To determine whether microvascular damage, indicated by cerebral microbleeds (CMBs) and retinal microvascular signs, is associated with cognitive function and dementia in older persons.
This is a ...cross-sectional study of 3,906 participants (mean age 76 years; 58% women) in the AGES-Reykjavik Study (2002-2006). We assessed CMBs on MRI and retinal microvascular signs on digital retinal images. Composite Z scores of memory, processing speed, and executive function were derived from a battery of neurocognitive tests. Dementia and subtypes were diagnosed following international criteria. Regression models were used to relate cognitive Z scores and dementia to CMBs and retinal microvascular signs, adjusting for demographics, cardiovascular factors, and brain ischemic lesions.
People with multiple (≥ 2) CMBs had lower Z scores on tests of processing speed (β-coefficient -0.16; 95% confidence interval -0.26 to -0.05) and executive function (-0.14; -0.24 to -0.04); results were strongest for having multiple CMBs located in the deep hemispheric or infratentorial areas. The odds ratio of vascular dementia was 2.32 (95% confidence interval 1.02 to 5.25) for multiple CMBs and 1.95 (1.04 to 3.62) for retinopathy. Having both CMBs and retinopathy, compared to having neither, was significantly associated with markedly slower processing speed (-0.25; -0.37 to -0.12), poorer executive function (-0.19; -0.31 to -0.07), and an increased odds ratio of vascular dementia (3.10; 1.11 to 8.62).
Having multiple CMBs or concomitant CMBs and retinopathy is associated with a profile of vascular cognitive impairment. These findings suggest that microvascular damage, as indicated by CMBs and retinopathy lesions, has functional consequences in older men and women living in the community.
The aim of this study was to investigate the associations between loss of a life partner and the development of dementia and decline in cognitive function in later life. We used an Icelandic cohort ...of 4,370 participants in the Age, Gene/Environment Susceptibility-Reykjavik Study who were living as married in 1978 (born in 1907-1935) and were either still married (unexposed cohort) or widowed (exposed cohort) at follow-up (in 2002-2006). We ascertained history of marital status and spouse's death by record linkage to the Registry of the Total Population, Statistics Iceland. The outcome measures were as follows: 1) dementia and mild cognitive impairment; and 2) memory, speed of processing, and executive function. During the observation period, 3,007 individuals remained married and 1,363 lost a spouse through death. We did not find any significant associations between loss of a spouse and our outcome variables, except that widowed women had poorer executive function (mean = -0.08) during the first 2 years after their husbands' deaths compared with still-married women (mean = 0.09). Our findings do not support the notion that the risk of dementia is increased following the loss of a spouse, yet women demonstrate a seemingly temporary decline in executive function following the death of a partner.
The plasma proteome can help bridge the gap between the genome and diseases. Here we describe genome-wide association studies (GWASs) of plasma protein levels measured with 4,907 aptamers in 35,559 ...Icelanders. We found 18,084 associations between sequence variants and levels of proteins in plasma (protein quantitative trait loci; pQTL), of which 19% were with rare variants (minor allele frequency (MAF) < 1%). We tested plasma protein levels for association with 373 diseases and other traits and identified 257,490 associations. We integrated pQTL and genetic associations with diseases and other traits and found that 12% of 45,334 lead associations in the GWAS Catalog are with variants in high linkage disequilibrium with pQTL. We identified 938 genes encoding potential drug targets with variants that influence levels of possible biomarkers. Combining proteomics, genomics and transcriptomics, we provide a valuable resource that can be used to improve understanding of disease pathogenesis and to assist with drug discovery and development.
We investigated whether, and the extent to which, vascular and degenerative lesions in the brain mediate the association of diabetes with poor cognitive performance.
This cross-sectional study ...included 4,206 participants (age > 65 years; 57.8% women) of the Age, Gene/Environment Susceptibility-Reykjavik Study. Data were collected through interview, clinical examination, psychological testing, and laboratory tests. The composite scores on memory, information-processing speed, and executive function were derived from a cognitive test battery. Markers of cerebral macrovascular (cortical infarcts), microvascular (subcortical infarcts, cerebral microbleeds, and higher white matter lesion volume), and neurodegenerative (lower gray matter, normal white matter, and total brain tissue volumes) processes were assessed on magnetic resonance images. Mediation models were employed to test the mediating effect of brain lesions on the association of diabetes with cognitive performance controlling for potential confounders.
There were 462 (11.0%) persons with diabetes. Diabetes was significantly associated with lower scores on processing speed and executive function, but not with memory function. Diabetes was significantly associated with all markers of brain pathology. All of these markers were significantly associated with lower scores on memory, processing speed, and executive function. Formal mediation tests suggested that markers of cerebrovascular and degenerative pathology significantly mediated the associations of diabetes with processing speed and executive function.
Diabetes is associated with poor performance on cognitive tests of information-processing speed and executive function. The association is largely mediated by markers of both neurodegeneration and cerebrovascular disease. Older people with diabetes should be monitored for cognitive problems and brain lesions.
Abstract
Background
Neuroinflammation has gained increasing attention as a potential contributing factor in the onset and progression of Alzheimer’s disease (AD). The objective of this study was to ...examine the association of selected cerebrospinal fluid (CSF) inflammatory and neuronal degeneration markers with signature CSF AD profile and cognitive functions among subjects at the symptomatic pre- and early dementia stages.
Methods
In this cross-sectional study, 52 subjects were selected from an Icelandic memory clinic cohort. Subjects were classified as having AD (
n
= 28, age = 70, 39% female, Mini-Mental State Examination MMSE = 27) or non-AD (
n
= 24, age = 67, 33% female, MMSE = 28) profile based on the ratio between CSF total-tau (T-tau) and amyloid-β
1–42
(Aβ
42
) values (cut-off point chosen as 0.52). Novel CSF biomarkers included neurofilament light (NFL), YKL-40, S100 calcium-binding protein B (S100B) and glial fibrillary acidic protein (GFAP), measured with enzyme-linked immunosorbent assays (ELISAs). Subjects underwent neuropsychological assessment for evaluation of different cognitive domains, including verbal episodic memory, non-verbal episodic memory, language, processing speed, and executive functions.
Results
Accuracy coefficient for distinguishing between the two CSF profiles was calculated for each CSF marker and test. Novel CSF markers performed poorly (area under curve AUC coefficients ranging from 0.61 to 0.64) compared to tests reflecting verbal episodic memory, which all performed fair (AUC > 70). LASSO regression with a stability approach was applied for the selection of CSF markers and demographic variables predicting performance on each cognitive domain, both among all subjects and only those with a CSF AD profile. Relationships between CSF markers and cognitive domains, where the CSF marker reached stability selection criteria of > 75%, were visualized with scatter plots. Before calculations of corresponding Pearson’s correlations coefficients, composite scores for cognitive domains were adjusted for age and education. GFAP correlated with executive functions (
r
= − 0.37,
p
= 0.01) overall, while GFAP correlated with processing speed (
r
= − 0.68,
p
< 0.001) and NFL with verbal episodic memory (
r
= − 0.43,
p
= 0.02) among subjects with a CSF AD profile.
Conclusions
The novel CSF markers NFL and GFAP show potential as markers for cognitive decline among individuals with core AD pathology at the symptomatic pre- and early stages of dementia.
Background
Several studies have indicated that older adults with cognitive impairment have a poorer lifestyle than their healthy peers including lower 25-hydroxy-vitamin D levels (25OHD).
Aim
To ...investigate the associations between lifestyle and 25OHD depending on cognitive status among old adults.
Methods
Community-dwelling old adults (65–96 years) participated in this cross-sectional study based on the Age-Gene/Environment-Susceptibility-Reykjavik-Study. The analytical sample included 5162 subjects who were stratified by cognitive status, i.e., dementia (
n
= 307), mild cognitive impairment (MCI,
n
= 492), and normal cognitive status (NCS,
n
= 4363). Lifestyle variables were assessed and 25OHD was measured. The associations between lifestyle and 25OHD were calculated using linear models correcting for potential confounders.
Results
According to linear regression models, 25OHD was significantly lower in older people with dementia (53.8 ± 19.6 nmol/L) than in NCS participants (57.6 ± 17.7 nmol/L). Cod liver oil (7.1–9.2 nmol/L,
P
< 0.001) and dietary supplements (4.4–11.5 nmol/L,
P
< 0.001) were associated with higher 25OHD in all three groups. However, physical activity ≥ 3 h/week (2.82 nmol/L,
P
< 0.001), BMI < 30 kg/m
2
(5.2 nmol/L,
P
< 0.001), non-smoking (4.8 nmol/L,
P
< 0.001), alcohol consumption (2.7 nmol/L,
P
< 0.001), and fatty fish consumption ≥ 3
x
/week (2.6 nmol/L,
P
< 0.001) were related to higher 25OHD in NCS only, but not in participants with dementia or MCI.
Discussion
Older people living in Iceland with dementia are at higher risk for 25OHD deficiency when compared to healthy individuals. Physical activity reported among participants with dementia, and MCI is low and is not significantly associated with 25OHD.
Conclusions
Lifestyle factors among NCS participants are associated with 25OHD levels. Importantly, healthy lifestyle should be promoted among individuals with MCI and dementia.
Cholinergic drugs are the most commonly used drugs for the treatment of Alzheimer's disease (AD). Therefore, a better understanding of the cholinergic system and its relation to both AD-related ...biomarkers and cognitive functions is of high importance.
To evaluate the relationships of cerebrospinal fluid (CSF) cholinergic enzymes with markers of amyloidosis, neurodegeneration, neurofibrillary tangles, inflammation and performance on verbal episodic memory in a memory clinic cohort.
In this cross-sectional study, 46 cholinergic drug-free subjects (median age = 71, 54% female, median MMSE = 28) were recruited from an Icelandic memory clinic cohort targeting early stages of cognitive impairment. Enzyme activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) was measured in CSF as well as levels of amyloid-β
(Aβ
), phosphorylated tau (P-tau), total-tau (T-tau), neurofilament light (NFL), YKL-40, S100 calcium-binding protein B (S100B), and glial fibrillary acidic protein (GFAP). Verbal episodic memory was assessed with the Rey Auditory Verbal Learning (RAVLT) and Story tests.
No significant relationships were found between CSF Aβ
levels and AChE or BuChE activity (
> 0.05). In contrast, T-tau (
= 0.46,
= 0.001) and P-tau (
= 0.45,
= 0.002) levels correlated significantly with AChE activity. Although neurodegeneration markers T-tau and NFL did correlate with each other (
= 0.59,
< 0.001), NFL did not correlate with AChE (
= 0.25,
= 0.09) or BuChE (
= 0.27,
= 0.06). Inflammation markers S100B and YKL-40 both correlated significantly with AChE (S100B:
= 0.43,
= 0.003; YKL-40:
= 0.32,
= 0.03) and BuChE (S100B:
= 0.47,
< 0.001; YKL-40:
= 0.38,
= 0.009) activity. A weak correlation was detected between AChE activity and the composite score reflecting verbal episodic memory (
= -0.34,
= 0.02). LASSO regression analyses with a stability approach were performed for the selection of a set of measures best predicting cholinergic activity and verbal episodic memory score. S100B was the predictor with the highest model selection frequency for both AChE (68%) and BuChE (73%) activity. Age (91%) was the most reliable predictor for verbal episodic memory, with selection frequency of both cholinergic enzymes below 10%.
Results indicate a relationship between higher activity of the ACh-degrading cholinergic enzymes with increased neurodegeneration, neurofibrillary tangles and inflammation in the stages of pre- and early symptomatic dementia, independent of CSF Aβ
levels.
To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and ...information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429-32,070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P-value=3.12 × 10(-8)) and in the joint discovery and replication meta-analysis (P-value=3.28 × 10(-9) after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 (CADM2) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex (P-value=4 × 10(-4)). The protein encoded by CADM2 is involved in glutamate signaling (P-value=7.22 × 10(-15)), gamma-aminobutyric acid (GABA) transport (P-value=1.36 × 10(-11)) and neuron cell-cell adhesion (P-value=1.48 × 10(-13)). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed.
Background. Among persons with white matter lesions (WMLs), there is a range of cognitive function. We examine whether participation in leisure activities modifies the effect of WML load on cognitive ...function. Methods. Data are from 2300 men and women (aged 66–92 years) participating in the population-based Age Gene/Environment Susceptibility-Reykjavik Study. Subcortical WML load was calculated as a weighted sum, based on size of lesions in the four lobes. Periventricular WML load was calculated as the sum of lesion scores, based on size, for the frontal caps, occipitoparietal caps and bands. The upper quartile of lesion load in either area was compared to the lower three quartiles. Composite scores of memory (MEM), speed of processing (SP), and executive function (EF) were constructed from a battery of neuropsychological tests. Frequency of participation in nine cognitively stimulating leisure activities was assessed via questionnaire; the upper quartile was compared to the lower three quartiles. Multiple regression, controlling for demographic and health factors and brain infarcts, was used to test the main effects and interaction of WMLs and leisure activity on cognitive function. Results. High leisure activity was associated with higher performance in all three cognitive abilities: MEM β = 0.20, 95% confidence interval CI, 0.11–0.29; SP β = 0.37, 95% CI, 0.29–0.45; and EF β = 0.23, 95% CI, 0.15–0.29. High WML load was associated with significantly lower performance in SP (β = −0.06, 95% CI, −0.13 to −0.01). The effect of WMLs on SP performance was modified by high leisure activity (p for interaction <.05). Conclusion. Participation in cognitively stimulating leisure activity may attenuate the effect of WML pathology on cognitive performance.
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