Original Article
PET of Brain Amyloid and Tau in Mild Cognitive Impairment
N Engl J Med 2006; 355:2652-2663December 21, 2006
- Abstract
Background
Amyloid senile plaques and tau neurofibrillary tangles are neuropathological hallmarks of Alzheimer's disease that accumulate in the cortical regions of the brain in persons with mild cognitive impairment who are at risk for Alzheimer's disease. Noninvasive methods to detect these abnormal proteins are potentially useful in developing surrogate markers for drug discovery and diagnostics.
Methods
We enrolled 83 volunteers with self-reported memory problems who had undergone neurologic and psychiatric evaluation and positron-emission tomography (PET). On the basis of cognitive testing, 25 volunteers were classified as having Alzheimer's disease, 28 as having mild cognitive impairment, and 30 as having no cognitive impairment (healthy controls). PET was performed after injection of 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile (FDDNP), a molecule that binds to plaques and tangles in vitro. All subjects also underwent 2-deoxy-2-[F-18]fluoro-D-glucose (FDG) PET, and 72 underwent magnetic resonance imaging (MRI).
Results
Global values for FDDNP-PET binding (average of the values for the temporal, parietal, posterior cingulate, and frontal regions) were lower in the control group than in the group with mild cognitive impairment (P<0.001), and the values for binding in the group with mild cognitive impairment were lower than in the group with Alzheimer's disease (P<0.001). FDDNP-PET binding differentiated among the diagnostic groups better than did metabolism on FDG-PET or volume on MRI.
Conclusions
FDDNP-PET scanning can differentiate persons with mild cognitive impairment from those with Alzheimer's disease and those with no cognitive impairment. This technique is potentially useful as a noninvasive method to determine regional cerebral patterns of amyloid plaques and tau neurofibrillary tangles.
Media in This Article
Figure 1
Eligibility Assessment, Neuropsychological Testing, and FDDNP Scanning of the Subjects Included in the Analysis.Figure 2
Baseline Values for FDDNP Global Binding (Panel A) and Medial Temporal Binding (Panel B), and Follow-up Values for FDDNP-PET (Panel C), According to Diagnostic Group.Article Activity
- Article
Mild cognitive impairment is a transitional stage between normal aging and Alzheimer's disease. A recent study suggests that the prevalence of mild cognitive impairment, characterized by a cognitive decline without impairment of the ability to carry out activities of daily living, is 19% among persons younger than 75 years of age and 29% among those 85 years of age or older.1 Among persons with mild cognitive impairment, about 30% have amnestic mild cognitive impairment, characterized by abnormal memory for age but normal general cognitive functioning.2,3 Approximately 12% of patients with amnestic mild cognitive impairment have progression to Alzheimer's disease each year, and up to 80% have progression to Alzheimer's disease after 6 years.2 Alzheimer's disease is also progressive, gradually resulting in cognitive impairments that leave patients completely dependent on others.
Neuropathological studies indicate that two proteins, β-amyloid (in senile plaques) and tau (in neurofibrillary tangles), accumulate abnormally in a predictable spatial pattern during aging and in Alzheimer's disease.4,5 These changes may begin even before the age of 30 years, and the prevalence of the lesions increases gradually with age. In patients with mild cognitive impairment, neurofibrillary tangles have been detected in the hippocampus and other medial temporal regions; as mild cognitive impairment progresses to Alzheimer's disease, these neurofibrillary tangles spread to the parietal and frontal neocortical areas of the brain. Neuritic plaques are rare in persons undergoing normal aging but in those with mild cognitive impairment, they begin to accumulate in the hippocampus and neocortex, where the plaques become more prevalent with the progression to Alzheimer's disease. The presence of high cerebral levels of amyloid senile plaques and neurofibrillary tangles is currently necessary for a diagnosis of definite Alzheimer's disease at autopsy.6
Treatments are being developed for Alzheimer's disease that are designed to prevent the accumulation of cerebral plaques and tangles or to disaggregate them once they are present. A noninvasive method of determining the regional cerebral patterns of these lesions would not only assist in early diagnosis of Alzheimer's disease but also facilitate monitoring of the efficacy of such treatments.
Until recently, plaques and tangles could be assessed only at autopsy or, rarely, on biopsy. Positron-emission tomography (PET) with the use of amyloid tracers has shown higher levels of cerebral amyloid in patients with dementia than in control subjects.7,8 For example, PET studies performed with the use of Pittsburgh Compound-B (PIB), an amyloid-binding radiotracer, have shown significantly greater cortical PIB retention in patients with Alzheimer's disease than in controls.7 We developed a small molecule, 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile (FDDNP), for use as an in vivo chemical marker of cerebral amyloid and tau proteins. Initial studies have shown that PET scans show significantly higher values for FDDNP binding in the temporal, parietal, and frontal regions of the brain in patients with Alzheimer's disease than in older control subjects without cognitive impairment.9 Both FDDNP and its parent molecule, 2-(1-[6-(dimethylamino)-2-naphthyl]ethylidene)malononitrile, are fluorescent and provide clear in vitro visualization of plaques and tangles in specimens of brain tissue obtained on autopsy from patients with Alzheimer's disease and examined with a confocal fluorescence microscope.10
We used in vivo cerebral imaging of these abnormal protein aggregates to study persons with mild cognitive impairment or Alzheimer's disease. Previous neuropathological studies led us to hypothesize that the intensity of FDDNP binding in those with mild cognitive impairment would be intermediate between the intensity found in healthy controls and in persons with Alzheimer's disease, and that in persons whose cognitive impairment progressed clinically, there would be corresponding increases in FDDNP binding.
Methods
Clinical Assessments
Baseline cognitive assessments and PET were performed in 108 persons selected from a pool of 737 volunteers who were middle-aged or older (range, 49 to 84 years). The pool of volunteers had been recruited through advertisements of a study of mild memory impairment, media coverage of the study, and referrals by physicians and families and had been screened in telephone interviews conducted by members of the research staff. The study protocol described in detail the methods, procedures, and prespecified inclusion and exclusion criteria. Because the study focused on Alzheimer's disease, subjects in whom other types of dementia had been diagnosed (e.g., Lewy body, vascular, or frontotemporal dementia) were excluded. From the original pool of volunteers, 40 persons taking medications that might affect cognition, such as sedatives, or nonsteroidal antiinflammatory drugs, which bind to amyloid plaques and thus can affect FDDNP binding values, were excluded.11 Others were excluded for a variety of reasons, including 9 because of head movement during scanning (6 with Alzheimer's disease, 1 with mild cognitive impairment, and 2 potential controls), resulting in a total of 83 subjects in the study sample (Figure 1Figure 1
Eligibility Assessment, Neuropsychological Testing, and FDDNP Scanning of the Subjects Included in the Analysis.). Investigators were unaware of the clinical data when excluding potential subjects on the basis of the quality of the PET scans and were unaware of the scans when excluding potential subjects on the basis of the clinical data. Of the 83 subjects included in the study, 10 with Alzheimer's disease and 6 with mild cognitive impairment had been receiving drugs to enhance cognitive performance (a cholinesterase inhibitor or an N-methyl-D-aspartate receptor antagonist) at a steady dose for at least 3 months before entering the study.All subjects underwent neurologic and psychiatric evaluation, screening laboratory testing, and structural imaging scanning to rule out other causes of cognitive impairment (e.g., stroke or tumor).6 Most of the subjects (72) underwent magnetic resonance imaging (MRI); the 11 subjects who could not tolerate MRI (because of claustrophobia or metal in the body) underwent computed tomography (CT). In addition to evaluation according to the Mini–Mental State Examination12 and the 17-item Hamilton Rating Scale for Depression,13 we administered a battery of neuropsychological tests14 to assess five cognitive domains: memory (Wechsler Memory Scale Logical Memory Test and Verbal Paired Associations II, Buschke–Fuld for Selective Reminding Test [Total Recall], and Rey–Osterreich Complex Figure Recall Test [Delayed Recall]), language (Boston Naming Test, Letter Fluency Test and Animal Naming Test), attention and speed of information processing (Trail Making Test A, Stroop Color Test [Kaplan version], and Digit Symbol Test, Wechsler Adult Intelligence Scale [WAIS]), executive functioning (Trail Making Test B, Stroop interference [Kaplan version], and Wisconsin Card Sorting Test, Perseverative Errors), and visuospatial functioning (WAIS Block Design Test, Rey–Osterreich Complex Figure Test [copy], and Benton Visual Retention Test).
To diagnose mild cognitive impairment, we used standard diagnostic criteria for amnestic mild cognitive impairment (memory impairment without other cognitive impairment). These include the subject's awareness of a memory problem, preferably as confirmed by another person; memory impairment detected with the use of standard assessment tests; normal overall thinking and reasoning skills; and the ability to perform normal activities of daily living.2 For a broad definition of mild cognitive impairment, we also used guidelines to identify subjects with other subtypes of mild cognitive impairment, including memory impairment and additional cognitive deficits and those with other cognitive deficits but intact memory.15 The diagnosis was corroborated by clinical judgment2; to increase the specificity in detecting impairments, we included only subjects with mild cognitive impairment who had a score of 1 SD or more below the age-corrected norms on at least two neuropsychological tests in one of the five cognitive domains assessed.16
Subjects included in the group with mild cognitive impairment did not meet the diagnostic criteria for Alzheimer's disease,6,17 and the presence of self-reported memory problems was documented with the use of a standardized subjective-memory instrument (the Memory Functioning Questionnaire)18 and a clinical interview. Of the 28 subjects with mild cognitive impairment, 24 had memory impairment that was consistent with either amnestic mild cognitive impairment (9 subjects) or amnestic mild cognitive impairment plus deficits in other cognitive areas (15 subjects), and 4 subjects had mild cognitive impairment without memory impairment (i.e., impairment only in other cognitive areas).
Subjects with Alzheimer's disease met the standard diagnostic criteria of memory impairment, impairment in at least one other cognitive domain, gradual onset and progressive decline, and impaired occupational or social functioning or both.6,17 Control subjects had normal cognitive functioning for their age and did not meet the criteria for mild cognitive impairment or Alzheimer's disease. Follow-up clinical evaluations and FDDNP-PET scans were available for 12 subjects (8 control subjects and 4 subjects with mild cognitive impairment) after approximately 2 years (mean, 24.3±6.1 months; range, 17 to 34). Of the 71 subjects not included in the follow-up, 37 had not participated in the study long enough and 34 had not completed the study (i.e., had moved, were unable to complete it, or had declined).
All clinical assessments and scanning procedures were performed within 4 weeks after study entry, and clinicians were unaware of the results of the baseline and follow-up studies. Written informed consent was obtained from all subjects or from a family member or guardian, in accordance with procedures of the Human Subjects Protection Committee of the University of California, Los Angeles. Cumulative radiation dosimetry for all scans was below the mandated maximum annual dose and in compliance with state and federal regulations. Four subjects had minor adverse events during PET: two subjects (one with Alzheimer's disease and one control) had minor bruising at venipuncture sites, and two others (one with Alzheimer's disease and one control) had transient headache.
Scanning and Imaging Procedures
The FDDNP was prepared at very high specific activities (>37 GBq per micromole), as described elsewhere.9,19 PET was performed with the ECAT HR or ECAT EXACT HR+ scanner (Siemens CTI), with subjects in the supine position and with the imaging plane parallel to the orbitomeatal line. A bolus of FDDNP (320 to 550 MBq) was injected through an indwelling venous catheter, and consecutive dynamic PET scans were obtained for 2 consecutive hours. Scans were corrected for decay and reconstructed with the use of filtered back-projection (Hann filter, 5.5 mm full width at half maximum), with correction for scatter and measured attenuation. The resulting images contained either 47 contiguous slices with a plane separation of 3.37 mm (with the ECAT HR) or 63 contiguous slices with a plane separation of 2.42 mm (with the EXACT HR+). The results did not differ significantly according to the scanner used.
Quantification of the data on FDDNP binding was performed with the Logan graphic method, with the cerebellum as the reference region for time points between 30 and 125 minutes.19,20 The slope of the linear portion of the Logan plot is the relative distribution volume (DVR), which is equal to the distribution volume of the tracer in a region of interest (ROI) divided by the distribution volume of the tracer in the reference region. The DVR parametric images (incorporating radioactivity levels measured during the 2-hour PET scanning) were generated and analyzed with the use of ROIs drawn on the coregistered MRI or CT scans for left and right parietal, medial temporal (limbic regions, including the hippocampus, parahippocampal areas, and entorhinal cortex), lateral temporal, posterior cingulate, and frontal regions, as previously described.19 Each regional DVR or binding value was expressed as an average of the left and right regions, and global DVR values were calculated as averages of the values for all these regions. Rules for ROI drawing were based on the identification of gyral and sulcal landmarks with respect to the atlas of Talairach and Tounoux.21
Scans of the same subjects repeated within 2 weeks after the initial scans indicated the stability of these values (approximately 2.2% of the regional values). Quantification of the amount of radiotracer uptake for FDG-PET was performed on summed images (within 30 to 60 minutes after the radiotracer had been injected), and ROIs were drawn, as previously described,19,22 on regions that are sensitive indicators of early neurodegeneration (the parietal and posterior cingulate regions)22,23; global values (the average of all ROIs) were also calculated. Values for ROIs were normalized to the value for the motor cortex.
Among the 72 subjects who underwent MRI, anatomical brain scans were obtained with the use of either a 1.5T (Signa) or 3T (General Electric or Siemens) scanner. For each of these subjects, 54 transverse planes were collected throughout the brain, superior to the cerebellum, with the use of a double-echo, fast spin-echo series with a 24-cm field of view and 256×256 matrix and 3-mm slices with no gap (repetition time, 6000 [3 T] or 2000 [1.5 T]; echo time, 17/85 [3 T] or 30/90 [1.5 T]). ROIs were drawn manually, as previously described,24 on the right and left medial temporal lobes (the entorhinal cortex, hippocampus, and parahippocampal gyrus) and the ventricles. For comparisons among the three diagnostic groups, we used whole medial temporal (right plus left) volumes and ventricular volumes, regions found to be sensitive indicators of neurodegeneration.24,25 All PET and MRI scans were read and the ROIs were drawn by investigators who were unaware of the clinical assessments.
Neuropathological Procedures
Of the 83 study subjects, 1 subject died 14 months after baseline scanning, and a neuropathological evaluation was performed after autopsy. After the removal of portions of the fresh brain to be snap-frozen, the remainder of the brain was fixed in 10% neutral buffered formalin for approximately 10 days, then sliced coronally at intervals of 1 cm. A standard brain-blocking protocol26 was carried out on the fixed slices, yielding representative fragments of all lobes of the cerebral hemispheres and the cingulate gyrus, the deep central gray matter, brain stem, and cerebellum. Representative sections were immunostained with primary antibodies to β-amyloid protein (1 to 42 amino acids in length) and to phosphorylated tau, with the use of commercially available antibodies routinely used in our laboratory.
Statistical Analysis
We used analysis of covariance to compare FDDNP binding values, FDG-PET metabolic rates, and MRI volumes among the three groups, controlling for age. We used receiver-operating-characteristic (ROC) curves to analyze the values measured with each type of imaging in order to determine the sensitivity, specificity, and area under the ROC curve (AUC). To determine relationships between values for FDDNP binding and other imaging values or between FDDNP binding and subjects' scores on cognitive testing, we used the Spearman rank correlation (rs). The analysis was performed with the use of SAS software (version 9.1) and macros (ROC, ROCPLOT) available for use with the software. All reported P values are two-sided.
Results
Group Comparisons
Of the 83 subjects in our sample, on the basis of cognitive testing, 25 were classified as having Alzheimer's disease, 28 as having mild cognitive impairment, and 30 as healthy controls. The three groups were similar with respect to the number of years of education, the proportion of women, and the proportion of subjects with a family history of dementia, but the control subjects were significantly younger than those with mild cognitive impairment or Alzheimer's disease (P=0.01). Expected differences were also observed according to cognitive measures (Table 1Table 1
Demographic and Clinical Characteristics and Mean Imaging Values, According to Diagnostic Group.). Mean (±SD) global values for FDDNP binding (DVR) differed significantly among the three groups: the values were significantly lower in the control group than in the group with mild cognitive impairment (P<0.001), and the mean global values in the group with mild cognitive impairment were significantly lower than those in the group with Alzheimer's disease (P<0.001) (Table 1 and Figure 2Figure 2Baseline Values for FDDNP Global Binding (Panel A) and Medial Temporal Binding (Panel B), and Follow-up Values for FDDNP-PET (Panel C), According to Diagnostic Group.). The estimated effect sizes (defined as the difference between the group means, divided by the pooled standard deviation) — 4.5 in the group with Alzheimer's disease as compared with the control group, 2.5 in the group with Alzheimer's disease as compared with the group with mild cognitive impairment, and 2.5 in the group with mild cognitive impairment as compared with control subjects — further demonstrated the robustness of global FDDNP binding for differentiating among the three diagnostic groups. The FDDNP-PET images in Figure 3Figure 3
FDDNP-PET Scans at Baseline and Follow-up. illustrate these differences.Mean values for regional FDDNP binding in the temporal, parietal, posterior cingulate, and frontal regions were also significantly different among the three groups (P<0.001) (Table 1). In all instances, the values for controls were significantly lower than those for subjects with mild cognitive impairment, and the values for subjects with mild cognitive impairment were significantly lower than those for subjects with Alzheimer's disease, with pairwise P values less than or equal to 0.001. Although the values for FDDNP binding in the medial temporal region differed significantly among the three groups (Table 1), 24 of the 28 subjects in the group with mild cognitive impairment had medial temporal FDDNP binding values of 1.13 or more, and 1.13 was the lowest value in the group classified as having Alzheimer's disease (Figure 2B).
In the ROC analysis comparing values for FDDNP-PET, FDG-PET, and MRI, FDDNP-PET global binding yielded the greatest diagnostic accuracy (Table 2Table 2
Analysis of Receiver-Operating-Characteristic (ROC) Curves from Imaging Studies Performed with the Use of FDDNP-PET, FDG-PET, and MRI.). For the comparison between the group with Alzheimer's disease and the group with mild cognitive impairment, the AUC for FDDNP global binding (0.98; 95% confidence interval [CI], 0.95 to 1.00) was significantly greater than the AUC for FDG global metabolism (0.87; 95% CI, 0.77 to 0.97; P=0.03), FDG posterior cingulate metabolism (0.82; 95% CI, 0.71 to 0.94; P=0.008), FDG parietal metabolism (0.80; 95% CI, 0.67 to 0.92; P=0.002), or MRI medial temporal volume (0.62; 95% CI, 0.45 to 0.79; P<0.001). The comparison of the AUC between the FDG and MRI studies also showed a significant difference (P=0.004). For the comparison between the group with mild cognitive impairment and the control group, the AUC for FDDNP global binding (0.95; 95% CI, 0.87 to 1.00) was significantly greater than those for FDG global metabolism (0.77; 95% CI, 0.65 to 0.90; P=0.009), FDG posterior cingulate metabolism (0.74; 95% CI, 0.61 to 0.88; P=0.006), FDG parietal metabolism (0.70; 95% CI, 0.57 to 0.84; P=0.001), or MRI medial temporal volume (0.64; 95% CI, 0.48 to 0.80; P<0.001). The difference in the AUC between the FDG and MRI studies was not significant.Among the subjects with mild cognitive impairment, comparisons of the global and regional FDDNP binding values between those with and those without memory impairment yielded no significant differences. There was no significant difference in the FDDNP binding values between the 10 subjects with Alzheimer's disease who were taking medications to enhance cognitive functioning (donepezil [Aricept, Pfizer] in 7 subjects and rivastigmine [Exelon, Novartis], memantine [Namenda, Forest], and donepezil plus memantine in 1 subject each) and those with dementia who were not taking such medications. In the group with mild cognitive impairment, there was no significant difference in the FDDNP binding values between the six subjects taking donepezil and those who were not taking medication to enhance cognitive functioning.
Correlations between FDDNP-PET Binding and Other Variables
As expected, higher values for global FDDNP binding correlated with lower values for FDG-PET in the posterior cingulate region (rs, −0.64; P<0.001) and the parietal region (rs, −0.62; P<0.001). Higher values for global FDDNP binding correlated significantly with lower MRI medial temporal volumes (rs, −0.28; P=0.02) and greater ventricular volumes (rs, 0.36; P=0.002).
Lower values for global FDDNP binding showed a strong correlation with higher scores on the Mini–Mental State Examination (rs, −0.75; P<0.001) and the Digit Symbol test, Wechsler Adult Intelligence Test, third edition (rs, −0.65; P<0.001). Among the subjects with mild cognitive impairment and control subjects who completed other, more challenging cognitive tests, values for global FDDNP binding showed significant correlations with results on the Wechsler Memory Scale Verbal Paired Associations II (rs, −0.57; P<0.001) and the Buschke–Fuld Selective Reminding Test (Total Recall) (rs, −0.52; P<0.001).
Subgroup with Longitudinal Follow-up
Longitudinal clinical and FDDNP-PET follow-up for approximately 2 years (mean, 24.3±6.1 months; range, 17 to 34) indicated that the nine clinically stable subjects (seven controls and two with mild cognitive impairment) had only minimal increases (≤3%) in global FDDNP binding. By contrast, the three subjects in whom there was clinical evidence of disease progression (one control subject was reclassified as having mild cognitive impairment, and two subjects with mild cognitive impairment were reclassified as having Alzheimer's disease) had greater increases in FDDNP binding, ranging from 5.5% to 11.2% (Figure 2C and Figure 3).
One subject with Alzheimer's disease (age, 78 years) died 14 months after the baseline clinical evaluation and FDDNP-PET scanning. Neuropathological studies of brain sections from this subject showed that regions with high in vitro concentrations of plaques and tangles closely matched those that showed increased in vivo FDDNP-PET binding (Figure 3C). The medial temporal regions (hippocampus and entorhinal cortex) with high values for FDDNP binding showed abundant immunoreactive tangles but less abundant plaques, whereas other neocortical regions (the lateral temporal, posterior cingulate, and frontal regions) showed high concentrations of immunoreactive plaques, as well as some tangles.
Discussion
The results of our study indicate that FDDNP-PET can differentiate mild cognitive impairment from normal aging and Alzheimer's disease. Moreover, evaluation at autopsy of one subject showed that regions of the brain with high values of FDDNP binding are characterized by high concentrations of plaques and tangles. These findings support the potential usefulness of FDDNP-PET in the development of surrogate markers for drug discovery aimed at blocking amyloid buildup and as a diagnostic tool, although the study does not provide definitive evidence of a basis for such uses. Because FDDNP-PET binding differentiates among clinical entities with varying severity of cognitive decline, it may eventually prove to be useful in the early detection of neurodegeneration.
The regional pattern of FDDNP binding that we observed was consistent with the patterns of accumulation of plaques and tangles observed in autopsy studies. Previous neuropathological studies in subjects with amnestic mild cognitive impairment27 showed concentrations of medial temporal tangles that were intermediate in amount between those that occur in normal aging and those that occur in Alzheimer's disease, as well as widely distributed neuritic and diffuse plaques and tangles throughout the neocortex and limbic structures. Price and Morris5 noted that the spatial pattern and the progression of the accumulation of abnormal protein are consistent with changes in the interaction between plaques and tangles, in which at some point β-amyloid peptides cause an acceleration in the accumulation of age-related tangles that would otherwise accumulate relatively slowly with age. Tangle load, but not plaque load, is associated with cognitive decline in elderly persons.27 Because FDDNP binds to both plaques and tangles, the regional binding patterns may be helpful in differentiating between early Alzheimer's disease and normal aging, nonamnestic mild cognitive impairment, and other forms of dementia. Initial FDDNP studies of frontotemporal dementia28 show binding in frontal and temporal regions but not in parietal regions, suggesting that FDDNP labels regional tau tangles and thus differentiates frontotemporal dementia from Alzheimer's disease according to the binding patterns.
The diagnosis of mild cognitive impairment refers to a presumed underlying pathobiologic state,2 but the course of the condition is heterogeneous. Several subtypes of mild cognitive impairment have been defined, including amnestic mild cognitive impairment, the progressive course of which suggests it is a prodrome or preclinical form of Alzheimer's disease.2,3,15,16,27 Among the subjects in our study, most of those with mild cognitive impairment also had memory impairment (with or without other cognitive changes), as well as high FDDNP binding in the medial temporal regions similar to that in subjects with Alzheimer's disease, a finding that is consistent with the previous observation that amnestic mild cognitive impairment is often a prodrome of Alzheimer's disease.
We found that the values of global FDDNP were more accurate than previously established sensitive measures for FDG-PET22,23,29 or volumetric MRI measures24,25,30 for diagnostic classification of subjects, suggesting that FDDNP may be useful in differentiating among Alzheimer's disease, mild cognitive impairment, and normal aging. In these comparisons, values for FDDNP-PET global binding were more effective in discriminating among diagnostic groups than FDG-PET metabolism in the posterior cingulate or parietal regions22,23 or MRI volumes of the medial temporal regions, which many clinicians currently rely on for diagnostic confirmation of Alzheimer's disease.25 Further studies are needed to determine whether combining several informative imaging techniques will improve diagnostic accuracy and whether the benefits of using multiple scans outweigh the added costs.
Some methodologic issues require comment. Only approximately 10% of the volunteers initially screened were included in the study, so the sample may not be representative of the populations studied. Our recruitment method yielded a sample of motivated, highly educated, physically healthy subjects concerned about age-related memory problems and could have resulted in higher values for FDDNP-PET binding: concern about memory problems could have been a subtle indication of presymptomatic disease in some control subjects. Despite this potential bias, the FDDNP-PET binding values in the control group were significantly lower than those in the group with mild cognitive impairment and the group with Alzheimer's disease. The healthy controls were significantly younger than the subjects with mild cognitive impairment and those with Alzheimer's disease; however, we corrected for age in the analyses, and the results were similar in additional analyses when subjects younger than 55 years of age were excluded, eliminating the significance of differences in age among the three study groups. Comparisons involving subjects between 80 and 90 years of age would be needed to determine whether our results hold true for elderly subjects with Alzheimer's disease. The group with Alzheimer's disease had relatively mild degrees of dementia — subjects with more advanced disease were more likely to have been excluded because of coexisting conditions (e.g., hypertension or diabetes) or an inability to tolerate the study procedures. Since we used a group with mild, rather than severe, dementia for comparison, our findings held up even when the clinical differences between the groups were relatively subtle.
The proportion of women among the three diagnostic groups differed, but the difference was not significant. Although sex differences in brain function31 and brain structure32 have been reported, we found no significant differences in values for FDDNP binding between women and men. Many other factors could influence the results of quantitative PET scanning in elderly persons, including variations in scanners, use of medication, and head motion during imaging studies.
In summary, the results of our study indicate that FDDNP-PET scans differentiate persons with mild cognitive impairment from those with Alzheimer's disease and those without cognitive impairment. Equally important, in vivo distributions of FDDNP in the brain follow patterns of pathological distribution seen at autopsy.4,5,27 These observations suggest that FDDNP-PET may be useful in the development of surrogate markers for monitoring the accumulation of these abnormal protein aggregates in the brain that are characteristic of Alzheimer's disease.
Supported by grants from the National Institutes of Health (AG13308, P50AG16570, MH/AG58156, MH52453, AG10123, M01-RR00865, and P01AG025831), the Department of Energy (DOE contract DE-FC03-87-ER60615), and the General Clinical Research Centers Program, the Rotary CART (Coins for Alzheimer's Research Trust) Fund, the Fran and Ray Stark Foundation Fund for Alzheimer's Disease Research, the Ahmanson Foundation, the Larry L. Hillblom Foundation, the Lovelace Foundation, the Judith Olenick Elgart Fund for Research on Brain Aging, the John D. French Foundation for Alzheimer's Research, and the Tamkin Foundation.
The University of California, Los Angeles (UCLA), owns a U.S. patent, “Methods for Labeling β-Amyloid Plaques and Neurofibrillary Tangles” (6,274,119), that uses the approach outlined in this article and has been licensed to Siemens. The FDDNP synthesis was performed at the UCLA Cyclotron Laboratory under Dr. Satyamurthy's direction. Drs. Small, Huang, Cole, Satyamurthy, and Barrio, who are among the inventors, report receiving royalties and will receive royalties on future sales. Dr. Small reports receiving consulting fees, lecture fees, or both from Abbott, Brainstorming, Dakim, Eisai, Forest, the Memory Fitness Institute, Myriad Genetics, Novartis, Ortho-McNeil, Pfizer, Radica, and Siemens, stock options from Dakim, and a grant from GlaxoSmithKline; Dr. Kepe, consulting fees from Siemens; Dr. Lavretsky, lecture fees from Eisai, Janssen, and Pfizer and a grant from Forest; Dr. Ercoli, lecture fees from the Memory Fitness Institute; Dr. Huang, lecture fees from GlaxoSmithKline; Dr. Satyamurthy, consulting fees from PETNet Pharmaceuticals and Siemens; and Dr. Barrio, consulting fees and lecture fees from Nihon Medi-Physics, Bristol-Myers Squibb, PETNet Pharmaceuticals, and Siemens. No other potential conflict of interest relevant to this article was reported.
The authors thank A. Kaplan, D. Dorsey, G. Byrd, and T. Crowe-Lear for help in recruitment, data management, and study coordination; G. Timbol and A. Halabi for help in image processing; and D. Guthrie for statistical advice.
Source Information
From the Department of Psychiatry and Biobehavioral Sciences and the Semel Institute for Neuroscience and Human Behavior (G.W.S., L.M.E., P.S., S.Y.B., K.J.M., H.L., A.C.B.), the Department of Molecular and Medical Pharmacology (V.K., S.-C.H., N.S., M.E.P., J.R.B.), the Departments of Neurology (G.M.C., P.M.T.) and Pathology and Laboratory Medicine (H.V.V.), the Brain Mapping Center (S.Y.B., A.C.B.), the Laboratory of Neuro Imaging (P.M.T.), the Alzheimer's Disease Center (G.W.S., G.M.C., H.V.V.), and the Center on Aging (G.W.S.) — all at the David Geffen School of Medicine at the University of California, Los Angeles.
Address reprint requests to Dr. Small at the Semel Institute, Suite 88-201, 760 Westwood Plaza, Los Angeles, CA 90024, or at gsmall@mednet.ucla.edu.
- References
References
1
Lopez OL ,Jagust WJ ,DeKosky ST , et al. Prevalence and classification of mild cognitive impairment in the Cardiovascular Health Study Cognition Study. Part 1. Arch Neurol 2003;60:1385-1389
CrossRef | Web of Science | Medline2
Petersen RC . Mild cognitive impairment as a diagnostic entity. J Intern Med 2004;256:183-194
CrossRef | Web of Science | Medline3
Lopez OL ,Becker JT ,Jagust WJ , et al. Neuropsychological characteristics of mild cognitive impairment subgroups. J Neurol Neurosurg Psychiatry 2006;77:159-165
CrossRef | Web of Science | Medline4
Braak H ,Braak E . Neuropathological staging of Alzheimer-related changes. Acta Neuropathol (Berl) 1991;82:239-259
CrossRef | Web of Science | Medline5
Price JL ,Morris JC . Tangles and plaques in nondemented aging and “preclinical” Alzheimer's disease. Ann Neurol 1999;45:358-368
CrossRef | Web of Science | Medline6
McKhann G ,Drachman D ,Folstein M ,Katzman R ,Price D ,Stadlan EM . Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of the Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 1984;34:939-944
Web of Science | Medline7
Klunk WE ,Engler H ,Nordberg A , et al. Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B. Ann Neurol 2004;55:306-319
CrossRef | Web of Science | Medline8
Verhoeff NPLG ,Wilson AA ,Takeshita S , et al. In-vivo imaging of Alzheimer disease β-amyloid with [11C]SB-13 PET. Am J Geriatr Psychiatry 2004;12:584-595
Web of Science | Medline9
Shoghi-Jadid K ,Small GW ,Agdeppa ED , et al. Localization of neurofibrillary tangles and beta-amyloid plaques in the brains of living patients with Alzheimer disease. Am J Geriatr Psychiatry 2002;10:24-35
Web of Science | Medline10
Agdeppa ED ,Kepe V ,Liu J , et al. Binding characteristics of radiofluorinated 6-dialkylamino-2-napthylethylidene derivatives as positron emission tomography imaging probes for β-amyloid plaques in Alzheimer's disease. J Neurosci 2001;21:RC189-RC189
Web of Science | Medline11
Agdeppa ED ,Kepe V ,Petric A , et al. In vitro detection of (S)-naproxen and ibuprofen binding to plaques in the Alzheimer's brain using the positron emission tomography molecular imaging probe 2-(1-{6-[(2-[18F]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile. Neuroscience 2003;117:723-730
CrossRef | Web of Science | Medline12
Folstein MF ,Folstein SE ,McHugh PR . “Mini-mental state”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189-198
CrossRef | Web of Science | Medline13
Hamilton M . A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;23:56-62
CrossRef | Web of Science | Medline14
Lezak MD, Howieson D, Loring D. Neuropsychological assessment. 4th ed. New York: Oxford University Press, 2004.
15
Winblad B ,Palmer K ,Kivipelto M , et al. Mild cognitive impairment -- beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment. J Intern Med 2004;256:240-246
CrossRef | Web of Science | Medline16
de Jager CA, Budge MM. Stability and predictability of the classification of mild cognitive impairment as assessed by episodic memory test performance over time. Neurocase 2005;11:72-9.
17
Diagnostic and statistical manual of mental disorders, 4th ed. rev.: DSM-IV-Tr (text revision). Washington, DC: American Psychiatric Association, 2000.
18
Gilewski MJ, Zelinski EM. Questionnaire assessment of memory complaints. In: Poon LW, ed. Handbook for clinical memory assessment of older adults. Washington, DC: American Psychological Association, 1986:93-107.
19
Kepe V ,Barrio JR ,Huang S-C , et al. Serotonin 1A receptors in the living brain of Alzheimer's disease patients. Proc Natl Acad Sci U S A 2006;103:702-707
CrossRef | Web of Science | Medline20
Logan J ,Fowler JS ,Volkow ND ,Wang GJ ,Ding YS ,Alexoff DL . Distribution volume ratios without blood sampling from graphical analysis of PET data. J Cereb Blood Flow Metab 1996;16:834-840
CrossRef | Web of Science | Medline21
Talairach J, Tounoux P. Coplanar stereotaxic atlas of the human brain: three-dimensional proportional system: an approach to cerebral imaging. New York: Thieme, 1988.
22
Small GW ,Ercoli LM ,Silverman DHS , et al. Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer's disease. Proc Natl Acad Sci U S A 2000;97:6037-6042
CrossRef | Web of Science | Medline23
Silverman DHS ,Small GW ,Chang CY , et al. Positron emission tomography in evaluation of dementia: regional brain metabolism and long-term clinical outcome. JAMA 2001;286:2120-2127
CrossRef | Web of Science | Medline24
Thompson PM ,Hayashi KM ,De Zubicaray GI , et al. Mapping hippocampal and ventricular change in Alzheimer disease. Neuroimage 2004;22:1754-1766
CrossRef | Web of Science | Medline25
Korf ES ,Wahlund LO ,Visser PJ ,Scheltens P . Medial temporal lobe atrophy on MRI predicts dementia in patients with mild cognitive impairment. Neurology 2004;63:94-100
Web of Science | Medline26
Vinters HV ,Klement IA ,Sung SH ,Farag ES . Pathologic issues and new methodologies in the evaluation of non-Alzheimer dementias. Clin Neurosci Res 2004;3:413-426
CrossRef27
Petersen RC ,Parisi JE ,Dickson DW , et al. Neuropathologic features of amnestic mild cognitive impairment. Arch Neurol 2006;63:665-672
CrossRef | Web of Science | Medline28
Small GW, Kepe V, Huang SC, et al. In vivo brain imaging of tau aggregation in frontal temporal dementia using [F-18]FDDNP positron emission tomography. Presented at the 9th International Conference on Alzheimer's Disease and Related Disorders, Philadelphia, July 17–22, 2004.
29
Chetelat G ,Desgranges B ,de la Sayette V ,Viader F ,Eustache F ,Baron JC . Mild cognitive impairment: can FDG-PET predict who is to rapidly convert to Alzheimer's disease? Neurology 2003;60:1374-1377
Web of Science | Medline30
Stoub TR ,Bulgakova M ,Leurgans S , et al. MRI predictors of risk of incident Alzheimer disease: a longitudinal study. Neurology 2005;64:1520-1524
CrossRef | Web of Science | Medline31
Small GW ,Kuhl DE ,Riege WH , et al. Cerebral glucose metabolic patterns in Alzheimer's disease: effect of gender and age at dementia onset. Arch Gen Psychiatry 1989;46:527-532
Web of Science | Medline32
Lemaitre H ,Crivello F ,Grassiot B ,Alperovitch A ,Tzourio C ,Mazover B . Age- and sex-related effects on the neuroanatomy of healthy elderly. Neuroimage 2005;26:900-911
CrossRef | Web of Science | Medline
- Citing Articles (192)
Citing Articles
1
Koon-Pong Wong, Vladimir Kepe, Magnus Dahlbom, Nagichettiar Satyamurthy, Gary W. Small, Jorge R. Barrio, Sung-Cheng Huang. (2012) Comparative evaluation of Logan and relative-equilibrium graphical methods for parametric imaging of dynamic [18F]FDDNP PET determinations. NeuroImage 60:1, 241-251
CrossRef2
Kanwar Virdee, Paul Cumming, Daniele Caprioli, Bianca Jupp, Axel Rominger, Franklin I. Aigbirhio, Tim D. Fryer, Patrick J. Riss, Jeffrey W. Dalley. (2012) Applications of positron emission tomography in animal models of neurological and neuropsychiatric disorders. Neuroscience & Biobehavioral Reviews
CrossRef3
V. Camus, P. Payoux, L. Barré, B. Desgranges, T. Voisin, C. Tauber, R. Joie, M. Tafani, C. Hommet, G. Chételat, K. Mondon, V. Sayette, J. P. Cottier, E. Beaufils, M. J. Ribeiro, V. Gissot, E. Vierron, J. Vercouillie, B. Vellas, F. Eustache, D. Guilloteau. (2012) Using PET with 18F-AV-45 (florbetapir) to quantify brain amyloid load in a clinical environment. European Journal of Nuclear Medicine and Molecular Imaging
CrossRef4
Heidi I.L. Jacobs, Martin P.J. Van Boxtel, Jelle Jolles, Frans R.J. Verhey, Harry B.M. Uylings. (2012) Parietal cortex matters in Alzheimer's disease: An overview of structural, functional and metabolic findings. Neuroscience & Biobehavioral Reviews 36:1, 297-309
CrossRef5
Marie M. Svedberg, Obaidur Rahman, Håkan Hall. (2012) Preclinical studies of potential amyloid binding PET/SPECT ligands in Alzheimer's disease. Nuclear Medicine and Biology
CrossRef6
Géraldine Poisnel, Martine Dhilly, Olivier Moustié, Jérôme Delamare, Ahmed Abbas, Denis Guilloteau, Louisa Barré. (2012) PET imaging with [18F]AV-45 in an APP/PS1-21 murine model of amyloid plaque deposition. Neurobiology of Aging
CrossRef7
William E. Klunk. (2011) Amyloid imaging as a biomarker for cerebral β-amyloidosis and risk prediction for Alzheimer dementia. Neurobiology of Aging 32, S20-S36
CrossRef8
Igor Yakushev, Matthias Schreckenberger, Matthias J. Müller, Ingrid Schermuly, Paul Cumming, Peter Stoeter, Alex Gerhard, Andreas Fellgiebel. (2011) Functional implications of hippocampal degeneration in early Alzheimer’s disease: a combined DTI and PET study. European Journal of Nuclear Medicine and Molecular Imaging 38:12, 2219-2227
CrossRef9
Michael Ewers, Giovanni B. Frisoni, Stefan J. Teipel, Lea T. Grinberg, Edson Amaro, Helmut Heinsen, Paul M. Thompson, Harald Hampel. (2011) Staging Alzheimer's disease progression with multimodality neuroimaging. Progress in Neurobiology 95:4, 535-546
CrossRef10
Bradford C. Dickerson. (2011) Quantitating Severity and Progression in Primary Progressive Aphasia. Journal of Molecular Neuroscience 45:3, 618-628
CrossRef11
Mariateresa Buongiorno, Yaroslau Compta, Maria J. Martí. (2011) Amyloid-β and τ biomarkers in Parkinson's disease–dementia. Journal of the Neurological Sciences 310:1-2, 25-30
CrossRef12
Geoffrey A Kerchner. (2011) Amyloid imaging for Alzheimer's disease. Expert Opinion on Medical Diagnostics 5:6, 527-538
CrossRef13
Andrei G. Vlassenko, Tammie L.S. Benzinger, John C. Morris. (2011) PET amyloid-beta imaging in preclinical Alzheimer's disease. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
CrossRef14
Bradford C. Dickerson. 2011. Molecular Neuroimaging of the Dementias. , 557-574.
CrossRef15
Harriet Quigley, Sean J. Colloby, John T. O'Brien. (2011) PET imaging of brain amyloid in dementia: a review. International Journal of Geriatric Psychiatry 26:10, 991-999
CrossRef16
Wolfgang Staffen, Gunther Ladurner, Yvonne Höller, Jürgen Bergmann, Markus Aichhorn, Stefan Golaszewski, Martin Kronbichler. (2011) Brain activation disturbance for target detection in patients with mild cognitive impairment: an fMRI study. Neurobiology of Aging
CrossRef17
Luiz K. Ferreira, Breno S. Diniz, Orestes V. Forlenza, Geraldo F. Busatto, Marcus V. Zanetti. (2011) Neurostructural predictors of Alzheimer's disease: A meta-analysis of VBM studies. Neurobiology of Aging 32:10, 1733-1741
CrossRef18
K.S. Rutgers, R.J.A. Nabuurs, S.A.A. van den Berg, G.J. Schenk, M. Rotman, C.T. Verrips, S.G. van Duinen, M.L. Maat-Schieman, M.A. van Buchem, A.G. de Boer, S.M. van der Maarel. (2011) Transmigration of beta amyloid specific heavy chain antibody fragments across the in vitro blood–brain barrier. Neuroscience 190, 37-42
CrossRef19
Edmond Teng, Vladimir Kepe, Sally A. Frautschy, Jie Liu, Nagichettiar Satyamurthy, Fusheng Yang, Ping-Ping Chen, Graham B. Cole, Mychica R. Jones, Sung-Cheng Huang, Dorothy G. Flood, Stephen P. Trusko, Gary W. Small, Gregory M. Cole, Jorge R. Barrio. (2011) [F-18]FDDNP microPET imaging correlates with brain Aβ burden in a transgenic rat model of Alzheimer disease: Effects of aging, in vivo blockade, and anti-Aβ antibody treatment. Neurobiology of Disease 43:3, 565-575
CrossRef20
Wendy Noble, Amy M Pooler, Diane P Hanger. (2011) Advances in tau-based drug discovery. Expert Opinion on Drug Discovery 6:8, 797-810
CrossRef21
Scott T. Harrison, James Mulhearn, Scott E. Wolkenberg, Patricia J. Miller, Stacey S. O’Malley, Zhizhen Zeng, David L. Williams, Eric D. Hostetler, Sandra Sanabria-Bohórquez, Linda Gammage, Hong Fan, Cyrille Sur, J. Christopher Culberson, Richard J. Hargreaves, Jacquelynn J. Cook, George D. Hartman, James C. Barrow. (2011) Synthesis and Evaluation of 5-Fluoro-2-aryloxazolo[5,4- b ]pyridines as β-Amyloid PET Ligands and Identification of MK-3328. ACS Medicinal Chemistry Letters 2:7, 498-502
CrossRef22
Shankar Vallabhajosula. (2011) Positron Emission Tomography Radiopharmaceuticals for Imaging Brain Beta-Amyloid. Seminars in Nuclear Medicine 41:4, 283-299
CrossRef23
Mengchao Cui, Zijing Li, Ruikun Tang, Hongmei Jia, Boli Liu. (2011) Novel (E)-5-styryl-2,2′-bithiophene derivatives as ligands for β-amyloid plaques. European Journal of Medicinal Chemistry 46:7, 2908-2916
CrossRef24
Faith M. Gunning, Gwenn S. Smith. (2011) Functional Neuroimaging in Geriatric Depression. Psychiatric Clinics of North America 34:2, 403-422
CrossRef25
Milap A. Nowrangi, Vani Rao, Constantine G. Lyketsos. (2011) Epidemiology, Assessment, and Treatment of Dementia. Psychiatric Clinics of North America 34:2, 275-294
CrossRef26
Valentina Berti, Alberto Pupi, Lisa Mosconi. (2011) PET/CT in diagnosis of dementia. Annals of the New York Academy of Sciences 1228:1, 81-92
CrossRef27
Namrta Sinha, Michael Firbank, John T. O'Brien. (2011) Biomarkers in dementia with Lewy bodies: a review. International Journal of Geriatric Psychiatryn/a-n/a
CrossRef28
Masahiro Ono, Shun Hayashi, Kenji Matsumura, Hiroyuki Kimura, Yoko Okamoto, Masafumi Ihara, Ryosuke Takahashi, Hiroshi Mori, Hideo Saji. (2011) Rhodanine and Thiohydantoin Derivatives for Detecting Tau Pathology in Alzheimer’s Brains. ACS Chemical Neuroscience 2:5, 269-275
CrossRef29
Jeffrey L. Cummings. (2011) Biomarkers in Alzheimer's disease drug development. Alzheimer's and Dementia 7:3, e13-e44
CrossRef30
Mengchao Cui, Masahiro Ono, Hiroyuki Kimura, Hidekazu Kawashima, Bo Li Liu, Hideo Saji. (2011) Radioiodinated benzimidazole derivatives as single photon emission computed tomography probes for imaging of β-amyloid plaques in Alzheimer's disease. Nuclear Medicine and Biology 38:3, 313-320
CrossRef31
David A. Merrill, Gary W. Small. (2011) Prevention in Psychiatry: Effects of Healthy Lifestyle on Cognition. Psychiatric Clinics of North America 34:1, 249-261
CrossRef32
Mengchao Cui, Ruikun Tang, Zijing Li, Huiying Ren, Boli Liu. (2011) 99mTc- and Re-labeled 6-dialkylamino-2-naphthylethylidene derivatives as imaging probes for β-amyloid plaques. Bioorganic & Medicinal Chemistry Letters 21:3, 1064-1068
CrossRef33
Dewen Yang, Zhiyong Xie, Diane Stephenson, Daniel Morton, Carol D. Hicks, Tracy M. Brown, Renuka Sriram, Sharon O'Neill, David Raunig, Thomas Bocan. (2011) Volumetric MRI and MRS provide sensitive measures of Alzheimer's disease neuropathology in inducible Tau transgenic mice (rTg4510). NeuroImage 54:4, 2652-2658
CrossRef34
Enrico Mossello, Elena Ballini, Anna Maria Mello, Francesca Tarantini, David Simoni, Samuele Baldasseroni, Niccolò Marchionni. (2011) Biomarkers of Alzheimer's Disease: From Central Nervous System to Periphery?. International Journal of Alzheimer's Disease 2011, 1-7
CrossRef35
Masahiro Ono, Hideo Saji. (2011) SPECT Imaging Agents for Detecting Cerebral β-Amyloid Plaques. International Journal of Molecular Imaging 2011, 1-12
CrossRef36
John M. Ringman, Karen H. Gylys, Luis D. Medina, Michelle Fox, Vladimir Kepe, Deborah L. Flores, Liana G. Apostolova, Jorge R. Barrio, Gary Small, Daniel H. Silverman, Erin Siu, Stephen Cederbaum, Silva Hecimovic, Martina Malnar, Suma Chakraverty, Alison M. Goate, Thomas D. Bird, James B. Leverenz. (2011) Biochemical, neuropathological, and neuroimaging characteristics of early-onset Alzheimer's disease due to a novel PSEN1 mutation. Neuroscience Letters 487:3, 287-292
CrossRef37
Chunming Xie, Joseph Goveas, Zhilin Wu, Wenjun Li, Guangyu Chen, Malgorzata Franczak, Piero G. Antuono, Jennifer L. Jones, Zhijun Zhang, Shi-Jiang Li. (2011) Neural basis of the association between depressive symptoms and memory deficits in nondemented subjects: resting-state fMRI study. Human Brain Mappingn/a-n/a
CrossRef38
Cheryl A. Luis, Laila Abdullah, Ghania Ait-Ghezala, Benoit Mouzon, Andrew P. Keegan, Fiona Crawford, Michael Mullan. (2011) Feasibility of Predicting MCI/AD Using Neuropsychological Tests and Serum β-Amyloid. International Journal of Alzheimer's Disease 2011, 1-7
CrossRef39
Robert Laforce, Gil D Rabinovici. (2011) Amyloid imaging in the differential diagnosis of dementia: review and potential clinical applications. Alzheimer's Research & Therapy 3:6, 31
CrossRef40
Jonghan Shin, Vladimir Kepe, Gary W. Small, Michael E. Phelps, Jorge R. Barrio. (2011) Multimodal Imaging of Alzheimer Pathophysiology in the Brain's Default Mode Network. International Journal of Alzheimer's Disease 2011, 1-8
CrossRef41
Alex D. Leow, Liana G. Apostolova, Paul M. Thompson. 2010. Computational Anatomy in Alzheimer's Disease. , 262-270.
CrossRef42
Markus Donix, Susan Y. Bookheimer, Gary W. Small. 2010. Physiological Neuroimaging in Ageing and Dementia: Metabolic and Molecular Scanning. , 257-261.
CrossRef43
Y. J. Hong, B. Yoon, Y. S. Shim, A. H. Cho, S. C. Lim, K. J. Ahn, D. W. Yang. (2010) Differences in Microstructural Alterations of the Hippocampus in Alzheimer Disease and Idiopathic Normal Pressure Hydrocephalus: A Diffusion Tensor Imaging Study. American Journal of Neuroradiology 31:10, 1867-1872
CrossRef44
Yajing Liu, Lin Zhu, Karl Plössl, Seok Rye Choi, Hongwen Qiao, Xiaotao Sun, Song Li, Zhihao Zha, Hank F. Kung. (2010) Optimization of automated radiosynthesis of [18F]AV-45: a new PET imaging agent for Alzheimer's disease. Nuclear Medicine and Biology 37:8, 917-925
CrossRef45
Meredith N. Braskie, Andrea D. Klunder, Kiralee M. Hayashi, Hillary Protas, Vladimir Kepe, Karen J. Miller, S.-C. Huang, Jorge R. Barrio, Linda M. Ercoli, Prabha Siddarth, Nagichettiar Satyamurthy, Jie Liu, Arthur W. Toga, Susan Y. Bookheimer, Gary W. Small, Paul M. Thompson. (2010) Plaque and tangle imaging and cognition in normal aging and Alzheimer's disease. Neurobiology of Aging 31:10, 1669-1678
CrossRef46
Andy Welch, Sally Pimlott. 2010. PET and SPECT in Drug Development. .
CrossRef47
Rik Vandenberghe, Koen Van Laere, Adrian Ivanoiu, Eric Salmon, Christine Bastin, Eric Triau, Steen Hasselbalch, Ian Law, Allan Andersen, Alex Korner, Lennart Minthon, Gaëtan Garraux, Natalie Nelissen, Guy Bormans, Chris Buckley, Rikard Owenius, Lennart Thurfjell, Gill Farrar, David J. Brooks. (2010) 18F-flutemetamol amyloid imaging in Alzheimer disease and mild cognitive impairment: A phase 2 trial. Annals of Neurology 68:3, 319-329
CrossRef48
Rawan Tarawneh, David M. Holtzman. (2010) Biomarkers in translational research of Alzheimer’s Disease. Neuropharmacology 59:4-5, 310-322
CrossRef49
Yang Yang, Lin Zhu, Mengchao Cui, Ruikun Tang, Huabei Zhang. (2010) Preparation of classical Re/99mTc(CO)3+ and novel 99mTc(CO)2(NO)2+ cores complexed with flavonol derivatives and their binding characteristics for Aβ(1–40) aggregates. Bioorganic & Medicinal Chemistry Letters 20:17, 5337-5344
CrossRef50
Liana G. Apostolova, Kristy S. Hwang, John P. Andrawis, Amity E. Green, Sona Babakchanian, Jonathan H. Morra, Jeffrey L. Cummings, Arthur W. Toga, John Q. Trojanowski, Leslie M. Shaw, Clifford R. Jack, Ronald C. Petersen, Paul S. Aisen, William J. Jagust, Robert A. Koeppe, Chester A. Mathis, Michael W. Weiner, Paul M. Thompson. (2010) 3D PIB and CSF biomarker associations with hippocampal atrophy in ADNI subjects. Neurobiology of Aging 31:8, 1284-1303
CrossRef51
Kjell Någren, Christer Halldin, Juha O. Rinne. (2010) Radiopharmaceuticals for positron emission tomography investigations of Alzheimer’s disease. European Journal of Nuclear Medicine and Molecular Imaging 37:8, 1575-1593
CrossRef52
Thomas Zetzsche, Dan Rujescu, John Hardy, Harald Hampel. (2010) Advances and perspectives from genetic research: development of biological markers in Alzheimer’s disease. Expert Review of Molecular Diagnostics 10:5, 667-690
CrossRef53
Nelleke Tolboom, Esther L.G.E. Koedam, Jonathan M. Schott, Maqsood Yaqub, Marinus A. Blankenstein, Frederik Barkhof, Yolande A.L. Pijnenburg, Adriaan A. Lammertsma, Philip Scheltens, Bart N. M. van Berckel. (2010) Dementia Mimicking Alzheimerʼs Disease Owing to a Tau Mutation: CSF and PET Findings. Alzheimer Disease & Associated Disorders1
CrossRef54
Juha O Rinne. (2010) Pittsburgh compound B as a marker of cognitive decline. Future Neurology 5:4, 519-526
CrossRef55
Harry LeVine. 2010. Imaging of Misfolded Proteins. , 645-671.
CrossRef56
Albertine Dubois, Anne-Sophie Hérard, Benoît Delatour, Philippe Hantraye, Gilles Bonvento, Marc Dhenain, Thierry Delzescaux. (2010) Detection by voxel-wise statistical analysis of significant changes in regional cerebral glucose uptake in an APP/PS1 transgenic mouse model of Alzheimer's disease. NeuroImage 51:2, 586-598
CrossRef57
Kewei Chen, Jessica B.S. Langbaum, Adam S. Fleisher, Napatkamon Ayutyanont, Cole Reschke, Wendy Lee, Xiaofen Liu, Dan Bandy, Gene E. Alexander, Paul M. Thompson, Norman L. Foster, Danielle J. Harvey, Mony J. de Leon, Robert A. Koeppe, William J. Jagust, Michael W. Weiner, Eric M. Reiman. (2010) Twelve-month metabolic declines in probable Alzheimer's disease and amnestic mild cognitive impairment assessed using an empirically pre-defined statistical region-of-interest: Findings from the Alzheimer's Disease Neuroimaging Initiative. NeuroImage 51:2, 654-664
CrossRef58
Nobuyuki Okamura, Yusei Shiga, Shozo Furumoto, Manabu Tashiro, Yoshio Tsuboi, Katsutoshi Furukawa, Kazuhiko Yanai, Ren Iwata, Hiroyuki Arai, Yukitsuka Kudo, Yasuhito Itoyama, Katsumi Doh-ura. (2010) In vivo detection of prion amyloid plaques using [11C]BF-227 PET. European Journal of Nuclear Medicine and Molecular Imaging 37:5, 934-941
CrossRef59
Katsutoshi Furukawa, Nobuyuki Okamura, Manabu Tashiro, Masaaki Waragai, Shozo Furumoto, Ren Iwata, Kazuhiko Yanai, Yukitsuka Kudo, Hiroyuki Arai. (2010) Amyloid PET in mild cognitive impairment and Alzheimer’s disease with BF-227: comparison to FDG–PET. Journal of Neurology 257:5, 721-727
CrossRef60
Raúl López-Grueso, Consuelo Borrás, Juan Gambini, José Viña. (2010) El envejecimiento y la ovariectomía causan una disminución del consumo cerebral de glucosa in vivo en ratas Wistar. Revista Española de Geriatría y Gerontología 45:3, 136-140
CrossRef61
Diana W. Shineman, Timothy A. Salthouse, Lenore J. Launer, Patrick R. Hof, George Bartzokis, Robin Kleiman, Victoria Luine, Jerry J. Buccafusco, Gary W. Small, Paul S. Aisen, David A. Lowe, Howard M. Fillit. (2010) Therapeutics for cognitive aging. Annals of the New York Academy of Sciences 1191, E1-E15
CrossRef62
R. S. Doody. (2010) Evolving early (pre-dementia) Alzheimer’s disease trials: Suit the outcomes to the population and study design. The journal of nutrition, health & aging 14:4, 299-302
CrossRef63
Meng-Chao Cui, Zi-Jing Li, Rui-Kun Tang, Bo-Li Liu. (2010) Synthesis and evaluation of novel benzothiazole derivatives based on the bithiophene structure as potential radiotracers for β-amyloid plaques in Alzheimer’s disease. Bioorganic & Medicinal Chemistry 18:7, 2777-2784
CrossRef64
L. Mosconi, J. O. Rinne, W. H. Tsui, V. Berti, Y. Li, H. Wang, J. Murray, N. Scheinin, K. Nagren, S. Williams, L. Glodzik, S. De Santi, S. Vallabhajosula, M. J. de Leon. (2010) Increased fibrillar amyloid- burden in normal individuals with a family history of late-onset Alzheimer's. Proceedings of the National Academy of Sciences 107:13, 5949-5954
CrossRef65
2010. Neuroimaging and Cognitive Assessments in early Drug Development. , 167-186.
CrossRef66
Koon-Pong Wong, Mirwais Wardak, Weber Shao, Magnus Dahlbom, Vladimir Kepe, Jie Liu, Nagichettiar Satyamurthy, Gary W. Small, Jorge R. Barrio, Sung-Cheng Huang. (2010) Quantitative analysis of [18F]FDDNP PET using subcortical white matter as reference region. European Journal of Nuclear Medicine and Molecular Imaging 37:3, 575-588
CrossRef67
James Patterson II, Alireza Minagar, Nirupama Natarajan, Amol Takalkar. (2010) Alzheimer’s disease detection with objective statistical evaluation of FDG-PET brain scans: essential methodology for early identification. Future Neurology 5:2, 259-276
CrossRef68
Britt-Marie Swahn, David Wensbo, Johan Sandell, Daniel Sohn, Can Slivo, David Pyring, Jonas Malmström, Erwan Arzel, Michaela Vallin, Margareta Bergh, Fredrik Jeppsson, Allan E. Johnson, Anders Juréus, Jan Neelissen, Samuel Svensson. (2010) Synthesis and evaluation of 2-pyridylbenzothiazole, 2-pyridylbenzoxazole and 2-pyridylbenzofuran derivatives as 11C-PET imaging agents for β-amyloid plaques. Bioorganic & Medicinal Chemistry Letters 20:6, 1976-1980
CrossRef69
Vladimir Kepe, Bernardino Ghetti, Martin R. Farlow, Mara Bresjanac, Karen Miller, Sung-Cheng Huang, Koon-Pong Wong, Jill R. Murrell, Pedro Piccardo, Francine Epperson, Grega Repovš, Lojze M. Smid, Andrej Petrič, Prabha Siddarth, Jie Liu, Nagichettiar Satyamurthy, Gary W. Small, Jorge R. Barrio. (2010) PET of Brain Prion Protein Amyloid in Gerstmann-Sträussler-Scheinker Disease. Brain Pathology 20:2, 419-430
CrossRef70
Agneta Nordberg, Juha O. Rinne, Ahmadul Kadir, Bengt Långström. (2010) The use of PET in Alzheimer disease. Nature Reviews Neurology 6:2, 78-87
CrossRef71
Charlotte L. Allan, Claire E. Sexton, David Welchew, Klaus P. Ebmeier. (2010) Imaging and biomarkers for Alzheimer's disease. Maturitas 65:2, 138-142
CrossRef72
M. Donix, C. Brons, L. Jurjanz, K. Poettrich, P. Winiecki, V. A. Holthoff. (2010) Overgenerality of Autobiographical Memory in People with Amnestic Mild Cognitive Impairment and Early Alzheimer's Disease. Archives of Clinical Neuropsychology 25:1, 22-27
CrossRef73
Alexander Drzezga. (2010) Amyloid-plaque imaging in early and differential diagnosis of dementia. Annals of Nuclear Medicine 24:2, 55-66
CrossRef74
R. S. Doody. (2010) Evolving early (pre-dementia) Alzheimer’s disease trials: Suit the outcomes to the population and study design. The journal of nutrition, health & aging
CrossRef75
Lihai Yu, Matthias Scheunemann, Winnie Deuther-Conrad, Achim Hiller, Steffen Fischer, Dietlind Sorger, Osama Sabri, Hongmei Jia, Jorg Steinbach, Peter Brust, Boli Liu. (2010) Novel Indole Derivatives as Potential Imaging Agents for Alzheimer's Disease. Bulletin of the Korean Chemical Society 31:1, 177-180
CrossRef76
Hiroyuki Arai, Nobuyuki Okamura, Katsutoshi Furukawa, Yukitsuka Kudo. (2010) Geriatric Medicine, Japanese Alzheimer's Disease Neuroimaging Initiative and Biomarker Development. The Tohoku Journal of Experimental Medicine 221:2, 87-95
CrossRef77
Victor L. Villemagne, Christopher C. Rowe. (2010) Amyloid PET Ligands for Dementia. PET Clinics 5:1, 33-53
CrossRef78
Kun-Lin Xiong, Qing-Wu Yang, Shui-Gen Gong, Wei-Guo Zhang. (2010) The role of positron emission tomography imaging of β-amyloid in patients with Alzheimerʼs disease. Nuclear Medicine Communications 31:1, 4-11
CrossRef79
Markus Weih, Ümüt Degirmenci, Sebastian Kreil, Piotr Lewczuk, Daniela Schmidt, Johannes Kornhuber, Torsten Kuwert. (2010) Perfusion Imaging with SPECT in the Era of Pathophysiology-Based Biomarkers for Alzheimer's Disease. International Journal of Alzheimer's Disease 2010, 1-5
CrossRef80
G. Gründer, I. Vernaleken, P. Bartenstein. (2010) Anwendungen von PET und SPECT in der Psychiatrie. Der Nervenarzt 81:1, 97-108
CrossRef81
Hiroko Nishi, Nobukatsu Sawamoto, Chihiro Namiki, Hidefumi Yoshida, Dinh Ha Duy Thuy, Koichi Ishizu, Kazuo Hashikawa, Hidenao Fukuyama. (2010) Correlation between Cognitive Deficits and Glucose Hypometabolism in Mild Cognitive Impairment. Journal of Neuroimaging 20:1, 29-36
CrossRef82
Maqsood Yaqub, Nelleke Tolboom, Bart N.M. van Berckel, Philip Scheltens, Adriaan A. Lammertsma, Ronald Boellaard. (2010) Simplified parametric methods for [18F]FDDNP studies. NeuroImage 49:1, 433-441
CrossRef83
R.S. Osorio, V. Berti, L. Mosconi, Y. Li, L. Glodzik, S. De Santi, M.J. de Leon. (2010) Evaluation of Early Dementia (Mild Cognitive Impairment). PET Clinics 5:1, 15-31
CrossRef84
H.D. Protas, S.-C. Huang, V. Kepe, K. Hayashi, A. Klunder, M.N. Braskie, L. Ercoli, S. Bookheimer, P.M. Thompson, G.W. Small, J.R. Barrio. (2010) FDDNP binding using MR derived cortical surface maps. NeuroImage 49:1, 240-248
CrossRef85
Bradford C Dickerson, Howard Eichenbaum. (2010) The Episodic Memory System: Neurocircuitry and Disorders. Neuropsychopharmacology 35:1, 86-104
CrossRef86
Johnny Vercouillie, Christian Prenant, Serge Maia, Patrick Emond, Stéphane Guillouet, Jean Bernard Deloye, Louisa Barré, Denis Guilloteau. (2010) Automated production of [ 18 F]FDDNP using a TRACERlab MX FDG. Journal of Labelled Compounds and Radiopharmaceuticalsn/a-n/a
CrossRef87
JAMIE TALAN. (2010) BIOMARKER IDENTIFIES AMYLOID PLAQUE AND TAU TANGLES. Neurology Today 10:2, 1
CrossRef88
Karen M. Rodrigue, Kristen M. Kennedy, Denise C. Park. (2009) Beta-Amyloid Deposition and the Aging Brain. Neuropsychology Review 19:4, 436-450
CrossRef89
Richard J. Perrin, Anne M. Fagan, David M. Holtzman. (2009) Multimodal techniques for diagnosis and prognosis of Alzheimer's disease. Nature 461:7266, 916-922
CrossRef90
Masaaki Waragai, Nobuyuki Okamura, Katsutoshi Furukawa, Manabu Tashiro, Shozo Furumoto, Yoshihito Funaki, Motohisa Kato, Ren Iwata, Kazuhiko Yanai, Yukitsuka Kudo, Hiroyuki Arai. (2009) Comparison study of amyloid PET and voxel-based morphometry analysis in mild cognitive impairment and Alzheimer's disease. Journal of the Neurological Sciences 285:1-2, 100-108
CrossRef91
Masahiro Ono, Shun Hayashi, Hiroyuki Kimura, Hidekazu Kawashima, Morio Nakayama, Hideo Saji. (2009) Push–pull benzothiazole derivatives as probes for detecting β-amyloid plaques in Alzheimer’s brains. Bioorganic & Medicinal Chemistry 17:19, 7002-7007
CrossRef92
Maqsood Yaqub, Ronald Boellaard, Bart N. M. Berckel, Nelleke Tolboom, Gert Luurtsema, Anke A. Dijkstra, Mark Lubberink, Albert D. Windhorst, Philip Scheltens, Adriaan A. Lammertsma. (2009) Evaluation of Tracer Kinetic Models for Analysis of [18F]FDDNP Studies. Molecular Imaging and Biology 11:5, 322-333
CrossRef93
Michelle T. Fodero-Tavoletti, Roberto Cappai, Catriona A. McLean, Kerryn E. Pike, Paul A. Adlard, Tiffany Cowie, Andrea R. Connor, Colin L. Masters, Christopher C. Rowe, Victor L. Villemagne. (2009) Amyloid Imaging in Alzheimer’s Disease and Other Dementias. Brain Imaging and Behavior 3:3, 246-261
CrossRef94
Anna Caroli, Giovanni B Frisoni. (2009) Quantitative evaluation of Alzheimer’s disease. Expert Review of Medical Devices 6:5, 569-588
CrossRef95
David A. Wolk, William E. Klunk. (2009) Update on amyloid imaging: From healthy aging to Alzheimer’s disease. Current Neurology and Neuroscience Reports 9:5, 345-352
CrossRef96
L. T. Grinberg, U. Rüb, R. E. L. Ferretti, R. Nitrini, J. M. Farfel, L. Polichiso, K. Gierga, W. Jacob-Filho, H. Heinsen, . (2009) The dorsal raphe nucleus shows phospho-tau neurofibrillary changes before the transentorhinal region in Alzheimer's disease. A precocious onset?. Neuropathology and Applied Neurobiology 35:4, 406-416
CrossRef97
R. S. Desikan, H. J. Cabral, C. P. Hess, W. P. Dillon, C. M. Glastonbury, M. W. Weiner, N. J. Schmansky, D. N. Greve, D. H. Salat, R. L. Buckner, B. Fischl, . (2009) Automated MRI measures identify individuals with mild cognitive impairment and Alzheimer's disease. Brain 132:8, 2048-2057
CrossRef98
Rebecca Craig-Schapiro, Anne M. Fagan, David M. Holtzman. (2009) Biomarkers of Alzheimer's disease. Neurobiology of Disease 35:2, 128-140
CrossRef99
John Darrell Van Horn, Arthur W Toga. (2009) Multisite neuroimaging trials. Current Opinion in Neurology 22:4, 370-378
CrossRef100
O. Querbes, F. Aubry, J. Pariente, J.-A. Lotterie, J.-F. Demonet, V. Duret, M. Puel, I. Berry, J.-C. Fort, P. Celsis, . (2009) Early diagnosis of Alzheimer's disease using cortical thickness: impact of cognitive reserve. Brain 132:8, 2036-2047
CrossRef101
William Jagust. (2009) Mapping brain β-amyloid. Current Opinion in Neurology 22:4, 356-361
CrossRef102
Claudia Kuntner, Adam L. Kesner, Martin Bauer, Robert Kremslehner, Thomas Wanek, Markus Mandler, Rudolf Karch, Johann Stanek, Tanja Wolf, Markus Müller, Oliver Langer. (2009) Limitations of Small Animal PET Imaging with [18F]FDDNP and FDG for Quantitative Studies in a Transgenic Mouse Model of Alzheimer’s Disease. Molecular Imaging and Biology 11:4, 236-240
CrossRef103
Terence C. Chua, Wei Wen, Xiaohua Chen, Nicole Kochan, Melissa J. Slavin, Julian N. Trollor, Henry Brodaty, Perminder S. Sachdev. (2009) Diffusion Tensor Imaging of the Posterior Cingulate is a Useful Biomarker of Mild Cognitive Impairment. American Journal of Geriatric Psychiatry 17:7, 602-613
CrossRef104
Helen Lavretsky, Prabha Siddarth, Vladimir Kepe, Linda M. Ercoli, Karen J. Miller, Alison C. Burggren, Susan Y. Bookheimer, Sung-Cheng Huang, Jorge R. Barrio, Gary W. Small. (2009) Depression and Anxiety Symptoms Are Associated With Cerebral FDDNP-PET Binding in Middle-Aged and Older Nondemented Adults. American Journal of Geriatric Psychiatry 17:6, 493-502
CrossRef105
David A. Wolk, Julie C. Price, Judy A. Saxton, Beth E. Snitz, Jeffrey A. James, Oscar L. Lopez, Howard J. Aizenstein, Ann D. Cohen, Lisa A. Weissfeld, Chester A. Mathis, William E. Klunk, Steven T. DeKosky. (2009) Amyloid imaging in mild cognitive impairment subtypes. Annals of Neurology 65:5, 557-568
CrossRef106
Linda M. Ercoli, Prabha Siddarth, Vladimir Kepe, Karen J. Miller, S -C. Huang, Gregory M. Cole, Helen Lavretsky, Susan Y. Bookheimer, Jeanne Kim, Michael E. Phelps, Jorge R. Barrio, Gary W. Small. (2009) Differential FDDNP PET Patterns in Nondemented Middle-Aged and Older Adults. American Journal of Geriatric Psychiatry 17:5, 397-406
CrossRef107
W. M. Flier, P. Scheltens. (2009) Knowing the natural course of biomarkers in AD: Longitudinal MRI, CSF and PET data. The Journal of Nutrition, Health and Aging 13:4, 353-355
CrossRef108
Susan Bookheimer, Alison Burggren. (2009) APOE-4 Genotype and Neurophysiological Vulnerability to Alzheimer's and Cognitive Aging. Annual Review of Clinical Psychology 5:1, 343-362
CrossRef109
Paul W. Thompson, Liang Ye, Jennifer L. Morgenstern, Lucia Sue, Thomas G. Beach, Duncan J. Judd, Nicholas J. Shipley, Vincenzo Libri, Andrew Lockhart. (2009) Interaction of the amyloid imaging tracer FDDNP with hallmark Alzheimer’s disease pathologies. Journal of Neurochemistry 109:2, 623-630
CrossRef110
M. Rutter, R. Plomin. (2009) Pathways from science findings to health benefits. Psychological Medicine 39:04, 529
CrossRef111
Hong I. Wan, Orest Hurko, Mark Day, J. Lynn Rutkowski. (2009) Translational medicine perspective in development of disease modifying therapies for Alzheimer's disease: biomarkers to buy down the risk. Drug Development Research 70:2, 60-69
CrossRef112
Maria C. Carrillo, Andrew Blackwell, Harald Hampel, Johan Lindborg, Reisa Sperling, Dale Schenk, Jeffrey J. Sevigny, Steven Ferris, David A. Bennett, Suzanne Craft, Timothy Hsu, William Klunk. (2009) Early risk assessment for Alzheimer's disease. Alzheimer's and Dementia 5:2, 182-196
CrossRef113
B. C. Dickerson, A. Bakkour, D. H. Salat, E. Feczko, J. Pacheco, D. N. Greve, F. Grodstein, C. I. Wright, D. Blacker, H. D. Rosas, R. A. Sperling, A. Atri, J. H. Growdon, B. T. Hyman, J. C. Morris, B. Fischl, R. L. Buckner. (2009) The Cortical Signature of Alzheimer's Disease: Regionally Specific Cortical Thinning Relates to Symptom Severity in Very Mild to Mild AD Dementia and is Detectable in Asymptomatic Amyloid-Positive Individuals. Cerebral Cortex 19:3, 497-510
CrossRef114
Xiaochun TAO, Chunya DAI, Xiongjie CAO, Lisheng CAI, Victor W. PIKE. (2009) Palladium-catalyzed Substitution of Ketone or Aldehyde Bearing Aryl Triflates by Amines or Amides. Chinese Journal of Chemistry 27:2, 403-407
CrossRef115
Jae Seung Kim, Seung Jun Oh, Dae Hyuk Moon. (2009) Molecular Imaging in Neurodegenerative Diseases. Journal of the Korean Medical Association 52:2, 151
CrossRef116
Masahiro Ono. (2009) Development of Positron-Emission Tomography/Single-Photon Emission Computed Tomography Imaging Probes for in Vivo Detection of β-Amyloid Plaques in Alzheimer's Brains. CHEMICAL & PHARMACEUTICAL BULLETIN 57:10, 1029-1039
CrossRef117
Douglas Mossman, Michael D. Bowen, David J. Vanness, David Bienenfeld, Terry Correll, Jerald Kay, William M. Klykylo, Douglas S. Lehrer. (2009) Quantifying the Accuracy of Forensic Examiners in the Absence of a “Gold Standard”. Law and Human Behavior 34:5, 402
CrossRef118
Ranjan Duara, Warren Barker, David Loewenstein, Lisa Bain. (2009) The basis for disease-modifying treatments for Alzheimer's disease: The Sixth Annual Mild Cognitive Impairment Symposium. Alzheimer's and Dementia 5:1, 66-74
CrossRef119
Rachel Mistur, Lisa Mosconi, Susan De Santi, Yi Li, Wai Tsui, Mony de Leon. (2009) Positron emission tomography in Alzheimer’s disease: early prediction and differentiation. Future Neurology 4:1, 23-38
CrossRef120
Rachel Mistur, Lisa Mosconi, Susan De Santi, Marla Guzman, Yi Li, Wai Tsui, Mony J. de Leon. (2009) Current Challenges for the Early Detection of Alzheimer's Disease: Brain Imaging and CSF Studies. Journal of Clinical Neurology 5:4, 153
CrossRef121
William E Klunk, Chester A Mathis. (2008) The future of amyloid-beta imaging: a tale of radionuclides and tracer proliferation. Current Opinion in Neurology 21:6, 683-687
CrossRef122
Gary W. Small, Prabha Siddarth, Daniel H.S. Silverman, Linda M. Ercoli, Karen J. Miller, Helen Lavretsky, Susan Y. Bookheimer, S-C Huang, Jorge R. Barrio, Michael E. Phelps. (2008) Cognitive and Cerebral Metabolic Effects of Celecoxib Versus Placebo in People With Age-Related Memory Loss: Randomized Controlled Study. American Journal of Geriatric Psychiatry 16:12, 999-1009
CrossRef123
Daniel M Blumberger, Zafiris J Daskalakis, Benoit H Mulsant. (2008) Biomarkers in geriatric psychiatry: searching for the holy grail?. Current Opinion in Psychiatry 21:6, 533-539
CrossRef124
Jonghan Shin, Sang-Yoon Lee, So-Hee Kim, Young-Bo Kim, Seong-Jin Cho. (2008) Multitracer PET imaging of amyloid plaques and neurofibrillary tangles in Alzheimer's disease. NeuroImage 43:2, 236-244
CrossRef125
Davangere P. Devanand, Xinhua Liu, Matthias H. Tabert, Gnanavalli Pradhaban, Katrina Cuasay, Karen Bell, Mony J. de Leon, Richard L. Doty, Yaakov Stern, Gregory H. Pelton. (2008) Combining Early Markers Strongly Predicts Conversion from Mild Cognitive Impairment to Alzheimer's Disease. Biological Psychiatry 64:10, 871-879
CrossRef126
Gert Luurtsema, Robert C. Schuit, Kevin Takkenkamp, Mark Lubberink, N. Harry Hendrikse, Albert D. Windhorst, Carla F.M. Molthoff, Nelleke Tolboom, Bart N.M. van Berckel, Adriaan A. Lammertsma. (2008) Peripheral metabolism of [18F]FDDNP and cerebral uptake of its labelled metabolites. Nuclear Medicine and Biology 35:8, 869-874
CrossRef127
P. Krolak-Salmon, J. Seguin, A. Perret-Liaudet, V. Desestret, A. Vighetto, M. Bonnefoy. (2008) Vers un diagnostic biologique de la maladie d’Alzheimer et des syndromes apparentés. La Revue de Médecine Interne 29:10, 785-793
CrossRef128
Dietmar Rudolf Thal, W. Sue T. Griffin, Heiko Braak. (2008) Parenchymal and vascular Aβ-deposition and its effects on the degeneration of neurons and cognition in Alzheimer's disease. Journal of Cellular and Molecular Medicine 12:5b, 1848-1862
CrossRef129
Anton Forsberg, Henry Engler, Ove Almkvist, Gunnar Blomquist, Göran Hagman, Anders Wall, Anna Ringheim, Bengt Långström, Agneta Nordberg. (2008) PET imaging of amyloid deposition in patients with mild cognitive impairment. Neurobiology of Aging 29:10, 1456-1465
CrossRef130
M. Haupt, J.A. González-Hernández, W.A. Scherbaum. (2008) Regions with different evoked frequency band responses during early-stage visual processing distinguish mild Alzheimer dementia from mild cognitive impairment and normal aging. Neuroscience Letters 442:3, 273-278
CrossRef131
María J. Moreno, María L. Lozano, V. Roldán, B. Bellosillo, N. García-Barberá, J. Rivera, L. Navarro-Núñez, C. Besses, V. Vicente, C. Martínez. (2008) JAK2 V617F, hemostatic polymorphisms, and clinical features as risk factors for arterial thrombotic events in essential thrombocythemia. Annals of Hematology 87:9, 763-765
CrossRef132
Hitoshi SHINOTOH, Tetsuya SUHARA. (2008) Beyond PIB: the next generation of amyloid-imaging ligands. Psychogeriatrics 8:3, 105-107
CrossRef133
Muthu Ramakrishnan, Thomas M. Wengenack, Karunya K. Kandimalla, Geoffry L. Curran, Emily J. Gilles, Marina Ramirez-Alvarado, Joseph Lin, Michael Garwood, Clifford R. Jack Jr., Joseph F. Poduslo. (2008) Selective Contrast Enhancement of Individual Alzheimer’s Disease Amyloid Plaques Using a Polyamine and Gd-DOTA Conjugated Antibody Fragment Against Fibrillar Aβ42 for Magnetic Resonance Molecular Imaging. Pharmaceutical Research 25:8, 1861-1872
CrossRef134
J Wesson Ashford. (2008) Screening for memory disorders, dementia and Alzheimer’s disease. Aging Health 4:4, 399-432
CrossRef135
Victor L. Villemagne, Michelle T. Fodero-Tavoletti, Kerryn E. Pike, Roberto Cappai, Colin L. Masters, Christopher C. Rowe. (2008) The ART of Loss: Aβ Imaging in the Evaluation of Alzheimer’s Disease and other Dementias. Molecular Neurobiology 38:1, 1-15
CrossRef136
Erik S. Musiek, Drew A. Torigian, Andrew B. Newberg. (2008) Investigation of Nonneoplastic Neurologic Disorders with PET and MRI. PET Clinics 3:3, 317-334
CrossRef137
Anja Schneider, Eckhard Mandelkow. (2008) Tau-based treatment strategies in neurodegenerative diseases. Neurotherapeutics 5:3, 443-457
CrossRef138
Randall J. Bateman, William E. Klunk. (2008) Measuring target effect of proposed disease-modifying therapies in Alzheimer’s disease. Neurotherapeutics 5:3, 381-390
CrossRef139
Daniel H.S. Silverman, Lisa Mosconi, Linda Ercoli, Wei Chen, Gary W. Small. (2008) Positron Emission Tomography Scans Obtained for the Evaluation of Cognitive Dysfunction. Seminars in Nuclear Medicine 38:4, 251-261
CrossRef140
Anand Kumar, Olusola Ajilore, Vladimir Kepe, Jorge R. Barrio, Gary Small. (2008) Mood, cognition andin vivo protein imaging: the emerging nexus in clinical neuroscience. International Journal of Geriatric Psychiatry 23:6, 555-563
CrossRef141
Dietmar Rudolf Thal, W. Sue T. Griffin, Rob A. I. Vos, Estifanos Ghebremedhin. (2008) Cerebral amyloid angiopathy and its relationship to Alzheimer’s disease. Acta Neuropathologica 115:6, 599-609
CrossRef142
Liang Ye, Ana Velasco, Graham Fraser, Thomas G. Beach, Lucia Sue, Tracy Osredkar, Vincenzo Libri, Maria Grazia Spillantini, Michel Goedert, Andrew Lockhart. (2008) In vitro high affinity α-synuclein binding sites for the amyloid imaging agent PIB are not matched by binding to Lewy bodies in postmortem human brain. Journal of Neurochemistry 105:4, 1428-1437
CrossRef143
Eline M. van der Beek, Patrick J.G.H. Kamphuis. (2008) The potential role of nutritional components in the management of Alzheimer's Disease. European Journal of Pharmacology 585:1, 197-207
CrossRef144
Ajit K. Parhi, Mei-Ping Kung, Karl Ploessl, Hank F. Kung. (2008) Synthesis of fluorescent probes based on stilbenes and diphenylacetylenes targeting β-amyloid plaques. Tetrahedron Letters 49:21, 3395-3399
CrossRef145
Paul Cutler, Emma L. Akuffo, Wanda M. Bodnar, Deborah M. Briggs, John B. Davis, Christine M. Debouck, Steven M. Fox, Rachel A. Gibson, Darren A. Gormley, Joanna D. Holbrook, A. Jacqueline Hunter, Emma E. Kinsey, Rabinder Prinjha, Jill C. Richardson, Allen D. Roses, Marjorie A. Smith, Nikos Tsokanas, David R. Willé, Wen Wu, John W. Yates, Israel S. Gloger. (2008) Proteomic identification and early validation of complement 1 inhibitor and pigment epithelium-derived factor: Two novel biomarkers of Alzheimer's disease in human plasma. PROTEOMICS – CLINICAL APPLICATIONS 2:4, 467-477
CrossRef146
Ursula Berndt, Christian Stanetty, Thomas Wanek, Claudia Kuntner, Johann Stanek, Michael Berger, Martin Bauer, Gjermund Henriksen, Hans-Jürgen Wester, Herbert Kvaternik, Peter Angelberger, Christian Noe. (2008) Synthesis of a [18F]fluorobenzothiazole as potential amyloid imaging agent. Journal of Labelled Compounds and Radiopharmaceuticals 51:3, 137-145
CrossRef147
Gjermund Henriksen, Behrooz H. Yousefi, Alexander Drzezga, Hans-Jürgen Wester. (2008) Development and evaluation of compounds for imaging of β-amyloid plaque by means of positron emission tomography. European Journal of Nuclear Medicine and Molecular Imaging 35:S1, 75-81
CrossRef148
Lisa Mosconi, Susan De Santi, Miroslaw Brys, Wai H. Tsui, Elizabeth Pirraglia, Lidia Glodzik-Sobanska, Kenneth E. Rich, Remigius Switalski, Pankaj D. Mehta, Domenico Pratico, Ray Zinkowski, Kay Blennow, Mony J. de Leon. (2008) Hypometabolism and Altered Cerebrospinal Fluid Markers in Normal Apolipoprotein E E4 Carriers with Subjective Memory Complaints. Biological Psychiatry 63:6, 609-618
CrossRef149
Osama Sabri, Kai Kendziorra, Henrike Wolf, Hermann-Josef Gertz, Peter Brust. (2008) Acetylcholine receptors in dementia and mild cognitive impairment. European Journal of Nuclear Medicine and Molecular Imaging 35:S1, 30-45
CrossRef150
Ana Velasco, Graham Fraser, Patrice Delobel, Bernardino Ghetti, Isabelle Lavenir, Michel Goedert. (2008) Detection of filamentous tau inclusions by the fluorescent Congo red derivative FSB [(trans,trans)-1-fluoro-2,5-bis(3-hydroxycarbonyl-4-hydroxy)styrylbenzene]. FEBS Letters 582:6, 901-906
CrossRef151
Agneta Nordberg. (2008) Amyloid plaque imaging in vivo: current achievement and future prospects. European Journal of Nuclear Medicine and Molecular Imaging 35:S1, 46-50
CrossRef152
Nunzio Pomara, Ken Belzer, Raymundo Hernando, Corazon De La Pena, John J. Sidtis. (2008) Increased Mental Slowing Associated With the APOE ϵ4 Allele After Trihexyphenidyl Oral Anticholinergic Challenge in Healthy Elderly. American Journal of Geriatric Psychiatry 16:2, 116-124
CrossRef153
Gary W Small, Susan Y Bookheimer, Paul M Thompson, Greg M Cole, S-C Huang, Vladimir Kepe, Jorge R Barrio. (2008) Current and future uses of neuroimaging for cognitively impaired patients. The Lancet Neurology 7:2, 161-172
CrossRef154
Xiangji Chen, Pingrong Yu, Lianfeng Zhang, Boli Liu. (2008) Synthesis and biological evaluation of 99mTc, Re-monoamine-monoamide conjugated to 2-(4-aminophenyl)benzothiazole as potential probes for β-amyloid plaques in the brain. Bioorganic & Medicinal Chemistry Letters 18:4, 1442-1445
CrossRef155
Giovanni B Frisoni. (2008) Imaging of amyloid comes of age. The Lancet Neurology 7:2, 114-115
CrossRef156
Christopher C Rowe, Uwe Ackerman, William Browne, Rachel Mulligan, Kerryn L Pike, Graeme O'Keefe, Henry Tochon-Danguy, Gordon Chan, Salvatore U Berlangieri, Gareth Jones, Kerryn L Dickinson-Rowe, Hank P Kung, Wei Zhang, Mei Ping Kung, Daniel Skovronsky, Thomas Dyrks, Gerhard Holl, Sabine Krause, Matthias Friebe, Lutz Lehman, Stefanie Lindemann, Ludger M Dinkelborg, Colin L Masters, Victor L Villemagne. (2008) Imaging of amyloid β in Alzheimer's disease with 18F-BAY94-9172, a novel PET tracer: proof of mechanism. The Lancet Neurology 7:2, 129-135
CrossRef157
M. D. Ikonomovic, W. E. Klunk, E. E. Abrahamson, C. A. Mathis, J. C. Price, N. D. Tsopelas, B. J. Lopresti, S. Ziolko, W. Bi, W. R. Paljug, M. L. Debnath, C. E. Hope, B. A. Isanski, R. L. Hamilton, S. T. DeKosky. (2008) Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer's disease. Brain 131:6, 1630-1645
CrossRef158
Lissy Jarvik, Asenath LaRue, Deborah Blacker, Margaret Gatz, Claudia Kawas, John J. McArdle, John C. Morris, James A. Mortimer, John M. Ringman, Linda Ercoli, Nelson Freimer, Izabella Gokhman, Jennifer J. Manly, Brenda L. Plassman, Natalie Rasgon, Jeffrey Scott Roberts, Trey Sunderland, Gary E. Swan, Phillip A. Wolf, Alan B. Zonderman. (2008) Children of Persons With Alzheimer Disease. Alzheimer Disease & Associated Disorders 22:1, 6-20
CrossRef159
Jeffrey L. Cummings. (2008) Optimizing phase II of drug development for disease-modifying compounds. Alzheimer's and Dementia 4:1, S15-S20
CrossRef160
Dale Schenk. (2008) Current challenges for the successful treatment and prevention of Alzheimer’s disease: Treating the pathologies of the disease to change its clinical course. Alzheimer's and Dementia 4:1, S119-S121
CrossRef161
J. R. Barrio, V. Kepe, N. Satyamurthy, S. C. Huang, G. Small. (2008) Amyloid and tau imaging, neuronal losses and function in mild cognitive impairment. The Journal of Nutrition Health and Aging 12:S1, S61-S65
CrossRef162
2008. Bibliographie. , 207-244.
CrossRef163
Norman L. Foster, Angela Y. Wang, Tolga Tasdizen, P. Thomas Fletcher, John M. Hoffman, Robert A. Koeppe. (2008) Realizing the potential of positron emission tomography with 18F-fluorodeoxyglucose to improve the treatment of Alzheimer’s disease. Alzheimer's and Dementia 4:1, S29-S36
CrossRef164
Nobuyuki Okamura, Kazuhiko Yanai. (2008) In vivo imaging of amyloid plaques. Folia Pharmacologica Japonica 131:5, 333-337
CrossRef165
2007. Standardized Neurocognitive Assessment of Traumatic Brain Injury. .
CrossRef166
Nobuyuki Okamura, Shozo Furumoto, Yoshihito Funaki, Takahiro Suemoto, Motohisa Kato, Yoichi Ishikawa, Satoshi Ito, Hiroyasu Akatsu, Takayuki Yamamoto, Tohru Sawada, Hiroyuki Arai, Yukitsuka Kudo, Kazuhiko Yanai. (2007) Binding and safety profile of novel benzoxazole derivative for in vivo imaging of amyloid deposits in Alzheimer's disease. Geriatrics & Gerontology International 7:4, 393-400
CrossRef167
Nicolaas PLG Verhoeff. (2007) Amyloid imaging in vivo : implications for Alzheimer's disease management. Expert Opinion on Medical Diagnostics 1:3, 337-349
CrossRef168
Masahiro Ono, Miyuki Hori, Mamoru Haratake, Takami Tomiyama, Hiroshi Mori, Morio Nakayama. (2007) Structure–activity relationship of chalcones and related derivatives as ligands for detecting of β-amyloid plaques in the brain. Bioorganic & Medicinal Chemistry 15:19, 6388-6396
CrossRef169
Chester A. Mathis, Brian J. Lopresti, William E. Klunk. (2007) Impact of amyloid imaging on drug development in Alzheimer's disease. Nuclear Medicine and Biology 34:7, 809-822
CrossRef170
Keith A. Johnson, Matt Gregas, John A. Becker, Catherine Kinnecom, David H. Salat, Erin K. Moran, Erin E. Smith, Jonathan Rosand, Dorene M. Rentz, William E. Klunk, Chester A. Mathis, Julie C. Price, Steven T. DeKosky, Alan J. Fischman, Steven M. Greenberg. (2007) Imaging of amyloid burden and distribution in cerebral amyloid angiopathy. Annals of Neurology 62:3, 229-234
CrossRef171
Harry V. Vinters. (2007) Imaging cerebral microvascular amyloid. Annals of Neurology 62:3, 209-212
CrossRef172
Masahiro Ono, Yoshifumi Maya, Mamoru Haratake, Kazuhiro Ito, Hiroshi Mori, Morio Nakayama. (2007) Aurones serve as probes of β-amyloid plaques in Alzheimer’s disease. Biochemical and Biophysical Research Communications 361:1, 116-121
CrossRef173
Rita Carrotta, Jennifer Barthès, Alessandro Longo, Vincenzo Martorana, Mauro Manno, Giuseppe Portale, Pier Luigi San Biagio. (2007) Large size fibrillar bundles of the Alzheimer amyloid β-protein. European Biophysics Journal 36:7, 701-709
CrossRef174
Nicholas Seneca, Lisheng Cai, Jeih-San Liow, Sami S. Zoghbi, Robert L. Gladding, Jinsoo Hong, Victor W. Pike, Robert B. Innis. (2007) Brain and whole-body imaging in nonhuman primates with [11C]MeS-IMPY, a candidate radioligand for β-amyloid plaques. Nuclear Medicine and Biology 34:6, 681-689
CrossRef175
Brendan J. Kelley, Ronald C. Petersen. (2007) Alzheimer's Disease and Mild Cognitive Impairment. Neurologic Clinics 25:3, 577-609
CrossRef176
(2007) Current awareness in geriatric psychiatry. International Journal of Geriatric Psychiatry 22:8, 820-827
CrossRef177
Agneta Nordberg. (2007) Amyloid imaging in Alzheimer??s disease. Current Opinion in Neurology 20:4, 398-402
CrossRef178
Ben Seltzer. (2007) Early detection of Alzheimer’s disease. Aging Health 3:4, 449-456
CrossRef179
Vesna Jelic, Lars-Olof Wahlund. (2007) Diagnostic imaging devices in Alzheimer’s disease. Expert Review of Medical Devices 4:4, 475-487
CrossRef180
Liana G. Apostolova, Paul M. Thompson. (2007) Brain mapping as a tool to study neurodegeneration. Neurotherapeutics 4:3, 387-400
CrossRef181
Paul M Matthews. (2007) Molecular imaging of brain amyloid in mild cognitive impairment and Alzheimer's disease. Nature Clinical Practice Neurology 3:7, 366-367
CrossRef182
Robert M. Cohen. (2007) The Application of Positron-Emitting Molecular Imaging Tracers in Alzheimer’s Disease. Molecular Imaging and Biology 9:4, 204-216
CrossRef183
Christina E. Wierenga, Mark W. Bondi. (2007) Use of Functional Magnetic Resonance Imaging in the Early Identification of Alzheimer's Disease. Neuropsychology Review 17:2, 127-143
CrossRef184
Ulf Andreasson, Erik Portelius, Malin E Andersson, Kaj Blennow, Henrik Zetterberg. (2007) Aspects of β-amyloid as a biomarker for Alzheimer’s disease. Biomarkers in Medicine 1:1, 59-78
CrossRef185
Yun Zhou, Susan M. Resnick, Weiguo Ye, Hong Fan, Daniel P. Holt, William E. Klunk, Chester A. Mathis, Robert Dannals, Dean F. Wong. (2007) Using a reference tissue model with spatial constraint to quantify [11C]Pittsburgh compound B PET for early diagnosis of Alzheimer's disease. NeuroImage 36:2, 298-312
CrossRef186
Cynthia Price, Heather Lindsey. (2007) DIAGNOSING AND TRACKING ALZHEIMER DISEASE. AJN, American Journal of Nursing 107:4, 74
CrossRef187
(2007) PET Scanning in Mild Cognitive Impairment. New England Journal of Medicine 356:11, 1175-1176
Full Text188
Giovanni Lucignani. (2007) How early? ASAP: molecular and functional imaging!. European Journal of Nuclear Medicine and Molecular Imaging 34:4, 596-601
CrossRef189
Bart NM van Berckel, Philip Scheltens. (2007) Getting a grip on Alzheimer's disease: imaging amyloid in the brain. The Lancet Neurology 6:3, 204-206
CrossRef190
Mony J de Leon, Lisa Mosconi, Jean Logan. (2007) Seeing what Alzheimer saw. Nature Medicine 13:2, 129-131
CrossRef191
Norra MacReady. (2007) PET Tracer Charts the Progress of Dementia. Neurology Today 7:4, 24,27
CrossRef192
2007. .
CrossRef
- Letters
