Objective

To examine the effect of education (a surrogate measure of cognitive reserve) on FDG-PET brain metabolism in elderly cognitively healthy (HC) subjects with preclinical Alzheimer disease (AD).

Methods

Fifty-two HC subjects (mean age 75 years) with FDG-PET and CSF measurement of Aβ1-42 were included from the prospective Alzheimer's Disease Neuroimaging Initiative biomarker study. HC subjects received a research classification of preclinical AD if CSF Aβ1-42 was <192 pg/mL (Aβ1-42 [+]) vs HC with normal Aβ (Aβ1-42 [-]). In regression analyses, we tested the interaction effect between education and CSF Aβ1-42 status (Aβ1-42 [+] vs Aβ1-42 [-]) on FDG-PET metabolism in regions of interest (ROIs) (posterior cingulate, angular gyrus, inferior/middle temporal gyrus) and the whole brain (voxel-based).

Results

An interaction between education and CSF Aβ1-42 status was observed for FDG-PET in the posterior cingulate (p < 0.001) and angular gyrus ROIs (p = 0.03), but was not significant for the inferior/middle temporal gyrus ROI (p = 0.06), controlled for age, sex, and global cognitive ability (Alzheimer's Disease Assessment Scale-cognitive subscale). The interaction effect was such that higher education was associated with lower FDG-PET in the Aβ1-42 (+) group, but with higher FDG-PET in the Aβ1-42 (-) group. Voxel-based analysis showed that this interaction effect was primarily restricted to temporo-parietal and ventral prefrontal brain areas.

Conclusions

Higher education was associated with lower FDG-PET in preclinical AD (Aβ1-42 [+]), suggesting that cognitive reserve had a compensatory function to sustain cognitive ability in presence of early AD pathology that alters FDG-PET metabolism.

With recent advances in our understanding of the continuous pathophysiological changes that begin many years prior to symptom onset, it is now apparent that Alzheimer's disease cannot be adequately described by discrete clinical stages, but should also incorporate the continuum of biological changes that precede and underlie the clinical representation of the disease. By jointly considering longitudinal changes of all available biomarkers and clinical assessments, variation within individuals can be integrated into a single continuous measure of disease progression and used to identify the earliest pathophysiological changes. Disease time, a measure of disease severity, was estimated using a Bayesian latent time joint mixed-effects model applied to an array of imaging, biomarker and neuropsychological data. Trajectories of regional amyloid β and tau PET uptake were estimated as a function of disease time. Regions with early signs of elevated amyloid β uptake were used to form an early, focal composite and compared to a commonly used global composite, in a separate validation sample. Disease time was estimated in 279 participants (183 cognitively unimpaired individuals, 61 mild cognitive impairment and 35 Alzheimer's disease dementia patients) with available amyloid β and tau PET data. Amyloid β PET uptake levels in the posterior cingulate and precuneus start high and immediately increase with small increases of disease time. Early elevation in tau PET uptake was found in the inferior temporal lobe, amygdala, banks of the superior temporal sulcus, entorhinal cortex, middle temporal lobe, inferior parietal lobe and the fusiform gyrus. In a separate validation sample of 188 cognitively unimpaired individuals, the early, focal amyloid β PET composite showed a 120% increase in the accumulation rate of amyloid β compared to the global composite (P < 0.001), resulting in a 60% increase in the power to detect a treatment effect in a primary prevention trial design. Ordering participants on a continuous disease time scale facilitates the inspection of the earliest signs of amyloid β and tau pathology. To detect early changes in amyloid β pathology, focusing on the earliest sites of amyloid β accumulation results in more powerful and efficient study designs in early Alzheimer's disease. Targeted composites could be used to re-examine the thresholds for amyloid β-related study inclusion, especially as the field shifts to focus on primary and secondary prevention. Clinical trials of anti-amyloid β treatments may benefit from the use of focal composites when estimating drug effects on amyloid β and tau changes in populations with minimal amyloid β and tau pathology and limited expected short-term accumulation.

The objective of this study was to determine the cognitive and functional decline and development of brain injury in individuals progressing from preclinical (β-amyloid positive cognitively normal) to prodromal Alzheimer's disease (AD) (β-amyloid positive mild cognitive impairment [MCI]), and compare this with individuals who progress to MCI in the absence of significant amyloid pathology. Seventy-five cognitively healthy participants who progressed to MCI were followed for 4 years on average and up to 10 years. We tested effects of β-amyloid (Aβ) on measures of cognition, functional status, depressive symptoms, and brain structure and metabolism. Preclinical AD subjects showed greater cognitive decline in multiple domains and increased cerebrospinal fluid phosphorylated tau levels at baseline while Aβ-negative progressors showed increased rates of white matter hyperintensity accumulation and had a greater frequency of depressive symptoms at baseline. Aβ status did not influence patterns of brain atrophy, but preclinical AD subjects showed greater decline of brain metabolism than Aβ-negative progressors. Several unique features separate the transition from preclinical to prodromal AD from other causes of cognitive decline. These features may facilitate early diagnosis and treatment of AD, especially in clinical trials aimed at halting the progression from preclinical to prodromal AD.

Background

Little is known about the effects of cigarette smoking on longitudinal brain morphological changes in the elderly. This study investigated the effects of a history of cigarette smoking on changes in regional brain volumes over 2 years in healthy, cognitively intact elderly individuals. We predicted that individuals with a history of cigarette smoking, compared with never smokers, demonstrate greater rate of atrophy over 2 years in regions that manifest morphological abnormalities in the early stages of Alzheimer's disease (AD), as well as in the extended brain reward/executive oversight system (BREOS), which is implicated in the development and maintenance of substance use disorders.

Methods

Participants were healthy, cognitively normal elderly control subjects (75.9 ± 4.8 years of age) with any lifetime history of cigarette smoking (n = 68) or no history of smoking (n = 118). Data were obtained through the Alzheimer Disease Neuroimaging Initiative from 2005 to 2010. Participants completed four magnetic resonance scans over 2 years. A standardized protocol using high-resolution three-dimensional T1-weighted sequences at 1.5 T was used for structural imaging and regional brain volumetric analyses.

Results

Smokers demonstrated a significantly greater atrophy rate over 2 years than nonsmokers in multiple brain regions associated with the early stages of AD, as well as in the BREOS system. Groups did not differ on the rate of global cortical atrophy.

Conclusions

A history of cigarette smoking in this healthy elderly cohort was associated with decreased structural integrity of multiple brain regions, which manifested as a greater rate of atrophy over 2 years in regions specifically affected by incipient AD as well as chronic substance abuse.

Importance

Alzheimer disease has a long preclinical stage characterized by β-amyloid (Aβ) accumulation without symptoms. Several trials focus on this stage and use biomarkers to include Aβ-positive participants, but an even earlier prevention of Aβ accumulation may be an effective treatment strategy.

Objective

To determine whether people who appear to be Aβ negative but are at high risk for Aβ positivity within the near future can be identified.

Design, setting, and participants

Longitudinal biomarker cohort study involving 35 cognitively healthy individuals who underwent cerebrospinal fluid (CSF) sampling for up to 3 years during the study (October 24, 2005, to September 1, 2014). All participants had normal CSF Aβ42 levels at baseline.

Main outcomes and measures

Predictors of future Aβ positivity (levels of CSF Aβ42 declining below a previously validated cutoff level of 192 ng/L) tested by random forest models. Tested predictors included levels of protein in the CSF, hippocampal volume, genetics, demographics, and cognitive scores.

Results

The CSF Aβ42 levels declined in 11 participants, and the CSF became Aβ positive. The baseline CSF Aβ42 level was a strong predictor of future positivity (accuracy, 79% [95% CI, 70%-87%]). Ten of 11 decliners had baseline CSF Aβ42 levels in the lower tertile of the reference range (<225 ng/L), and 22 of 24 nondecliners had baseline CSF Aβ42 levels in the upper 2 tertiles (≥225 ng/L). A high CSF P-tau level was associated with decline (accuracy, 68%; 95% CI, 55%-81%).

Conclusions and relevance

Baseline CSF Aβ42 levels in the lower part of the reference range are strongly associated with future Aβ positivity. This finding can be used in trials on very early prevention of Alzheimer disease to identify people at high risk for Aβ accumulation as defined by low CSF Aβ42 levels.

Background and objectives

There is considerable heterogeneity in the association between increasing β-amyloid (Aβ) pathology and early cognitive dysfunction in preclinical Alzheimer disease (AD). At this stage, some individuals show no signs of cognitive dysfunction, while others show clear signs of decline. The factors explaining this heterogeneity are particularly important for understanding progression in AD but remain largely unknown. In this study, we examined an array of genetic variants that may influence the relationships among Aβ, brain structure, and cognitive performance in 2 large cohorts.

Methods

In 2,953 cognitively unimpaired participants from the Anti-Amyloid Treatment in Asymptomatic Alzheimer disease (A4) study, interactions between genetic variants and 18F-Florbetapir PET standardized uptake value ratio (SUVR) to predict the Preclinical Alzheimer Cognitive Composite (PACC) were assessed. Genetic variants identified in the A4 study were evaluated in the Alzheimer Disease Neuroimaging Initiative (ADNI, N = 527) for their association with longitudinal cognition and brain atrophy in both cognitively unimpaired participants and those with mild cognitive impairment.

Results

In the A4 study, 4 genetic variants significantly moderated the association between Aβ load and cognition. Minor alleles of 3 variants were associated with additional decreases in PACC scores with increasing Aβ SUVR (rs78021285, β = -2.29, SE = 0.40, p _FDR = 0.02, nearest gene ARPP21; rs71567499, β = -2.16, SE = 0.38, p _FDR = 0.02, nearest gene PPARD; and rs10974405, β = -1.68, SE = 0.29, p _FDR = 0.02, nearest gene GLIS3). The minor allele of rs7825645 was associated with less decrease in PACC scores with increasing Aβ SUVR (β = 0.71, SE = 0.13, p _FDR = 0.04, nearest gene FGF20). The genetic variant rs76366637, in linkage disequilibrium with rs78021285, was available in both the A4 and ADNI. In the A4, rs76366637 was strongly associated with reduced PACC scores with increasing Aβ SUVR (β = -1.01, SE = 0.21, t = -4.90, p < 0.001). In the ADNI, rs76366637 was associated with accelerated cognitive decline (χ² = 15.3, p = 0.004) and atrophy over time (χ² = 26.8, p < 0.001), with increasing Aβ SUVR.

Discussion

Patterns of increased cognitive dysfunction and accelerated atrophy due to specific genetic variation may explain some of the heterogeneity in cognition in preclinical and prodromal AD. The genetic variant near ARPP21 associated with lower cognitive scores in the A4 and accelerated cognitive decline and brain atrophy in the ADNI may help to identify those at the highest risk of accelerated progression of AD.

Objective

Use latent class analysis (LCA) to identify patterns of cognitive functioning in a sample of older adults with clinical depression and without dementia and assess demographic, psychiatric, and neurobiological predictors of class membership.

Method

Neuropsychological assessment data from 121 participants in the Alzheimer's Disease Neuroimaging Initiative-Depression project (ADNI-D) were analyzed, including measures of executive functioning, verbal and visual memory, visuospatial and language functioning, and processing speed. These data were analyzed using LCA, with predictors of class membership such as depression severity, depression and treatment history, amyloid burden, and APOE e4 allele also assessed.

Results

A two-class model of cognitive functioning best fit the data, with the Lower Cognitive Class (46.1% of the sample) performing approximately one standard deviation below the Higher Cognitive Class (53.9%) on most tests. When predictors of class membership were assessed, carrying an APOE e4 allele was significantly associated with membership in the Lower Cognitive Class. Demographic characteristics, age of depression onset, depression severity, history of psychopharmacological treatment for depression, and amyloid positivity did not predict class membership.

Conclusion

LCA allows for identification of subgroups of cognitive functioning in a mostly cognitively intact late life depression (LLD) population. One subgroup, the Lower Cognitive Class, more likely to carry an APOE e4 allele, may be at a greater risk for subsequent cognitive decline, even though current performance on neuropsychological testing is within normal limits. These findings have implications for early identification of those at greatest risk, risk factors, and avenues for preventive intervention.

Background

Reduced cerebrospinal fluid (CSF) α-synuclein has been described in synucleinopathies, including dementia with Lewy bodies (DLB). Common symptoms of DLB include visual hallucinations and visuospatial and executive deficits. Co-occurrence of Lewy body pathology is common in Alzheimer's disease (AD) patients, but it is unknown if reduced CSF α-synuclein is associated with Lewy body-like symptomatology in AD.

Objective

Determine associations between CSF α-synuclein and Lewy body-like symptomatology.

Methods

We included 73 controls (NC), 121 mild cognitive impairment (MCI) patients, and 61 AD patients (median follow-up 3.5 years, range 0.6-7.8). We tested associations between baseline CSF α-synuclein and visual hallucinations and (longitudinal) cognition. Models were tested with and without co-varying for CSF total tau (T-tau), which is elevated in AD patients, and believed to reflect neurodegeneration.

Results

Hallucinations were reported in 20% of AD patients, 13% of MCI patients, and 8% of NC. In AD, low CSF α-synuclein was associated with hallucinations. When adjusting for CSF T-tau, low CSF α-synuclein was associated with accelerated decline of executive function (NC, MCI, and AD), memory (MCI and AD), and language (MCI).

Conclusion

The associations of low CSF α-synuclein with hallucinations and poor executive function, which are hallmarks of DLB, indirectly suggest that this biomarker may reflect underlying synuclein pathology. The associations with memory and language in MCI and AD suggests either that reduced CSF α-synuclein also partly reflects global impaired neuronal/synaptic function, or that non-specific overall cognitive deterioration is accelerated in the presence of synuclein related pathology. The findings will require autopsy verification.

Background

Cerebrospinal fluid (CSF) α-synuclein is reduced in synucleinopathies, including dementia with Lewy bodies, and some studies have found increased CSF α-synuclein in Alzheimer's disease (AD). No study has explored effects of CSF α-synuclein on brain atrophy. Here we tested if baseline CSF α-synuclein affects brain atrophy rates and if these effects vary across brain regions, and across the cognitive spectrum from healthy elders (NL), to patients with mild cognitive impairment (MCI) and AD.

Methods

Baseline CSF α-synuclein measurements and longitudinal structural brain magnetic resonance imaging was performed in 74 NL, 118 MCI patients and 55 AD patients. Effects of baseline CSF α-synuclein on regional atrophy rates were tested in 1) four pre-hoc defined regions possibly associated with Lewy body and/or AD pathology (amygdala, caudate, hippocampus, brainstem), and 2) all available regions of interest. Differences across diagnoses were tested by assessing the interaction of CSF α-synuclein and diagnosis (testing NL versus MCI, and NL versus AD).

Results

The effects of CSF α-synuclein on longitudinal atrophy rates were not significant after correction for multiple comparisons. There were tendencies for effects in AD in caudate (higher atrophy rates in subjects with higher CSF α-synuclein, P=0.046) and brainstem (higher atrophy rates in subjects with lower CSF α-synuclein, P=0.063). CSF α-synuclein had significantly different effects on atrophy rates in NL and AD in brainstem (P=0.037) and caudate (P=0.006).

Discussion

With the possible exception of caudate and brainstem, the overall weak effects of CSF α-synuclein on atrophy rates in NL, MCI and AD argues against CSF α-synuclein as a biomarker related to longitudinal brain atrophy in these diagnostic groups. Any effects of CSF α-synuclein may be attenuated by possible simultaneous occurrence of AD-related neuronal injury and concomitant Lewy body pathology, which may elevate and reduce CSF α-synuclein levels, respectively.

OBJECTIVES: Late Life Depression (LLD) is associated with persistent cognitive dysfunction even after depression symptoms improve. The present study was designed to examine cognitive outcomes associated with the pattern of depression severity change during psychotherapy intervention for LLD. METHODS: 96 community-dwelling adults ages 65-91 with major depressive disorder completed 12 sessions of Problem-Solving Therapy at the University of California, San Francisco. Nonlinear trajectories of depression severity ratings using the Hamilton Depression Rating Scale were computed from multiple time points collected throughout the weekly psychotherapy intervention. Performance on measures of cognition (information processing speed, executive functioning, verbal learning, memory) was assessed at baseline and post-treatment. Linear mixed-effects models examined associations between nonlinear depression severity trajectories and post-treatment change in cognitive performance. RESULTS: Broadly, different patterns of depression change during treatment were associated with improved cognition post-treatment. Greater and more consistent interval improvements in depression ratings were differentially associated with improvements in aspects of verbal learning, memory, and executive function post-treatment, while no associations were found with information processing speed. CONCLUSIONS: The heterogeneity of depression trajectories associated with improved cognitive outcomes suggests that the temporal pattern of depression response may impact specific cognitive processes distinctly. Results suggest that use of nonlinear depression severity trajectories may help to elucidate complex associations between the time course of depression response and cognitive outcomes of psychotherapy in LLD. These findings have important implications for identifying treatment targets to enhance clinical and cognitive outcomes of psychotherapy in LLD.