Search

Interstitial concentration of amyloid beta (Aß) is positively related to synaptic activity in animal experiments. In humans, Aß deposition in Alzheimer's disease overlaps with cortical regions highly active earlier in life. White matter lesions (WML) disrupt connections between gray matter (GM) regions which in turn changes their activation patterns. Here, we tested if WML are related to Aß accumulation (measured with PiB-PET) and glucose uptake (measured with FDG-PET) in connected GM. WML masks from 72 cognitively normal (age 61.7 ± 9.6 years, 71% women) individuals were obtained from T2-FLAIR. MRI and PET images were normalized into common space, segmented and parcellated into gray matter (GM) regions. The effects of WML on connected GM regions were assessed using the Change in Connectivity (ChaCo) score. Defined for each GM region, ChaCo is the percentage of WM tracts connecting to that region that pass through the WML mask. The regional relationship between ChaCo, glucose uptake and Aß was explored via linear regression. Subcortical regions of the bilateral caudate, putamen, calcarine, insula, thalamus and anterior cingulum had WM connections with the most lesions, followed by frontal, occipital, temporal, parietal and cerebellar regions. Regional analysis revealed that GM with more lesions in connecting WM and thus impaired connectivity had lower FDG-PET (r = 0.20, p

Background: Structural magnetic resonance imaging is used to longitudinally monitor the progression of Alzheimer disease from its presymptomatic to symptomatic phases. Using magnetic resonance imaging data from the Alzheimer's Disease Neuroimaging Initiative, we tested the hypothesis that surgery would impact brain parameters associated with progression of dementia.Methods: Brain images from the neuroimaging initiative database were used to study normal volunteer subjects and patients with mild cognitive impairment for the age group 55 to 90 inclusive. We compared changes in regional brain anatomy for three visits that defined two intervisit intervals for a surgical cohort (n = 41) and a propensity matched nonsurgical control cohort (n = 123). The first interval for the surgical cohort contained the surgical date. Regional brain volumes were determined with Freesurfer and quantitatively described with J-image software (University of California at San Francisco, San Francisco, California). Statistical analysis used Repeated Measures ANCOVA (SPSS, v.18.0; Chicago, IL).Results: We found that surgical patients, during the first follow-up interval (5-9 months), but not subsequently, had increased rates of atrophy for cortical gray matter and hippocampus, and lateral ventricle enlargement, as compared with nonsurgical controls. A composite score of five cognitive tests during this interval showed reduced performance for surgical patients with mild cognitive impairment.Conclusions: Elderly subjects after surgery experienced an increased rate of brain atrophy during the initial evaluation interval, a time associated with enhanced risk for postoperative cognitive dysfunction. Although there was no difference in atrophy rate by diagnosis, subjects with mild cognitive impairment suffered greater subsequent cognitive effects. [ABSTRACT FROM AUTHOR]

Background: The pathophysiological process of Alzheimer's disease (AD) begins many years before the emergence of clinical symptoms (preclinical AD). A hypothetical biomarker progression in the pathogenesis of AD has been suggested, beginning with the deposition of amyloid-β (Aβ) and followed by increases in neurofibrillary tangles, synaptic loss, hippocampal atrophy, and lastly, cognitive impairment. Objective: We explored the effect of several risk factors for AD on the pattern of AD biomarker expression in normal subjects. Methods: AD biomarker evidence was examined at baseline in 96 cognitively normal elderly subjects with none or at least one of the following: ApoE4+ allele, a maternal history of AD (mFHx), sleep-disordered breathing (SDB), and longitudinal evidence of decline to mild cognitive impairment or AD (decliners) at follow-up. Results: Decliners and ApoE4+ subjects presented with expected reduced cerebrospinal fluid Aβ42, elevated P-tau and T-tau. In addition, decliners had fluorodeoxyglucose positron emission tomography hypometabolism in the medial temporal lobe. Individuals with mFHx demonstrated no Aβ42 effect, but had elevations in P-tau and T-tau. SDB was found to be associated with elevated Aβ42, P-tau and T-tau, as well as with reduced medial temporal lobe glucose metabolic rates. Conclusion: Our results indicate a heterogeneous biomarker expression, suggesting diversity of AD pathways in at-risk presymptomatic subjects. © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Introduction: We examined whether hypertension (HTN) was associated with Alzheimer's disease-related biomarkers in cerebrospinal fluid (CSF) and how changes in blood pressure (BP) related to changes in CSF biomarkers over time., Methods: A longitudinal observation of cognitively healthy normotensive subjects (n = 134, BP < 140/90, with no antihypertensive medication), controlled HTN (n = 36, BP < 140/90, taking antihypertensive medication), and 35 subjects with uncontrolled HTN (BP ≥ 140/90). The follow-up range was 0.5to15.6 years., Results: Total tau (T-tau) and phospho-tau181 (P-tau 181) increased in all but controlled HTN subjects (group×time interaction: p < 0.05 for both), but no significant Aβ42 changes were seen. Significant BP reduction was observed in uncontrolled HTN, and it was related to increase in T-tau (p = 0.001) and P-tau 181 (p < 0.001)., Discussion: Longitudinal increases in T-tau and P-tau 181 were observed in most subjects; however, only uncontrolled HTN had both markers increase alongside BP reductions. We speculate cumulative vascular injury renders the brain susceptible to relative hypoperfusion with BP reduction., Highlights: Over the course of the study, participants with uncontrolled HTN at baseline showed greater accumulation of CSF total tau and phospho-tau181 (P-tau 181) than subjects with normal BP or with controlled HTN. In the group with uncontrolled HTN, increases in total tau and P-tau 181 coincided with reduction in BP. We believe this highlights the role of HTN in vascular injury and suggests decline in cerebral perfusion resulting in increased biomarker concentrations in CSF. Medication use was the main factor differentiating controlled from uncontrolled HTN, indicating that earlier treatment was beneficial for preventing accumulations of pathology., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Abnormal cognitive ageing, including dementia, poses serious challenges to health and social systems in ageing populations. As such, characterizing factors associated with abnormal cognitive ageing and developing needed preventive measures are of great importance. The ε4 allele of the Apolipoprotein E gene (APOE4) is a well-known genetic risk factor for late-onset Alzheimer's disease. APOE4 carriers are also at elevated risk of cardiovascular diseases which are associated with increased risk of cognitive impairment. On the other hand, APOE4 is known to be associated with reduced risk of multiple common types of cancer-a major age-related disease and leading cause of mortality. We conducted the first-ever study of APOE4's opposing effects on cognitive decline and mortality using competing risk models considering two types of death-death with high-amounts versus low-amounts of autopsy-assessed Alzheimer's neuropathology. We observed that APOE4 was associated with decreased mortality risk in people who died with low amounts of Alzheimer's-type neuropathology, but APOE4 was associated with increased mortality risk in people who died with high amounts of Alzheimer's-type neuropathology, a major risk factor of cognitive impairment. Possible preventive measures of abnormal cognitive ageing are also discussed., (© 2023. Springer Nature Limited.)

Background: In sporadic Alzheimer's disease (AD), brain amyloid-beta (Aβ) deposition is believed to be a consequence of impaired Aβ clearance, but this relationship is not well established in living humans. CSF clearance, a major feature of brain glymphatic clearance (BGC), has been shown to be abnormal in AD murine models. MRI phase contrast and intrathecally delivered contrast studies have reported reduced CSF flow in AD. Using PET and tau tracer 18 F-THK5117, we previously reported that the ventricular CSF clearance of the PET tracer was reduced in AD and associated with elevated brain Aβ levels., Methods: In the present study, we use two PET tracers, 18 F-THK5351 and 11 C-PiB to estimate CSF clearance calculated from early dynamic PET frames in 9 normal controls and 15 AD participants., Results: we observed that the ventricular CSF clearance measures were correlated (r = 0.66, p < 0.01), with reductions in AD of 18 and 27%, respectively. We also replicated a significant relationship between ventricular CSF clearance ( 18 F-THK5351) and brain Aβ load (r =  - 0.64, n = 24, p < 0.01). With a larger sample size, we extended our observations to show that reduced CSF clearance is associated with reductions in cortical thickness and cognitive performance., Conclusions: Overall, the findings support the hypothesis that failed CSF clearance is a feature of AD that is related to Aβ deposition and to the pathology of AD. Longitudinal studies are needed to determine whether failed CSF clearance is a predictor of progressive amyloidosis or its consequence., (© 2022. The Author(s).)

Objective: This study evaluated costs and healthcare utilization associated with a culturally-sensitive, medical and education program for pediatric Latino patients with type 1 diabetes., Research Design and Methods: Program participants included Latino children ages 1-20 years old diagnosed with type 1 diabetes (n = 57). Control subjects with type 1 diabetes were matched by age, sex, and zip code to intervention participants from the Colorado All Payer Claims Database. Data included emergency department (ED) visits, hospitalizations, demographic information, and health insurance claims data 180 days prior to program start/index date through 1 year after program start/index date. We tracked program staff time and estimated costs for healthcare utilization using data from the scientific literature. Generalized Estimating Equation (GEE) models with logit link were used to estimate group differences in probabilities of ED visits and hospitalizations over 6-month periods pre/post-study, accounting for correlation of within-subject data across time points. Sensitivity analyses modeled longer-term cost differences under different assumptions., Results: The intervention group had fewer hospitalizations, 2% versus 12% of controls (p = 0.047,OR = 0.13;95%CI: 0.02-0.97) for 6 months following start date. The intervention group had fewer ED visits, 19% versus 32% in controls (n.s.; p = 0.079,OR = 0.52;95%CI:0.25-1.08) and significantly fewer hospitalizations, 4% versus 15% of controls (p = 0.039,OR = 0.21;95%CI: 0.05-0.93) 6-12 months post-start date. One-year per-patient program costs of $633 and healthcare cost savings of $2710 yielded total per-patient savings of $2077, or a 5-year cost savings of $14,106., Conclusion: This unique type 1 diabetes management program altered health service utilization of program participants, reducing major healthcare cost drivers, ED visits, and hospitalizations., (© 2021 John Wiley & Sons A/S . Published by John Wiley & Sons Ltd.)

Quality Improvement Success Stories are published by the American Diabetes Association in collaboration with the American College of Physicians, Inc., and the National Diabetes Education Program. This series is intended to highlight best practices and strategies from programs and clinics that have successfully improved the quality of care for people with diabetes or related conditions. Each article in the series is reviewed and follows a standard format developed by the editors of Clinical Diabetes . The following article describes the establishment of a Diabetes Prevention Clinic for veterans with prediabetes., (© 2020 by the American Diabetes Association.)

Background: Relaxation, biofeedback, and cognitive behavioral therapy are evidence-based behavioral therapies for migraine. Despite such efficacy, research shows that only about half of patients initiate behavioral therapy recommended by their headache specialists., Objective: Motivational interviewing (MI) is a widely used method to help patients explore and overcome ambivalence to enact positive life changes. We tested the hypothesis that telephone-based MI would improve initiation, scheduling, and attending behavioral therapy for migraine., Methods: Single-blind randomized controlled trial comparing telephone-based MI to treatment as usual (TAU). Participants were recruited during their appointments with headache specialists at two sites of a New York City medical center., Inclusion Criteria: ages from 16 to 80, migraine diagnosis by United Council of Neurologic Subspecialty fellowship trained and/or certified headache specialist, and referral for behavioral therapy for prevention in the appointment of recruitment., Exclusion Criteria: having done behavioral therapy for migraine in the past year. Participants in the MI group received up to 5 MI calls. TAU participants were called after 3 months for general follow-up data. The prespecified primary outcome was scheduling a behavioral therapy appointment, and secondary outcomes were initiating and attending a behavioral therapy appointment., Results: 76 patients were enrolled and randomized (MI = 36, TAU = 40). At baseline, the mean number of headache days was 12.0 ± 9.0. Self-reported anxiety was present for 36/52 (69.2%) and depression for 30/52 (57.7%). Follow-up assessments were completed for 77.6% (59/76, MI = 32, TAU = 27). The mean number of MI calls per participant was 2.69 ± 1.56 [0 to 5]. There was a greater likelihood of those in the MI group to initiating an appointment (22/32, 68.8% vs 11/27, 40.7%, P = .0309). There were no differences in appointment scheduling or attendance. Reasons stated for not initiating behavioral therapy were lack of time, lack of insurance/funding, prioritizing other treatments, and travel plans., Conclusions: Brief telephone-based MI may improve rates of initiation of behavioral therapy for migraine, but other barriers appear to lessen the impact on scheduling and attending behavioral therapy appointments., (© 2020 American Headache Society.)

Introduction: Ductal carcinoma in situ (DCIS) with foci of invasion measuring ≤ 1 mm (DCISM), represents < 1% of all invasive breast cancers. Sentinel lymph node biopsy (SLNB) has been a standard component of surgery for patients with invasive carcinoma or extensive DCIS. We hypothesize that selective performance of SLNB may be appropriate given the low incidence of sentinel node (SN) metastasis for DCISM. We investigated the clinicopathologic predictors for SN positivity in DCISM, to identify which patients might benefit from SLNB., Methods: A retrospective review of the National Cancer Database was performed for cases from 2012 to 2015. Clinical and tumor characteristics, including SN results, were evaluated, and Pearson's Chi square tests and logistic regression were performed., Results: Of 7803 patients with DCISM, 306 (4%) had at least one positive SN. Patients with positive SNs were younger, more often of Black race, had higher-grade histology and larger tumor size, and were more likely to have lymphovascular invasion (LVI; all p < 0.001). In an adjusted model, the presence of LVI was associated with the highest odds ratio (OR) for node positivity (OR 8.80, 95% confidence interval 4.56-16.96)., Conclusions: Among women with DCISM, only 4% had a positive SN. Node positivity was associated with more extensive and higher-grade DCIS, and the presence of LVI was strongly correlated with node positivity. Our data suggest that LVI is the most important factor in determining which patients with DCISM will benefit from SN biopsy.

Background: Growing evidence suggests that the tumor immune microenvironment influences breast cancer development and prognosis. Density of tumor-infiltrating lymphocytes (TILs) within invasive breast cancer is correlated with response to therapy, especially in triple-negative disease. The clinical relevance and outcomes of TILs within ductal carcinoma in situ (DCIS) are less understood., Methods: Our institutional database of 668 patients with pure DCIS from 2010 to 2018 was queried. TILs were evaluated by International TILs Working Group guidelines. Percentage of TILs was assessed from the densest focus (hotspot) in one high-power field of stroma touching the basement membrane. Statistical methods included cluster analyses (to define sparse versus dense TILs), logistic, and Cox regression models., Results: Sixty-nine patients with DCIS and TILs were evaluated, of whom 54 (78%) were treated by breast-conserving surgery. Thirteen (19%) patients had ipsilateral recurrence. Each recurrence (n = 13) was matched to four controls (n = 56) based on date of surgery. Median follow-up was 6.7 years. TILs were defined as sparse (< 45%) or dense (≥ 45%). Dense TILs were associated with younger age (p = 0.045), larger tumor size (p < 0.001), high nuclear grade (p = 0.010), comedo histology (p = 0.033), necrosis (p = 0.027), estrogen receptor (ER) negativity (p = 0.037), and ipsilateral recurrence (p = 0.001). Nine patients with dense TILs had mean time to recurrence of 73.5 months compared with four patients with sparse TILs with mean time to recurrence of 97.9 months (p = 0.003)., Conclusions: Dense TILs were significantly associated with age, tumor size, nuclear grade, comedo histology, necrosis, and ER status and was a significant predictor of recurrence in patients with pure DCIS.

Introduction: Plasma tau may be an accessible biomarker for Alzheimer's disease (AD), but the correlation between plasma and cerebrospinal fluid (CSF) tau and the value of combining plasma tau with CSF tau and phospho-tau (P-tau) are still unclear., Methods: Plasma-tau, CSF-tau, and P-tau were measured in 97 subjects, including elderly cognitively normal controls (n = 68) and patients with AD (n = 29) recruited at the NYU Center for Brain Health, with comprehensive neuropsychological and magnetic resonance imaging evaluations., Results: Plasma tau was higher in patients with AD than cognitively normal controls ( P  < .001, area under the receiver operating characteristic curve = 0.79) similarly to CSF tau and CSF P-tau and was negatively correlated with cognition in AD. Plasma and CSF tau measures were poorly correlated. Adding plasma tau to CSF tau or CSF P-tau significantly increased the areas under the receiver operating characteristic curve from 0.80 and 0.82 to 0.87 and 0.88, respectively., Discussion: Plasma tau is higher in AD independently from CSF-tau. Importantly, adding plasma tau to CSF tau or P-tau improves diagnostic accuracy, suggesting that plasma tau may represent a useful biomarker for AD, especially when added to CSF tau measures.

Study Objectives: To determine the effect of self-reported clinical diagnosis of obstructive sleep apnea (OSA) on longitudinal changes in brain amyloid PET and CSF biomarkers (Aβ42, T-tau, and P-tau) in cognitively normal (NL), mild cognitive impairment (MCI), and Alzheimer's disease (AD) elderly., Methods: Longitudinal study with mean follow-up time of 2.52 ± 0.51 years. Data were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Participants included 516 NL, 798 MCI, and 325 AD elderly. Main outcomes were annual rate of change in brain amyloid burden (i.e. longitudinal increases in florbetapir PET uptake or decreases in CSF Aβ42 levels); and tau protein aggregation (i.e. longitudinal increases in CSF total tau [T-tau] and phosphorylated tau [P-tau]). Adjusted multilevel mixed effects linear regression models with randomly varying intercepts and slopes was used to test whether the rate of biomarker change differed between participants with and without OSA., Results: In NL and MCI groups, OSA+ subjects experienced faster annual increase in florbetapir uptake (B = .06, 95% CI = .02, .11 and B = .08, 95% CI = .05, .12, respectively) and decrease in CSF Aβ42 levels (B = -2.71, 95% CI = -3.11, -2.35 and B = -2.62, 95% CI = -3.23, -2.03, respectively); as well as increases in CSF T-tau (B = 3.68, 95% CI = 3.31, 4.07 and B = 2.21, 95% CI = 1.58, 2.86, respectively) and P-tau (B = 1.221, 95% CI = 1.02, 1.42 and B = 1.74, 95% CI = 1.22, 2.27, respectively); compared with OSA- participants. No significant variations in the biomarker changes over time were seen in the AD group., Conclusions: In both NL and MCI, elderly, clinical interventions aimed to treat OSA are needed to test if OSA treatment may affect the progression of cognitive impairment due to AD., (© Sleep Research Society 2019. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.)

Although there is an increasing agreement that hypertension is associated with cerebrovascular compromise, relationships between blood pressure (BP) and cerebral blood flow are not fully understood. It is not known what BP level, and consequently what therapeutic goal, is optimal for brain perfusion. Moreover, there is limited data on how BP affects hippocampal perfusion, a structure critically involved in memory. We conducted a cross-sectional (n=445) and longitudinal (n=185) study of adults and elderly without dementia or clinically apparent stroke, who underwent clinical examination and brain perfusion assessment (age 69.2±7.5 years, 62% women, 45% hypertensive). Linear models were used to test baseline BP-blood flow relationship and to examine how changes in BP influence changes in perfusion. In the entire group, systolic BP (SBP) was negatively related to cortical (β=-0.13, P=0.005) and hippocampal blood flow (β=-0.12, P=0.01). Notably, this negative relationship was apparent already in subjects without hypertension. Hypertensive subjects showed a quadratic relationship between SBP and hippocampal blood flow (β=-1.55, P=0.03): Perfusion was the highest in subjects with mid-range SBP around 125 mm Hg. Longitudinally, in hypertensive subjects perfusion increased with increased SBP at low baseline SBP but increased with decreased SBP at high baseline SBP. Cortical and hippocampal perfusion decrease with increasing SBP across the entire BP spectrum. However, in hypertension, there seems to be a window of mid-range SBP which maximizes perfusion.

Purpose: Off-target binding in the reference region is a challenge for recent tau tracers 18 F-AV-1451 and 18 F-THK5351. The conventional standardized uptake value ratio (SUVR) method relies on the average uptake from an unaffected tissue sample, and therefore is susceptible to biases from off-target binding as well as variability among individuals in the reference region. We propose a new method, standardized uptake value peak-alignment (SUVP), to reduce the bias of the SUVR, and improve the quantitative assessment of tau deposition., Methods: The SUVP normalizes uptake values by their mode and standard deviation. Instead of using a reference region, the SUVP derives the contrast from unaffected voxels over the whole brain. Using SUVP and SUVR methods, we evaluated the global and regional tau binding of 18 F-THK5351 and 18 F-AV-1451 on two independent cohorts (N = 18 and 32, respectively), each with cognitively normal (NL) subjects and Alzheimer's disease (AD) subjects., Results: Both tracers showed significantly increased binding for AD in the targeted cortical areas. In the temporal cortex, SUVP had a higher classification success rate (CSR) than SUVR (0.96 vs 0.89 for 18 F-THK5351; 0.86 vs 0.75 for 18 F-AV-1451), as well as higher specificity under fixed sensitivity around 0.80 (0.70 vs 0.45 specificity for 18 F-THK5351; 1.00 vs 0.78 for 18 F-AV-1451). In the cerebellar cortex, an AD-NL group difference with effect size (Cohen's d) of 0.62 was observed for AV-1451, confirming the limitation of the SUVR approach using this region as a reference. A smaller cerebellar effect size (0.09) was observed for THK5351., Conclusion: The SUVP method reduces the bias of the reference region and improves the NL-AD classification compared to the SUVR approach.

Alzheimer's disease (AD) is known to be associated with loss of cholinergic neurons in the nucleus basalis of Meynert, located in the posterior basal forebrain. Structural changes of septal nuclei, located in the anterior basal forebrain, have not been well studied in AD. Using a validated algorithm, we manually traced septal nuclei on high-resolution coronal magnetic resonance imaging (MRI) in 40 subjects with mild cognitive impairment (MCI) or AD, 89 healthy controls, and 18 subjects who were cognitively normal at the time of MRI but went on to develop AD an average of 2.8 years later. We found that cognitively normal subjects destined to develop AD in the future had enlarged septal nuclei as compared to both healthy controls and patients with current MCI or AD. To our knowledge, this is the first time a brain structure has been found to be enlarged in association with risk of AD. Further research is needed to determine if septal enlargement reflects neuroplastic compensation, amyloid deposition, inflammation, or another process and to determine whether it can serve as an early MRI biomarker of AD., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Rationale: Recent evidence suggests that obstructive sleep apnea (OSA) may be a risk factor for developing mild cognitive impairment and Alzheimer's disease. However, how sleep apnea affects longitudinal risk for Alzheimer's disease is less well understood., Objectives: To test the hypothesis that there is an association between severity of OSA and longitudinal increase in amyloid burden in cognitively normal elderly., Methods: Data were derived from a 2-year prospective longitudinal study that sampled community-dwelling healthy cognitively normal elderly. Subjects were healthy volunteers between the ages of 55 and 90, were nondepressed, and had a consensus clinical diagnosis of cognitively normal. Cerebrospinal fluid amyloid β was measured using ELISA. Subjects received Pittsburgh compound B positron emission tomography scans following standardized procedures. Monitoring of OSA was completed using a home sleep recording device., Measurements and Main Results: We found that severity of OSA indices (AHIall [F 1,88  = 4.26; P < 0.05] and AHI4% [F 1,87  = 4.36; P < 0.05]) were associated with annual rate of change of cerebrospinal fluid amyloid β 42 using linear regression after adjusting for age, sex, body mass index, and apolipoprotein E4 status. AHIall and AHI4% were not associated with increases in AD PiB -mask (Alzheimer's disease vulnerable regions of interest Pittsburg compound B positron emission tomography mask) most likely because of the small sample size, although there was a trend for AHIall (F 1,28  = 2.96, P = 0.09; and F 1,28  = 2.32, not significant, respectively)., Conclusions: In a sample of cognitively normal elderly, OSA was associated with markers of increased amyloid burden over the 2-year follow-up. Sleep fragmentation and/or intermittent hypoxia from OSA are likely candidate mechanisms. If confirmed, clinical interventions for OSA may be useful in preventing amyloid build-up in cognitively normal elderly.

Cerebrospinal fluid (CSF) studies consistently show that CSF levels of amyloid-beta 1-42 (Aβ42) are reduced and tau levels increased prior to the onset of cognitive decline related to Alzheimer's disease (AD). However, the preclinical prediction accuracy for low CSF Aβ42 levels, a surrogate for brain Aβ42 deposits, is not high. Moreover, the pathology data suggests a course initiated by tauopathy contradicting the contemporary clinical view of an Aβ initiated cascade. CSF Aβ42 and tau data from 3 normal aging cohorts (45-90 years) were combined to test both cross-sectional (n = 766) and longitudinal (n = 651) hypotheses: 1) that the relationship between CSF levels of Aβ42 and tau are not linear over the adult life-span; and 2) that non-linear models improve the prediction of cognitive decline. Supporting the hypotheses, the results showed that a u-shaped quadratic fit (Aβ2) best describes the relationship for CSF Aβ42 with CSF tau levels. Furthermore we found that the relationship between Aβ42 and tau changes with age-between 45 and 70 years there is a positive linear association, whereas between 71 and 90 years there is a negative linear association between Aβ42 and tau. The quadratic effect appears to be unique to Aβ42, as Aβ38 and Aβ40 showed only positive linear relationships with age and CSF tau. Importantly, we observed the prediction of cognitive decline was improved by considering both high and low levels of Aβ42. Overall, these data suggest an earlier preclinical stage than currently appreciated, marked by CSF elevations in tau and accompanied by either elevations or reductions in Aβ42. Future studies are needed to examine potential mechanisms such as failing CSF clearance as a common factor elevating CSF Aβxx analyte levels prior to Aβ42 deposition in brain.

Objective: To assess whether multifocal, high-frequency repetitive transcranial magnetic stimulation (rTMS) of motor and prefrontal cortex benefits motor and mood symptoms in patients with Parkinson disease (PD)., Methods: Patients with PD and depression were enrolled in this multicenter, double-blind, sham-controlled, parallel-group study of real or realistic (electric) sham rTMS. Patients were randomized to 1 of 4 groups: bilateral M1 ( + sham dorsolateral prefrontal cortex [DLPFC]), DLPFC ( + sham M1), M1 + DLPFC, or double sham. The TMS course consisted of 10 daily sessions of 2,000 stimuli for the left DLPFC and 1,000 stimuli for each M1 (50 × 4-second trains of 40 stimuli at 10 Hz). Patients were evaluated at baseline, at 1 week, and at 1, 3, and 6 months after treatment. Primary endpoints were changes in motor function assessed with the Unified Parkinson's Disease Rating Scale-III and in mood with the Hamilton Depression Rating Scale at 1 month., Results: Of the 160 patients planned for recruitment, 85 were screened, 61 were randomized, and 50 completed all study visits. Real M1 rTMS resulted in greater improvement in motor function than sham at the primary endpoint (p < 0.05). There was no improvement in mood in the DLPFC group compared to the double-sham group, as well as no benefit to combining M1 and DLPFC stimulation for either motor or mood symptoms., Conclusions: In patients with PD with depression, M1 rTMS is an effective treatment of motor symptoms, while mood benefit after 2 weeks of DLPFC rTMS is not better than sham. Targeting both M1 and DLPFC in each rTMS session showed no evidence of synergistic effects., Clinicaltrialsgov Identifier: NCT01080794., Classification of Evidence: This study provides Class I evidence that in patients with PD with depression, M1 rTMS leads to improvement in motor function while DLPFC rTMS does not lead to improvement in depression compared to sham rTMS., (© 2016 American Academy of Neurology.)

Study Objectives: Emerging evidence suggests a role for sleep in contributing to the progression of Alzheimer disease (AD). Slow wave sleep (SWS) is the stage during which synaptic activity is minimal and clearance of neuronal metabolites is high, making it an ideal state to regulate levels of amyloid beta (Aβ). We thus aimed to examine relationships between concentrations of Aβ42 in the cerebrospinal fluid (CSF) and measures of SWS in cognitively normal elderly subjects., Methods: Thirty-six subjects underwent a clinical and cognitive assessment, a structural MRI, a morning to early afternoon lumbar puncture, and nocturnal polysomnography. Correlations and linear regression analyses were used to assess for associations between CSF Aβ42 levels and measures of SWS controlling for potential confounders. Resulting models were compared to each other using ordinary least squared linear regression analysis. Additionally, the participant sample was dichotomized into "high" and "low" Aβ42 groups to compare SWS bout length using survival analyses., Results: A significant inverse correlation was found between CSF Aβ42 levels, SWS duration and other SWS characteristics. Collectively, total SWA in the frontal lead was the best predictor of reduced CSF Aβ42 levels when controlling for age and ApoE status. Total sleep time, time spent in NREM1, NREM2, or REM sleep were not correlated with CSF Aβ42., Conclusions: In cognitively normal elderly, reduced and fragmented SWS is associated with increases in CSF Aβ42, suggesting that disturbed sleep might drive an increase in soluble brain Aβ levels prior to amyloid deposition., (© 2016 Associated Professional Sleep Societies, LLC.)

Increasingly, postoperative cognitive dysfunction (POCD) is recognized as a complication after surgery in the elderly; but it's etiology remains unclear. Here we examine changes in cytokine levels during both the pre-operative and postoperative period, comparing them with long term variation in cognitive test scores. Forty-one patients aged 65 and older undergoing major surgery with general anesthesia were recruited after written consent in this IRB approved study. Thirty went on to complete this prospective, non-interven-tional and non-randomized study. Plasma levels of cytokines Il-6, Il-8, Il-10, and TNF were determined using ELISA with MILLIPLEX Multi-Analyte Profiling (Billerica, MA). All subjects had neurocognitive tests pre-operatively and 6 months post-surgery, including Paragraph Recall Immediate and Delayed, Digit Span Forward (DSF) and Backward (DSB), and Trail Making A and B. Spearman's Rho and repeated measure rank analysis were used to examine the dependence of z score changes in cognitive tests (baseline versus 6 months) as a function of 3 cytokine time points (presurgical, post anesthesia care unit (PACU), and post-operative day one (POD1)). A greater increase in PACU inflammatory burden correlated with a greater decline in performance on the DSB (IL6, IL8; r>-0.560; p<= 0.008). DSF changes correlated slightly better with pre-surgical cytokines, declining more with higher cytokines (IL6, r= -0.551, p=0.002; IL8, -0.468, 0.009). TNF, examining all 3 values, changed only slightly postoperatively, but still correlated with a decline in DSB (p=0.014). Thus, cognitive performance, over 6 months post surgery, declines with elevated perioperative inflammation. Specific cytokines at specific perioperative times may impact specific cognitive functions, serving as diagnostics as well as contributing causation.

Study Objectives: To evaluate the role of orexin-A with respect to cerebrospinal fluid (CSF) Alzheimer disease (AD) biomarkers, and explore its relationship to cognition and sleep characteristics in a group of cognitively normal elderly individuals., Methods: Subjects were recruited from multiple community sources for National Institutes of Health supported studies on normal aging, sleep and CSF biomarkers. Sixty-three participants underwent home monitoring for sleep-disordered breathing, clinical, sleep and cognitive evaluations, as well as a lumbar puncture to obtain CSF. Individuals with medical history or with magnetic resonance imaging evidence of disorders that may affect brain structure or function were excluded. Correlation and linear regression analyses were used to assess the relationship between orexin-A and CSF AD-biomarkers controlling for potential sociodemographic and sleep confounders., Results: Levels of orexin-A, amyloid beta 42 (Aβ42), phosphorylated-tau (P-Tau), total-tau (T-Tau), Apolipoprotein E4 status, age, years of education, reported total sleep time, number of awakenings, apnea-hypopnea indices (AHI), excessive daytime sleepiness, and a cognitive battery were analyzed. Subjects were 69.59 ± 8.55 years of age, 57.1% were female, and 30.2% were apolipoprotein E4+. Orexin-A was positively correlated with Aβ42, P-Tau, and T-Tau. The associations between orexin-A and the AD-biomarkers were driven mainly by the relationship between orexin-A and P-Tau and were not influenced by other clinical or sleep characteristics that were available., Conclusions: Orexin-A is associated with increased P-Tau in normal elderly individuals. Increases in orexin-A and P-Tau might be a consequence of the reduction in the proportion of the deeper, more restorative slow wave sleep and rapid eye movement sleep reported with aging., Clinical Trial Registration: Clinicaltrials.gov registration number NCT01962779., (© 2016 Associated Professional Sleep Societies, LLC.)

Introduction: Hypertension, hypercholesterolemia, and obesity increase the risk of dementia. Although their detection is commonly followed by an introduction of treatment, little is known about how medications frequently used to treat vascular risk affect amyloid deposition., Methods: A cross-sectional study of 156 subjects who underwent positron emission tomography with PiB. Using linear regression, we tested whether blood pressure, cholesterol, overweight/obese status, angiotensin receptor blockers (ARBs), beta-blockers, diuretics, angiotensin converting enzyme inhibitors, and statins predicted amyloid deposition., Results: The use of ARBs (β = -.15, P = .044) and diuretics (β = -.20, P = .006) predicted less amyloid accumulation; older age (β = .29, P < .001) and statins (β = .23, P = .004) were related to greater amyloid deposition. Overweight and/or obese women had more cortical amyloid than their peers., Discussion: Prospective studies should confirm effects of drugs and increased body weight on amyloid accumulation and establish whether they translate into measurable clinical outcomes. Women may be more susceptible to harmful effects of obesity.

Cerebrospinal fluid (CSF) measures of phosphorylated-tau (P-tau) 231 and P-tau181 are two biomarkers for the identification of tau pathology as related to Alzheimer's disease (AD). While both are pathologically validated, their relative diagnostic performances are not well known. This cross-sectional diagnostic study of 87 normal (NL) subjects and 28 AD subjects compared CSF P-tau231 with CSF P-tau181. Logistic regression modeling demonstrated that the P-tau231 was superior to the P-tau181 in the diagnostic classifications. At a fixed 85% sensitivity cutoff, the ROC analysis shows that P-tau231 has greater overall specificity than P-tau181. While both P-tau analytes demonstrated equivalent negative predictive accuracies, P-tau231 yielded significantly fewer false positives. Moreover, P-tau231, but not P-tau181, demonstrated sensitivity to the E4 genotype. A postmortem validation with 9 AD subjects confirmed the superiority of the CSF P-tau231 specificity. This study suggests that P-tau231 has the potential to improve the CSF tau biomarker diagnosis of AD.

Objective: To examine whether the presence of sleep-disordered breathing (SDB) is associated with an earlier age at mild cognitive impairment (MCI) or Alzheimer disease (AD)-dementia onset in participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. We also examined whether continuous positive airway pressure (CPAP) use is associated with delayed onset of cognitive decline., Methods: From the ADNI cohort, 3 subsets with progressively stringent criteria were created in a step-wise manner. Age at MCI or AD-dementia onset was the main outcome variable. Analyses were performed separately for each subset in untreated SDB+ vs SDB- and untreated SDB+ vs CPAP+ groups. Chi-square and t tests were performed to examine between-group differences. Survival analyses were performed using the Kaplan-Meier method, compared by the log-rank test, and assessed by multivariate Cox regression adjusting for potential confounders., Results: SDB+ patients had a younger age at MCI onset in all subsets (MC1: 72.63 vs 83.67; MC2: 72.15 vs 83.45; MC3: 77.40 vs 89.89; p < 0.01). SDB+ patients had a younger age at AD-dementia onset only in our most conservative subset (AC3: 83.46 vs 88.13; p < 0.05). In a combined outcome analysis, SDB+ patients had a younger age at onset to MCI or AD-dementia in all subsets. In subsets 1 and 2, CPAP use delayed the age at MCI onset (CMC1: 72.63 vs 82.10; CMC2: 72.11 vs 82.10; p < 0.01)., Conclusions: Consistent with our hypothesis, the presence of SDB was associated with an earlier age at cognitive decline. Our findings in CPAP+ participants suggest that CPAP treatment of SDB may delay progression of cognitive impairment., (© 2015 American Academy of Neurology.)

The accumulation of amyloid-β (Aβ) plaques is a central feature of Alzheimer's disease (AD). First reported in animal models, it remains uncertain if peripheral inflammatory and/or infectious conditions in humans can promote Aβ brain accumulation. Periodontal disease, a common chronic infection, has been previously reported to be associated with AD. Thirty-eight cognitively normal, healthy, and community-residing elderly (mean age, 61 and 68% female) were examined in an Alzheimer's Disease Research Center and a University-Based Dental School. Linear regression models (adjusted for age, apolipoprotein E, and smoking) were used to test the hypothesis that periodontal disease assessed by clinical attachment loss was associated with brain Aβ load using (11)C-Pittsburgh compound B (PIB) positron emission tomography imaging. After adjusting for confounders, clinical attachment loss (≥3 mm), representing a history of periodontal inflammatory/infectious burden, was associated with increased PIB uptake in Aβ vulnerable brain regions (p = 0.002). We show for the first time in humans an association between periodontal disease and brain Aβ load. These data are consistent with the previous animal studies showing that peripheral inflammation/infections are sufficient to produce brain Aβ accumulations., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Unlabelled: Neurofibrillary tau pathology and amyloid β (Aβ) plaques, characteristic lesions of Alzheimer disease (AD), show different neocortical laminar distributions. Neurofibrillary-tangle tau pathology tends to be closer to the gray matter-white matter boundary, whereas Aβ is dispersed throughout the width of the cortical ribbon., Methods: Using PET radiotracers for tau and Aβ lesions, we developed an image analysis tool to measure the distance of tracer-positive voxels from the gray matter-white matter boundary. We studied 5 AD and 5 healthy subjects with both (18)F-THK5117 (tau) and (11)C-Pittsburgh compound B (Aβ) PET., Results: On average, tau-positive voxels were closer to the white matter than were Aβ-positive voxels. This effect was found for all AD subjects and for all regions, both before and after regionally adjusting for the nonspecific white matter binding of both tracers. The differential laminar pattern was validated through postmortem examination., Conclusion: Within cortical lamina, distance measures may be of value in testing PET tracers for their anatomic selectivity., (© 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Purpose: One of the interesting features of the amyloid tracer Pittsburgh compound B (PiB) is that it generates a signal in the white matter (WM) in both healthy subjects and cognitively impaired individuals. This characteristic gave rise to the possibility that PiB could be used to trace WM pathology. In a group of cognitively healthy elderly we examined PiB retention in normal-appearing WM (NAWM) and WM lesions (WML), one of the most common brain pathologies in aging., Methods: We segmented WML and NAWM on fluid attenuation inversion recovery (FLAIR) images of 73 subjects (age 61.9 ± 10.0, 71 % women). PiB PET images were corrected for partial volume effects and coregistered to FLAIR images and WM masks. WML and NAWM PiB signals were then extracted., Results: PiB retention in WML was lower than in NAWM (p < 0.001, 14.6 % reduction). This was true both for periventricular WML (p < 0.001, 17.8 % reduction) and deep WML (p = 0.001, 7.5 % reduction)., Conclusion: PiB binding in WM is influenced by the presence of WML, which lower the signal. Our findings add to the growing evidence that PiB can depict WM pathology and should prompt further investigations into PiB binding targets in WM.

Septal nuclei, located in basal forebrain, are strongly connected with hippocampi and important in learning and memory, but have received limited research attention in human MRI studies. While probabilistic maps for estimating septal volume on MRI are now available, they have not been independently validated against manual tracing of MRI, typically considered the gold standard for delineating brain structures. We developed a protocol for manual tracing of the human septal region on MRI based on examination of neuroanatomical specimens. We applied this tracing protocol to T1 MRI scans (n=86) from subjects with temporal epilepsy and healthy controls to measure septal volume. To assess the inter-rater reliability of the protocol, a second tracer used the same protocol on 20 scans that were randomly selected from the 72 healthy controls. In addition to measuring septal volume, maximum septal thickness between the ventricles was measured and recorded. The same scans (n=86) were also analyzed using septal probabilistic maps and DARTEL toolbox in SPM. Results show that our manual tracing algorithm is reliable, and that septal volume measurements obtained via manual and automated methods correlate significantly with each other (p<.001). Both manual and automated methods detected significantly enlarged septal nuclei in patients with temporal lobe epilepsy in accord with a proposed compensatory neuroplastic process related to the strong connections between septal nuclei and hippocampi. Septal thickness, which was simple to measure with excellent inter-rater reliability, correlated well with both manual and automated septal volume, suggesting it could serve as an easy-to-measure surrogate for septal volume in future studies. Our results call attention to the important though understudied human septal region, confirm its enlargement in temporal lobe epilepsy, and provide a reliable new manual delineation protocol that will facilitate continued study of this critical region., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Previous studies have suggested a link between sleep disordered breathing (SDB) and dementia risk. In the present study, we analyzed the relationship between SDB severity, cerebrospinal fluid (CSF) Alzheimer's disease-biomarkers, and the ApoE alleles. A total of 95 cognitively normal elderly participants were analyzed for SDB severity, CSF measures of phosphorylated-tau (p-tau), total-tau (t-tau), and amyloid beta 42 (Aβ-42), as well as ApoE allele status. In ApoE3+ subjects, significant differences were found between sleep groups for p-tau (F[df2] = 4.3, p = 0.017), and t-tau (F[df2] = 3.3, p = 0.043). Additionally, among ApoE3+ subjects, the apnea and/or hypopnea with 4% O2-desaturation index was positively correlated with p-tau (r = 0.30, p = 0.023), t-tau (r = 0.31, p = 0.021), and Aβ-42 (r = 0.31, p = 0.021). In ApoE2+ subjects, the apnea and/or hypopnea with 4% O2-desaturation index was correlated with lower levels of CSF Aβ-42 (r = -0.71, p = 0.004), similarly to ApoE4+ subjects where there was also a trend toward lower CSF Aβ-42 levels. Our observations suggest that there is an association between SDB and CSF Alzheimer's disease-biomarkers in cognitively normal elderly individuals. Existing therapies for SDB such as continuous positive airway pressure could delay the onset to mild cognitive impairment or dementia in normal elderly individuals., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Having a parent affected by late-onset Alzheimer's disease (AD) is a major risk factor for cognitively normal (NL) individuals. This study explores the potential of PET with 18 F-FDG and the amyloid- β (A β ) tracer 11 C-Pittsburgh Compound B (PiB) for detection of individual risk in NL adults with AD-parents., Methods: FDG- and PiB-PET was performed in 119 young to late-middle aged NL individuals including 80 NL with positive family history of AD (FH+) and 39 NL with negative family history of any dementia (FH-). The FH+ group included 50 subjects with maternal (FHm) and 30 with paternal family history (FHp). Individual FDG and PiB scans were Z scored on a voxel-wise basis relative to modality-specific reference databases using automated procedures and rated as positive or negative (+/-) for AD-typical abnormalities using predefined criteria. To determine the effect of age, the cohort was separated into younger (49 ± 9 y) and older (68 ± 5 y) groups relative to the median age (60 y)., Results: Among individuals of age >60 y, as compared to controls, NL FH+ showed a higher frequency of FDG+ scans vs. FH- (53% vs. 6% p < 0.003), and a trend for PiB+ scans (27% vs. 11%; p = 0.19). This effect was observed for both FHm and FHp groups. Among individuals of age ≤60 y, NL FHm showed a higher frequency of FDG+ scans (29%) compared to FH- (5%, p = 0.04) and a trend compared to FHp (11%) (p = 0.07), while the distribution of PiB+ scans was not different between groups. In both age cohorts, FDG+ scans were more frequent than PiB+ scans among NL FH+, especially FHm (p < 0.03). FDG-PET was a significant predictor of FH+ status. Classification according to PiB status was significantly less successful., Conclusions: Automated analysis of FDG- and PiB-PET demonstrates higher rates of abnormalities in at-risk FH+ vs FH- subjects, indicating potentially ongoing early AD-pathology in this population. The frequency of metabolic abnormalities was higher than that of A β pathology in the younger cohort, suggesting that neuronal dysfunction may precede major aggregated A β burden in young NL FH+. Longitudinal follow-up is required to determine if the observed abnormalities predict future AD.

In hypertension (HTN), cerebral blood flow regulation limits are changed, and the threshold for blood pressure (BP) at which perfusion is safely maintained is higher. This shift may increase the brain's vulnerability to lower BP in subjects with vascular disease. We investigated whether longitudinal reduction in mean arterial pressure (MAP) was related to changes in cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease in a group of cognitively healthy elderly with and without HTN. The relationships among MAP, memory decline, and hippocampal atrophy were also examined. Seventy-seven subjects (age 63.4 ± 9.4, range 44-86 years; education 16.9 ± 2.1, range 10-22 years; 60% women) were assessed twice, 2 ± 0.5 years apart. At both time points, all subjects underwent full medical and neuropsychological evaluations, lumbar punctures, and magnetic resonance imaging examinations. Twenty-five subjects had HTN. Hyper- and normotensive subjects did not differ in their CSF biomarkers, hippocampal volumes (HipVs), or memory scores at baseline. In the entire study group, the increase in tau phosphorylated at threonine 181 (p-tau(181)) was associated with a decline in verbal episodic memory (β = -0.30, p = 0.01) and HipV reduction (β = -0.27, p = 0.02). However, longitudinal decrease in MAP was related to memory decline (β = 0.50, p = 0.01) and an increase in p-tau(181) (β = -0.50, p = 0.01) only in subjects with HTN. Our findings suggest that the hypertensive group may be sensitive to BP reductions., (Copyright © 2014 Elsevier Inc. All rights reserved.)

This study examines the relationship between fibrillar beta-amyloid (Aβ) deposition and reduced glucose metabolism, a proxy for neuronal dysfunction, in cognitively normal (NL) individuals with a parent affected by late-onset Alzheimer's disease (AD). Forty-seven 40-80-year-old NL received positron emission tomography (PET) with (11)C-Pittsburgh compound B (PiB) and 18F-fluoro-2-deoxy-d-glucose (FDG). These included 19 NL with a maternal history (MH), 12 NL with a paternal history (PH), and 16 NL with negative family history of AD (NH). Automated regions of interest, statistical parametric mapping, voxel-wise intermodality correlations, and logistic regressions were used to examine cerebral-to-cerebellar PiB and FDG standardized uptake value ratios across groups. The MH group showed higher PiB retention and lower metabolism in AD regions compared with NH and PH, which were negatively correlated in posterior cingulate, frontal, and parieto-temporal regions (Pearson r ≤ -0.57, p ≤ 0.05). No correlations were observed in NH and PH. The combination of Aβ deposition and metabolism yielded accuracy ≥ 69% for MH vs. NH and ≥ 71% for MH vs. PH, with relative risk = 1.9-5.1 (p values < 0.005). NL individuals with AD-affected mothers show co-occurring Aβ increases and hypometabolism in AD-vulnerable regions, suggesting an increased risk for AD., (Published by Elsevier Inc.)

It is not well known whether Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers are associated with brain damage in cognitively normal elderly. The combined influence of CSF biomarkers and hypertension (HTN) on the gray matter (GM) is also not well described. One hundred fifteen cognitively healthy subjects (mean age 62.6 ± 9.5%, 62% women) received clinical assessment, a high resolution magnetic resonance imaging (MRI), and a lumbar puncture. The CSF levels of total tau (t-tau), hyperphosphorylated tau (p-tau(231)), amyloid beta (Aβ42/Aβ40), p-tau(231)/Aβ42, and t-tau/Aβ42 were dichotomized as "high" and "low" based on accepted cut off values. Statistical parametric mapping was used to examine MRI scans for regional GM density, studied as a function of the CSF markers, HTN, and combination of both. Global and medial temporal lobe (MTL) GM was also assessed. Voxel based morphometry revealed that higher t-tau was associated with lower GM density in the precunei. Subjects with higher p-tau(231) and p-tau(231)/Aβ42 had less GM in temporal lobes. Low Aβ42/Aβ40 was related to less GM in the thalami, caudate, and midbrain. Subjects with hypertension showed more GM atrophy in the cerebellum, occipital, and frontal regions. Simultaneous presence of elevated CSF AD biomarkers and HTN was associated with more GM atrophy than either marker individually, but no interaction effects were identified. In conclusion, in normal elderly CSF tau markers were associated predominantly with lower GM estimates in structures typically affected early in the AD process. In this presymptomatic stage when no cognitive impairment is present, AD biomarkers and HTN have additive effects on gray matter damage., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Cognitively normal (NL) individuals with a maternal history of late-onset Alzheimer's disease (MH) show reduced brain glucose metabolism on FDG-PET as compared to those with a paternal history (PH) and those with negative family history (NH) of Alzheimer's disease (AD). This FDG-PET study investigates whether metabolic deficits in NL MH are associated with advancing maternal age at birth. Ninety-six NL individuals with FDG-PET were examined, including 36 MH, 24 PH, and 36 NH. Regional-to-whole brain gray matter standardized FDG uptake value ratios were examined for associations with parental age across groups using automated regions-of-interest and statistical parametric mapping. Groups were comparable for clinical and neuropsychological measures. Brain metabolism in AD-vulnerable regions was lower in MH compared to NH and PH, and negatively correlated with maternal age at birth only in MH. There were no associations between paternal age and metabolism in any group. Evidence for a maternally inherited, maternal age-related mechanism provides further insight on risk factors and genetic transmission in late-onset AD., (Published by Elsevier Inc.)