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Medial temporal lobe and temporoparietal brain regions are among the earliest neocortical sites to undergo pathophysiologic alterations in Alzheimer's disease (AD), although the underlying white matter changes in these regions is less well known. We employed diffusion tensor imaging to evaluate early alterations in regional white matter integrity in participants diagnosed with mild cognitive impairment (MCI). The following regions of interests (ROIs) were examined: 1) anterior cingulum (AC); 2) posterior cingulum (PC); 3) genu of the corpus callosum; 4) splenium of the corpus callosum; and 5) as a control site for comparison, posterior limb of the internal capsule. Forty nondemented participants were divided into demographically-similar groups based on cognitive status (MCI: n = 20; normal control: n = 20), and fractional anisotropy (FA) estimates of each ROI were obtained. MCI participants showed greater posterior white matter (i.e., PC, splenium) but not anterior white matter (i.e., AC, genu) changes, after adjusting for age, stroke risk, and whole brain volume. FA differences of the posterior white matter were best accounted for by changes in radial but not axial diffusivity. PC FA was also significantly positively correlated with hippocampal volume as well as with performance on tests of verbal memory, whereas stroke risk was significantly correlated with genu FA and was unrelated to PC FA. When investigating subtypes of our MCI population, amnestic MCI participants showed lower PC white matter integrity relative to those with non-amnestic MCI. Findings implicate involvement of posterior microstructural white matter degeneration in the development of MCI-related cognitive changes and suggest that reduced FA of the PC may be a candidate neuroimaging marker of AD risk. [ABSTRACT FROM AUTHOR]

Elevated pulse pressure (PP) is associated with cognitive decline and increased risk of Alzheimer's disease (AD) in older adults, although the mechanisms behind these associations remain unclear. To address this question, we examined whether antemortem late-life PP elevation predicted vascular or AD pathology in autopsy-confirmed AD patients. Sixty-five elderly patients (mean age 74.2 years) clinically diagnosed with possible or probable AD underwent neuropsychological testing and blood pressure examinations. Postmortem histopathological measures of cerebrovascular disease (CVD) and AD neuropathology were later obtained on these same patients. We expected that antemortem PP elevation, but not standard blood pressure measures such as systolic or diastolic blood pressure, would predict the autopsy-based presence of CVD, and possibly AD pathology, in elderly AD patients. Results demonstrated that antemortem PP elevation was associated with the presence and severity of CVD at autopsy. For every 5 mmHg increase in antemortem PP there was an estimated 36% increase in the odds of having CVD at autopsy. Additionally, PP accounted for 12% of variance in CVD severity. No significant associations were present for cerebral amyloid angiopathy or Braak and Braak staging of the severity of AD pathology. Other standard blood pressure measures also did not significantly predict neuropathology. The association between antemortem PP and CVD at autopsy suggests that in older adults with AD, PP elevation may increase the risk of CVD. These findings may have treatment implications since some antihypertensive medications specifically address the pulsatile component of blood pressure (e.g., renin-angiotensin system inhibitors, calcium channel blockers). [ABSTRACT FROM AUTHOR]

Background: The uncompetitive NMDA antagonist, memantine (MEM), enhances prepulse inhibition of startle (PPI) across species. MEM is used to treat Alzheimer's disease (AD); conceivably, its acute impact on PPI might be used to predict a patient's sensitivity to MEM's therapeutic effects., Objective: To begin to test this possibility, we studied MEM effects on PPI and related measures in AD patients., Methods: 18 carefully screened individuals with AD (mean age = 72.8 y; M:F=9 : 9) completed double-blind order-balanced testing with MEM (placebo versus 20 mg), assessing acoustic startle magnitude, habituation, PPI, and latency., Results: Fifteen out of 18 participants exhibited reliable startle responses. MEM did not significantly impact startle magnitude or habituation. Compared to placebo responses, PPI was significantly increased after MEM (p < 0.04; d = 0.40); this comparison reached a large effect size for the 60 ms interval (d = 0.62), where maximal MEM effects on PPI were previously detected. Prepulses reduced peak startle latency ("latency facilitation") and this effect was amplified after MEM (p = 0.03; d = 0.41; for 60 ms intervals, d = 0.69). No effects of MEM were detected on cognition, nor were MEM effects on startle associated with cognitive or clinical measures., Conclusion: MEM enhances prepulse effects on startle magnitude and latency in AD; these changes in PPI and latency facilitation with MEM suggest that these measures can be used to detect an AD patient's neural sensitivity to acute MEM challenge. Studies in progress will determine whether such a "biomarker" measured at the outset on treatment can predict sensitivity to MEM's therapeutic effects.

Background: Altered cerebral blood flow (CBF) has been linked to increased risk for Alzheimer's disease (AD). However, whether altered CBF contributes to AD risk by accelerating cognitive decline remains unclear. It also remains unclear whether reductions in CBF accelerate neurodegeneration and development of small vessel cerebrovascular disease., Objective: To examine associations between CBF and trajectories of memory performance, regional brain atrophy, and global white matter hyperintensity (WMH) volume., Method: 147 Alzheimer's Disease Neuroimaging Initiative participants free of dementia underwent arterial spin labeling (ASL) magnetic resonance imaging (MRI) to measure CBF and serial neuropsychological and structural MRI examinations. Linear mixed effects models examined 5-year rate of change in memory and 4-year rate of change in regional brain atrophy and global WMH volumes as a function of baseline regional CBF. Entorhinal and hippocampal CBF were examined in separate models., Results: Adjusting for demographic characteristics, pulse pressure, apolipoprotein E ɛ4 positivity, cerebrospinal fluid p-tau/Aβ ratio, and neuronal metabolism (i.e., fluorodeoxyglucose standardized uptake value ratio), lower baseline entorhinal CBF predicted faster rates of decline in memory as well as faster entorhinal thinning and WMH progression. Hippocampal CBF did not predict cognitive or brain structure trajectories., Conclusion: Findings highlight the importance of early cerebrovascular dysfunction in AD risk and suggest that entorhinal CBF as measured by noninvasive ASL MRI is a useful biomarker predictive of future cognitive decline and of risk of both.

Background: Cognitively-defined subgroups are well-documented within neurodegeneration., Objective: We examined such profiles in diverse non-demented older adults and considered how resulting subgroups relate to modifiable factors associated with neurodegeneration., Methods: 121 non-demented (MMSE = 28.62) diverse (46%non-Latino Black, 40%non-Latino White, 15%Latino) community-dwelling adults (age = 67.7 years) completed cognitive, cardiovascular, physical activity, and diet evaluations. Latent profile analyses (LPA) employed six cognitive scores (letter fluency, letter-number sequencing, confrontational naming, 'animal' fluency, list-learning delayed recall, and recognition discriminability) to characterize cognitively-defined subgroups. Differences between resulting subgroups on cardiovascular (composite scores of overall health; specific health components including fasting blood levels) and lifestyle (sedentary behavior; moderate-to-vigorous physical activity; Mediterranean diet consumption) factors were examined using ANCOVAs adjusting for relevant confounders., Results: Based on sample means across cognitive scores, LPA resulted in the following cognitive subgroups: 1) high-average cognition, 55%non-Latino White and 64%female participants; 2) average cognition, 58%non-Latino Black and 68%male participants; 3) lower memory, 58%non-Latino Black participants; and 4) lower executive functioning, 70%Latinos. The high-average subgroup reported significantly higher Mediterranean diet consumption than the average subgroup (p = 0.001). The lower executive functioning group had higher fasting glucose and hemoglobin A1c than all other subgroups (p-values<0.001)., Conclusion: LPA revealed two average subgroups reflecting level differences in cognition previously reported between non-Latino White and Black adults, and two lower cognition subgroups in domains similar to those documented in neurodegeneration. These subgroups, and their differences, suggest the importance of considering social determinants of health in cognitive aging and modifiable risk.

Background: Age-related cerebrovascular and neuroinflammatory processes have been independently identified as key mechanisms of Alzheimer's disease (AD), although their interactive effects have yet to be fully examined., Objective: The current study examined 1) the influence of pulse pressure (PP) and inflammatory markers on AD protein levels and 2) links between protein biomarkers and cognitive function in older adults with and without mild cognitive impairment (MCI)., Methods: This study included 218 ADNI (81 cognitively normal [CN], 137 MCI) participants who underwent lumbar punctures, apolipoprotein E (APOE) genotyping, and cognitive testing. Cerebrospinal (CSF) levels of eight pro-inflammatory markers were used to create an inflammation composite, and amyloid-beta 1-42 (Aβ42), phosphorylated tau (p-tau), and total tau (t-tau) were quantified., Results: Multiple regression analyses controlling for age, education, and APOE ɛ4 genotype revealed significant PP x inflammation interactions for t-tau (B = 0.88, p = 0.01) and p-tau (B = 0.84, p = 0.02); higher inflammation was associated with higher levels of tau within the MCI group. However, within the CN group, analyses revealed a significant PP x inflammation interaction for Aβ42 (B = -1.01, p = 0.02); greater inflammation was associated with higher levels of Aβ42 (indicative of lower cerebral amyloid burden) in those with lower PP. Finally, higher levels of tau were associated with poorer memory performance within the MCI group only (p s < 0.05)., Conclusion: PP and inflammation exert differential effects on AD CSF proteins and provide evidence that vascular risk is associated with greater AD pathology across our sample of CN and MCI older adults.

Background: Working memory (WM) is often assessed with serial order tests such as repeating digits backward. In prior dementia research using the Backward Digit Span Test (BDT), only aggregate test performance was examined., Objective: The current research tallied primacy/recency effects, out-of-sequence transposition errors, perseverations, and omissions to assess WM deficits in patients with mild cognitive impairment (MCI)., Methods: Memory clinic patients (n = 66) were classified into three groups: single domain amnestic MCI (aMCI), combined mixed domain/dysexecutive MCI (mixed/dys MCI), and non-MCI where patients did not meet criteria for MCI. Serial order/WM ability was assessed by asking participants to repeat 7 trials of five digits backwards. Serial order position accuracy, transposition errors, perseverations, and omission errors were tallied., Results: A 3 (group)×5 (serial position) repeated measures ANOVA yielded a significant group×trial interaction. Follow-up analyses found attenuation of the recency effect for mixed/dys MCI patients. Mixed/dys MCI patients scored lower than non-MCI patients for serial position 3 (p < 0.003) serial position 4 (p < 0.002); and lower than both group for serial position 5 (recency; p < 0.002). Mixed/dys MCI patients also produced more transposition errors than both groups (p < 0.010); and more omissions (p < 0.020), and perseverations errors (p < 0.018) than non-MCI patients., Conclusions: The attenuation of a recency effect using serial order parameters obtained from the BDT may provide a useful operational definition as well as additional diagnostic information regarding working memory deficits in MCI.

Background/objective: The APOE ɛ4 allele and increased vascular risk have both been independently linked to cognitive impairment and dementia. Since few studies have characterized how these risk factors affect everyday functioning, we investigated the relationship between APOE ɛ4 genotype and elevated pulse pressure (PP) on functional change in cognitively normal participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI)., Methods: 738 normally aging participants underwent APOE genotyping, and baseline PP was calculated from blood pressure indices. The Functional Activities Questionnaire (FAQ) was completed by participants' informant at baseline and 6, 12, 24, 36, and 48-month follow-up visits. Multiple linear regression and multilevel modeling were used to examine the effects of PP and APOE ɛ4 genotype on cross-sectional and longitudinal FAQ scores, respectively., Results: Adjusting for demographic and clinical covariates, results showed that both APOE ɛ4 status and elevated PP predicted greater functional difficulty trajectories across four years of follow-up. Interestingly, however, elevated PP was associated with greater functional decline over time in ɛ4 non-carriers versus carriers., Conclusion: Results show that, although APOE ɛ4 status is the prominent predictor of functional difficulty for ɛ4 carriers, an effect of arterial stiffening on functional difficulty was observed in non-carriers. Future studies are needed in order to clarify the etiology of the association between PP and different brain aging processes, and further explore its utility as a marker of dementia risk. The present study underscores the importance of targeting modifiable risk factors such as elevated PP to prevent or slow functional decline and pathological brain aging.

Subjective memory complaints (SMC) are required when diagnosing amnestic mild cognitive impairment (aMCI), although their relationship with objective memory performance and Alzheimer's disease (AD) pathology remains unclear. We investigated whether the sex of the patient/participant moderates these associations. Participants were 940 normal control (NC) and aMCI participants from the Alzheimer's Disease Neuroimaging Initiative. SMC were assessed via the memory scale of the Everyday Cognition questionnaire. Discrepancy scores were calculated between self- and informant-reports and categorized into "overestimates," "comparable estimates", and "underestimates" of SMC. We conducted linear and logistic regressions to examine the interaction of sex with self- and informant-reported SMC and discrepancy group on the Rey Auditory Verbal Learning Test (RAVLT) Immediate and Delayed Recall and on PET measures of amyloid-β (Aβ) positivity. Diagnosis-stratified analyses were also conducted. Overall, there were sex by self- and informant-reported SMC interactions for Immediate and Delayed Recall. Despite a higher proportion of "overestimates" in women, greater self- and informant-reported SMC showed a stronger relationship to poorer RAVLT scores in women versus men. Diagnosis-stratified analyses revealed that results were driven by aMCI participants. Conversely, overall, greater self- and informant-reported SMC related to greater odds of Aβ positivity regardless of sex. In diagnosis-stratified analyses, only informant-reported SMC related to Aβ positivity in aMCI. Relative to "comparable estimates," "underestimates" of SMC were associated with poorer RAVLT scores across sexes in the overall sample and in aMCI. The predictive utility of self-report SMC may be limited to women in aMCI. Sex differences should be considered when evaluating SMC.

Elevated blood glucose and the apolipoprotein (APOE) ɛ4 allele have both been associated with increased dementia risk; however, the neuropathological mechanisms underlying these associations remain unclear. We examined the impact of APOE genotype and midlife blood glucose on post-mortem vascular and Alzheimer's disease (AD) neuropathology. Ninety-four participants from the Framingham Heart Study without diagnosed diabetes underwent health examination at midlife and brain autopsy at death. Histopathological measures of vascular and AD neuropathology were obtained and analyzed. Results demonstrated that, among APOE ɛ4 carriers, elevated blood glucose was associated with more severe AD pathology. There was no such relationship with vascular pathology. In a relatively healthy sample with low vascular risk burden, midlife elevated blood glucose was associated with greater AD pathology among APOE ɛ4 carriers. A better understanding of interactive effects of APOE genotype and vascular risk on neuropathology has implications for identification of individuals at risk for decline and long-term preventive treatment.

Mild cognitive impairment (MCI) is typically diagnosed using subjective complaints, screening measures, clinical judgment, and a single memory score. Our prior work has shown that this method is highly susceptible to false-positive diagnostic errors. We examined whether the criteria also lead to "false-negative" errors by diagnostically reclassifying 520 participants using novel actuarial neuropsychological criteria. Results revealed a false-negative error rate of 7.1%. Participants' neuropsychological performance, cerebrospinal fluid biomarkers, and rate of decline provided evidence that an MCI diagnosis is warranted. The impact of "missed" cases of MCI has direct relevance to clinical practice, research studies, and clinical trials of prodromal Alzheimer's disease.

We examined cortical amyloid-β (Aβ) levels and interactions with apolipoprotein (APOE) ɛ4 genotype status across empirically-derived mild cognitive impairment (MCI) subgroups and cognitively normal older adults. Participants were 583 ADNI participants (444 MCI, 139 normal controls [NC]) with baseline florbetapir positron emission tomography (PET) amyloid imaging and neuropsychological testing. Of those with ADNI-defined MCI, a previous cluster analysis [1] classified 51% (n = 227) of the current sample as amnestic MCI, 8% (n = 37) as dysexecutive/mixed MCI, and 41% (n = 180) as cluster-derived normal (cognitively normal). Results demonstrated that the dysexecutive/mixed and amnestic MCI groups showed significantly greater levels of amyloid relative to the cluster-derived normal and NC groups who did not differ from each other. Additionally, 78% of the dysexecutive/mixed, 63% of the amnestic MCI, 42% of the cluster-derived normal, and 34% of the NC group exceeded the amyloid positivity threshold. Finally, a group by APOE genotype interaction demonstrated that APOE ɛ4 carriers within the amnestic MCI, cluster-derived normal, and NC groups showed significantly greater amyloid accumulation compared to non-carriers of their respective group. Such an interaction was not revealed within the dysexecutive/mixed MCI group which was characterized by both greater cognitive impairment and amyloid accumulation compared to the other participant groups. Our results from the ADNI cohort show considerable heterogeneity in Aβ across all groups studied, even within a group of robust NC participants. Findings suggest that conventional criteria for MCI may be susceptible to false positive diagnostic errors, and that onset of Aβ accumulation may occur earlier in APOE ɛ4 carriers compared to non-carriers.

The NIA-AA criteria for "preclinical" Alzheimer's disease (AD) propose a staging method in which AD biomarkers follow an invariable temporal sequence in accordance with the amyloid cascade hypothesis. However, recent findings do not align with the proposed temporal sequence and "subtle cognitive decline," which has not been definitively operationalized, may occur earlier than suggested in preclinical AD. We aimed to define "subtle cognitive decline" using sensitive and reliable neuropsychological tests, and to examine the number and sequence of biomarker abnormalities in the Alzheimer's Disease Neuroimaging Initiative (ADNI). 570 cognitively normal ADNI participants were classified based on NIA-AA criteria and separately based on the number of abnormal biomarkers/cognitive markers associated with preclinical AD that each individual possessed. Results revealed that neurodegeneration alone was 2.5 times more common than amyloidosis alone at baseline. For those who demonstrated only one abnormal biomarker at baseline and later progressed to mild cognitive impairment/AD, neurodegeneration alone was most common, followed by amyloidosis alone or subtle cognitive decline alone, which were equally common. Findings suggest that most individuals do not follow the temporal order proposed by NIA-AA criteria. We provide an operational definition of subtle cognitive decline that captures both cognitive and functional decline. Additionally, we offer a new approach for staging preclinical AD based on number of abnormal biomarkers, without regard to their temporal order of occurrence. This method of characterizing preclinical AD is more parsimonious than the NIA-AA staging system and does not presume that all patients follow a singular invariant expression of the disease.

We compared two methods of diagnosing mild cognitive impairment (MCI): conventional Petersen/Winblad criteria as operationalized by the Alzheimer's Disease Neuroimaging Initiative (ADNI) and an actuarial neuropsychological method put forward by Jak and Bondi designed to balance sensitivity and reliability. 1,150 ADNI participants were diagnosed at baseline as cognitively normal (CN) or MCI via ADNI criteria (MCI: n = 846; CN: n = 304) or Jak/Bondi criteria (MCI: n = 401; CN: n = 749), and the two MCI samples were submitted to cluster and discriminant function analyses. Resulting cluster groups were then compared and further examined for APOE allelic frequencies, cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarker levels, and clinical outcomes. Results revealed that both criteria produced a mildly impaired Amnestic subtype and a more severely impaired Dysexecutive/Mixed subtype. The neuropsychological Jak/Bondi criteria uniquely yielded a third Impaired Language subtype, whereas conventional Petersen/Winblad ADNI criteria produced a third subtype comprising nearly one-third of the sample that performed within normal limits across the cognitive measures, suggesting this method's susceptibility to false positive diagnoses. MCI participants diagnosed via neuropsychological criteria yielded dissociable cognitive phenotypes, significant CSF AD biomarker associations, more stable diagnoses, and identified greater percentages of participants who progressed to dementia than conventional MCI diagnostic criteria. Importantly, the actuarial neuropsychological method did not produce a subtype that performed within normal limits on the cognitive testing, unlike the conventional diagnostic method. Findings support the need for refinement of MCI diagnoses to incorporate more comprehensive neuropsychological methods, with resulting gains in empirical characterization of specific cognitive phenotypes, biomarker associations, stability of diagnoses, and prediction of progression. Refinement of MCI diagnostic methods may also yield gains in biomarker and clinical trial study findings because of improvements in sample compositions of 'true positive' cases and removal of 'false positive' cases.

Background: Epidemiologic autopsy studies show mixed Alzheimer's disease (AD)/vascular pathology in many patients. Moreover, clinical research shows that it is not uncommon for AD and vascular dementia (VaD) patients to be equally impaired on memory, executive, or other neurocognitive tests. However, this clinical heterogeneity has not been incorporated into the new diagnostic criteria for AD (Dubois et al., 2010; McKhann et al., 2011)., Objective: The current research applied Latent Class Analysis (LCA) to a protocol of six neuropsychological parameters to identify phenotypic subtypes from a large group of AD/VaD participants. Follow-up analyses examined difference between groups on neuroradiological parameters and neuropsychological measures of process and errors., Methods: 223 AD/VaD patients were administered a comprehensive neuropsychological protocol. Measures of whole brain and hippocampal volume were available for a portion of the sample (n = 76)., Results: LCA identified four distinct groups: moderate/mixed dementia (n = 54; 24.21%), mild/mixed dementia (n = 91; 40.80%); dysexecutive (n = 49, 21.97%), and amnestic (n = 29, 13.00%). Follow-up analyses comparing the groups on neuropsychological process and error scores showed that the dysexecutive group exhibited difficulty sustaining mental set. The moderate/mixed group evidenced pronounced impairment on tests of lexical retrieval/naming along with significant amnesia. Amnestic patients also presented with gross amnesia, but showed relative sparing on other neuropsychological measures. Mild/mixed patients exhibited milder memory deficits that were intermediary between the amnestic and moderate/mixed groups., Conclusions: There are distinct neuropsychological profiles in patients independent of clinical diagnosis, suggesting that the two are not wholly separate and that this information should be integrated into new AD diagnostic paradigms.

Background: Reduced regional cerebral blood flow (rCBF) is a well-established finding in Alzheimer's disease (AD), although fewer studies have examined the role of increased regional cerebrovascular resistance. By calculating the ratio of mean arterial pressure to rCBF, it is possible to estimate an index of regional cerebrovascular resistance (CVRi) that may be a sensitive measure of occult cerebrovascular disease., Objective: To compare probable AD patients to mild cognitive impairment (MCI) and normal control (NC) participants on CVRi, the ratio of mean arterial pressure to rCBF., Methods: Eighty-one participants (12 AD, 23 MCI, 46 NC) were compared on CVRi using voxel-wise analyses. Region-of-interest analyses examined correlations between subcortical CVRi and both cognition and white matter lesion (WML) volume., Results: Voxel-wise analyses revealed CVRi elevation in AD relative to NCs (subcortical, medial temporal, posterior cingulate, precuneus, inferior parietal, superior temporal) and MCI (subcortical, posterior cingulate). MCI participants exhibited intermediate CVRi values within cortical and medial temporal areas. Significant CVRi clusters were larger and more widespread than those of parallel CBF analyses. Among MCI and AD participants, subcortical CVRi elevation was associated with lower Dementia Rating Scale score (r = -0.52, p = 0.001, for both thalamus and caudate), and caudate CVRi correlated with WML volume (r = 0.45, p = 0.001)., Conclusions: Cortical and subcortical CVRi is elevated in AD, particularly within the caudate and thalamus, where it is associated with decreased cognitive performance and increased WMLs. Findings suggest CVRi may play a role in cognitive decline and cerebrovascular disease in MCI and AD.