Florbetapir F 18 PET can image amyloid-β (Aβ) aggregates in the brains of living subjects. We prospectively evaluated the prognostic utility of detecting Aβ pathology using florbetapir PET in subjects at risk for progressive cognitive decline.
A total of 151 subjects who previously participated in a multicenter florbetapir PET imaging study were recruited for longitudinal assessment. Subjects included 51 with recently diagnosed mild cognitive impairment (MCI), 69 cognitively normal controls (CN), and 31 with clinically diagnosed Alzheimer disease dementia (AD). PET images were visually scored as positive (Aβ+) or negative (Aβ−) for pathologic levels of β-amyloid aggregation, blind to diagnostic classification. Cerebral to cerebellar standardized uptake value ratios (SUVr) were determined from the baseline PET images. Subjects were followed for 18 months to evaluate changes in cognition and diagnostic status. Analysis of covariance and correlation analyses were conducted to evaluate the association between baseline PET amyloid status and subsequent cognitive decline.
In both MCI and CN, baseline Aβ+ scans were associated with greater clinical worsening on the Alzheimer's Disease Assessment Scale–Cognitive subscale (ADAS-Cog (p < 0.01) and Clinical Dementia Rating–sum of boxes (CDR-SB) (p < 0.02). In MCI Aβ+ scans were also associated with greater decline in memory, Digit Symbol Substitution (DSS), and Mini-Mental State Examination (MMSE) (p < 0.05). In MCI, higher baseline SUVr similarly correlated with greater subsequent decline on the ADAS-Cog (p < 0.01), CDR-SB (p < 0.03), a memory measure, DSS, and MMSE (p < 0.05). Aβ+ MCI tended to convert to AD dementia at a higher rate than Aβ− subjects (p < 0.10).
Florbetapir PET may help identify individuals at increased risk for progressive cognitive decline.
Using data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) population, we examined (1) cross-sectional relationships between amyloid deposition, hypometabolism, and cognition, and (2) associations between amyloid and hypometabolism measurements and longitudinal cognitive measurements.
We examined associations between mean cortical florbetapir uptake, mean 18F-fluorodeoxyglucose–positron emission tomography (FDG-PET) within a set of predefined regions, and Alzhiemer’s Disease Assessment Scale (ADAS-cog) performance in 426 ADNI participants (126 normal, 162 early mild cognitive impairment [EMCI], 85 late MCI [LMCI], 53 Alzheimer disease [AD] patients). For a subset of these (76 normal, 81 LMCI) we determined whether florbetapir and FDG-PET were associated with retrospective decline in longitudinal ADAS-cog measurements.
Twenty-nine percent of normal subjects, 43% of EMCI patients, 62% of LMCI patients, and 77% of AD patients were categorized as florbetapir positive. Florbetapir was negatively associated with concurrent FDG and ADAS-cog in both MCI groups. In longitudinal analyses, florbetapir-positive subjects in both normal and LMCI groups had greater ongoing ADAS-cog decline than those who were florbetapir negative. However, in normal subjects, florbetapir positivity was associated with greater ADAS-cog decline than FDG, whereas in LMCI, FDG positivity was associated with greater decline than florbetapir.
Although both hypometabolism and β-amyloid (Aβ) deposition are detectable in normal subjects and all diagnostic groups, Aβ showed greater associations with cognitive decline in normal participants. In view of the minimal cognitive deterioration overall in this group, this suggests that amyloid deposition has an early and subclinical impact on cognition that precedes metabolic changes. At moderate and later stages of disease (LMCI/AD), hypometabolism becomes more pronounced and more closely linked to ongoing cognitive decline.
11C-Pittsburgh compound B (11C-PiB) and 18F-florbetapir amyloid-β (Aβ) PET radioligands have had a substantial impact on Alzheimer disease research. Although there is evidence that both radioligands bind to fibrillar Aβ in the brain, direct comparisons in the same individuals have not been reported. Here, we evaluated PiB and florbetapir in a retrospective convenience sample of cognitively normal older controls, patients with mild cognitive impairment, and patients with Alzheimer disease from the Alzheimer’s Disease Neuroimaging Initiative (ADNI).
From the ADNI database, 32 participants were identified who had undergone at least 1 PiB study and subsequently underwent a florbetapir study approximately 1.5 y after the last PiB study. Cortical PiB and florbetapir retention was quantified using several different methods to determine the effect of preprocessing factors (such as smoothing and reference region selection) and image processing pipelines.
There was a strong association between PiB and florbetapir cortical retention ratios (Spearman ρ = 0.86–0.95), and these were slightly lower than cortical retention ratios for consecutive PiB scans (Spearman ρ = 0.96–0.98) made approximately 1.1 y apart. Cortical retention ratios for Aβ-positive subjects tended to be higher for PiB than for florbetapir images, yielding slopes for linear regression of florbetapir against PiB of 0.59–0.64. Associations between consecutive PiB scans and between PiB and florbetapir scans remained strong, regardless of processing methods such as smoothing, spatial normalization to a PET template, and use of reference regions. The PiB–florbetapir association was used to interconvert cutoffs for Aβ positivity and negativity between the 2 radioligands, and these cutoffs were highly consistent in their assignment of Aβ status.
PiB and florbetapir retention ratios were strongly associated in the same individuals, and this relationship was consistent across several data analysis methods, despite scan–rescan intervals of more than a year. Cutoff thresholds for determining positive or negative Aβ status can be reliably transformed from PiB to florbetapir units or vice versa using a population scanned with both radioligands.
amyloid-β; Alzheimer’s disease; PET imaging
Pretreatment brain activity in major depressive disorder correlates with response to antidepressant therapies, including pharmacotherapies and transcranial magnetic stimulation. The purpose of this trial was to examine whether pretreatment regional metabolic activity in selected regions of interest (ROIs) predicts antidepressant response following 12 months of vagus nerve stimulation (VNS) in 15 patients with treatment-resistant major depression (TRMD).
Fluorodeoxyglucose positron emission tomography (FDG PET) was used to assess regional mean relative cerebral metabolic rate for glucose (CMRGlu) in four ROIs (anterior insular, orbitofrontal, anterior cingulate, and dorsolateral prefrontal cortices) at baseline (prior to VNS activation). Depression severity was assessed at baseline and after 12 months of VNS using the Hamilton Depression Rating Scale (HDRS), with response defined as ≥50% reduction in HDRS from baseline.
Baseline CMRGlu in the anterior insular cortex differentiated VNS responders (n = 11) from nonresponders (n = 4) and correlated with HDRS change (r = .64, p = .01). In a regression analysis, lower anterior insular cortex CMRGlu (p = .004) and higher orbitofrontal cortex CMRGlu (p = .047) together predicted HDRS change (R2 = .58, p = .005). In a whole brain, voxel-wise analysis, baseline CMRGlu in the right anterior insular cortex correlated with HDRS change (r = .78, p = .001).
Sample size was small, limiting statistical power; patients remained on their psychiatric medications; study was open-label and uncontrolled.
This preliminary study suggests that pretreatment regional CMRGlu may be useful in predicting response to VNS in TRMD patients.
Vagus nerve stimulation; Depression; Positron emission tomography; Treatment-resistant depression; Fluorodeoxyglucose PET; Treatment response
Existing neuroimaging studies of vagus nerve stimulation (VNS) in treatment resistant major depression (TRMD) suggest that many brain regions (e.g., prefrontal cortex, thalamus, cingulate cortex, insular cortex) associated with mood disorders undergo alterations in blood flow/metabolism.
Positron emission tomography (PET oxygen-15 labeled water or PET [15O] H2O) was used to identify changes in regional cerebral blood flow (rCBF) in response to immediate VNS in 13 subjects with TRMD. We hypothesized rCBF changes along the afferent pathway of the vagus and in regions associated with depression (e.g., orbitofrontal cortex, amygdala, insular cortex).
Six 90-second PET [15O] H2O scans were performed on 13 subjects in a VNS off-on sequence. Following normalization for global uptake and realignment to standard atlas space, statistical t-images (p < 0.005) were used to evaluate rCBF change.
VNS induced significant rCBF decreases in the left and right lateral orbitofrontal cortex and left inferior temporal lobe. Significant increases were found in the right dorsal anterior cingulate, left posterior limb of the internal capsule/medial putamen, the right superior temporal gyrus, and the left cerebellar body. Post-hoc analysis found small to moderate correlations between baseline acute change in rCBF and antidepressant response following 12 months of VNS.
Regions undergoing rCBF change in response to acute VNS are consistent with the known afferent pathway of the vagus nerve and models of brain network in depression. Larger studies assessing the correlation between acute stimulation patterns and antidepressant outcomes with VNS are needed.
Vagus nerve stimulation; Depression; Positron emission tomography; Regional blood flow; Treatment-resistant depression
4-(Dimethylamino)-N-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-benzamide (WC-10), a N-phenyl piperazine analog, displays high affinity and moderate selectivity for dopamine D3 receptors versus dopamine D2 receptors (Chu et al.  Bioorg Med Chem 13:77–87). In this study, WC-10 was radiolabeled with tritium (specific activity = 80 Ci/mmol), and quantitative autoradiography studies were conducted using rhesus monkey and Sprague-Dawley rat brain sections. Kd values for the binding of [3H]WC-10 to D3 receptors obtained from quantitative autoradiography with rhesus monkey and rat brain sections are in agreement with Kd values obtained from cloned human and rat receptors (Xu et al.  Synapse 63:717-728). The D2 selective antagonist [3H]raclopride binds with 11-fold higher affinity to human HEK D2L (Kd = 1.6 nM) than HEK D3 (Kd = 18 nM) receptors; [3H]raclopride binds to rat Sf9 rD2L receptors with a Kd of 6.79 nM, a value that is 4-fold lower than binding to human HEK D2L receptors and 2.5-fold higher than binding to rat Sf9 rD3 receptors. In vitro quantitative autoradiography studies with [3H]WC-10 and [3H]raclopride were conducted on adult rat and rhesus monkey brain sections. A mathematical model for calculating the absolute densities of dopamine D2 and D3 receptors based on the in vitro receptor binding data of [3H]WC-10 and [3H]raclopride was developed.
dopamine; DA D3/D2 receptors; quantitative autoradiography
APOE ε4 status has been associated with greater cortical amyloid deposition whereas exercise has been associated with less in cognitively normal adults. The primary objective here was to examine whether physical exercise moderates the association between APOE genotype and amyloid deposition in cognitively normal adults.
APOE genotyping and a questionnaire on physical exercise engagement over the last decade were obtained in conjunction with cerebrospinal fluid (CSF) samples and amyloid imaging with PET-PIB. Participants were classified as either low or high exercisers based on exercise guidelines of the American Heart Association.
201 cognitively normal adults (135 females) aged 45–88 were recruited from the Knight Alzheimer Disease Research Center at Washington University. CSF samples were collected from 165 participants. Amyloid imaging was performed on 163 participants.
APOE ε4 carriers evidenced higher PIB binding (p<.001) and lower CSF Aβ42 levels (p<.001) than non-carriers. Our previous findings of higher PIB binding (p=.005) and lower CSF Aβ42 levels (p=.009) in more sedentary individuals were replicated. Most importantly, we observed a novel interaction between APOE status and exercise engagement for PIB binding (p=.008) such that a more sedentary lifestyle was significantly associated with higher PIB binding for ε4 carriers (p=.013) but not for ε4 non-carriers (p=.208). All findings remained significant after controlling for age, gender, education, hypertension, body mass index, diabetes, heart problems, history of depression and interval between assessments.
Collectively, these results suggest that cognitively normal sedentary APOE ε4+ individuals may be at augmented risk for cerebral amyloid deposition.
The amyloid hypothesis predicts that increased production or decreased clearance of amyloid beta (Aβ) leads to amyloidosis, ultimately culminating in Alzheimer’s disease (AD). Dynamic changes in human CNS Aβ levels may be altered by aging or AD pathology and contribute to the risk of AD.
In this study, hourly cerebrospinal fluid (CSF) Aβ concentrations were compared with age, PIB PET amyloid status and electroencephalography (EEG) and video recording data.
Linear increases of CSF Aβ concentrations over time were observed in younger control participants and older Amyloid- participants, but not in older Amyloid+ participants. Significant CSF Aβ circadian patterns were observed in younger control participants; however circadian amplitudes were decreased in both Amyloid- and Amyloid+ older participants. Aβ diurnal concentrations were correlated to the amount of sleep, but not various awake activities.
Decreased linear rise of CSF Aβ levels associated with amyloid deposition, and decreased CSF Aβ diurnal pattern associated with increasing age disrupt the normal physiology of Aβ dynamics, and may contribute to AD.
Beta-amyloid plaques (Aβ plaques) in the brain are associated with cerebral amyloid angiopathy (CAA). Imaging agents that could target the Aβ plaques in the living human brain would be potentially valuable as biomarkers in patients with CAA. A new series of 18F styrylpyridine derivatives with high molecular weights for selectively targeting Aβ plaques in the blood vessels of the brain, but excluded from the brain parenchyma is reported. The styrylpyridine derivatives, 8a–c, display high binding affinities and specificity to Aβ plaques (Ki = 2.87 nM, 3.24 and 7.71 nM, respectively). In vitro autoradiography of [18F]8a shows labeling of β-amyloid plaques associated with blood vessel walls in human brain sections of subjects with CAA, and also in the tissue of AD brain sections. The results suggest that [18F]8a may be a useful PET imaging agent for selectively detecting Aβ plaques associated with cerebral vessels in the living human brain.
PET imaging; Alzheimer’s disease; cerebral blood vessels; β–amyloid plaque; cerebral amyloid angiopathy; autoradiography and in vivo biodistribution
Amyloid-beta (Aβ) accumulation was evaluated with two PIB PET scans about 2.5 years apart in 146 cognitively normal adults. Seventeen of 21 participants with initially elevated Aβ deposition demonstrated subsequent Aβ plaque growth (approximately 8.0% per year) and none reverted to a state of no Aβ deposits. Ten individuals converted from negative to positive PIB status, based on a threshold of the mean cortical binding potential, representing a conversion rate of 3.1% per year. Individuals with an ε4 allele of apolipoprotein E demonstrated increased incidence of conversion (7.0% per year). Our findings suggest that the major growth in Aβ burden occurs during a preclinical stage of AD, prior to the onset of AD-related symptoms.
preclinical Alzheimer disease; amyloid-beta accumulation; apolipoprotein E; positron emission tomography; [11C]PIB
Down syndrome appears to be associated with a virtually certain risk of fibrillar amyloid-β (Aβ) pathology by the age of 40 and a very high risk of dementia at older ages. The positron emission tomography (PET) ligand florbetapir F18 has been shown to characterize fibrillar Aβ in the living human brain and to provide a close correlation with subsequent Aβ neuropathology in individuals proximate to and after the end of life. The extent to which the most frequently used PET ligands can be used to detect fibrillar Aβ in patients with Down syndrome remains to be determined.
To characterize PET estimates of fibrillar Aβ burden in a Down syndrome patient very close to the end of life and to compare them with neuropathologic assessment made after his death.
With the family’s informed consent, florbetapir PET was used to study a 55-year-old Down syndrome patient with Alzheimer disease near the end of life; his brain was donated for neuropathologic assessment when he died 14 days later. Visual ratings of cerebral florbetapir uptake were performed by trained readers who were masked to the patient’s diagnosis as part of a larger study, and an automated algorithm was used to characterize regional-to-cerebellar standard uptake value ratios in 6 cerebral regions of interest. Neuropathologic assessments were performed masked to the patient’s diagnosis or PET measurements.
Visual ratings and automated analyses of the PET image revealed a heavy fibrillar Aβ burden in cortical, striatal, and thalamic regions, similar to that reported for patients with late-onset Alzheimer disease. This matched neuropathologic findings of frequent neuritic and diffuse plaques, as well as frequent amyloid angiopathy, except for neuropathologically demonstrated frequent cerebellar diffuse plaques and amyloid angiopathy that were not detected by the PET scan.
Florbetapir PET can be used to detect increased cerebral-to-cerebellar fibrillar Aβ burden in a Down syndrome patient with Alzheimer disease, even in the presence of frequent amyloid angiopathy and diffuse plaques in the cerebellum. Additional studies are needed to determine the extent to which PET could be used to detect and to track fibrillar Aβ and to evaluate investigational Aβ-modifying treatments in the presymptomatic and symptomatic stages of Alzheimer disease.
To evaluate the combination of cerebrospinal fluid biomarkers of Aβ42, tau, and phosphorylated tau (ptau181) with education and normalized whole brain volume (nWBV) to predict incident cognitive impairment and test the cognitive/brain reserve hypothesis.
Longitudinal cohort study.
Charles F. and Joanne Knight Alzheimer’s Disease Research Center of Washington University, St. Louis, Missouri.
Convenience sample of 197 participants aged 50 years and above, with normal cognition (Clinical Dementia Rating [CDR] of 0) at baseline, followed for a mean of 3.3 years.
Main outcome measure
Time to cognitive impairment (CDR ≥ 0.5).
Three-factor interactions between the baseline biomarker values, education, and nWBV were found for Cox proportional hazards models testing tau (p=.03) and ptau (p=.008). Among those with lower tau values, nWBV (hazard ratio [HR]=.54, 95% confidence interval [CI]=.31–.91; p=.02), but not education, was related to time to cognitive impairment. For participants with higher tau values, education interacted with nWBV to predict incident impairment (p=.01). For individuals with lower ptau values, there was no effect of education or nWBV. Education interacted with nWBV to predict incident cognitive impairment among those with higher ptau values (p=.02). In models testing Aβ42, larger nWBV was associated with a slower time to cognitive impairment (HR=.84, 95%CI=.71–.99, p=.0348), but there was no effect of Aβ42 or education.
Among individuals with higher levels of CSF tau and ptau, but normal cognition at baseline, time to incident cognitive impairment is moderated by education and brain volume as predicted by the cognitive/brain reserve hypothesis.
A series of microPET imaging studies were conducted in anesthetized rhesus monkeys using the dopamine D3-selective partial agonist, [18F]5. There was variable uptake in regions of brain known to express a high density of D3 receptors under baseline conditions. Pretreatment with lorazepam (1 mg/kg, i.v. 30 min) to reduce endogenous dopamine activity prior to tracer injection resulted in a dramatic increase in uptake in the caudate, putamen, and thalamus, and an increase in the binding potential (BP) values, a measure of D3 receptor binding in vivo. These data indicate that there is a high level of competition between [18F]5 and endogenous dopamine for D3 receptors in vivo.
D3 receptors; Positron Emission Tomography; endogenous dopamine
There is a growing need to identify cerebrospinal fluid (CSF) markers that can detect Alzheimer’s disease (AD) pathology in cognitively normal individuals since it is in this population that disease-modifying therapies may have the greatest chance of success. While AD pathology is estimated to begin ~10–15 years prior to the onset of cognitive decline, substantial neuronal loss is present by the time the earliest signs of cognitive impairment appear. Visinin-like protein −1 (VILIP-1) has demonstrated potential utility as a marker of neuronal injury. We here investigate CSF VILIP-1 and VILIP-1/amyloid-β42 (Aβ42) ratio as diagnostic and prognostic markers in early AD.
We assessed CSF levels of VILIP-1, tau, phosphorylated-tau181 (p-tau181), and Aβ42 in cognitively normal controls [CNC] (n=211), individuals with early symptomatic AD (n=98), and individuals with other dementias (n=19). Structural magnetic resonance imaging (n=192) and amyloid imaging with Pittsburgh Compound-B (n=156) were obtained in subsets of this cohort. Among the CNC cohort, 164 individuals had follow-up annual cognitive assessments for 2–3 years.
CSF VILIP-1 levels differentiated individuals with AD from CNC and individuals with other dementias. CSF VILIP-1 levels correlated with CSF tau, p-tau181, and brain volumes in AD. VILIP-1 and VILIP-1/Aβ42 predicted future cognitive impairment in CNC over the follow-up period. Importantly, CSF VILIP-1/Aβ42 predicted future cognitive impairment at least as well as tau/Aβ42 and p-tau181/Aβ42.
These findings suggest that CSF VILIP-1 and VILIP-1/Aβ42 offer diagnostic utility for early AD, and can predict future cognitive impairment in cognitively normal individuals similarly to tau and tau/Aβ42, respectively.
Visinin-like protein-1; Alzheimer’s disease; biomarkers; cerebrospinal fluid; neuronal injury
To assess whether family history (FH) of Alzheimer’s disease (AD) alone influences AD biomarker abnormalities.
Adult Children Study (ACS).
Washington University's Knight Alzheimer's Disease Research Center.
Cognitively normal middle to older age individuals with and without a FH for AD (n=269).
Main Outcome Measures
Clinical and cognitive measures, magnetic resonance imaging (MRI)-based brain volumes, diffusion tensor imaging (DTI)-based white matter microstructure, cerebrospinal fluid (CSF) biomarkers, and molecular imaging of cerebral fibrillar amyloid with positron emission tomography (PET) using the [11C] benzothiazole tracer, Pittsburgh Compound-B (PIB).
A positive FH for AD was associated with an age-related decrease of CSF Aβ42; the ε4 allele of apolipoprotein E (APOE4) did not alter this effect. Age-adjusted CSF Aβ42 was decreased for individuals with APOE4 compared with those without, and the decrease was larger for individuals with a positive FH compared with those without. The variation of CSF tau and PIB mean cortical binding potential (MCBP) increased by age. For individuals younger than 55, an age-related increase in MCBP was associated with APOE4, but not FH. For individuals older than 55, a positive FH and a positive APOE4 implied the fastest age-related increase in MCBP. A positive FH was associated with decreased fractional anisotropy from DTI in the genu and splenium of the corpus callosum.
Independent of APOE4, FH is associated with age-related change of several CSF, PIB and DTI biomarkers in cognitively normal middle to older age individuals, suggesting that non-APOE susceptibility genes for AD influence AD biomarkers.
Disease-modifying therapies for Alzheimer’s disease (AD) would be most beneficial if applied during the ‘preclinical’ stage (pathology present with cognition intact) before significant neuronal loss occurs. Therefore, biomarkers that can detect AD pathology in its early stages and predict dementia onset and progression will be invaluable for patient care and efficient clinical trial design.
2D–difference gel electrophoresis and liquid chromatography tandem mass spectrometry were used to measure AD-associated changes in cerebrospinal fluid (CSF). Concentrations of CSF YKL-40 were further evaluated by enzyme-linked immunosorbent assay in the discovery cohort (N=47), an independent sample set (N=292) with paired plasma samples (N=237), frontotemporal lobar degeneration (N=9), and progressive supranuclear palsy (PSP, N=6). Human AD brain was studied immunohistochemically to identify potential source(s) of YKL-40.
In the discovery and validation cohorts, mean CSF YKL-40 was higher in very mild and mild AD-type dementia (Clinical Dementia Rating [CDR] 0.5 and 1) vs. controls (CDR 0) and PSP. Importantly, CSF YKL-40/Aβ42 ratio predicted risk of developing cognitive impairment (CDR 0 to CDR>0 conversion) as well as the best CSF biomarkers identified to date, tau/Aβ42 and p-tau181/Aβ42. Mean plasma YKL-40 was higher in CDR 0.5 and 1 vs. CDR 0 groups, and correlated with CSF levels. YKL-40 immunoreactivity was observed within astrocytes near a subset of amyloid plaques, implicating YKL-40 in the neuroinflammatory response to Aβ deposition.
These data demonstrate that YKL-40, a putative indicator of neuroinflammation, is elevated in AD, and that, together with Aβ42, has potential prognostic utility as a biomarker for preclinical AD.
YKL-40; Alzheimer’s disease; biomarkers; cerebrospinal fluid; chitinase-3 like-1; inflammation
Screening tests for Alzheimer’s disease lack sensitivity and specificity. We developed the AD8, a brief dementia screening interview validated against clinical and cognitive evaluations, as an improvement over current screening methods. Because insufficient follow-up has occurred to validate the AD8 against the neuropathologic findings of Alzheimer’s disease, we investigated whether AD8 scores correspond to impairment in episodic memory testing and changes in biomarkers of Alzheimer’s disease (cerebrospinal fluid and amyloid imaging with Pittsburgh compound B) characteristic of symptomatic Alzheimer’s disease. We also compared informant-based assessments with brief performance-based dementia screening measurements such as the Mini Mental State Exam. The sample (n = 257) had a mean age of 75.4 years with 15.1 years of education; 88.7% were Caucasian and 45.5% were male. The sample was divided into two groups based on their AD8 scores: those with a negative dementia screening test (AD8 score 0 or 1, n = 137) and those with a positive dementia screening test (AD8 score ≥2, n = 120). Individuals with positive AD8 scores had abnormal Pittsburgh compound B binding (P < 0.001) and cerebrospinal fluid biomarkers (P < 0.001) compared with individuals with negative AD8 scores. Individuals with positive AD8 tests and positive biomarkers scored in the impaired range on the Wechsler Logical Memory Story A (mean score 7.0 ± 4.5 for Pittsburgh compound B; mean score 7.6 ± 5.3 for cerebrospinal fluid amyloid beta protein 1–42). The AD8 area under the curve for Pittsburgh compound B was 0.737 (95% confidence interval: 0.64–0.83) and for cerebrospinal fluid amyloid beta protein 1–42 was 0.685 (95% confidence interval: 0.60–0.77) suggesting good discrimination. The AD8 had superior sensitivity in detecting early stages of dementia compared with the Mini Mental State Examination. The AD8 had a likelihood ratio of a positive test of 5.8 (95% confidence interval: 5.4–6.3) and likelihood ratio of a negative test of 0.04 (95% confidence interval: 0.03–0.06), increasing the pre-test probability of an individual having symptomatic Alzheimer’s disease. Individuals with AD8 scores of ≥2 had a biomarker phenotype consistent with Alzheimer’s disease and lower performance on episodic memory tests, supporting a diagnosis of Alzheimer’s disease. Informant-based assessments may be superior to performance-based screening measures such as the Mini Mental State Examination in corresponding to underlying Alzheimer’s disease pathology, particularly at the earliest stages of decline. The use of a brief test such as the AD8 may improve strategies for detecting dementia in community settings where biomarkers may not be readily available, and may enrich clinical trial recruitment by increasing the likelihood that participants have underlying biomarker abnormalities.
AD8; Alzheimer’s disease; screening; biomarkers; preclinical; cognition
Current theory suggests that β-amyloid accumulation may be an early step in the cascade that leads to cognitive impairment in Alzheimer's disease. β-Amyloid targeted positron emission tomography (PET) imaging potentially provides a direct, relatively noninvasive estimate of brain β-amyloid burden. This has recently been supported by demonstration that amyloid plaque binding on PET was strongly correlated with brain β-amyloid burden at autopsy. Additionally, there is growing consensus that PET imaging can identify subjects with elevated β-amyloid burden, even at early stages of disease. Finally, preliminary evidence suggests that abnormal β-amyloid accumulation, as evidenced by PET imaging, has implications for both present nd future cognitive performance. Although large longitudinal studies like the ongoing ADNI trial will be required for definitive evaluation, present data suggest that PET amyloid imaging has the potential to promote earlier and more specific diagnosis of dementia.
Cerebrospinal fluid (CSF) biomarkers of Alzheimer’s disease (AD) are currently being considered for inclusion in revised diagnostic criteria for research and/or clinical purposes to increase the certainty of ante-mortem diagnosis. Establishing biomarker validity requires demonstration that the assays are true markers of underlying disease pathology (e.g., amyloid plaques and/or neurofibrillary tangles) in living individuals.
We compared the performances of the two most commonly used platforms, INNOTEST® ELISA and INNO-BIA AlzBio3 for measurement of CSF amyloid-beta (Aβ) and tau(s), for identifying the presence of amyloid plaques in a research cohort (n=103). Values obtained for CSF Aβ1-42, total tau and phosphorylated tau181 (p-tau181) using the two assay platforms were compared to brain amyloid load as assessed by positron emission tomography using the amyloid imaging agent, Pittsburgh Compound B (PIB).
Research volunteers who are cognitively normal or have very mild to moderate AD dementia.
The two assay platforms yielded different (~2–6-fold) absolute values for the various analytes, but relative values were highly correlated. CSF Aβ1-42 correlated inversely, and tau and p-tau181 correlated positively, with the amount of cortical PIB binding, albeit to differing degrees. Both assays yielded similar patterns of CSF biomarker correlations with amyloid load. The ratios of total tau/Aβ1-42 and p-tau181/Aβ1-42 outperformed any single analyte, including Aβ1-2, in discriminating individuals with versus without cortical amyloid.
The INNOTEST® and INNO-BIA CSF platforms performed equally well in identifying individuals with underlying amyloid plaque pathology. Differences in absolute values, however, point to the need for assay-specific diagnostic cut-point values.
Alzheimer’s disease; amyloid; biomarkers; cerebrospinal fluid; imaging (PET, MRI) in dementias; Pittsburgh Compound B
In addition to the increasingly recognized role of physical exercise in maintaining cognition, exercise may influence Alzheimer's disease (AD) pathology as transgenic mouse studies show lowered levels of AD pathology in exercise groups. The objective of this study was to elucidate the association between exercise and AD pathology in humans using Pittsburgh Compound B (PIB), amyloid-β (Aβ)42, tau, and phosphorylated tau (ptau)181 biomarkers.
Sixty-nine older adults (17 males, 52 females) aged 55–88 were recruited and confirmed to be cognitively normal. A questionnaire on physical exercise levels over the last decade was administered to all. Cerebrospinal fluid (CSF) samples were collected from 56 participants, and amyloid imaging with PIB was performed on 54 participants.
Participants were classified based on biomarker levels. Those with elevated PIB (p=.030), tau (p=.040) and ptau181 ((p=.044) had significantly lower exercise with a non-significant trend for lower Aβ42 (p=.135) to be associated with less exercise. Results were similar for PIB after controlling for covariates; tau (p=.115) and ptau181 (p=.123) differences were reduced to non-significant trends. Additional analyses also demonstrated that active individuals who met the exercise guidelines set by the American Heart Association (AHA) had significantly lower PIB binding and higher Aβ42 levels with and without controlling for covariates (PIB: p=.006 and p=.001; Aβ42: p=.042 and p=.046). Lastly, the associations between exercise engagement and PIB levels were more prominent in APOE epsilon 4 non-carriers.
Collectively, these results are supportive of an association between exercise engagement and AD biomarkers in cognitively normal older adults.
The goal of this study was to examine the effectiveness and safety of low-frequency rTMS to the temporoparietal junction in a cohort of patients with bothersome tinnitus.
Cross-over, double-blind, randomized clinical trial.
Outpatient, academic medical center
14 adults between the ages of 42 and 59 with subjective, unilateral or bilateral, non-pulsatile tinnitus of 6 months duration or greater, and a score of 38 or greater on the Tinnitus Handicap Inventory (THI).
Low-frequency (1 Hz) 110% motor threshold rTMS or sham to left temporoparietal junction for 2 weeks.
Main Outcome Measure
The difference in the change of the Tinnitus Handicap Inventory score between active and sham rTMS.
Active treatment was associated with a median (95% CI) reduction in THI of 5 points (0 to 14) and sham treatment was associated with a median reduction in THI of 6 points (−2 to 12). The difference in THI between the change associated with active and sham rTMS ranged from 34 points reduction in THI score after active treatment when compared to THI score after sham, to an increase of 22 points, with a median difference change of only 1 point (−6 to 4).
Daily low-frequency rTMS to the left temporoparietal junction area for 2 weeks was no more effective than placebo for patients with chronic bothersome tinnitus. Possible explanations for the negative findings are short duration of treatment, failure of rTMS stimulation over the temporoparietal area to affect auditory cortex buried within the Sylvian fissure, or more widespread cortical network changes associated with severe bothersome tinnitus not amenable to localized rTMS effects.
Identifying high risk populations is an important component of disease prevention strategies. One approach is examining neuroimaging parameters that differ in Alzheimer’s disease (AD), including functional connections known to be disrupted within the “default mode network” (DMN). We have previously shown these same disruptions in cognitively normal elderly, who have amyloid-beta (Aβ) plaques detected using PIB PET imaging, suggesting neuronal toxicity of plaques. Here we sought to determine if pathological effects of apolipoprotein E ε4 (APOE4) genotype could be seen independent of Aβ plaque toxicity by examining resting state fMRI functional connectivity (fcMRI ) in participants without preclinical fibrillar amyloid deposition (PIB−). Cognitively normal participants enrolled in longitudinal studies (n = 100, mean age = 62) who were PIB− were categorized into those with and without an APOE 4 allele and studied using fcMRI. APOE 4 allele carriers (E4+) differed significantly from E4− in functional connectivity of the precuneus to several regions previously defined as having abnormal connectivity in a group of AD participants. These effects were observed prior to any manifestations of cognitive changes and in the absence of brain fibrillar amyloid-beta (Aβ) plaque deposition, suggesting that early manifestations of a genetic effect can be detected using fcMRI and that these changes may antedate the pathological effects of fibrillar amyloid plaque toxicity.
PIB; fMRI; amyloid; Alzheimer’s disease; resting state; precuneus; hippocampus; APOE4
Important functional connections within the “default mode network” (DMN) are disrupted in Alzheimer’s disease (AD), likely from amyloid-beta (Aβ) plaque-associated neuronal toxicity. Here we sought to determine if pathological effects of Aβ amyloid plaques could be seen even in the absence of a task by examining functional connectivity in cognitively normal participants with and without preclinical amyloid deposition.
Participants with Alzheimer’s disease (AD) (n= 35) were compared with 68 cognitively normal participants who were further subdivided by PET PIB imaging into those without evidence of brain amyloid (PIB−) and those with brain amyloid (PIB+) deposition.
Resting state fMRI demonstrated that, compared with the PIB− group, the PIB+ group differed significantly in functional connectivity of the precuneus to hippocampus, parahippocampus, anterior cingulate, dorsal cingulate, gyrus rectus, superior precuneus and visual cortex. These differences were in the same regions, and in the same direction, as differences found in the AD group.
Thus, prior to any manifestations of cognitive or behavioral changes there were differences in resting state connectivity in cognitively normal subjects with brain amyloid deposition, suggesting that early manifestation of Aβ toxicity can be detected using resting state fMRI.
PIB; fMRI; amyloid; Alzheimers Disease; resting state; precuneus; hippocampus
To date, all known Alzheimer's disease genes influence amyloid beta (Aβ). The development of in vivo imaging of Aβ deposition in the human brain using Pittsburgh compound B (PIB) offers the possibility of using cortical PIB binding as a quantitative endophenotype for genetic studies of late-onset Alzheimer's disease (LOAD).
Heritability of Aβ deposition was determined using 82 elderly siblings from 35 families. Correlation with other Aβ related traits was determined using an unrelated sample of 112 individuals. For both samples, APOE ε4 was genotyped and PET imaging was performed using the PIB ligand. Mean cortical binding potential (MCBP) was computed from several regions-of-interest.
MCBP has a high heritability (0.61, p=0.043). Furthermore, most of the heritable component (74%) cannot be explained by APOE ε4 genotype. Analysis of the unrelated sample reveals that a third of the variance of MCBP cannot be predicted by other biological traits, including CSF Aβ42 levels.
These findings demonstrate that MCBP is a genetic trait and that other more easily measured Aβ related traits such as CSF Aβ42 do not fully explain the variance in MCBP. Thus, mean cortical PIB binding is a useful trait for large-scale genetic studies of LOAD.
Recently, a novel method for detection of DNA synthesis has been developed based on the incorporation of 5–ethynyl–2′–deoxyuridine (EdU), a thymidine analogue, into cellular DNA and the subsequent reaction of EdU with a fluorescent azide in a copper–catalyzed [3+2] cycloaddition (“Click” reaction). In the present study, we evaluated this method for studying cell proliferation in the adult central nervous system in comparison with the “gold standard” method of 5–bromo–2′–deoxyuridine (BrdU) staining using two behavioral paradigms, voluntary exercise and restraint stress. Our data demonstrate that the number of EdU positive cells in the dentate gyrus of the hippocampus (DG) slightly increased in an EdU dose–dependent manner in both the control and voluntary exercise (running) mouse groups. The number of EdU–labeled cells was comparable to the number of BrdU–labeled cells in both the control and running mice. Furthermore, EdU and BrdU co–localized to the same cells within the DG. Voluntary exercise significantly increased the number of EdU and BrdU positive cells in the DG. In contrast, restraint stress significantly decreased the number of EdU positive cells. The EdU positive cells differentiated into mature neurons. EdU staining is compatible with immunohistochemical staining of other antigens. Moreover, our data demonstrated EdU staining can be combined with BrdU staining, providing a valuable tool of double labeling DNA synthesis, e.g., for tracking the two populations of neurons generated at different time points. In conclusion, our results suggest that EdU staining is a fast, sensitive and reproducible method to study cell proliferation in the central nervous system.
5–ethynyl–2′–deoxyuridine; 5–bromo–2′–deoxyuridine; BrdU; adult neurogenesis; hippocampus