Eric van Exel

Association between high‐density lipoprotein and cognitive impairment in the oldest old

Low high‐density lipoprotein cholesterol is associated with an increased risk for cardiovascular disease and stroke. At the same time, cardiovascular disease and stroke are important risk factors for dementia. We assessed the association between total and fractionated cholesterol and cognitive impairment and explored whether observed associations were dependent on or independent of atherosclerotic disease. In a population‐based study, total cholesterol, triglycerides, low‐density lipoprotein cholesterol, and high‐density lipoprotein cholesterol were measured in 561 subjects 85 years old and grouped in three equal strata representing decreasing serum concentrations. History of cardiovascular disease and stroke was determined. All subjects completed the Mini‐Mental State Examination (MMSE), and the presence of dementia was determined. Median MMSE scores were significantly lower in subjects with low high‐density lipoprotein cholesterol (25 points vs 27 points, p < 0.001). No differences in MMSE scores were found for other lipids and lipoproteins. MMSE scores in subjects with and without cardiovascular disease were 26 and 27 points (p = 0.007), respectively, and in subjects with and without stroke were 21 and 26 points (p < 0.001), respectively. The associations between low MMSE scores and low high‐density lipoprotein cholesterol remained significant after subjects with cardiovascular disease or stroke were excluded. In a comparison of subjects with low high‐density lipoprotein cholesterol with subjects with high high‐density lipoprotein cholesterol, the odds ratio for dementia was 2.3 (95% confidence interval, 1.2–4.3), and in subjects without cardiovascular disease or stroke, it was 3.7 (95% confidence interval, 1.3–10.1). All odds ratios were unaffected by education, low‐density lipoprotein cholesterol, triglycerides, and survival. Low high‐density lipoprotein cholesterol is associated with cognitive impairment and dementia. At least part of the association between high‐density lipoprotein cholesterol and cognitive function is independent of atherosclerotic disease.

Common chronic diseases and general impairments as determinants of walking disability in the oldest-old population.

OBJECTIVES: Walking disability affects older peoples autonomy and well‐being. We investigated the relative effect of common chronic diseases and general impairments on walking disability in the general oldest‐old population.

Vascular Factors and Markers of Inflammation in Offspring With a Parental History of Late-Onset Alzheimer Disease

CONTEXT Alzheimer disease (AD) is a complex disorder with a strong heritable component. Amyloid pathology, vascular factors, and inflammation are postulated to be involved in its pathogenesis, but causality has not been established unequivocally. OBJECTIVE To identify heritable traits in middle age that contribute to AD. DESIGN We used a proven family design, comparing middle-aged offspring with and without a parental history of AD. In such a design, the offspring under study are enriched for risk factors of AD but do not yet have the disease. SETTING The Netherlands. PARTICIPANTS Two hundred six offspring of 92 families with a parental history of late-onset AD and 200 offspring of 97 families without a parental history of AD. MAIN OUTCOME MEASURES The APOE epsilon4 genotype, vascular factors, production capacity of pro- and anti-inflammatory cytokines upon stimulation with lipopolysaccharide, and circulating markers of inflammation. All outcome measures were assessed in the offspring only and not in the parental generation. RESULTS More offspring with a parental history of AD carried APOE epsilon4 than those without a parental history of the disease (47% vs 21%, P < .001). Those with a parental history of AD also had higher systolic blood pressures (P = .006), higher diastolic blood pressures (P < .001), and lower ankle brachial indices (P = .005) when compared with offspring without a family history of dementia. Production capacity of pro-inflammatory cytokines in offspring with a parental history of AD was also different, with higher levels of IL-1beta (interleukin 1beta) (P < .001), IL-1beta to IL-1ra ratio (P < .001), tumor necrosis factor alpha (P = .008), IL-6 (P = .04), and interferon gamma (P = .01). All of these positive associations were independent of APOE epsilon4 genotype. CONCLUSIONS Hypertension and the expression of an innate pro-inflammatory cytokine profile in middle age are early risk factors of AD in old age. For the offspring of affected families, it provides clues for screening and preventive strategies, of which blood pressure control can be implemented directly.

Whether, when and how chronic inflammation increases the risk of developing late-onset Alzheimer's disease

Neuropathological studies have revealed the presence of a broad variety of inflammation-related proteins (complement factors, acute-phase proteins, pro-inflammatory cytokines) in Alzheimers disease (AD) brains. These constituents of innate immunity are involved in several crucial pathogenic events of the underlying pathological cascade in AD, and recent studies have shown that innate immunity is involved in the etiology of late-onset AD. Genome-wide association studies have demonstrated gene loci that are linked to the complement system. Neuropathological and experimental studies indicate that fibrillar amyloid-β (Aβ) can activate the innate immunity-related CD14 and Toll-like receptor signaling pathways of glial cells for pro-inflammatory cytokine production. The production capacity of this pathway is under genetic control and offspring with a parental history of late-onset AD have a higher production capacity for pro-inflammatory cytokines. The activation of microglia by fibrillar Aβ deposits in the early preclinical stages of AD can make the brain susceptible later on for a second immune challenge leading to enhanced production of pro-inflammatory cytokines. An example of a second immune challenge could be systemic inflammation in patients with preclinical AD. Prospective epidemiological studies show that elevated serum levels of acute phase reactants can be considered as a risk factor for AD. Clinical studies suggest that peripheral inflammation increases the risk of dementia, especially in patients with preexistent cognitive impairment, and accelerates further deterioration in demented patients. The view that peripheral inflammation can increase the risk of dementia in older people provides scope for prevention.

Childhood abuse in late-life depression

BACKGROUND Little is known about the role of childhood abuse in late-life depression. The aim of the study is therefore to study whether childhood abuse is associated with late-life depression according to its onset, and which clinical characteristics play a role in this association. METHODS Data were used from 378 depressed and 132 non-depressed persons, aged 60-93 years, from the Netherlands Study of Depression in Older persons (NESDO). Childhood abuse included psychological, physical and sexual abuse and emotional neglect. RESULTS 53% of the depressed older adults reported childhood abuse, compared to 16% of the non-depressed older adults (p<0.001). Using logistic regression analyses adjusted for age, sex and level of education, depression was strongest associated with physical abuse (Odds Ratio ((OR) 13.71; 95% Confidence Interval (CI) 3.25-57.91) and least with sexual abuse (OR 5.35; 95% CI 2.36-12.14). Childhood abuse was associated with early-onset (OR 13.73, 95% CI 7.31-25.80), middle age-onset (OR 5.36, 95% CI 2.90-9.90) and late-onset depression (OR 4.74, 95% CI 2.51-8.95). In the late-onset group childhood abuse was associated with an increased number of chronic diseases. LIMITATIONS Age of depression onset and childhood abuse were asked retrospectively, which may have biased the results. CONCLUSIONS Childhood abuse is strongly related to late-life depression and its comorbidities, even in the case of late-onset depression. This might suggest that psychological wellbeing can be maintained throughout middle age, but may be disturbed in later life.

White Matter Hyperintensities, Medial Temporal Lobe Atrophy, Cortical Atrophy, and Response to Electroconvulsive Therapy in Severely Depressed Elderly Patients

OBJECTIVE Electroconvulsive therapy (ECT) is a valuable treatment option in severely depressed elderly patients. Structural abnormalities in the brain, such as white matter hyperintensities, medial temporal lobe atrophy (MTA), or global cortical atrophy, may influence therapeutic response. The respective value of these factors in response prediction is unclear. METHOD In a naturalistic clinical cohort of 81 elderly patients diagnosed with DSM-IV major depressive disorder, magnetic resonance imaging (MRI) was recorded and rated before ECT treatment. The study was conducted at the clinic for Geriatric Psychiatry of the VU University Medical Center/Stichting Buitenamstel Geestgronden, Amsterdam, The Netherlands, over a 5-year period (2001-2006). Severity of depressive symptoms was measured by using the Montgomery-Asberg Depression Rating Scale (MADRS). Response to ECT was defined as a decrease of at least 50 percent on the MADRS, and remission was defined as a score below 10 points on the MADRS. RESULTS Patients with moderate or severe MTA had a lower mean percentage decrease in MADRS scores after ECT (37.9% in those with MTA, compared to 66.2% in those without MTA, P = .008). Patients without MTA had a 3 times greater chance of remitting from their depression compared to patients with moderate or severe MTA, ie, the hazard ratio for remission was 3.22 (95% CI, 1.30 to 7.69, P = .01). In contrast, no differences in change in MADRS scores were found for white matter hyperintensities or global cortical atrophy. CONCLUSIONS Medial temporal lobe atrophy--not white matter hyperintensities or global cortical atrophy--contributes to poor response to ECT in severely depressed elderly patients. These findings suggest that assessment of MTA in severely depressed elderly patients may be useful in the prediction of potential ECT response.

Gene dose of apolipoprotein E and age-related hearing loss

Next to outer hair cell dysfunction, age-related hearing loss may be explained by apolipoprotein E (APOE) genotype. In the Leiden 85-plus Study, a population-based study, the participants were 85 years old. We measured hearing loss by pure-tone audiometry in 435 participants in relation to APOE. Results demonstrated that those with the APOE-ε4/ε4 genotype had the highest levels of hearing loss (n = 6; 56.1 dB), those with the APOE-ε3/ε4 or ε2/ε4 genotype (n = 89) had intermediate levels of hearing loss (51.0 dB), and those without the APOE-ε4 allele (n = 340) had the lowest levels of hearing loss (48.9 dB), p for trend = 0.02. Eighty percent of participants had hearing loss of 35 dB and more, that is, hearing impairment. The APOE-ε4 allele was associated with a 2.0-fold increased risk of hearing impairment (confidence interval [CI 95%], 1.0-4.0), compared with those without the APOE-ε4 allele. The risk for hearing impairment in subjects with the APOE-ε4 allele remained similar after adjustment for cardiovascular disease, stroke, and cognitive impairment. Our results suggest that the APOE-ε4 allele contributes to age-related hearing loss.

The structure of the geriatric depressed brain and response to electroconvulsive therapy

Electroconvulsive therapy (ECT) is the treatment of choice in severe geriatric depression. High remission rates may be influenced by specific brain morphology characteristic of geriatric depression. Our objective was to identify the relationship between brain structure, symptom profile, and ECT response. In a naturalistic cohort of 55 patients with a major depressive disorder, structural magnetic resonance imaging (MRI) was performed before ECT. Voxel-based morphometry was applied to determine regional differences in gray matter (GM) volume between patients and 23 matched healthy controls. Depressed patients with psychotic symptoms showed significantly higher remission rates and smaller regional GM volume of the left inferior frontal gyrus (IFG). Patients with late onset depression showed smaller regional GM volume of the bilateral lateral temporal cortex. Larger size of response in the whole patient group was related to smaller pretreatment regional GM volume of the right lateral temporal cortex, whereas faster speed of response was related to smaller pretreatment regional GM volume of the right IFG. ECT is most effective in depressed patients with psychotic symptoms. In this study the presence of psychotic symptoms was related to pretreatment smaller GM volume of the left IFG and bilateral temporal cortex. Smaller volume of the IFG pretreatment was related to faster treatment response, and smaller volume of the right lateral temporal cortex pretreatment was related to larger response to ECT. These results are possibly explained by the connectivity between these brain regions and an interconnected network that is particularly activated by the ECT-induced seizures.

Early- and Late-Onset Depression in Late Life: A Prospective Study on Clinical and Structural Brain Characteristics and Response to Electroconvulsive Therapy

OBJECTIVE The clinical profile of late-life depression (LLD) is frequently associated with cognitive impairment, aging-related brain changes, and somatic comorbidity. This two-site naturalistic longitudinal study aimed to explore differences in clinical and brain characteristics and response to electroconvulsive therapy (ECT) in early- (EOD) versus late-onset (LOD) late-life depression (respectively onset <55 and ≥55 years). METHODS Between January 2011 and December 2013, 110 patients aged 55 years and older with ECT-treated unipolar depression were included in The Mood Disorders in Elderly treated with ECT study. Clinical profile and somatic health were assessed. Magnetic resonance imaging (MRI) scans were performed before the first ECT and visually rated. RESULTS Response rate was 78.2% and similar between the two sites but significantly higher in LOD compared with EOD (86.9 versus 67.3%). Clinical, somatic, and brain characteristics were not different between EOD and LOD. Response to ECT was associated with late age at onset and presence of psychotic symptoms and not with structural MRI characteristics. In EOD only, the odds for a higher response were associated with a shorter index episode. CONCLUSION The clinical profile, somatic comorbidities, and brain characteristics in LLD were similar in EOD and LOD. Nevertheless, patients with LOD showed a superior response to ECT compared with patients with EOD. Our results indicate that ECT is very effective in LLD, even in vascular burdened patients.

Implementing an outreaching, preference-led stepped care intervention programme to reduce late life depressive symptoms: results of a mixed-methods study

BackgroundDepressive symptoms are highly prevalent in old age, but they remain mostly untreated. Several clinical trials have shown promising results in preventing or reducing depressive symptoms. However, it is not clear how robust these effects are in the real world of day-to-day care. Therefore, we have implemented the ‘Lust for Life’ programme, which significantly reduced depressive symptoms in community-dwelling older adults in the first three months after implementation. This mixed-methods study was conducted alongside the trial to develop a contextualised understanding of factors affecting the implementation.MethodsA total of 263 persons of 65 years and older with depressive symptoms were recruited from 18 general practices and home care organizations in the Netherlands. We used qualitative data (in-depth interviews and focus group discussions with participants with depressive symptoms and healthcare professionals) as well as quantitative data (longitudinal data on the severity of depressive symptoms) to explore hindering and facilitating factors to the implementation of the ‘Lust for Life’ programme.ResultsThe uptake of the routine screening was poor and imposed significant burdens on participants and healthcare professionals, and drop-out rates were high. Participants’ perceived mental problems and need for care played a key role in their decision to participate in the programme and to step up to consequent interventions. Older people preferred interventions that focused on interpersonal contact. The programme was only effective when delivered by mental healthcare nurses, compared to home care nurses with limited experience in providing mental healthcare.ConclusionsThe intervention programme was effective in reducing depressive symptoms, and valuable lessons can be learned from this implementation trial. Given the low uptake and high investment, we advise against routine screening for depressive symptoms in general healthcare. Further, agreement between the participant and healthcare professional on perceived need for care and intervention is vital. Rather than providing a stepped care intervention programme, we showed that offering only one single preference-led intervention is effective. Lastly, since the provision of the interventions seems to ask for specific skills and experiences, it might require mental healthcare nurses to offer the programme.Trial registrationDutch trial register NTR2241