Publications by authors named "Lidia Glodzik"

55 Publications

Global brain volume and N-acetyl-aspartate decline over seven decades of normal aging.

Neurobiol Aging 2021 Feb 28;98:42-51. Epub 2020 Oct 28.

Department of Radiology, Center for Advanced Imaging Innovation and Research (CAI(2)R), Bernard and Irene Schwartz Center for Biomedical Imaging, New York University Grossman School of Medicine, New York, NY, USA. Electronic address:

We characterize the whole-brain N-acetyl-aspartate (WBNAA) and brain tissue fractions across the adult lifespan and test the hypothesis that, despite age-related atrophy, neuronal integrity (reflected by WBNAA) is preserved in normal aging. Two-hundred-and-seven participants: 133 cognitively intact older adults (73.6 ± 7.4 mean ± standard deviation, range: 60-90 year old) and 84 young (37.9 ± 11, range: 21-59 year old) were scanned with proton magnetic resonance spectroscopy and T-weighted MRI. Their WBNAA, fractional brain parenchyma, and gray and white matter volumes (fBPV, fGM, and fWM) were compared and modeled as functions of age and sex. Compared with young, older-adults' WBNAA was lower by ~35%, and fBPV, fGM and fWM were lower by ~10%. Linear regressions found 0.5%/year WBNAA and 0.2%/year fBPV and fGM declines, whereas fWM rose to age ~40 years, and declined thereafter. fBPV and fGM were 1.8% and 4% higher in women, with no sex decline rates difference. We conclude that contrary to our hypothesis, atrophy was accompanied by WBNAA decline. Across the entire age range, women's brains showed less atrophy than men's. Formulas to estimate WBNAA and brain tissue fractions in healthy adults are provided to help differentiate normal from abnormal aging.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.10.024DOI Listing
February 2021

Precisely-Measured Hydration Status Correlates with Hippocampal Volume in Healthy Older Adults.

Am J Geriatr Psychiatry 2019 06 11;27(6):653-654. Epub 2019 Feb 11.

Department of Nephrology (JM), New York University Winthrop University, Mineola, New York.

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http://dx.doi.org/10.1016/j.jagp.2019.02.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925571PMC
June 2019

Sleep oscillation-specific associations with Alzheimer's disease CSF biomarkers: novel roles for sleep spindles and tau.

Mol Neurodegener 2019 02 21;14(1):10. Epub 2019 Feb 21.

Department of Psychiatry, NYU School of Medicine, New York, NY, 10016, USA.

Background: Based on associations between sleep spindles, cognition, and sleep-dependent memory processing, here we evaluated potential relationships between levels of CSF Aβ, P-tau, and T-tau with sleep spindle density and other biophysical properties of sleep spindles in a sample of cognitively normal elderly individuals.

Methods: One-night in-lab nocturnal polysomnography (NPSG) and morning to early afternoon CSF collection were performed to measure CSF Aβ, P-tau and T-tau. Seven days of actigraphy were collected to assess habitual total sleep time.

Results: Spindle density during NREM stage 2 (N2) sleep was negatively correlated with CSF Aβ, P-tau and T-tau. From the three, CSF T-tau was the most significantly associated with spindle density, after adjusting for age, sex and ApoE4. Spindle duration, count and fast spindle density were also negatively correlated with T-tau levels. Sleep duration and other measures of sleep quality were not correlated with spindle characteristics and did not modify the associations between sleep spindle characteristics and the CSF biomarkers of AD.

Conclusions: Reduced spindles during N2 sleep may represent an early dysfunction related to tau, possibly reflecting axonal damage or altered neuronal tau secretion, rendering it a potentially novel biomarker for early neuronal dysfunction. Given their putative role in memory consolidation and neuroplasticity, sleep spindles may represent a mechanism by which tau impairs memory consolidation, as well as a possible target for therapeutic interventions in cognitive decline.
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http://dx.doi.org/10.1186/s13024-019-0309-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6385427PMC
February 2019

Different Relationship Between Systolic Blood Pressure and Cerebral Perfusion in Subjects With and Without Hypertension.

Hypertension 2019 01;73(1):197-205

From the Center for Brain Health, Department of Psychiatry (L.G., W.T., E.P., A.D., Y.L., C.R., J.C., R.S.O., T.B., E.T., P.H., M.J.d.L.), New York University (NYU) School of Medicine, New York.

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.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.118.11233DOI Listing
January 2019

Basal forebrain septal nuclei are enlarged in healthy subjects prior to the development of Alzheimer's disease.

Neurobiol Aging 2018 05 2;65:201-205. Epub 2018 Feb 2.

New York University School of Medicine, NYU Center for Brain Health, Department of Psychiatry, New York, NY, USA.

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.
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http://dx.doi.org/10.1016/j.neurobiolaging.2018.01.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413730PMC
May 2018

The nonlinear relationship between cerebrospinal fluid Aβ42 and tau in preclinical Alzheimer's disease.

PLoS One 2018 7;13(2):e0191240. Epub 2018 Feb 7.

Sahlgrenska University Hospital, University of Gothenburg, Mölndal, Sweden.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0191240PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5802432PMC
March 2018

Obstructive Sleep Apnea Severity Affects Amyloid Burden in Cognitively Normal Elderly. A Longitudinal Study.

Am J Respir Crit Care Med 2018 04;197(7):933-943

1 Center for Brain Health, Department of Psychiatry, and.

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 = 4.26; P < 0.05] and AHI4% [F = 4.36; P < 0.05]) were associated with annual rate of change of cerebrospinal fluid amyloid β 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-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 = 2.96, P = 0.09; and F = 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.
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http://dx.doi.org/10.1164/rccm.201704-0704OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6020410PMC
April 2018

Cerebrospinal fluid and blood biomarkers for neurodegenerative dementias: An update of the Consensus of the Task Force on Biological Markers in Psychiatry of the World Federation of Societies of Biological Psychiatry.

World J Biol Psychiatry 2018 06 27;19(4):244-328. Epub 2017 Oct 27.

a Department of Psychiatry and Psychotherapy , Universitätsklinikum Erlangen, and Friedrich-Alexander Universität Erlangen-Nürnberg , Erlangen , Germany.

In the 12 years since the publication of the first Consensus Paper of the WFSBP on biomarkers of neurodegenerative dementias, enormous advancement has taken place in the field, and the Task Force takes now the opportunity to extend and update the original paper. New concepts of Alzheimer's disease (AD) and the conceptual interactions between AD and dementia due to AD were developed, resulting in two sets for diagnostic/research criteria. Procedures for pre-analytical sample handling, biobanking, analyses and post-analytical interpretation of the results were intensively studied and optimised. A global quality control project was introduced to evaluate and monitor the inter-centre variability in measurements with the goal of harmonisation of results. Contexts of use and how to approach candidate biomarkers in biological specimens other than cerebrospinal fluid (CSF), e.g. blood, were precisely defined. Important development was achieved in neuroimaging techniques, including studies comparing amyloid-β positron emission tomography results to fluid-based modalities. Similarly, development in research laboratory technologies, such as ultra-sensitive methods, raises our hopes to further improve analytical and diagnostic accuracy of classic and novel candidate biomarkers. Synergistically, advancement in clinical trials of anti-dementia therapies energises and motivates the efforts to find and optimise the most reliable early diagnostic modalities. Finally, the first studies were published addressing the potential of cost-effectiveness of the biomarkers-based diagnosis of neurodegenerative disorders.
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http://dx.doi.org/10.1080/15622975.2017.1375556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5916324PMC
June 2018

Cerebrospinal Fluid Clearance in Alzheimer Disease Measured with Dynamic PET.

J Nucl Med 2017 09 16;58(9):1471-1476. Epub 2017 Mar 16.

Department of Radiology, New York University Center School of Medicine, New York, New York.

Evidence supporting the hypothesis that reduced cerebrospinal fluid (CSF) clearance is involved in the pathophysiology of Alzheimer disease (AD) comes primarily from rodent models. However, unlike rodents, in which predominant extracranial CSF egress is via olfactory nerves traversing the cribriform plate, human CSF clearance pathways are not well characterized. Dynamic PET with F-THK5117, a tracer for tau pathology, was used to estimate the ventricular CSF time-activity as a biomarker for CSF clearance. We tested 3 hypotheses: extracranial CSF is detected at the superior turbinates; CSF clearance is reduced in AD; and CSF clearance is inversely associated with amyloid deposition. Fifteen subjects, 8 with AD and 7 normal control volunteers, were examined with F-THK5117. Ten subjects additionally underwent C-Pittsburgh compound B (C-PiB) PET scanning, and 8 were C-PiB-positive. Ventricular time-activity curves of F-THK5117 were used to identify highly correlated time-activity curves from extracranial voxels. For all subjects, the greatest density of CSF-positive extracranial voxels was in the nasal turbinates. Tracer concentration analyses validated the superior nasal turbinate CSF signal intensity. AD patients showed ventricular tracer clearance reduced by 23% and 66% fewer superior turbinate CSF egress sites. Ventricular CSF clearance was inversely associated with amyloid deposition. The human nasal turbinate is part of the CSF clearance system. Lateral ventricle and superior nasal turbinate CSF clearance abnormalities are found in AD. Ventricular CSF clearance reductions are associated with increased brain amyloid depositions. These data suggest that PET-measured CSF clearance is a biomarker of potential interest in AD and other neurodegenerative diseases.
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http://dx.doi.org/10.2967/jnumed.116.187211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5577629PMC
September 2017

Reduced Slow-Wave Sleep Is Associated with High Cerebrospinal Fluid Aβ42 Levels in Cognitively Normal Elderly.

Sleep 2016 Nov 1;39(11):2041-2048. Epub 2016 Nov 1.

Center for Brain Health, Department of Psychiatry, NYU Langone Medical Center, New York, NY.

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.
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http://dx.doi.org/10.5665/sleep.6240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5070758PMC
November 2016

Transient and chronic seizure-induced inflammation in human focal epilepsy.

Epilepsia 2016 09 6;57(9):e191-4. Epub 2016 Jul 6.

Department of Neurology, New York University School of Medicine, NYU Comprehensive Epilepsy Center, New York, New York, U.S.A.

In animal models, inflammation is both a cause and consequence of seizures. Less is known about the role of inflammation in human epilepsy. We performed positron emission tomography (PET) using a radiotracer sensitive to brain inflammation in a patient with frontal epilepsy ~36 h after a seizure as well as during a seizure-free period. When statistically compared to a group of 12 matched controls, both of the patient's scans identified a frontal (supplementary motor area) region of increased inflammation corresponding to his clinically defined seizure focus, but the postseizure scan showed significantly greater inflammation intensity and spatial extent. These results provide new information about transient and chronic neuroinflammation in human epilepsy and may be relevant to understanding the process of epileptogenesis and guiding therapy.
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http://dx.doi.org/10.1111/epi.13457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5266563PMC
September 2016

Effects of vascular risk factors, statins, and antihypertensive drugs on PiB deposition in cognitively normal subjects.

Alzheimers Dement (Amst) 2016 19;2:95-104. Epub 2016 Apr 19.

Department of Psychiatry, Center for Brain Health, NYU School of Medicine, New York, USA.

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.
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http://dx.doi.org/10.1016/j.dadm.2016.02.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879519PMC
May 2016

Periodontal disease's contribution to Alzheimer's disease progression in Down syndrome.

Alzheimers Dement (Amst) 2016 4;2:49-57. Epub 2016 Feb 4.

Department of Psychiatry, Center for Brain Health, School of Medicine, New York, NY, USA.

People with Down syndrome (DS) are at an increased risk for Alzheimer's disease (AD). After 60 years of age, >50% of DS subjects acquire dementia. Nevertheless, the age of onset is highly variable possibly because of both genetic and environmental factors. Genetics cannot be modified, but environmental risk factors present a potentially relevant intervention for DS persons at risk for AD. Among them, inflammation, important in AD of DS type, is potential target. Consistent with this hypothesis, chronic peripheral inflammation and infections may contribute to AD pathogenesis in DS. People with DS have an aggressive form of periodontitis characterized by rapid progression, significant bacterial and inflammatory burden, and an onset as early as 6 years of age. This review offers a hypothetical mechanistic link between periodontitis and AD in the DS population. Because periodontitis is a treatable condition, it may be a readily modifiable risk factor for AD.
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http://dx.doi.org/10.1016/j.dadm.2016.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879643PMC
May 2016

Orexin-A is Associated with Increases in Cerebrospinal Fluid Phosphorylated-Tau in Cognitively Normal Elderly Subjects.

Sleep 2016 06 1;39(6):1253-60. Epub 2016 Jun 1.

Center for Brain Health, NYU School of Medicine, New York, NY.

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.
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http://dx.doi.org/10.5665/sleep.5846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4863214PMC
June 2016

Greater specificity for cerebrospinal fluid P-tau231 over P-tau181 in the differentiation of healthy controls from Alzheimer's disease.

J Alzheimers Dis 2016 ;49(1):93-100

New York University, School of Medicine, Center for Brain Health, New York, NY, USA.

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.
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http://dx.doi.org/10.3233/JAD-150167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4694576PMC
September 2016

Alzheimer's disease cerebrospinal fluid biomarker in cognitively normal subjects.

Brain 2015 Sep 27;138(Pt 9):2701-15. Epub 2015 Jul 27.

1 Department of Pathology and Laboratory Medicine, Institute on Aging, Centre for Neurodegenerative Disease Research, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

In a large multicentre sample of cognitively normal subjects, as a function of age, gender and APOE genotype, we studied the frequency of abnormal cerebrospinal fluid levels of Alzheimer's disease biomarkers including: total tau, phosphorylated tau and amyloid-β1-42. Fifteen cohorts from 12 different centres with either enzyme-linked immunosorbent assays or Luminex® measurements were selected for this study. Each centre sent nine new cerebrospinal fluid aliquots that were used to measure total tau, phosphorylated tau and amyloid-β1-42 in the Gothenburg laboratory. Seven centres showed a high correlation with the new Gothenburg measurements; therefore, 10 cohorts from these centres are included in the analyses here (1233 healthy control subjects, 40-84 years old). Amyloid-β amyloid status (negative or positive) and neurodegeneration status (negative or positive) was established based on the pathological cerebrospinal fluid Alzheimer's disease cut-off values for cerebrospinal fluid amyloid-β1-42 and total tau, respectively. While gender did not affect these biomarker values, APOE genotype modified the age-associated changes in cerebrospinal fluid biomarkers such that APOE ε4 carriers showed stronger age-related changes in cerebrospinal fluid phosphorylated tau, total tau and amyloid-β1-42 values and APOE ε2 carriers showed the opposite effect. At 40 years of age, 76% of the subjects were classified as amyloid negative, neurodegeneration negative and their frequency decreased to 32% at 85 years. The amyloid-positive neurodegeneration-negative group remained stable. The amyloid-negative neurodegeneration-positive group frequency increased slowly from 1% at 44 years to 16% at 85 years, but its frequency was not affected by APOE genotype. The amyloid-positive neurodegeneration-positive frequency increased from 1% at 53 years to 28% at 85 years. Abnormally low cerebrospinal fluid amyloid-β1-42 levels were already frequent in midlife and APOE genotype strongly affects the levels of cerebrospinal fluid amyloid-β1-42, phosphorylated tau and total tau across the lifespan without influencing the frequency of subjects with suspected non-amyloid pathology.
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http://dx.doi.org/10.1093/brain/awv199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4643624PMC
September 2015

Clearance systems in the brain-implications for Alzheimer disease.

Nat Rev Neurol 2015 Aug 21;11(8):457-70. Epub 2015 Jul 21.

New York University School of Medicine, 145 East 32nd Street, New York, NY 10016, USA.

Accumulation of toxic protein aggregates-amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles-is the pathological hallmark of Alzheimer disease (AD). Aβ accumulation has been hypothesized to result from an imbalance between Aβ production and clearance; indeed, Aβ clearance seems to be impaired in both early and late forms of AD. To develop efficient strategies to slow down or halt AD, it is critical to understand how Aβ is cleared from the brain. Extracellular Aβ deposits can be removed from the brain by various clearance systems, most importantly, transport across the blood-brain barrier. Findings from the past few years suggest that astroglial-mediated interstitial fluid (ISF) bulk flow, known as the glymphatic system, might contribute to a larger portion of extracellular Aβ (eAβ) clearance than previously thought. The meningeal lymphatic vessels, discovered in 2015, might provide another clearance route. Because these clearance systems act together to drive eAβ from the brain, any alteration to their function could contribute to AD. An understanding of Aβ clearance might provide strategies to reduce excess Aβ deposits and delay, or even prevent, disease onset. In this Review, we describe the clearance systems of the brain as they relate to proteins implicated in AD pathology, with the main focus on Aβ.
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http://dx.doi.org/10.1038/nrneurol.2015.119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4694579PMC
August 2015

Sleep-disordered breathing advances cognitive decline in the elderly.

Neurology 2015 May 15;84(19):1964-71. Epub 2015 Apr 15.

From the Center for Brain Health (R.S.O., T.G., E.P., M.E.W., L.G., L.M., M.J.d.L.) and Division of Pulmonary, Critical Care, and Sleep Medicine (A.W.V., J.L., E.L.D., V.K., I.A., D.M.R.), NYU School of Medicine, New York, NY; and Department of Biostatistics (S.-e.L.), Rutgers School of Public Health, Piscataway, NJ.

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.
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http://dx.doi.org/10.1212/WNL.0000000000001566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4433459PMC
May 2015

FDG and Amyloid PET in Cognitively Normal Individuals at Risk for Late-Onset Alzheimer's Disease.

Adv J Mol Imaging 2014 Apr;4(2):15-26

New York University School of Medicine, New York, USA.

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 F-FDG and the amyloid- (A) tracer 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 pathology in the younger cohort, suggesting that neuronal dysfunction may precede major aggregated A burden in young NL FH+. Longitudinal follow-up is required to determine if the observed abnormalities predict future AD.
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http://dx.doi.org/10.4236/ami.2014.42003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4270202PMC
April 2014

Periodontal disease associates with higher brain amyloid load in normal elderly.

Neurobiol Aging 2015 Feb 5;36(2):627-33. Epub 2014 Nov 5.

School of Medicine, Department of Psychiatry, Center for Brain Health, New York, NY, USA.

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.
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http://dx.doi.org/10.1016/j.neurobiolaging.2014.10.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4399973PMC
February 2015

Reduced retention of Pittsburgh compound B in white matter lesions.

Eur J Nucl Med Mol Imaging 2015 Jan 21;42(1):97-102. Epub 2014 Oct 21.

Center for Brain Health, Department of Psychiatry, New York University School of Medicine, 145 East 32nd Street, New York, NY, 10016, USA,

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.
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http://dx.doi.org/10.1007/s00259-014-2897-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4415610PMC
January 2015

Global N-acetylaspartate in normal subjects, mild cognitive impairment and Alzheimer's disease patients.

J Alzheimers Dis 2015 ;43(3):939-47

Department of Radiology, New York University School of Medicine, New York, NY, USA.

Background: Mild cognitive impairment (MCI) is an intermediary state on the way to Alzheimer's disease (AD). Little is known about whole brain concentration of the neuronal marker, N-acetylaspartate (NAA) in MCI patients.

Objective: To test the hypothesis that since MCI and AD are both neurodegenerative, quantification of the NAA in their whole brain (WBNAA) could differentiate them from cognitively-intact matched controls.

Methods: Proton MR spectroscopy to quantify the WBNAA was applied to 197 subjects (86 females) 72.6 ± 8.4 years old (mean ± standard deviation). Of these, 102 were cognitively intact, 42 diagnosed as MCI, and 53 as probable AD. Their WBNAA amounts were converted into absolute concentration by dividing with the brain volume segmented from the MRI that also yielded the fractional brain volume (fBPV), an atrophy metric.

Results: WBNAA concentration of MCI and AD patients (10.5 ± 3.0 and 10.1 ± 2.9 mM) were not significantly different (p = 0.85). They were, however, highly significantly 25-29% lower than the 14.1 ± 2.4 mM of normal matched controls (p < 10-4). The fBPV of MCI and AD patients (72.9 ± 4.9 and 69.9 ± 4.7%) differed significantly from each other (4%, p = 0.02) and both were significantly lower than the 74.6 ± 4.4% of normal elderly (2%, p = 0.003 for MCI; 6%, p < 10-4 for AD). ROC curve analysis has shown WBNAA to have 70.5% sensitivity and 84.3% specificity to differentiate MCI or AD patients from normal elderly versus just 68.4 and 65.7% for fBPV.

Conclusion: Low WBNAA in MCI patients compared with cognitively normal contemporaries may indicate early neuronal damage accumulation and supports the notion of MCI as an early stage of AD. It also suggests WBNAA as a potential marker of early AD pathology.
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http://dx.doi.org/10.3233/JAD-140609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4445651PMC
August 2015

Nutrient intake and brain biomarkers of Alzheimer's disease in at-risk cognitively normal individuals: a cross-sectional neuroimaging pilot study.

BMJ Open 2014 Jun 24;4(6):e004850. Epub 2014 Jun 24.

Department of Psychiatry, New York University School of Medicine, New York, USA.

Objective: There is increasing evidence to suggest that diet, one of the most important modifiable environmental factors, may play a role in preventing or delaying cognitive decline and Alzheimer's disease (AD). This study examines the relationship between dietary nutrients and brain biomarkers of AD in cognitively normal individuals (NL) with and without AD risk factors.

Design: As part of an ongoing brain imaging study, participants received clinical and laboratory examinations, a neurocognitive test battery, positron emission tomography (PET) with (11)C-Pittsburgh Compound-B (PiB; a measure of amyloid-β (Aβ) load) and (18)F-fluorodeoxyglucose (FDG; a proxy of neuronal activity), and completed semiquantitative food frequency questionnaires.

Setting: Research centre affiliated with the Alzheimer's disease Core Center at New York University School of Medicine.

Participants: 49 NL individuals (age 25-72 years, 69% women) with dietary information, (11)C-PiB and (18)F-FDG PET scans were examined.

Results: Controlling for age and total caloric intake, higher intake of vitamin B12, vitamin D and ω-3 polyunsaturated fatty acid (PUFA) was associated with lower Aβ load in AD regions on PiB-PET, while higher intake of β-carotene and folate was associated with higher glucose metabolism on FDG-PET. β-carotene and folate were associated with reduced glucose metabolism for women, apolipoprotein E epsilon 4 (APOE4) carriers and participants with positive AD family history, but not for their risk-free counterparts. The associations of vitamin B12, vitamin D and ω-3 PUFA with PiB retention were independent of gender, APOE and family history. The identified nutrient combination was associated with higher intake of vegetables, fruit, whole grains, fish and legumes, and lower intake of high-fat dairies, meat and sweets.

Conclusions: Our data provide a potential pathophysiological mechanism for epidemiological findings showing that dietary interventions may play a role in the prevention of AD. Longitudinal studies are needed to determine whether there is a direct link between nutrient intake, brain biomarkers and risk of AD.
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http://dx.doi.org/10.1136/bmjopen-2014-004850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4078781PMC
June 2014

A conceptual framework for research on subjective cognitive decline in preclinical Alzheimer's disease.

Alzheimers Dement 2014 Nov 3;10(6):844-52. Epub 2014 May 3.

Department of Psychiatry, University of Bonn, Bonn, Germany; Clinical Treatment and Research Center for Neurodegenerative Disease (KBFZ), University of Bonn, Bonn, Germany; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.

There is increasing evidence that subjective cognitive decline (SCD) in individuals with unimpaired performance on cognitive tests may represent the first symptomatic manifestation of Alzheimer's disease (AD). The research on SCD in early AD, however, is limited by the absence of common standards. The working group of the Subjective Cognitive Decline Initiative (SCD-I) addressed this deficiency by reaching consensus on terminology and on a conceptual framework for research on SCD in AD. In this publication, research criteria for SCD in pre-mild cognitive impairment (MCI) are presented. In addition, a list of core features proposed for reporting in SCD studies is provided, which will enable comparability of research across different settings. Finally, a set of features is presented, which in accordance with current knowledge, increases the likelihood of the presence of preclinical AD in individuals with SCD. This list is referred to as SCD plus.
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http://dx.doi.org/10.1016/j.jalz.2014.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4317324PMC
November 2014

Comparison of human septal nuclei MRI measurements using automated segmentation and a new manual protocol based on histology.

Neuroimage 2014 Aug 13;97:245-51. Epub 2014 Apr 13.

Comprehensive Epilepsy Center, Department of Neurology, New York University School of Medicine, 223 East 34th Street, New York, NY 10016, USA.

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.
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http://dx.doi.org/10.1016/j.neuroimage.2014.04.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4180657PMC
August 2014

Brain imaging of cognitively normal individuals with 2 parents affected by late-onset AD.

Neurology 2014 Mar 12;82(9):752-60. Epub 2014 Feb 12.

From the New York University School of Medicine (L.M., J.M., W.H.T., Y.L., N.S., A.G., S.W., R.O., P.M., L.G., M.J.d.L.); and Weill Cornell Medical College (S.V.), New York.

Objectives: This brain imaging study examines whether cognitively normal (NL) individuals with 2 parents affected by late-onset Alzheimer disease (LOAD) show evidence of more extensive Alzheimer disease pathology compared with those who have a single parent affected by LOAD.

Methods: Fifty-two NL individuals received MRI, (11)C-Pittsburgh compound B (PiB)-PET, and (18)F-fluoro-2-deoxyglucose (FDG)-PET. These included 4 demographically balanced groups (n = 13/group, aged 32-72 years, 60% female, 30% APOE ε4 carriers) of NL individuals with maternal (FHm), paternal (FHp), and maternal and paternal (FHmp) family history of LOAD, and with negative family history (FH-). Statistical parametric mapping, voxel-based morphometry, and z-score mapping were used to compare MRI gray matter volumes (GMVs), partial volume-corrected PiB retention, and FDG metabolism across FH groups and vs FH-.

Results: NL FHmp showed more severe abnormalities in all 3 biomarkers vs the other groups regarding the number of regions affected and magnitude of impairment. PiB retention and hypometabolism were most pronounced in FHmp, intermediate in FHm, and lowest in FHp and FH-. GMV reductions were highest in FHmp and intermediate in FHm and FHp vs FH-. In all FH+ groups, amyloid-β deposition exceeded GMV loss and hypometabolism exceeded GMV loss (p < 0.001), while amyloid-β deposition exceeded hypometabolism in FHmp and FHp but not in FHm.

Conclusions: These biomarker findings show a "LOAD parent-dose effect" in NL individuals several years, if not decades, before possible clinical symptoms.
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http://dx.doi.org/10.1212/WNL.0000000000000181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3945651PMC
March 2014

Interaction between sleep-disordered breathing and apolipoprotein E genotype on cerebrospinal fluid biomarkers for Alzheimer's disease in cognitively normal elderly individuals.

Neurobiol Aging 2014 Jun 27;35(6):1318-24. Epub 2013 Dec 27.

Center for Brain Health, NYU School of Medicine, New York, NY, USA.

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.
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http://dx.doi.org/10.1016/j.neurobiolaging.2013.12.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4022140PMC
June 2014

Blood pressure decrease correlates with tau pathology and memory decline in hypertensive elderly.

Neurobiol Aging 2014 Jan 19;35(1):64-71. Epub 2013 Aug 19.

Department of Psychiatry, Center for Brain Health, New York University School of Medicine, New York, NY, USA; Department of Radiology, New York University School of Medicine, New York, NY, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.neurobiolaging.2013.06.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3799812PMC
January 2014

Cerebrospinal fluid biomarkers of Alzheimer's disease in healthy elderly.

Front Biosci (Landmark Ed) 2013 Jun 1;18:1150-73. Epub 2013 Jun 1.

Center for Brain Health, New York, NY 10016, USA.

Numerous studies have shown that Alzheimer's Disease (AD) pathology begins before the onset of clinical symptoms. Because therapies are likely to be more effective if they are implemented early in the disease progression, it is necessary to identify reliable biomarkers to detect AD pathology in the early stages of the disease, ideally in presymptomatic individuals. Recent research has identified three candidate cerebrospinal fluid (CSF) biomarkers that reflect AD pathology: amyloid beta, total tau protein (t-tau), and tau protein phosphorylated at AD-specific epitopes (p-tau). They are useful in supporting the AD diagnosis and have predictive value for AD when patients are in the stage of mild cognitive impairment (MCI). However, their predictive utility in cognitively healthy subjects is still being evaluated. We conducted a review of studies published between 1993 and 2011 and summarized their findings on the role of CSF biomarkers for AD in healthy elderly.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3904672PMC
http://dx.doi.org/10.2741/4170DOI Listing
June 2013