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1.  Klotho in the cerebrospinal fluid of adults with and without Alzheimer's disease 
Neuroscience letters  2013;558:37-40.
The aging-suppressor gene klotho encodes a single-pass transmembrane protein that is predominantly secreted by the choroid plexus of the brain and in the kidney. Klotho-deficient mice develop multiple aging phenotypes, including impaired cognition. Klotho concentrations have not been described in the CSF of humans. We measured klotho in the CSF of 20 older adults with Alzheimer's disease and in 20 older and 20 younger adults with normal cognition. In 10 adults, aged 38-87 years, CSF klotho measurements were made at baseline and every 6 hours up to 18-30 hours later. Mean (95% Confidence Interval [C.I.]) CSF klotho in men versus women were 899 (814, 983) and 716 (632, 801) pg/mL, respectively (P = 0.002). Mean (95% C.I.) CSF klotho in older adults with and without Alzheimer's disease were 664 (603, 725) and 776 (705, 828) pg/mL, respectively (P = 0.02), adjusting for sex. Mean (95% C.I.) klotho in older versus younger adults were 766 (658, 874) and 992 (884, 1100) pg/mL, respectively (P = 0.005), adjusting for sex. In the longitudinal study of CSF klotho, no significant circadian fluctuations were found in CSF klotho levels. This study suggests that CSF klotho concentrations are lower in females compared with males, in Alzheimer's disease, and in older versus younger adults.
doi:10.1016/j.neulet.2013.10.058
PMCID: PMC4037850  PMID: 24211693
Aging; Alzheimer's Disease; Brain; Cerebrospinal Fluid; Klotho
3.  Relationship of cognitive reserve and CSF biomarkers to emergence of clinical symptoms in preclinical Alzheimer’s Disease 
Neurobiology of aging  2013;34(12):10.1016/j.neurobiolaging.2013.06.017.
Levels of β-amyloid and phosphorylated tau (p-tau), as measured in cerebrospinal fluid (CSF), have been associated with risk of progressing from normal cognition to onset of clinical symptoms during preclinical Alzheimer’s disease (AD). We examined whether cognitive reserve (CR) modifies this association. CSF was obtained at baseline from 239 participants (mean age 57.2 years) who had been followed for up to 17 years with clinical and cognitive assessments (mean follow-up 8 years). A composite score based on the National Adult Reading Test (NART), vocabulary, and years of education at baseline was used as an index of CR. Cox regression models showed that increased risk of progressing from normal cognition to symptom onset was associated with lower CR, lower baseline β-amyloid, and higher baseline p-tau. There was no interaction between CR and β-amyloid, suggesting that the protective effects of higher CR are equivalent across the observed range of amyloid levels. By contrast, both tau and p-tau interacted with CR, indicating that CR was more protective at lower levels of tau and p-tau.
doi:10.1016/j.neurobiolaging.2013.06.017
PMCID: PMC3823238  PMID: 23916061
cognitive reserve; preclinical Alzheimer’s disease; Mild Cognitive Impairment; cerebrospinal fluid; tau; amyloid; cohort studies; biomarkers
4.  CSF biomarker changes precede symptom onset of mild cognitive impairment 
Neurology  2013;81(20):1753-1758.
Objective:
This study evaluated longitudinal CSF biomarker measures collected when participants were cognitively normal to determine the magnitude and time course of biomarker changes before the onset of clinical symptoms in subjects with mild cognitive impairment (MCI).
Methods:
Longitudinal CSF collection and cognitive assessments were performed on a cohort of 265 participants who were cognitively normal at their baseline assessment and subsequently developed MCI or dementia. CSF β-amyloid 1–42 (Aβ1–42), total tau (t-tau), and phosphorylated tau (p-tau) were determined longitudinally. Consensus diagnoses were completed annually. Cox regression analyses were performed, with baseline CSF values and time-dependent rate of change in CSF values as covariates (adjusted by baseline age, race, and education), in relation to time to onset of mild cognitive symptoms.
Results:
The mean time from baseline to onset of mild cognitive symptoms was 5.41 years. Increased risk of progressing from normal cognition to onset of clinical symptoms was associated with baseline values of Aβ1–42, p-tau, and the ratios of p-tau/Aβ1–42 and t-tau/Aβ1–42 (p < 0.002). Additionally, the rate of change in the ratios of t-tau/Aβ1–42 (p < 0.004) and p-tau/Aβ1–42 (p < 0.02) was greater among participants who were subsequently diagnosed with MCI.
Conclusions:
Baseline differences in CSF values were predictive of clinical symptoms that were a harbinger of a diagnosis of MCI more than 5 years before symptom onset, and continue to show longitudinal changes as cognitive symptoms develop, demonstrating that baseline and longitudinal changes in CSF biomarkers are evident during the preclinical phase of Alzheimer disease.
doi:10.1212/01.wnl.0000435558.98447.17
PMCID: PMC3821715  PMID: 24132375
5.  Relationship of Cognitive Reserve and APOE Status to the Emergence of Clinical Symptoms in Preclinical Alzheimer’s Disease 
Cognitive neuroscience  2013;4(0):10.1080/17588928.2013.831820.
The APOE ε4 allele increases the risk of developing Alzheimer’s disease, whereas the APOE ε2 allele reduces risk. We examined whether cognitive reserve (CR), as measured by an index consisting of education, reading, and vocabulary, modifies these associations. CR was measured at baseline in 257 cognitively normal individuals (mean age 57.2 years) who have been followed for up to 17 years (mean follow-up = 9.2 years). Cox regression models showed that CR and APOE ε4 independently affected the risk of progressing from normal cognition to onset of clinical symptoms: CR reduced risk by about 50% in both ε4 carriers and non-carriers, while ε4 increased risk by about 150%. In contrast, APOE ε2 interacted with CR, such that CR was more protective in ε2 carriers than non-carriers. This suggests that individuals with an ε2 genotype may disproportionately benefit from lifetime experiences that enhance cognition.
doi:10.1080/17588928.2013.831820
PMCID: PMC3836845  PMID: 24168200
6.  Obesity and Headache: Part II – Potential Mechanism and Treatment Considerations 
Headache  2014;54(3):459-471.
Obesity and headache are both associated with a substantial personal and societal impact, and epidemiologic studies have consistently identified a positive association between obesity and headache in general, as well as obesity and migraine specifically (see part I). In the current manuscript, we will discuss the potential mechanisms for the migraine–obesity association, with a focus on the central and peripheral pathophysiological pathways which overlap between migraine and those modulating the drive to feed. We then discuss surgical, behavioral, and pharmacological treatment considerations for overweight and obese migraineurs as well as for those with idiopathic intracranial hypertension. We close by briefly discussing where future research may be headed in light of this data.
doi:10.1111/head.12297
PMCID: PMC3975621  PMID: 24511882
headache; migraine; obesity; body mass index
7.  An In Vivo Evaluation of Cerebral Cortical Amyloid with [18F]Flutemetamol Using Positron Emission Tomography Compared with Parietal Biopsy Samples in Living Normal Pressure Hydrocephalus Patients 
Purpose
The primary objectives of this study were to assess the safety of [18F]flutemetamol injection and determine the level of association between the quantitative estimates of brain uptake of [18F] flutemetamol and the quantitative immunohistochemical (IHC) estimates of amyloid levels in cerebral cortex biopsies obtained during shunt placement in patients with normal pressure hydrocephalus (NPH).
Procedures
Parietal lobe biopsies were obtained from 12 subjects (mean (SD), 71 (8.1) years), during shunt placement for NPH. Shunt procedures and biopsies were performed within 8 weeks after the positron emission tomography (PET) imaging, and followed by a computed tomography scan. The quantitative estimates of the brain uptake of [18F]flutemetamol (standard uptake value ratios (SUVRs)) from the biopsy site, contralateral to the biopsy site, and composite were made from the analysis of PET images. The quantitative IHC levels of amyloid load were estimated using a monoclonal antiamyloid β antibody, 4 G8 (in percent area), as the standard of truth (N=8, of which 5 had full histopathology staining). The primary analysis determined the level of association between the SUVR (with cerebellum as the reference region) from the biopsy site, and the level of amyloid was determined from IHC estimates of amyloid in the biopsy sample.
Results
[18F]Flutemetamol injection was found to be well tolerated. The biopsied area well represented the amyloid deposition throughout the cortex in this small sample. The biopsy site SUVR was significantly correlated with the biopsy specimen amyloid β level (expressed as percent of biopsy specimen area staining with 4 G8). The full model was significant (p=0.0174). In the secondary efficacy analyses, contralateral (to biopsy site) and composite SUVR values correlated significantly with the percent of biopsy specimen staining for amyloid β based on 4 G8. Blinded visual [18F]flutemetamol image interpretations showed a sensitivity of 100 % and a specificity of 100 % with pathology reads staining for amyloid plaque with Bielschowsky and thioflavin S and overall pathology read. The results of the blinded reader agreement for [18F] flutemetamol PET showed full agreement among three readers.
Conclusions
PET imaging of NPH patients following the administration of [18F]flutemetamol injection was highly correlated with the presence of fibrillar amyloid β in subsequent cortical biopsy samples in this small sample. Administration of [18F]flutemetamol injection was well tolerated.
doi:10.1007/s11307-012-0583-x
PMCID: PMC3936021  PMID: 22878921
Amyloid; Biopsy; Flutemetamol; NPH; Positron emission tomography
8.  Obesity and Headache: Part I – A Systematic Review of the Epidemiology of Obesity and Headache 
Headache  2014;54(2):219-234.
Individually, both obesity and headache are conditions associated with a substantial personal and societal impact. Recent data support that obesity is comorbid with headache in general and migraine specifically, as well as with certain secondary headache conditions such as idiopathic intracranial hypertension. In the current manuscript, we first briefly review the epidemiology of obesity and common primary and secondary headache disorders individually. This is followed by a systematic review of the general population data evaluating the association between obesity and headache in general, and then obesity and migraine and tension-type headache disorders. Finally, we briefly discuss the data on the association between obesity and a common secondary headache disorder that is associated with obesity, idiopathic intracranial hypertension. Taken together, these data suggest that it is important for clinicians and patients to be aware of the headache/migraine-obesity association, given that it is potentially modifiable. Hypotheses for mechanisms of the obesity-migraine association and treatment considerations for overweight and obese headache sufferers are discussed in the companion manuscript, as part II of this topic.
doi:10.1111/head.12296
PMCID: PMC3971380  PMID: 24512574
headache; migraine; obesity; body mass index
9.  Cerebral White Matter Disease is Associated with Alzheimer Pathology in a Prospective Cohort 
Background
Although MRI detected white matter disease has been correlated with cognitive decline in the elderly, it is unclear whether white matter disease is primarily responsible for the cognitive deterioration or whether another process is common to white matter disease and dementia.
Methods
We examined the relationship between Alzheimer type brain pathology at autopsy and MRI detected cerebral white matter disease in 50 participants from the Baltimore Longitudinal Study of Aging (BLSA) Autopsy Program, a prospective study of aging which includes detailed cognitive assessments.
Results
White matter disease was quantitated in pre- and postmortem MRI scans using the Cardiovascular Health Study (CHS) criteria in a blinded fashion. We found that several measures of Alzheimer disease (AD) pathology including CERAD score, Braak score and a composite AD pathology score, along with hypertension, were significantly associated with CHS white matter score using univariate and multivariate ordinal regression. In contrast, amyloid angiopathy was not independently related to with CHS score. While a clinical diagnosis of dementia was associated with CHS score in univariate analysis, the association disappeared after accounting for AD pathology.
Conclusion
Alzheimer’s pathology at autopsy is associated with MRI detected cerebral white matter disease. This relationship may explain, in part, the association between cerebral white matter disease and cognitive decline in the elderly.
doi:10.1016/j.jalz.2012.04.006
PMCID: PMC3474974  PMID: 23021624
Alzheimer’s; Dementia; MRI; White Matter Disease; Hypertension; Atherosclerosis
10.  The Alzheimer’s Association external quality control program for cerebrospinal fluid biomarkers 
Mattsson, Niklas | Andreasson, Ulf | Persson, Staffan | Arai, Hiroyuki | Batish, Sat Dev | Bernardini, Sergio | Bocchio-Chiavetto, Luisella | Blankenstein, Marinus A. | Carrillo, Maria C. | Chalbot, Sonia | Coart, Els | Chiasserini, Davide | Cutler, Neal | Dahlfors, Gunilla | Duller, Stefan | Fagan, Anne M. | Forlenza, Orestes | Frisoni, Giovanni B. | Galasko, Douglas | Galimberti, Daniela | Hampel, Harald | Handberg, Aase | Heneka, Michael T. | Herskovits, Adrianna Z. | Herukka, Sanna-Kaisa | Holtzman, David M. | Humpel, Christian | Hyman, Bradley T. | Iqbal, Khalid | Jucker, Mathias | Kaeser, Stephan A. | Kaiser, Elmar | Kapaki, Elisabeth | Kidd, Daniel | Klivenyi, Peter | Knudsen, Cindy S. | Kummer, Markus P. | Lui, James | Lladó, Albert | Lewczuk, Piotr | Li, Qiao-Xin | Martins, Ralph | Masters, Colin | McAuliffe, John | Mercken, Marc | Moghekar, Abhay | Molinuevo, José Luis | Montine, Thomas J. | Nowatzke, William | O’Brien, Richard | Otto, Markus | Paraskevas, George P. | Parnetti, Lucilla | Petersen, Ronald C. | Prvulovic, David | de Reus, Herman P. M. | Rissman, Robert A. | Scarpini, Elio | Stefani, Alessandro | Soininen, Hilkka | Schröder, Johannes | Shaw, Leslie M. | Skinningsrud, Anders | Skrogstad, Brith | Spreer, Annette | Talib, Leda | Teunissen, Charlotte | Trojanowski, John Q. | Tumani, Hayrettin | Umek, Robert M. | Van Broeck, Bianca | Vanderstichele, Hugo | Vecsei, Laszlo | Verbeek, Marcel M. | Windisch, Manfred | Zhang, Jing | Zetterberg, Henrik | Blennow, Kaj
Background
The cerebrospinal fluid (CSF) biomarkers amyloid β (Aβ)-42, total-tau (T-tau), and phosphorylated-tau (P-tau) demonstrate good diagnostic accuracy for Alzheimer’s disease (AD). However, there are large variations in biomarker measurements between studies, and between and within laboratories. The Alzheimer’s Association has initiated a global quality control program to estimate and monitor variability of measurements, quantify batch-to-batch assay variations, and identify sources of variability. In this article, we present the results from the first two rounds of the program.
Methods
The program is open for laboratories using commercially available kits for Aβ, T-tau, or P-tau. CSF samples (aliquots of pooled CSF) are sent for analysis several times a year from the Clinical Neurochemistry Laboratory at the Molndal campus of the University of Gothenburg, Sweden. Each round consists of three quality control samples.
Results
Forty laboratories participated. Twenty-six used INNOTESTenzyme-linked immunosorbent assay kits, 14 used Luminex xMAP with the INNO-BIA AlzBio3 kit (both measure Aβ-(1-42), P-tau(181P), and T-tau), and 5 used Meso Scale Discovery with the Aβ triplex (AβN-42, AβN-40, and AβN-38) or T-tau kits. The total coefficients of variation between the laboratories were 13% to 36%. Five laboratories analyzed the samples six times on different occasions. Within-laboratory precisions differed considerably between biomarkers within individual laboratories.
Conclusions
Measurements of CSF AD biomarkers show large between-laboratory variability, likely caused by factors related to analytical procedures and the analytical kits. Standardization of laboratory procedures and efforts by kit vendors to increase kit performance might lower variability, and will likely increase the usefulness of CSF AD biomarkers.
doi:10.1016/j.jalz.2011.05.2243
PMCID: PMC3710290  PMID: 21784349
Alzheimer’s disease; Cerebrospinal fluid; Biomarkers; External assurance; External control; Proficiency testing
11.  Con: Alzheimer's disease and circadian dysfunction: chicken or egg? 
The development of late-onset Alzheimer's disease is believed to be influenced by genetic, socioeconomic, and lifestyle factors. Recently, converging research in animal and human studies has found that beta-amyloid (Aβ) levels in cerebrospinal fluid are modulated by sleep-wake cycles. This raises the possibility that chronic sleep loss causes brain amyloid accumulation over time and leads to the development of Alzheimer's disease. The observation that circadian rhythm modulates Aβ levels has not yet been replicated by other groups, and subject selection and methodologies are potential explanations for this. While acute suppression of sleep may raise Aβ levels, it is not known whether chronic sleep loss has the same effect. It is conceivable that altered circadian rhythms are a manifestation of a disrupted sleep network because of preclinical disease, as has been observed in other neurodegenerative disorders. The findings that circadian variation in Aβ levels in cerebrospinal fluid is a direct result of sleep-wake cycles and that altering normal rhythms increases the risk for brain amyloid accumulation need to be replicated in larger cohorts. Prospective studies are needed to decipher whether circadian rhythm dysfunction is a cause, or a result of, amyloid accumulation.
doi:10.1186/alzrt129
PMCID: PMC3506940  PMID: 22883923
12.  Cerebrospinal Fluid Aβ and Tau Level Fluctuation in an Older Clinical Cohort 
Archives of Neurology  2012;69(2):246-250.
Objective
To determine whether cerebrospinal fluid (CSF) biomarkers for Alzheimer disease fluctuate significantly over time in a cohort of older, mildly symptomatic individuals.
Design
Biomarker validation in a clinical cohort.
Setting
University hospital inpatient unit.
Participants
Ten patients admitted for CSF drainage for diagnostic purposes.
Main Outcome Measures
The CSF levels of Aβ1–40, Aβ1–42, tau, and phosphorylated tau on threonine 181 (p-tau181) were measured every 6 hours for 24 or 36 hours.
Results
The mean coefficient of variation values for each biomarker assessed in our 10 patients were 5.5% (95% CI, 3.8%–10.0%) for Aβ1–42, 12.2% (9.0%–24.2%) for Aβ1–40, 8.2% (5.7%–15.1%) for total tau, and 11.9% (8.5%–23.0%) for p-tau181. These values are only slightly higher than the variability in the assay. In addition, no significant circadian fluctuation in any Alzheimer disease biomarker was observed given the limitations of our sampling frequency.
Conclusion
In a cohort of elderly patients, little fluctuation in the levels of important Alzheimer disease biomarkers in lumbar CSF is seen as a function of time.
doi:10.1001/archneurol.2011.732
PMCID: PMC3310240  PMID: 22332192
13.  Cerebrospinal Fluid Profiles Predict Prospective Course and Outcome Among Persons with Amnestic Mild Cognitive Impairment 
Archives of neurology  2011;68(1):113-119.
Objectives
To examine the effect of specific “CSF profiles” on the rate of cognitive decline, disease progression, and risk of conversion to Alzheimer's disease (AD) dementia in patients with amnestic mild cognitive impairment (MCI).
Design
Total tau (t-tau), tau phosphorylated at threonine 181 (p-tau181), and β-amyloid 1-42 peptide (Aβ42) were immunoassayed in CSF samples obtained from MCI patients enrolled in the Alzheimer's Disease Neuroimaging Initiative. Patients were then stratified by “CSF profiles”: (1) normal t-tau and Aβ42 levels (i.e., normal–t-tauAβ42), (2) normal t-tau but abnormal Aβ42 (i.e., abnormal–Aβ42), (3) abnormal t-tau but normal Aβ42 (i.e., abnormal–t-tau), and (4) abnormal t-tau and Aβ42 (i.e., abnormal–t-tauAβ42).
Setting
Fifty-eight sites in the US and Canada.
Participants
One hundred ninety-five MCI patients.
Main Outcome Measures
A composite cognitive measure, the CDR-Sum of Boxes, and conversion to AD.
Results
MCI patients with a CSF profile of abnormal–Aβ42 or abnormal–t-tauAβ42 experienced a faster rate of decline on the composite cognitive measure and the CDR-Sum of Boxes compared to those with normal–t-tauAβ42. They also had a greater risk of converting to AD relative to the normal–t-tauAβ42 group. In contrast, those with a CSF profile of abnormal–t-tau did not differ from the normal–t-tauAβ42 group on any outcome. These findings were generally replicated when the sample was reclassified by patterns of p-tau181 and Aβ42 abnormalities.
Conclusions
β-amyloid abnormalities, but not tau alterations, are associated with cognitive deterioration, disease progression, and increased risk of conversion to AD dementia in patients with MCI. Patients with abnormal levels of Aβ42 may be prime targets for drug treatment and clinical trials in MCI.
doi:10.1001/archneurol.2010.334
PMCID: PMC3058271  PMID: 21220682
CSF; MCI; cognitive decline; disease progression; conversion to AD
14.  Activity Dependent Localization of Synaptic NMDA Receptors in Spinal Neurons 
In cultured spinal neurons, NMDA receptors are absent from excitatory synapses under basal conditions, but can be made to appear at excitatory synapses following blockade of excitatory synaptic activity. The activity dependent synaptic localization of NMDA receptors is critically dependent on both the gradual, global accumulation of the NR2A and NR2B subunits and on a rapid, surface redistribution phase that is primed by the accumulation of NR2A and NR2B and inhibited by synaptic activity. Global changes in NR2A and NR2B accumulation and heterogeneous increases in synaptic NMDA receptor localization can also result from inhibitors of proteasomal processing, from manipulations of proteasomal subunit composition and from media conditioned by neurons undergoing synaptic scaling. While proteasomal processing is a mechanism shared with AMPA receptor scaling in cultured spinal neurons, diffusible factors, heterogeneity, and a rapid surface redistribution phase appear to be unique to activity dependent synaptic NMDA receptor localization.
doi:10.1016/j.mcn.2006.12.008
PMCID: PMC2735016  PMID: 17306986
NMDA; Scaling; Plasticity; Activity; Synapse; Glutamate

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