Effects of Beta-Amyloid on Resting State Functional Connectivity Within and Between Networks Reflect Known Patterns of Regional Vulnerability.

Beta-amyloid (Aß) deposition is one of the hallmarks of Alzheimer's disease (AD). However, it is also present in some cognitively normal elderly adults and may represent a preclinical disease state. While AD patients exhibit disrupted functional connectivity (FC) both within and between resting-state networks, studies of preclinical cases have focused primarily on the default mode network (DMN). The extent to which Aß-related effects occur outside of the DMN and between networks remains unclear. In the present study, we examine how within- and between-network FC are related to both global and regional Aß deposition as measured by [(11)C]PIB-PET in 92 cognitively normal older people. We found that within-network FC changes occurred in multiple networks, including the DMN. Changes of between-network FC were also apparent, suggesting that regions maintaining connections to multiple networks may be particularly susceptible to Aß-induced alterations. Cortical regions showing altered FC clustered in parietal and temporal cortex, areas known to be susceptible to AD pathology. These results likely represent a mix of local network disruption, compensatory reorganization, and impaired control network function. They indicate the presence of Aß-related dysfunction of neural systems in cognitively normal people well before these areas become hypometabolic with the onset of cognitive decline.

Intrinsic connectivity networks in healthy subjects explain clinical variability in Alzheimer's disease.

Although previous studies have emphasized the vulnerability of the default mode network (DMN) in Alzheimer's disease (AD), little is known about the involvement of other functional networks and their relationship to clinical phenotype. To test whether clinicoanatomic heterogeneity in AD is driven by the involvement of specific networks, network connectivity was assessed in healthy subjects by seeding regions commonly and specifically atrophied in three clinical AD variants: early-onset AD (age at onset, <65 y; memory and executive deficits), logopenic variant primary progressive aphasia (language deficits), and posterior cortical atrophy (visuospatial deficits). Four-millimeter seed regions of interest were used to obtain intrinsic connectivity maps in 131 healthy controls (age, 65.5 ± 3.5 y). Atrophy patterns in independent cohorts of AD variant patients and their correspondence to connectivity networks in controls were also assessed. The connectivity maps of commonly atrophied regions of interest support posterior DMN and precuneus network involvement across AD variants, whereas seeding regions specifically atrophied in each AD variant revealed distinct, syndrome-specific connectivity patterns. Goodness-of-fit analysis of each connectivity map with network templates showed the highest correspondence between the early-onset AD seed connectivity map and anterior salience and right executive-control networks, the logopenic aphasia seed connectivity map and the language network, and the posterior cortical atrophy seed connectivity map and the higher visual network. Connectivity maps derived from controls matched regions commonly and specifically atrophied in the patients. Our findings indicate that the posterior DMN and precuneus network are commonly affected in AD variants, whereas syndrome-specific neurodegenerative patterns are driven by the involvement of specific networks outside the DMN.

Alzheimer Disease Biomarkers as Outcome Measures for Clinical Trials in MCI.

BACKGROUND: The aim of this study was to compare the performance and power of the best-established diagnostic biological markers as outcome measures for clinical trials in patients with mild cognitive impairment (MCI). METHODS: Magnetic resonance imaging, F-18 fluorodeoxyglucose positron emission tomography markers, and Alzheimer's Disease Assessment Scale-cognitive subscale were compared in terms of effect size and statistical power over different follow-up periods in 2 MCI groups, selected from Alzheimer's Disease Neuroimaging Initiative data set based on cerebrospinal fluid (abnormal cerebrospinal fluid Aß1-42 concentration-ABETA+) or magnetic resonance imaging evidence of Alzheimer disease (positivity to hippocampal atrophy-HIPPO+). Biomarkers progression was modeled through mixed effect models. Scaled slope was chosen as measure of effect size. Biomarkers power was estimated using simulation algorithms. RESULTS: Seventy-four ABETA+ and 51 HIPPO+ MCI patients were included in the study. Imaging biomarkers of neurodegeneration, especially MR measurements, showed highest performance. For all biomarkers and both MCI groups, power increased with increasing follow-up time, irrespective of biomarker assessment frequency. CONCLUSION: These findings provide information about biomarker enrichment and outcome measurements that could be employed to reduce MCI patient samples and treatment duration in future clinical trials.

Alzheimer's disease neurodegenerative biomarkers are associated with decreased cognitive function but not ß-amyloid in cognitively normal older individuals.

ß-Amyloid (Aß) plaque deposition and neurodegeneration within temporoparietal and hippocampal regions may indicate increased risk of Alzheimer's disease (AD). This study examined relationships between AD biomarkers of Aß and neurodegeneration as well as cognitive performance in cognitively normal older individuals. Aß burden was quantified in 72 normal older human subjects from the Berkeley Aging Cohort (BAC) using [(11)C] Pittsburgh compound B (PIB) positron emission tomography. In the same individuals, we measured hippocampal volume, as well as glucose metabolism and cortical thickness, which were extracted from a template of cortical AD-affected regions. The three functional and structural biomarkers were merged into a highly AD-sensitive multimodality biomarker reflecting neural integrity. In the normal older individuals, there was no association between elevated PIB uptake and either the single-modality or the multimodality neurodegenerative biomarkers. Lower neural integrity within the AD-affected regions and a control area (the visual cortex) was related to lower scores on memory and executive function tests; the same association was not found with PIB retention. The relationship between cognition and the multimodality AD biomarker was stronger in individuals with the highest PIB uptake. The findings indicate that neurodegeneration occurs within AD regions regardless of Aß deposition and accounts for worse cognition in cognitively normal older people. The impact of neural integrity on cognitive functions is, however, enhanced in the presence of high Aß burden for brain regions that are most affected in AD.

Aß Deposition in aging is associated with increases in brain activation during successful memory encoding.

To investigate early effects of beta-amyloid (Aß) on neuronal function, elderly normal controls (NCs, age range 58-97) were scanned with Pittsburgh Compound-B (PIB) positron emission tomography (a measure of Aß) as well as functional magnetic resonance imaging (a measure of brain activation) while performing an episodic memory-encoding task of natural scenes (also performed by young NCs; age range 18-30). Relationships between Aß and activation were assessed across task-positive (regions that activate for subsequently remembered vs. forgotten scenes) and task-negative regions (regions that deactivate for subsequently remembered vs. forgotten scenes). Significant task-related activation was present in a distributed network spanning ventrolateral prefrontal, lateral occipital, lateral parietal, posterior inferior temporal cortices, and the right parahippocampal/hippocampus, whereas deactivation was present in many default mode network regions (posteromedial, medial prefrontal, and lateral temporoparietal cortices). Task-positive activation was higher in PIB+ compared with PIB- subjects, and this activation was positively correlated with memory measures in PIB+ subjects. Although task deactivation was not impaired in PIB+ NCs, deactivation was reduced in old versus young subjects and was correlated with worse task memory performance among old subjects. Overall, these results suggest that heightened activation during episodic memory encoding is present in NC elderly subjects with high Aß.

Not quite PIB-positive, not quite PIB-negative: slight PIB elevations in elderly normal control subjects are biologically relevant.

Researchers employing Pittsburgh Compound B positron emission tomography (PIB-PET) imaging have consistently indentified old normal control (oNC) subjects with elevated tracer uptake, suggesting the presence of beta-amyloid deposition in these individuals. However, a consensus regarding the level at which PIB reveals a biologically meaningful signal does not exist (ie. an appropriate cutoff value for PIB positivity remains unclear). In this exploratory study, we sought to investigate the range of PIB distribution volume ratio (DVR) values present in our oNC cohort (N=75, age range=58-97). oNC subjects were classified based on global PIB index values (average DVR across prefrontal, parietal, lateral temporal and cingulate cortices) by employing two approaches: (1) an iterative outlier approach that revealed a cutoff value of 1.16 (IO-cutoff) and (2) an approach using data from a sample of young normal control subjects (N=11, age range=20-30) that yielded a cutoff value of 1.08 (yNC-cutoff). oNC subjects falling above the IO-cutoff had values similar to AD subjects ("PIB+", 15%). Subjects falling between the 2 cutoffs were considered to have ambiguous PIB status ("Ambig", 20%) and the remaining oNC were considered "PIB-" (65%). Additional measures capturing focal DVR magnitude and extent of elevated DVR values were consistent with the classification scheme using PIB index values, and revealed evidence for elevated DVR values in a subset of PIB- oNC subjects. Furthermore, there were a greater proportion of ambiguously elevated values compared to low values, and these elevated values were present in regions known to show amyloid deposition. The analyses presented in this study, in conjunction with recently published pathological data, suggest a biological relevance of slight PIB elevations in aging.

Relationships between ß-amyloid and functional connectivity in different components of the default mode network in aging.

Although beta-amyloid (Aß) deposition is a characteristic feature of Alzheimer's disease (AD), this pathology is commonly found in elderly normal controls (NC). The pattern of Aß deposition as detected with Pittsburgh compound-B positron emission tomography (PIB-PET) imaging shows substantial spatial overlap with the default mode network (DMN), a group of brain regions that typically deactivates during externally driven cognitive tasks. In this study, we show that DMN functional connectivity (FC) during rest is altered with increasing levels of PIB uptake in NC. Specifically, FC decreases were identified in regions implicated in episodic memory (EM) processing (posteromedial cortex, ventral medial prefrontal cortex, and angular gyrus), whereas connectivity increases were detected in dorsal and anterior medial prefrontal and lateral temporal cortices. This pattern of decreases is consistent with previous studies that suggest heightened vulnerability of EM-related brain regions in AD, whereas the observed increases in FC may reflect a compensatory response.

Correlations of striatal dopamine synthesis with default network deactivations during working memory in younger adults.

Age-related deficits have been demonstrated in working memory performance and in the dopamine system thought to support it. We performed positron emission tomography (PET) scans on 12 younger (mean 22.7 years) and 19 older (mean 65.8 years) adults using the radiotracer 6-[(18)F]-fluoro-L-m-tyrosine (FMT), which measures dopamine synthesis capacity. Subjects also underwent functional magnetic resonance imaging (fMRI) while performing a delayed recognition working memory task. We evaluated age-related fMRI activity differences and examined how they related to FMT signal variations in dorsal caudate within each age group. In posterior cingulate cortex and precuneus (PCC/Pc), older adults showed diminished fMRI deactivations during memory recognition compared with younger adults. Greater task-induced deactivation (in younger adults only) was associated both with higher FMT signal and with worse memory performance. Our results suggest that dopamine synthesis helps modulate default network activity in younger adults and that alterations to the dopamine system may contribute to age-related changes in working memory function.

Relationship of striatal dopamine synthesis capacity to age and cognition.

Past research has demonstrated that performance on frontal lobe-dependent tasks is associated with dopamine system integrity and that various dopamine system deficits occur with aging. The positron emission tomography (PET) radiotracer 6-[(18)F]fluoro-l-m-tyrosine (FMT) is a substrate of the dopamine-synthesizing enzyme, aromatic amino acid decarboxylase (AADC). Studies using 6-[(18)F]fluorodopa (FDOPA) (another AADC substrate) to measure how striatal PET signal and age relate have had inconsistent outcomes. The varying results occur in part from tracer processing that renders FDOPA signal subject to aspects of postrelease metabolism, which may themselves change with aging. In contrast, FMT remains a purer measure of AADC function. We used partial volume-corrected FMT PET scans to measure age-related striatal dopamine synthesis capacity in 21 older (mean, 66.9) and 16 younger (mean, 22.8) healthy adults. We also investigated how striatal FMT signal related to a cognitive measure of frontal lobe function. Older adults showed significantly greater striatal FMT signal than younger adults. Within the older group, FMT signal in dorsal caudate (DCA) and dorsal putamen was greater with age, suggesting compensation for deficits elsewhere in the dopamine system. In younger adults, FMT signal in DCA was lower with age, likely related to ongoing developmental processes. Younger adults who performed worse on tests of frontal lobe function showed greater FMT signal in right DCA, independent of age effects. Our data suggest that higher striatal FMT signal represents nonoptimal dopamine processing. They further support a relationship between striatal dopamine processing and frontal lobe cognitive function.

Parallel ICA of FDG-PET and PiB-PET in three conditions with underlying Alzheimer's pathology.

The relationships between clinical phenotype, ß-amyloid (Aß) deposition and neurodegeneration in Alzheimer's disease (AD) are incompletely understood yet have important ramifications for future therapy. The goal of this study was to utilize multimodality positron emission tomography (PET) data from a clinically heterogeneous population of patients with probable AD in order to: (1) identify spatial patterns of Aß deposition measured by ((11)C)-labeled Pittsburgh Compound B (PiB-PET) and glucose metabolism measured by FDG-PET that correlate with specific clinical presentation and (2) explore associations between spatial patterns of Aß deposition and glucose metabolism across the AD population. We included all patients meeting the criteria for probable AD (NIA-AA) who had undergone MRI, PiB and FDG-PET at our center (N = 46, mean age 63.0 ± 7.7, Mini-Mental State Examination 22.0 ± 4.8). Patients were subclassified based on their cognitive profiles into an amnestic/dysexecutive group (AD-memory; n = 27), a language-predominant group (AD-language; n = 10) and a visuospatial-predominant group (AD-visuospatial; n = 9). All patients were required to have evidence of amyloid deposition on PiB-PET. To capture the spatial distribution of Aß deposition and glucose metabolism, we employed parallel independent component analysis (pICA), a method that enables joint analyses of multimodal imaging data. The relationships between PET components and clinical group were examined using a Receiver Operator Characteristic approach, including age, gender, education and apolipoprotein E ε4 allele carrier status as covariates. Results of the first set of analyses independently examining the relationship between components from each modality and clinical group showed three significant components for FDG: a left inferior frontal and temporoparietal component associated with AD-language (area under the curve [AUC] 0.82, p = 0.011), and two components associated with AD-visuospatial (bilateral occipito-parieto-temporal [AUC 0.85, p = 0.009] and right posterior cingulate cortex [PCC]/precuneus and right lateral parietal [AUC 0.69, p = 0.045]). The AD-memory associated component included predominantly bilateral inferior frontal, cuneus and inferior temporal, and right inferior parietal hypometabolism but did not reach significance (AUC 0.65, p = 0.062). None of the PiB components correlated with clinical group. Joint analysis of PiB and FDG with pICA revealed a correlated component pair, in which increased frontal and decreased PCC/precuneus PiB correlated with decreased FDG in the frontal, occipital and temporal regions (partial r = 0.75, p < 0.0001). Using multivariate data analysis, this study reinforced the notion that clinical phenotype in AD is tightly linked to patterns of glucose hypometabolism but not amyloid deposition. These findings are strikingly similar to those of univariate paradigms and provide additional support in favor of specific involvement of the language network, higher-order visual network, and default mode network in clinical variants of AD. The inverse relationship between Aß deposition and glucose metabolism in partially overlapping brain regions suggests that Aß may exert both local and remote effects on brain metabolism. Applying multivariate approaches such as pICA to multimodal imaging data is a promising approach for unraveling the complex relationships between different elements of AD pathophysiology.

Neural compensation in older people with brain amyloid-ß deposition.

Recruitment of extra neural resources may allow people to maintain normal cognition despite amyloid-ß (Aß) plaques. Previous fMRI studies have reported such hyperactivation, but it is unclear whether increases represent compensation or aberrant overexcitation. We found that older adults with Aß deposition had reduced deactivations in task-negative regions, but increased activation in task-positive regions related to more detailed memory encoding. The association between higher activity and more detailed memories suggests that Aß-related hyperactivation is compensatory.

Vascular risk and Aß interact to reduce cortical thickness in AD vulnerable brain regions.

OBJECTIVE: The objective of this study was to define whether vascular risk factors interact with ß-amyloid (Aß) in producing changes in brain structure that could underlie the increased risk of Alzheimer disease (AD). METHODS: Sixty-six cognitively normal and mildly impaired older individuals with a wide range of vascular risk factors were included in this study. The presence of Aß was assessed using [(11)C]Pittsburgh compound B-PET imaging, and cortical thickness was measured using 3-tesla MRI. Vascular risk was measured with the Framingham Coronary Risk Profile Index. RESULTS: Individuals with high levels of vascular risk factors have thinner frontotemporal cortex independent of Aß. These frontotemporal regions are also affected in individuals with Aß deposition, but the latter show additional thinning in parietal cortices. Aß and vascular risk were found to interact in posterior (especially in parietal) brain regions, where Aß has its greatest effect. In this way, the negative effect of Aß in posterior regions is increased by the presence of vascular risk. CONCLUSION: Aß and vascular risk interact to enhance cortical thinning in posterior brain regions that are particularly vulnerable to AD. These findings give insight concerning the mechanisms whereby vascular risk increases the likelihood of developing AD and supports the therapeutic intervention of controlling vascular risk for the prevention of AD.

Cortical thickness mediates the effect of ß-amyloid on episodic memory.

OBJECTIVE: To investigate the associations among ß-amyloid (Aß), cortical thickness, and episodic memory in a cohort of cognitively normal to mildly impaired individuals at increased risk of vascular disease. METHODS: In 67 subjects specifically recruited to span a continuum of cognitive function and vascular risk, we measured brain Aß deposition using [(11)C] Pittsburgh compound B-PET imaging and cortical thickness using MRI. Episodic memory was tested using a standardized composite score of verbal memory, and vascular risk was quantified using the Framingham Coronary Risk Profile index. RESULTS: Increased Aß was associated with cortical thinning, notably in frontoparietal regions. This relationship was strongest in persons with high Aß deposition. Increased Aß was also associated with lower episodic memory performance. Cortical thickness was found to mediate the relationship between Aß and memory performance. While age had a marginal effect on these associations, the relationship between Aß and cortical thickness was eliminated after controlling for vascular risk except when examined in only Pittsburgh compound B-positive subjects, in whom Aß remained associated with thinner cortex in precuneus and occipital lobe. In addition, only the precuneus was found to mediate the relationship between Aß and memory after controlling for vascular risk. CONCLUSION: These results suggest strong links among Aß, cortical thickness, and memory. They highlight that, in individuals without dementia, vascular risk also contributes to cortical thickness and influences the relationships among Aß, cortical thickness, and memory.

Associations between Alzheimer disease biomarkers, neurodegeneration, and cognition in cognitively normal older people.

IMPORTANCE: Criteria for preclinical Alzheimer disease (AD) propose ß-amyloid (Aß) plaques to initiate neurodegeneration within AD-affected regions. However, some cognitively normal older individuals harbor neural injury similar to patients with AD, without concurrent Aß burden. Such findings challenge the proposed sequence and suggest that Aß-independent precursors underlie AD-typical neurodegenerative patterns. OBJECTIVE To examine relationships between Aß and non-Aß factors as well as neurodegeneration within AD regions in cognitively normal older adults. The study quantified neurodegenerative abnormalities using imaging biomarkers and examined cross-sectional relationships with Aß deposition; white matter lesions (WMLs), a marker of cerebrovascular disease; and cognitive functions. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional study in a community-based convenience sample of 72 cognitively normal older individuals (mean [SD] age, 74.9 [5.7] years; 48 women; mean [SD] 17.0 [1.9] years of education) of the Berkeley Aging Cohort. INTERVENTION: Each individual underwent a standardized neuropsychological test session, magnetic resonance imaging, and positron emission tomography scanning. MAIN OUTCOMES AND MEASURES: For each individual, 3 AD-sensitive neurodegeneration biomarkers were measured: hippocampal volume, glucose metabolism, and gray matter thickness, the latter 2 sampled from cortical AD-affected regions. To quantify neurodegenerative abnormalities, each biomarker was age adjusted, dichotomized into a normal or abnormal status (using cutoff thresholds derived from an independent AD sample), and summarized into 0, 1, or more than 1 abnormal neurodegenerative biomarker. Degree and topographic patterns of neurodegenerative abnormalities were assessed and their relationships with cognitive functions, WML volume, and Aß deposition (quantified using carbon 11-labeled Pittsburgh compound B positron emission tomography). RESULTS: Of our cognitively normal elderly individuals, 40% (n = 29) displayed at least 1 abnormal neurodegenerative biomarker, 26% (n = 19) of whom had no evidence of elevated Pittsburgh compound B retention. In those people who were classified as having abnormal cortical thickness, degree and topographic specificity of neurodegenerative abnormalities were similar to patients with AD. Accumulation of neurodegenerative abnormalities was related to poor memory and executive functions as well as larger WML volumes but not elevated Pittsburgh compound B retention. CONCLUSIONS AND RELEVANCE: Our study confirms that a substantial proportion of cognitively normal older adults harbor neurodegeneration, without Aß burden. Associations of neurodegenerative abnormalities with cerebrovascular disease and cognitive performance indicate that neurodegenerative pathology can emerge through non-Aß pathways within regions most affected by AD.

The aging brain and cognition: contribution of vascular injury and aß to mild cognitive dysfunction.

IMPORTANCE: ß-Amyloid (Aß) deposition and vascular brain injury (VBI) frequently co-occur and are both associated with cognitive decline in aging. Determining whether a direct relationship exists between them has been challenging. We sought to understand VBI's influence on cognition and clinical impairment, separate from and in conjunction with pathologic changes associated with Alzheimer disease (AD). OBJECTIVE: To examine the relationship between neuroimaging measures of VBI and brain Aß deposition and their associations with cognition. DESIGN AND SETTING: A cross-sectional study in a community- and clinic-based sample recruited for elevated vascular disease risk factors. PARTICIPANTS: Clinically normal (mean age, 77.1 years [N = 30]), cognitively impaired (mean age, 78.0 years [N = 24]), and mildly demented (mean age, 79.8 years [N = 7]) participants. INTERVENTIONS: Magnetic resonance imaging, Aß (Pittsburgh Compound B-positron emission tomographic [PiB-PET]) imaging, and cognitive testing. MAIN OUTCOME MEASURES: Magnetic resonance images were rated for the presence and location of infarct (34 infarct-positive participants, 27 infarct-negative participants) and were used to quantify white matter lesion volume. The PiB-PET uptake ratios were used to create a PiB index by averaging uptake across regions vulnerable to early Aß deposition; PiB positivity (29 PiB-positive participants, 32 PiB-negative participants) was determined from a data-derived threshold. Standardized composite cognitive measures included executive function and verbal and nonverbal memory. RESULTS: Vascular brain injury and Aß were independent in both cognitively normal and impaired participants. Infarction, particularly in cortical and subcortical gray matter, was associated with lower cognitive performance in all domains (P < .05 for all comparisons). Pittsburgh Compound B positivity was neither a significant predictor of cognition nor interacted with VBI. CONCLUSIONS AND RELEVANCE: In this elderly sample with normal cognition to mild dementia, enriched for vascular disease, VBI was more influential than Aß in contemporaneous cognitive function and remained predictive after including the possible influence of Aß. There was no evidence that VBI increases the likelihood of Aß deposition. This finding highlights the importance of VBI in mild cognitive impairment and suggests that the impact of cerebrovascular disease should be considered with respect to defining the etiology of mild cognitive impairment.

Subjective cognition and amyloid deposition imaging: a Pittsburgh Compound B positron emission tomography study in normal elderly individuals.

OBJECTIVE: To study the relationship between subjective cognition and the neuropathological hallmark of Alzheimer disease (AD), amyloid-ß (Aß) deposition, using carbon 11-labeled Pittsburgh Compound B (PiB) positron emission tomography in normal elderly individuals. DESIGN: Cross-sectional analysis. SUBJECTS: Forty-eight cognitively normal elderly subjects (11 with high PiB uptake and 28 with low PiB uptake) were included. All underwent clinical and neuropsychological evaluations, magnetic resonance imaging, and positron emission tomography. SETTING: Berkeley Aging Cohort Study. MAIN OUTCOME MEASURE: Relationship between PiB uptake and subjective cognition measures. RESULTS: Subjects with high PiB uptake showed significantly lower performance than those with low PiB uptake on an episodic memory measure and were less confident about their general memory abilities when required to evaluate themselves relative to other people of the same age. High and low PiB uptake groups did not differ on the accuracy of their cognitive self-reports compared with objective cognitive performance. General memory self-reports from the whole group were significantly correlated with regional PiB uptake in the right medial prefrontal cortex and anterior cingulate cortex and in the right precuneus and posterior cingulate cortex. Reduced confidence about memory abilities was associated with greater PiB uptake in these brain regions. All results were independent of demographic variables and depressive affects. CONCLUSIONS: A decrease of self-confidence about memory abilities in cognitively normal elderly subjects may be related to the neuropathological hallmark of AD measured with PiB-positron emission tomography. Subjective cognitive impairment may represent a very early clinical manifestation of AD.

Cerebrovascular disease, ß-amyloid, and cognition in aging.

The present study evaluated cerebrovascular disease (CVD), ß-amyloid (Aß), and cognition in clinically normal elderly adults. Fifty-four participants underwent magnetic resonance imaging (MRI), Pittsburgh compound B (PIB)-positron emission tomography (PET) imaging, and neuropsychological evaluation. High white matter hyperintensity burden and/or presence of infarct defined CVD status (CVD-: n = 27; CVD+: n = 27). PIB-positron emission tomography ratios of Aß deposition were extracted using Logan plotting (cerebellar reference). Presence of high levels of Aß in prespecified regions determined PIB status (PIB-: n = 33; PIB+: n = 21). Executive functioning and episodic memory were measured using composite scales. CVD and Aß, defined as dichotomous or continuous variables, were unrelated to one another. CVD+ participants showed lower executive functioning (p = 0.001) when compared with CVD- individuals. Neither PIB status nor amount of Aß affected cognition (ps ≥ 0.45), and there was no statistical interaction between CVD and PIB on either cognitive measure. Within this spectrum of normal aging CVD and Aß aggregation appear to be independent processes with CVD primarily affecting cognition.

Summary metrics to assess Alzheimer disease-related hypometabolic pattern with 18F-FDG PET: head-to-head comparison.

UNLABELLED: In the recently revised diagnostic criteria for Alzheimer disease (AD), the National Institute on Aging and Alzheimer Association suggested that confidence in diagnosing dementia due to AD and mild cognitive impairment (MCI) due to AD could be improved by the use of certain biomarkers, such as (18)F-FDG PET evidence of hypometabolism in AD-affected brain regions. Three groups have developed automated data analysis techniques to characterize the AD-related pattern of hypometabolism in a single measurement. In this study, we sought to directly compare the ability of these three (18)F-FDG PET data analysis techniques--the PMOD Alzheimer discrimination analysis tool, the hypometabolic convergence index, and a set of meta-analytically derived regions of interest reflecting AD hypometabolism pattern (metaROI)--to distinguish moderate or mild AD dementia patients and MCI patients who subsequently converted to AD dementia from cognitively normal older adults. METHODS: One hundred sixty-six (18)F-FDG PET patients from the AD Neuroimaging Initiative, 308 from the Network for Efficiency and Standardization of Dementia Diagnosis, and 176 from the European Alzheimer Disease Consortium PET study were categorized, with masking of group classification, as AD, MCI, or healthy control. For each AD-related (18)F-FDG PET index, receiver-operating-characteristic curves were used to characterize and compare subject group classifications. RESULTS: The 3 techniques were roughly comparable in their ability to distinguish each of the clinical groups from cognitively normal older adults with high sensitivity and specificity. Accuracy of classification (in terms of area under the curve) in each clinical group varied more as a function of dataset than by technique. All techniques were differentially sensitive to disease severity, with the classification accuracy for MCI due to AD to moderate AD varying from 0.800 to 0.949 (PMOD Alzheimer tool), from 0.774 to 0.967 (metaROI), and from 0.801 to 0.983 (hypometabolic convergence index). CONCLUSION: The 3 tested techniques have the potential to help detect AD in research and clinical settings. Additional efforts are needed to clarify their ability to address particular scientific and clinical questions. Their incremental diagnostic value over other imaging and biologic markers makes them easier to implement by other groups for these purposes.

Associations between cognitive, functional, and FDG-PET measures of decline in AD and MCI.

The Functional Activities Questionnaire (FAQ) and Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) are frequently used indices of cognitive decline in Alzheimer's disease (AD). The goal of this study was to compare FDG-PET and clinical measurements in a large sample of elderly subjects with memory disturbance. We examined relationships between glucose metabolism in FDG-PET regions of interest (FDG-ROIs), and ADAS-cog and FAQ scores in AD and mild cognitive impairment (MCI) patients enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Low glucose metabolism at baseline predicted subsequent ADAS-cog and FAQ decline. In addition, longitudinal glucose metabolism decline was associated with concurrent ADAS-cog and FAQ decline. Finally, a power analysis revealed that FDG-ROI values have greater statistical power than ADAS-cog to detect attenuation of cognitive decline in AD and MCI patients. Glucose metabolism is a sensitive measure of change in cognition and functional ability in AD and MCI, and has value in predicting future cognitive decline.