Asymptomatic Alzheimer disease Hohman, Timothy J; McLare, Donald G; Mormino, Elizabeth C ...
Neurology,
12/2016, Letnik:
87, Številka:
23
Journal Article
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Objective: To define robust resilience metrics by leveraging CSF biomarkers of Alzheimer disease (AD) pathology within a latent variable framework and to demonstrate the ability of such metrics to ...predict slower rates of cognitive decline and protection against diagnostic conversion. Methods: Participants with normal cognition (n = 297) and mild cognitive impairment (n = 432) were drawn from the Alzheimer's Disease Neuroimaging Initiative. Resilience metrics were defined at baseline by examining the residuals when regressing brain aging outcomes (hippocampal volume and cognition) on CSF biomarkers. A positive residual reflected better outcomes than expected for a given level of pathology (high resilience). Residuals were integrated into a latent variable model of resilience and validated by testing their ability to independently predict diagnostic conversion, cognitive decline, and the rate of ventricular dilation. Results: Latent variables of resilience predicted a decreased risk of conversion (hazard ratio < 0.54, p< 0.0001), slower cognitive decline (beta > 0.02, p< 0.001), and slower rates of ventricular dilation (beta < ?4.7, p< 2 x 10 super(?15)). These results were significant even when analyses were restricted to clinically normal individuals. Furthermore, resilience metrics interacted with biomarker status such that biomarker-positive individuals with low resilience showed the greatest risk of subsequent decline. Conclusions: Robust phenotypes of resilience calculated by leveraging AD biomarkers and baseline brain aging outcomes provide insight into which individuals are at greatest risk of short-term decline. Such comprehensive definitions of resilience are needed to further our understanding of the mechanisms that protect individuals from the clinical manifestation of AD dementia, especially among biomarker-positive individuals.
Cerebrospinal fluid (CSF) soluble triggering receptor expressed on myeloid cells-2 (sTREM2) is an emerging biomarker of neuroinflammation in Alzheimer's disease (AD). Yet, sTREM2 expression has not ...been systematically evaluated in relation to concomitant drivers of neuroinflammation. While associations between sTREM2 and tau in CSF are established, we sought to determine additional biological correlates of CSF sTREM2 during the prodromal stages of AD by evaluating CSF Aβ species (Aβx-40), a fluid biomarker of blood-brain barrier integrity (CSF/plasma albumin ratio), and CSF biomarkers of neurodegeneration measured in 155 participants from the Vanderbilt Memory and Aging Project. A novel association between high CSF levels of both sTREM2 and Aβx-40 was observed and replicated in an independent dataset. Aβx-40 levels, as well as the CSF/plasma albumin ratio, explained additional and unique variance in sTREM2 levels above and beyond that of CSF biomarkers of neurodegeneration. The component of sTREM2 levels correlated with Aβx-40 levels best predicted future cognitive performance. We highlight potential contributions of Aβ homeostasis and blood-brain barrier integrity to elevated CSF sTREM2, underscoring novel biomarker associations relevant to disease progression and clinical outcome measures.
•We describe a novel association between sTREM2 and Aβx-40 levels in cerebrospinal fluid important for cognitive memory trajectory in an aged cohort.•Aβx-40 levels and a fluid biomarker of blood-brain barrier integrity explain sTREM2 signal above and beyond established associations with tau.•Aβx-40, the CSF/plasma albumin ratio, and p-tau independently relate to sTREM2 and jointly explain 36% of variance in sTREM2 levels.
Research increasingly suggests that subjective cognitive decline (SCD) in older adults, in the absence of objective cognitive dysfunction or depression, may be a harbinger of non-normative cognitive ...decline and eventual progression to dementia. Little is known, however, about the key features of self-report measures currently used to assess SCD. The Subjective Cognitive Decline Initiative (SCD-I) Working Group is an international consortium established to develop a conceptual framework and research criteria for SCD (Jessen et al., 2014, Alzheimers Dement 10, 844-852). In the current study we systematically compared cognitive self-report items used by 19 SCD-I Working Group studies, representing 8 countries and 5 languages. We identified 34 self-report measures comprising 640 cognitive self-report items. There was little overlap among measures- approximately 75% of measures were used by only one study. Wide variation existed in response options and item content. Items pertaining to the memory domain predominated, accounting for about 60% of items surveyed, followed by executive function and attention, with 16% and 11% of the items, respectively. Items relating to memory for the names of people and the placement of common objects were represented on the greatest percentage of measures (56% each). Working group members reported that instrument selection decisions were often based on practical considerations beyond the study of SCD specifically, such as availability and brevity of measures. Results document the heterogeneity of approaches across studies to the emerging construct of SCD. We offer preliminary recommendations for instrument selection and future research directions including identifying items and measure formats associated with important clinical outcomes.
Enlarged perivascular spaces (ePVS) are difficult to quantify, and their etiologies and consequences are poorly understood. Vanderbilt Memory and Aging Project participants (n = 327, 73 ± 7 years) ...completed 3T brain MRI to quantify ePVS volume and count, longitudinal neuropsychological assessment, and cardiac MRI to quantify aortic stiffness. Linear regressions related (1) PWV to ePVS burden and (2) ePVS burden to cross-sectional and longitudinal neuropsychological performance adjusting for key demographic and medical factors. Higher aortic stiffness related to greater basal ganglia ePVS volume (β = 7.0×10−5, p = 0.04). Higher baseline ePVS volume was associated with worse baseline information processing (β = -974, p = 0.003), executive function (β = -81.9, p < 0.001), and visuospatial performances (β = -192, p = 0.02) and worse longitudinal language (β = -54.9, p = 0.05), information processing (β = -147, p = 0.03), executive function (β = -10.9, p = 0.03), and episodic memory performances (β = -10.6, p = 0.02). Results were similar for ePVS count. Greater arterial stiffness relates to worse basal ganglia ePVS burden, suggesting cardiovascular aging as an etiology. ePVS burden is associated with adverse cognitive trajectory, emphasizing the clinical relevance of ePVS.
Autopsy measures of Alzheimer's disease neuropathology have been leveraged as endophenotypes in previous genome-wide association studies (GWAS). However, despite evidence of sex differences in ...Alzheimer's disease risk, sex-stratified models have not been incorporated into previous GWAS analyses. We looked for sex-specific genetic associations with Alzheimer's disease endophenotypes from six brain bank data repositories. The pooled dataset included 2701 males and 3275 females, the majority of whom were diagnosed with Alzheimer's disease at autopsy (70%). Sex-stratified GWAS were performed within each dataset and then meta-analysed. Loci that reached genome-wide significance (P < 5 × 10-8) in stratified models were further assessed for sex interactions. Additional analyses were performed in independent datasets leveraging cognitive, neuroimaging and CSF endophenotypes, along with age-at-onset data. Outside of the APOE region, one locus on chromosome 7 (rs34331204) showed a sex-specific association with neurofibrillary tangles among males (P = 2.5 × 10-8) but not females (P = 0.85, sex-interaction P = 2.9 × 10-4). In follow-up analyses, rs34331204 was also associated with hippocampal volume, executive function, and age-at-onset only among males. These results implicate a novel locus that confers male-specific protection from tau pathology and highlight the value of assessing genetic associations in a sex-specific manner.
Recent evidence suggests that Alzheimer's disease (AD) genetic risk variants (rs1582763 and rs6591561) of the MS4A locus are genome-wide significant regulators of soluble TREM2 levels such that the ...minor allele of the protective variant (rs1582763) is associated with higher sTREM2 and lower AD risk while the minor allele of (rs6591561) relates to lower sTREM2 and higher AD risk. Our group previously found that higher sTREM2 relates to higher Aβ
, worse blood-brain barrier (BBB) integrity (measured with the CSF/plasma albumin ratio), and higher CSF tau, suggesting strong associations with amyloid abundance and both BBB and neurodegeneration complicate interpretation. We expand on this work by leveraging these common variants as genetic tools to tune the interpretation of high CSF sTREM2, and by exploring the potential modifying role of these variants on the well-established associations between CSF sTREM2 as well as TREM2 transcript levels in the brain with AD neuropathology. Biomarker analyses leveraged data from the Vanderbilt Memory & Aging Project (n = 127, age = 72 ± 6.43) and were replicated in the Alzheimer's Disease Neuroimaging Initiative (n = 399, age = 73 ± 7.39). Autopsy analyses were performed leveraging data from the Religious Orders Study and Rush Memory and Aging Project (n = 577, age = 89 ± 6.46). We found that the protective variant rs1582763 attenuated the association between CSF sTREM2 and Aβ
(β = -0.44, p-value = 0.017) and replicated this interaction in ADNI (β = -0.27, p = 0.017). We did not observe this same interaction effect between TREM2 mRNA levels and Aβ peptides in brain (Aβ total β = -0.14, p = 0.629; Aβ
, β = 0.11, p = 0.200). In contrast to the effects on Aβ, the minor allele of this same variant seemed to enhance the association with blood-brain barrier dysfunction (β = 7.0e-4, p = 0.009), suggesting that elevated sTREM2 may carry a much different interpretation in carriers vs. non-carriers of this allele. When evaluating the risk variant (rs6591561) across datasets, we did not observe a statistically significant interaction against any outcome in VMAP and observed opposing directions of associations in ADNI and ROS/MAP on Aβ levels. Together, our results suggest that the protective effect of rs1582763 may act by decoupling the associations between sTREM2 and amyloid abundance, providing important mechanistic insight into sTREM2 changes and highlighting the need to incorporate genetic context into the analysis of sTREM2 levels, particularly if leveraged as a clinical biomarker of disease in the future.
OBJECTIVES
Physical frailty (or loss of physiologic reserve) is associated with cognitive impairment and dementia. Subjective cognitive decline (SCD) may represent early pathologic changes of ...dementia. The association between these disease markers is unclear.
DESIGN
Cross‐sectional analysis.
SETTING
Community‐based participants from the Vanderbilt Memory & Aging Project.
PARTICIPANTS
A total of 306 older adults with normal cognition (NC; n = 174) or mild cognitive impairment (MCI; n = 132).
MEASUREMENTS
Frailty was measured using standard methods, and a composite frailty score was calculated. SCD was quantified using the Everyday Cognition Scale (ECog; total score and four domain scores). Objective cognition was assessed with the Montreal Cognitive Assessment (MoCA). Proportional odds models, stratified by sex, related the frailty composite to MoCA and total ECog score adjusting for age, education, body mass index, cognitive diagnosis, depressed mood, Framingham Stroke Risk Profile, apolipoprotein E (APOE ε4) carrier status, and height (for gait speed models). Secondary models related individual frailty components to SCD domains and explored associations in NC only.
RESULTS
In women, frailty composite was related to MoCA (odds ratio OR = .56; P = .04), a finding attenuated in sensitivity analysis (OR = .59; P = .08). Frailty composite related to ECog total (OR = 2.27; P = .02), planning (OR = 2.63; P = .02), and organization scores (OR = 2.39; P = .03). Increasing gait speed related to lower ECog total (OR = .06; P = .003) and memory scores (OR = .03; P < .001). Grip strength related to lower ECog planning score (OR = .91; P = .04). In men, frailty was unrelated to objective and subjective cognition (P values >.07). Findings were consistent in the NC group.
CONCLUSION
Frailty component and composite scores are related to SCD before the presence of overt dementia. Results suggest that this association is present before overt cognitive impairment. Results suggest a possible sex difference in the clinical manifestation of frailty, with primary associations noted in women. Further studies should investigate mechanisms linking early changes among frailty, SCD, and cognition. J Am Geriatr Soc, 1–9, 2019. J Am Geriatr Soc 67:1803–1811, 2019
To test the hypothesis that increased aortic stiffening is associated with greater CSF evidence of core Alzheimer disease pathology (β-amyloid Aβ, phosphorylated tau p-tau), neurodegeneration (total ...tau t-tau), synaptic dysfunction (neurogranin), neuroaxonal injury (neurofilament light NFL), and neuroinflammation (YKL-40, soluble triggering receptor expressed on myeloid cells 2 sTREM2), we analyzed pulse wave velocity (PWV) data and CSF data among older adults.
Participants free of stroke and dementia from the Vanderbilt Memory and Aging Project, an observational community-based study, underwent cardiac magnetic resonance to assess aortic PWV (meters per second) and lumbar puncture to obtain CSF. Linear regressions related aortic PWV to CSF Aβ, p-tau, t-tau, neurogranin, NFL, YKL-40, and sTREM2 concentrations after adjustment for age, race/ethnicity, education, apolipoprotein (APOE) ε4 status, Framingham Stroke Risk Profile, and cognitive diagnosis. Models were repeated testing PWV interactions with age, diagnosis,
ε4, and hypertension on each biomarker.
One hundred forty-six participants were examined (age 72 ± 6 years). Aortic PWV interacted with age on p-tau (β = 0.31,
= 0.04), t-tau, (β = 2.67,
= 0.05), neurogranin (β = 0.94,
= 0.04), and sTREM2 (β = 20.4,
= 0.05). Among participants >73 years of age, higher aortic PWV related to higher p-tau (β = 2.4,
= 0.03), t-tau (β = 19.3,
= 0.05), neurogranin (β = 8.4,
= 0.01), and YKL-40 concentrations (β = 7,880,
= 0.005). Aortic PWV had modest interactions with diagnosis on neurogranin (β = -10.76,
= 0.03) and hypertension status on YKL-40 (β = 18,020,
< 0.001).
Among our oldest participants, ≥74 years of age, greater aortic stiffening is associated with in vivo biomarker evidence of neuroinflammation, tau phosphorylation, synaptic dysfunction, and neurodegeneration, but not amyloidosis. Central arterial stiffening may lead to cumulative cerebral microcirculatory damage and reduced blood flow delivery to tissue, resulting in neuroinflammation and neurodegeneration in more advanced age.
Biomarker definitions for preclinical Alzheimer's disease (AD) have identified individuals with neurodegeneration (ND+) without β-amyloidosis (Aβ-) and labeled them with suspected non-AD ...pathophysiology (SNAP). We evaluated Apolipoprotein E (APOE) ε2 and ε4 allele frequencies across biomarker definitions-Aβ-/ND- (n = 268), Aβ+/ND- (n = 236), Aβ-/ND+ or SNAP (n = 78), Aβ+/ND+ (n = 204)-hypothesizing that SNAP would have an APOE profile comparable to Aβ-/ND-. Using AD Neuroimaging Initiative data (n = 786, 72±7 years, 48% female), amyloid status (Aβ+ or Aβ-) was defined by cerebrospinal fluid (CSF) Aβ-42 levels, and neurodegeneration status (ND+ or ND-) was defined by hippocampal volume from MRI. Binary logistic regression related biomarker status to APOE ε2 and ε4 allele carrier status, adjusting for age, sex, education, and cognitive diagnosis. Compared to the biomarker negative (Aβ-/ND-) participants, higher proportions of ε4 and lower proportions of ε2 carriers were observed among Aβ+/ND- (ε4: OR = 6.23, p<0.001; ε2: OR = 0.53, p = 0.03) and Aβ+/ND+ participants (ε4: OR = 12.07, p<0.001; ε2: OR = 0.29, p = 0.004). SNAP participants were statistically comparable to biomarker negative participants (p-values>0.30). In supplemental analyses, comparable results were observed when coding SNAP using amyloid imaging and when using CSF tau levels. In contrast to APOE, a polygenic risk score for AD that excluded APOE did not show an association with amyloidosis or neurodegeneration (p-values>0.15), but did show an association with SNAP defined using CSF tau (β = 0.004, p = 0.02). Thus, in a population with low levels of cerebrovascular disease and a lower prevalence of SNAP than the general population, APOE and known genetic drivers of AD do not appear to contribute to the neurodegeneration observed in SNAP. Additional work in population based samples is needed to better elucidate the genetic contributors to various etiological drivers of SNAP.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
OBJECTIVE:To assess cross-sectionally whether lower cardiac index relates to lower resting cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) among older adults.
METHODS:Vanderbilt Memory ...& Aging Project participants free of stroke, dementia, and heart failure were studied (n = 314, age 73 ± 7 years, 59% male, 39% with mild cognitive impairment). Cardiac index (liters per minute per meter squared) was quantified from echocardiography. Resting CBF (milliliters per 100 grams per minute) and hypercapnia-induced CVR were quantified from pseudo-continuous arterial spin-labeling MRI. Linear regressions with ordinary least-square estimates related cardiac index to regional CBF, with adjustment for age, education, race/ethnicity, Framingham Stroke Risk Profile score (systolic blood pressure, antihypertensive medication use, diabetes mellitus, current cigarette smoking, left ventricular hypertrophy, prevalent cardiovascular disease CVD, atrial fibrillation), APOE ε4 status, cognitive diagnosis, and regional tissue volume.
RESULTS:Lower cardiac index corresponded to lower resting CBF in the left (β = 2.4, p = 0.001) and right (β = 2.5, p = 0.001) temporal lobes. Results were similar when participants with prevalent CVD and atrial fibrillation were excluded (left temporal lobe β = 2.3, p = 0.003; right temporal lobe β = 2.5, p = 0.003). Cardiac index was unrelated to CBF in other regions assessed (p > 0.25) and CVR in all regions (p > 0.05). In secondary cardiac index × cognitive diagnosis interaction models, cardiac index and CBF associations were present only in cognitively normal participants and affected a majority of regions assessed with effects strongest in the left (p < 0.0001) and right (p < 0.0001) temporal lobes.
CONCLUSIONS:Among older adults without stroke, dementia, or heart failure, systemic blood flow correlates with cerebral CBF in the temporal lobe, independently of prevalent CVD, but not CVR.
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