuropsychiatric symptoms. Investigating its relationship with progression to Alzheimer's disease (AD) would provide insight on its importance as a predictor of AD. METHODS: Cognitively normal participants (N = 11,372) from the National Alzheimer's Coordinating Center were stratified by MBI status, using the Neuropsychiatric Inventory-Questionnaire. We investigated whether MBI and its domains were predictors of progression to clinically-diagnosed AD. MBI as a predictor of progression to neuropathology-confirmed AD was also investigated in those with neuropathological data. RESULTS: Six percent (N = 671) of participants progressed to AD. MBI (N = 2765) was a significant predictor of progression to clinically-diagnosed (hazard ratio [HR] = 1.75) and neuropathology-confirmed AD (HR = 1.59). MBI domains were also associated with clinically-diagnosed AD, with psychosis having the greatest effect (HR = 6.49). DISCUSSION: These findings support the biological underpinnings of MBI, emphasizing the importance of later life behavioral changes in dementia detection and prognostication.

Depression and Increased Risk of Alzheimer's Dementia: Longitudinal Analyses of Modifiable Risk and Sex-Related Factors.

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.

Exercise priming with transcranial direct current stimulation: a study protocol for a randomized, parallel-design, sham-controlled trial in mild cognitive impairment and Alzheimer's disease.

BACKGROUND: Transcranial direct current stimulation (tDCS) is a non-invasive type of brain stimulation that uses electrical currents to modulate neuronal activity. A small number of studies have investigated the effects of tDCS on cognition in patients with Mild Cognitive Impairment (MCI) and Alzheimer's disease (AD), and have demonstrated variable effects. Emerging evidence suggests that tDCS is most effective when applied to active brain circuits. Aerobic exercise is known to increase cortical excitability and improve brain network connectivity. Exercise may therefore be an effective, yet previously unexplored primer for tDCS to improve cognition in MCI and mild AD. METHODS: Participants with MCI or AD will be randomized to receive 10 sessions over 2 weeks of either exercise primed tDCS, exercise primed sham tDCS, or tDCS alone in a blinded, parallel-design trial. Those randomized to an exercise intervention will receive individualized 30-min aerobic exercise prescriptions to achieve a moderate-intensity dosage, equivalent to the ventilatory anaerobic threshold determined by cardiopulmonary assessment, to sufficiently increase cortical excitability. The tDCS protocol consists of 20 min sessions at 2 mA, 5 times per week for 2 weeks applied through 35 cm2 bitemporal electrodes. Our primary aim is to assess the efficacy of exercise primed tDCS for improving global cognition using the Montreal Cognitive Assessment (MoCA). Our secondary aims are to evaluate the efficacy of exercise primed tDCS for improving specific cognitive domains using various cognitive tests (n-back, Word Recall and Word Recognition Tasks from the Alzheimer's Disease Assessment Scale-Cognitive subscale) and neuropsychiatric symptoms (Neuropsychiatric Inventory). We will also explore whether exercise primed tDCS is associated with an increase in markers of neurogenesis, oxidative stress and angiogenesis, and if changes in these markers are correlated with cognitive improvement. DISCUSSION: We describe a novel clinical trial to investigate the effects of exercise priming before tDCS in patients with MCI or mild AD. This proof-of-concept study may identify a previously unexplored, non-invasive, non-pharmacological combination intervention that improves cognitive symptoms in patients. Findings from this study may also identify potential mechanistic actions of tDCS in MCI and mild AD. TRIAL REGISTRATION: Clinicaltrials.gov, NCT03670615 . Registered on September 13, 2018.

Agitation, Oxidative Stress, and Cytokines in Alzheimer Disease: Biomarker Analyses From a Clinical Trial With Nabilone for Agitation.

The endocannabinoid system has been a target of interest for agitation in Alzheimer disease (AD) because of potential behavioral effects and its potential impact on mechanisms implicated in AD such as oxidative stress (OS) and neuroinflammation. We explored whether serum markers of OS and neuroinflammation were associated with response to the cannabinoid nabilone in agitated patients with AD (N = 38). All participants were enrolled in a 14-week, double-blind, cross-over trial comparing nabilone to placebo (6 weeks each) with a 1-week washout between phases. Samples were collected at the start and end of each phase. The cross-sectional relationship agitation (Cohen Mansfield Agitation Inventory) and OS and inflammatory markers were investigated to select markers of interest. Significant markers were then explored for their relationship with response. The OS marker, 4-hydroxynonenal (4-HNE; F1, 35 = 6.41, P = .016), and the proinflammatory cytokine, tumor necrosis factor-α (TNF-α; F1, 29 = 3.97, P = .06), were associated with agitation severity, and TNF-α remained significantly associated (F2, 25 = 3.69, P = .04) after adjustment for cognition. In the placebo phase, lower baseline 4-HNE was associated with decreases in agitation severity only (b = 0.01, P = .01), while lower baseline TNF-α was associated with decreases in agitation severity in the nabilone phase only (b = 1.14, P = .045). Changes in 4-HNE were not associated with changes in agitation severity in either phase. In the nabilone phase, lower baseline TNF-α was associated with decreases in agitation severity (b = 1.14, P = .045), and decreases in TNF-α were associated with decreases in agitation severity (b = 1.12, P = .006). These findings suggest that OS and neuroinflammation may be associated with agitation severity, while nabilone may have anti-inflammatory effects.

Intensive control of hypertension and risk of Alzheimer's dementia in older adults with depression.

OBJECTIVES: Intensive control of hypertension has been reported to decrease risk of cognitive decline. However, the effect of this in older adults with hypertension and comorbid depression is not well understood. We aim to identify whether intensive control of systolic blood pressure (BP) is associated with reduced risk of Alzheimer's dementia (AD) in a clinical population. METHODS: Using data from the National Alzheimer's Coordinating Center, we conducted survival analyses in older adults with normal cognition at baseline and treated hypertension. We also examined those with comorbid depression, to determine if intensive control of systolic BP (≤120 mmHg) was associated with reduced risk of AD. RESULTS: In all older adults with treated hypertension (n = 4505), 298 (6.6%) developed AD during a median follow-up duration of 4.2 years. In the comorbid depression subgroup (n = 1327), 152 (11.5%) developed AD. Intensive control of systolic BP was not significantly associated with reduced risk of AD in the overall sample (HR 1.13, 95%, 0.79-1.64). However, in the comorbid depression subgroup, intensive control of systolic BP (≤120 mmHg) was associated with increased risk of AD (HR 1.49, 95%, 1.03-2.15) compared to standard control (121-139 mmHg). CONCLUSIONS: In a clinical population of older adults with hypertension and comorbid depression, we found that an intensive systolic BP target of ≤120 mmHg was associated with increased risk of AD. While these findings are preliminary, they suggest that a more cautious approach to hypertension treatment may be warranted in this vulnerable subgroup.

A Pilot Study Comparing Effects of Bifrontal Versus Bitemporal Transcranial Direct Current Stimulation in Mild Cognitive Impairment and Mild Alzheimer Disease.

OBJECTIVE: While transcranial direct current stimulation (tDCS) can enhance aspects of memory in patients with mild cognitive impairment (MCI) and Alzheimer disease (AD), there has been wide variability in both the placement of tDCS electrodes and treatment response. This study compared the effects of bifrontal (anodal stimulation over the dorsolateral prefrontal cortices), bitemporal (anodal stimulation over the temporal cortices), and sham tDCS on cognitive performance in MCI and AD. METHODS: Seventeen patients diagnosed with MCI or mild AD received 3 sessions of anodal tDCS (bifrontal, bitemporal, 2 mA for 20 minutes; and sham) in random order. Sessions were separated by 1 week. The Alzheimer's Disease Assessment Scale-Cognitive Word Recognition Task, Alzheimer's Disease Assessment Scale-Cognitive Word Recall Task, 2-back, and Montreal Cognitive Assessment were used to assess cognition. RESULTS: There was a significant effect of stimulation condition on 2-back accuracy (F2,28 = 5.28 P = 0.01, ηp = 0.27), with greater improvements following bitemporal tDCS compared with both bifrontal and sham stimulations. There were no significant changes on other outcome measures following any stimulation. Adverse effects from stimulation were mild and temporary. CONCLUSIONS: These findings demonstrate that improvements in specific memory tasks can be safely achieved after a single session of bitemporal tDCS in MCI and mild AD patients.

The Roles of Apathy and Depression in Predicting Alzheimer Disease: A Longitudinal Analysis in Older Adults With Mild Cognitive Impairment.

OBJECTIVE: Apathy and depression have each been associated with an increased risk of conversion from mild cognitive impairment (MCI) to Alzheimer disease (AD).These symptoms often co-occur and the contribution of each to risk of AD is not clear. METHODS: National Alzheimer's Coordinating Center participants diagnosed with MCI at baseline and followed until development of AD or loss to follow-up (n = 4,932) were included. The risks of developing AD in MCI patients with neuropsychiatric symptoms (NPS) (apathy only, depression only, or both) were compared to that in those without NPS in a multivariate Cox regression survival analysis adjusting for baseline cognitive impairment, years of smoking, antidepressant use, and AD medication use. RESULTS: Thirty-seven percent (N = 1713) of MCI patients developed AD (median follow-up 23 months). MCI patients with both apathy and depression had the greatest risk (hazard ratio [HR] = 1.37; 95% confidence interval [CI]: 1.17-1.61; p < 0.0001; Wald χ2 = 14.70; df = 1). Those with apathy only also had a greater risk (HR = 1.24; 95% CI: 1.05-1.47; p = 0.01; Wald χ2 = 6.22; df = 1), but not those with depression only (HR = 1.08; 95% CI: 0.95-1.22; p=0.25; Wald χ2 = 1.30; df = 1). Post-hoc analyses suggested depression may exacerbate cognitive decline in MCI patients with apathy (odds ratio = 0.70; 95% CI 0.52-0.95; p = 0.02; Wald χ2 = 5.28; df = 1), compared to those without apathy. CONCLUSION: MCI patients with apathy alone or both apathy and depression are at a greater risk of developing AD compared to those with no NPS. Interventions targeting apathy and depression may reduce risk of AD.

Randomized Placebo-Controlled Trial of Nabilone for Agitation in Alzheimer's Disease.

OBJECTIVE: To investigate the efficacy and safety of nabilone for agitation in patients with moderate-to-severe Alzheimer's disease (AD). DESIGN: This 14-week randomized double-blind crossover trial compared nabilone to placebo (6 weeks each) with a 1-week washout between phases. SETTING: Patients were recruited from a long-term care facility and geriatric psychiatry clinics. PARTICIPANTS: Patients had AD (standardized Mini-Mental State Examination [sMMSE ≤24]) and agitation (Neuropsychiatric Inventory-Nursing Home version [NPI-NH]-agitation/aggression subscore ≥3). INTERVENTION: Nabilone (target 1-2 mg) versus placebo. MEASUREMENTS: The primary outcome was agitation (Cohen Mansfield Agitation Inventory [CMAI]). Secondary outcomes included NPI-NH total, NPI-NH caregiver distress, cognition (sMMSE and Severe Impairment Battery [SIB] or Alzheimer's Disease Assessment Scale of Cognition), global impression (Clinician's Global Impression of Change [CGIC]), and adverse events. RESULTS: Thirty-nine patients (mean ± SD age = 87 ± 10, sMMSE = 6.5 ± 6.8, CMAI = 67.9 ± 17.6, NPI-NH total = 34.3 ± 15.8, 77% male, nabilone dose = 1.6 ± 0.5 mg) were randomized. There were no crossover or treatment-order effects. Using a linear mixed model, treatment differences (95% CI) in CMAI (b = -4.0 [-6.5 to -1.5], t(30.2) = -3.3, p = 0.003), NPI-NH total (b = -4.6 [-7.5 to -1.6], t(32.9) = -3.1, p = 0.004), NPI-NH caregiver distress (b = -1.7 [-3.4 to -0.07, t(33.7) = -2.1, p = 0.041), and sMMSE (b = 1.1 [0.1-2.0], t(22.6) = 2.4, p = 0.026) all favored nabilone. However, in those who completed the SIB (n = 25) treatment differences favored placebo (b = -4.6 [-7.3 to -1.8], t(20.7) = -4.8, p = 0.003). CGIC improvement during nabilone (47%) and placebo (23%) was not significantly different (McNemar's test, exact p = 0.09). There was more sedation during nabilone (45%) compared to placebo (16%) phases (McNemar's test, exact p = 0.02), but treatment-limiting sedation was not significantly different (McNemar's test, exact p = 0.22). CONCLUSIONS: Nabilone may be an effective treatment for agitation. However, sedation and cognition should be closely monitored.

Depression and Risk of Alzheimer Dementia: A Longitudinal Analysis to Determine Predictors of Increased Risk among Older Adults with Depression.

OBJECTIVE: Older adults with depression are at increased risk of Alzheimer dementia, but predictors of increased risk remain incompletely understood. We aim to identify characteristics of older adults with depression most at risk of progressing to Alzheimer dementia. Identification of high-risk subgroups could facilitate future interventional strategies to reduce risk of Alzheimer dementia in older adults with depression. METHODS: Using data from the National Alzheimer's Coordinating Center, 1,965 participants with clinically defined depression and mild cognitive impairment at baseline were followed until development of Alzheimer dementia or loss to follow-up. RESULTS: Seven hundred and eighty (39.7%) developed Alzheimer dementia over a median follow-up duration of 27 months. In survival analyses, age (hazard ratio [HR] 1.04, 95% 1.03-1.05), baseline Mini-Mental State Exam (HR 0.85, 95% confidence interval 0.83-0.87), amnestic subtype of mild cognitive impairment (HR 1.66, 95% 1.30-2.12), presence of APOE4 allele (HR 1.99, 1.69-2.36), and presence of active depression within the last two years (HR 1.44, 95% confidence interval 1.16-1.79) were all independently associated with increased risk of Alzheimer dementia. Six hundred and fifty-six (41.7%) participants with mild cognitive impairment and active depression within the last two years developed Alzheimer dementia compared to 120 (31.6%) of those with a more remote history of depression. CONCLUSION: Older adults with depression and mild cognitive impairment demonstrated a high rate of progression to Alzheimer dementia over a relatively short duration of follow-up. Individuals with a combination of mild cognitive impairment and recently active depression are a particularly high-risk subgroup.

Exercise for Cognitive Symptoms in Depression: A Systematic Review of Interventional Studies.

OBJECTIVE: To explore the effect of exercise on cognition in depression as well as the impact of potential moderators and intervention type. METHOD: Controlled and uncontrolled interventional studies that described an exercise intervention and cognitive outcomes in participants with major depressive disorder (MDD) were included following a search of Pubmed, Ovid Medline, PsycInfo and Embase from inception to January 2017. Meta-analyses were conducted to calculate Hedges' g using a random-effects model. Meta-regression explored the relationships among age, baseline cognition, frequency and duration of exercise, and cognitive outcomes. Subgroup analyses were also conducted according to type and intensity of exercise interventions. RESULTS: Of 12 controlled studies and 3 uncontrolled studies that met inclusion criteria, 9 (642 patients) were included in the meta-analysis. No significant effect of exercise was found on global cognition (Hedges' g = 0.08, P = 0.33, I2 = 0%) or on individual cognitive domains. Meta-regression analyses failed to find significant relationships among participant age, baseline cognition, number of exercise sessions per wk, duration of exercise per wk, total duration of exercise during the intervention, or improvement in global cognition. Interventions combining physical with cognitive activity significantly improved global cognition ( P = 0.048), whereas low-intensity interventions were also positive ( P = 0.048). CONCLUSIONS: No impact of physical exercise was found on cognition in MDD overall. However, we found that interventions combining physical and cognitive activities had a positive impact, and that lower-intensity interventions, where adherence was improved, also impacted positively. There remains a lack of high-quality data in this population.

Depression with inflammation: longitudinal analysis of a proposed depressive subtype in community dwelling older adults.

OBJECTIVE: It has been proposed that inflammation may be causally related to depression. If this is the case, it may be possible to distinguish an inflammatory depressive subtype according to illness course, pattern of co-morbidity and symptom profile. METHODS: Eight hundred and eleven community dwelling older adults with depression (8 item Center for Epidemiologic Studies scale ≥ 4) from the English Longitudinal study of Ageing (ELSA) were followed for a median of 47 months. Participants with depression and inflammation (C Reactive Protein > 3 mg/l) were compared to those with depression alone. RESULTS: In a longitudinal analysis, depression with associated inflammation was more likely to persist over time. This association was independent of baseline depression severity and medical co-morbidity (OR 1.47 95% CI 1.03 - 2.10, p = 0.034) but was no longer significant following further adjustment for body mass index (OR 1.37 95% CI 0.94 - 2.01, p = 0.106). Inflammation either partially or completely mediated the association between medical co-morbidity, body mass index and depression at follow-up. Depression with inflammation was associated with more amotivation, less sadness, greater medical co-morbidity and higher body mass index. CONCLUSIONS: Our findings provide some support for an inflammatory contribution to depression. This subgroup has a worse prognosis and may benefit from interventions targeting co-morbidity, body mass index and associated inflammation. Copyright © 2016 John Wiley & Sons, Ltd.

Neuropsychiatric Symptoms in Mild Cognitive Impairment.

OBJECTIVE: Neuropsychiatric symptoms (NPS) may be the first manifestation of an underlying neurocognitive disorder. We undertook a review to provide an update on the epidemiology and etiological mechanisms of NPS that occur in mild cognitive impairment (MCI) and just before the onset of MCI. We discuss common clinical presentations and the implications for diagnosis and care. METHOD: The authors conducted a selective review of the literature regarding the emergence of NPS in late life, before and after the onset of MCI. We discuss recent publications that explore the epidemiology and etiological mechanisms of NPS in the earliest clinical stages of these disorders. RESULTS: NPS have been reported in 35% to 85% of adults with MCI and also occur in advance of cognitive decline. The occurrence of NPS for the first time in later life should increase suspicion for an underlying neurocognitive disorder. The presenting symptom may provide a clue regarding the etiology of the underlying disorder, and the co-occurrence of NPS may herald a more accelerated cognitive decline. CONCLUSIONS: NPS are prevalent in the early clinical stages of neurocognitive disorders and can serve as both useful diagnostic and prognostic indicators. Recognition of NPS as early manifestations of neurocognitive disorders will become increasingly important as we move towards preventative strategies and disease-modifying treatments that may be most effective when deployed in the earliest stages of disease.

Suicide in the oldest old: an observational study and cluster analysis.

OBJECTIVES: The older population are at a high risk for suicide. This study sought to learn more about the characteristics of suicide in the oldest-old and to use a cluster analysis to determine if oldest-old suicide victims assort into clinically meaningful subgroups. METHODS: Data were collected from a coroner's chart review of suicide victims in Toronto from 1998 to 2011. We compared two age groups (65-79 year olds, n = 335, and 80+ year olds, n = 191) and then conducted a hierarchical agglomerative cluster analysis using Ward's method to identify distinct clusters in the 80+ group. RESULTS: The younger and older age groups differed according to marital status, living circumstances and pattern of stressors. The cluster analysis identified three distinct clusters in the 80+ group. Cluster 1 was the largest (n = 124) and included people who were either married or widowed who had significantly more depression and somewhat more medical health stressors. In contrast, cluster 2 (n = 50) comprised people who were almost all single and living alone with significantly less identified depression and slightly fewer medical health stressors. All members of cluster 3 (n = 17) lived in a retirement residence or nursing home, and this group had the highest rates of depression, dementia, other mental illness and past suicide attempts. CONCLUSIONS: This is the first study to use the cluster analysis technique to identify meaningful subgroups among suicide victims in the oldest-old. The results reveal different patterns of suicide in the older population that may be relevant for clinical care.

Frailty: a costly phenomenon in caring for elders with cognitive impairment.

OBJECTIVES: Dementia draws on a variety of public and private resources. There is increasing pressure to define the cost components in this area to improve resource allocation and accountability. The aim of this study was to characterize frailty in a group of cognitively impaired community-dwelling elders and evaluate its relationship with cost and resource utilization. METHODS: We assessed a cross-sectional, convenient sample of 115 cognitively impaired patients of age >55 years who attended the National Memory Clinic in St James' University Hospital, a Trinity College-affiliated hospital in Dublin, Ireland. Participants had a clinical diagnosis of possible Alzheimer's disease or mild cognitive impairment. Frailty was measured using the biological syndrome model. Formal health and social care costs and daily informal caregiving costs were collected and the total costs of care estimated by applying the appropriate unit cost estimate for each resource activity. Stepwise regression models were constructed to establish the factors associated with increased care costs. RESULTS: Patient dependence, frailty and number of co-morbid illnesses explained 43.3% of the variance in observed daily informal care costs in dementia and cognitively impaired patients. Dependence was the sole factor retained in an optimal model explaining 19% of the variance in formal health and social care costs. CONCLUSION: Frailty retained a strong association with daily informal care costs even in the context of other known risk factors for increasing care costs. Interventions that reduce frailty as well as patient dependence on others may be associated with cost savings.

Longitudinal costs of caring for people with Alzheimer's disease.

BACKGROUND: There has been an increasing interest in the relationship between severity of disease and costs in the care of people with dementia. Much of the current evidence is based on cross-sectional data, suggesting the need to examine trends over time for this important and growing cohort of the population. METHODS: This paper estimates resource use and costs of care based on longitudinal data for 72 people with dementia in Ireland. Data were collected from the Enhancing Care in Alzheimer's Disease (ECAD) study at two time points: baseline and follow-up, two years later. Patients' dependence on others was measured using the Dependence Scale (DS), while patient function was measured using the Disability Assessment for Dementia (DAD) scale. Univariate and multivariate analysis were used to explore the effects of a range of variables on formal and informal care costs. RESULTS: Total costs of formal and informal care over six months rose from €9,266 (Standard Deviation (SD): 12,947) per patient at baseline to €21,266 (SD: 26,883) at follow-up, two years later. This constituted a statistically significant (p = 0.0014) increase in costs over time, driven primarily by an increase in estimated informal care costs. In the multivariate analysis, a one-point increase in the DS score, that is a one-unit increase in patient's dependence on others, was associated with a 19% increase in total costs (p = 0.0610). CONCLUSIONS: Higher levels of dependence in people with Alzheimer's disease are significantly associated with increased costs of informal care as the disease progresses. Formal care services did not respond to increased dependence in people with dementia, leaving it to families to fill the caring gap, mainly through increased supervision with the progress of disease.