APOE and BCHE as modulators of cerebral amyloid deposition: a florbetapir PET genome-wide association study.

Deposition of amyloid-ß (Aß) in the cerebral cortex is thought to be a pivotal event in Alzheimer's disease (AD) pathogenesis with a significant genetic contribution. Molecular imaging can provide an early noninvasive phenotype, but small samples have prohibited genome-wide association studies (GWAS) of cortical Aß load until now. We employed florbetapir ((18)F) positron emission tomography (PET) imaging to assess brain Aß levels in vivo for 555 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). More than six million common genetic variants were tested for association to quantitative global cortical Aß load controlling for age, gender and diagnosis. Independent genome-wide significant associations were identified on chromosome 19 within APOE (apolipoprotein E) (rs429358, P=5.5 × 10(-14)) and on chromosome 3 upstream of BCHE (butyrylcholinesterase) (rs509208, P=2.7 × 10(-8)) in a region previously associated with serum BCHE activity. Together, these loci explained 15% of the variance in cortical Aß levels in this sample (APOE 10.7%, BCHE 4.3%). Suggestive associations were identified within ITGA6, near EFNA5, EDIL3, ITGA1, PIK3R1, NFIB and ARID1B, and between NUAK1 and C12orf75. These results confirm the association of APOE with Aß deposition and represent the largest known effect of BCHE on an AD-related phenotype. BCHE has been found in senile plaques and this new association of genetic variation at the BCHE locus with Aß burden in humans may have implications for potential disease-modifying effects of BCHE-modulating agents in the AD spectrum.

Amyloid PET imaging in Alzheimer's disease: a comparison of three radiotracers.

PURPOSE: The increasing use of amyloid PET in Alzheimer's disease research and clinical trials has motivated efforts to standardize methodology. We compared retention of the (11)C radiotracer Pittsburgh Compound B (PiB) and that of two (18)F amyloid radiotracers (florbetapir and flutemetamol) using two study populations. We also examined the feasibility of converting between tracer-specific measures, using PiB as the common link between the two (18)F tracers. METHODS: One group of 40 subjects underwent PiB and flutemetamol imaging sessions and a separate group of 32 subjects underwent PiB and florbetapir imaging sessions. We compared cortical and white matter retention for each (18)F tracer relative to that of PiB, as well as retention in several reference regions and image analysis methods. Correlations between tracer pairs were used to convert tracer-specific threshold values for amyloid positivity between tracers. RESULTS: Cortical retention for each pair of tracers was strongly correlated regardless of reference region (PiB-flutemetamol, ρ = 0.84-0.99; PiB-florbetapir, ρ = 0.83-0.97) and analysis method (ρ = 0.90-0.99). Compared to PiB, flutemetamol had higher white matter retention, while florbetapir had lower cortical retention. Two previously established independent thresholds for amyloid positivity were highly consistent when values were converted between tracer pairs. CONCLUSION: Despite differing white and grey matter retention characteristics, cortical retention for each (18)F tracer was highly correlated with that of PiB, enabling conversion of thresholds across tracer measurement scales with a high level of internal consistency. Standardization of analysis methods and measurement scales may facilitate the comparison of amyloid PET data obtained using different tracers.

Episodic memory loss is related to hippocampal-mediated beta-amyloid deposition in elderly subjects.

Although beta-amyloid (Abeta) plaques are a primary diagnostic criterion for Alzheimer's disease, this pathology is commonly observed in the brains of non-demented older individuals. To explore the importance of this pathology in the absence of dementia, we compared levels of amyloid deposition (via 'Pittsburgh Compound-B' (PIB) positron emission tomography (PET) imaging) to hippocampus volume (HV) and episodic memory (EM) in three groups: (i) normal controls (NC) from the Berkeley Aging Cohort (BAC NC, n = 20); (ii) normal controls (NC) from the Alzheimer's disease neuroimaging initiative (ADNI NC, n = 17); and (iii) PIB+ mild cognitive impairment subjects from the ADNI (ADNI PIB+ MCI, n = 39). Age, gender and education were controlled for in each statistical model, and HV was adjusted for intracranial volume (aHV). In BAC NC, elevated PIB uptake was significantly associated with smaller aHV (P = 0.0016) and worse EM (P = 0.0086). Within ADNI NC, elevated PIB uptake was significantly associated with smaller aHV (P = 0.047) but not EM (P = 0.60); within ADNI PIB+ MCI, elevated PIB uptake was significantly associated with both smaller aHV (P = 0.00070) and worse EM (P = 0.046). To further understand these relationships, a recursive regression procedure was conducted within all ADNI NC and PIB+ MCI subjects (n = 56) to test the hypothesis that HV mediates the relationship between Abeta and EM. Significant correlations were found between PIB index and EM (P = 0.0044), PIB index and aHV (P < 0.0001), as well as between aHV and EM (P < 0.0001). When both aHV and PIB were included in the same model to predict EM, aHV remained significant (P = 0.0015) whereas PIB index was no longer significantly associated with EM (P = 0.50). These results are consistent with a model in which Abeta deposition, hippocampal atrophy, and EM occur sequentially in elderly subjects, with Abeta deposition as the primary event in this cascade. This pattern suggests that declining EM in older individuals may be caused by Abeta-induced hippocampus atrophy.

Performance of FDG PET for detection of Alzheimer's disease in two independent multicentre samples (NEST-DD and ADNI).

AIM: We investigated the performance of FDG PET using an automated procedure for discrimination between Alzheimer's disease (AD) and controls, and studied the influence of demographic and technical factors. METHODS: FDG PET data were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) [102 controls (76.0 +/- 4.9 years) and 89 AD patients (75.7 +/- 7.6 years, MMSE 23.5 +/- 2.1) and the Network for Standardisation of Dementia Diagnosis (NEST-DD) [36 controls (62.2 +/- 5.0 years) and 237 AD patients (70.8 +/- 8.3 years, MMSE 20.9 +/- 4.4). The procedure created t-maps of abnormal voxels. The sum of t-values in predefined areas that are typically affected by AD (AD t-sum) provided a measure of scan abnormality associated with a preset threshold for discrimination between patients and controls. RESULTS: AD patients had much higher AD t-sum scores compared to controls (p < 0.01), which were significantly related to dementia severity (ADNI: r = -0.62, p < 0.01; NEST-DD: r = -0.59, p < 0.01). Early-onset AD patients had significantly higher AD t-sum scores than late-onset AD patients (p < 0.01). Differences between databases were mainly due to different age distributions. The predefined AD t-sum threshold yielded a sensitivity and specificity of 83 and 78% in ADNI and 78 and 94% in NEST-DD, respectively. CONCLUSION: The automated FDG PET analysis procedure provided good discrimination power, and was most accurate for early-onset AD.

Low erythrocyte folate, but not plasma vitamin B-12 or homocysteine,is associated with dementia in elderly Latinos.

The relationship between B vitamin status and cognitive function has been of interest for many years. There is evidence of relationships between intake and status of folate and vitamin B-12 with neurological, cognitive, and memory impairment, but results have been inconsistent. Plasma B-12, erythrocyte folate, methylmalonic acid,and homocysteine were evaluated as predictors of cognitive function in a large population based sample of Latino elderly living in the Sacramento, California region. The hypothesis tested was that low folate and/or B-12 status predicts cognitive function impairment and dementia. Logistic regression was used to examine the differences in B-vitamin status by cognitive function category. Erythrocyte folate was related to dementia after controlling for age, gender, education, income, diabetes diagnosis, serum creatinine, and depressive symptoms. The highest prevalence of low erythrocyte folate occurred in the Dementia group and was significantly higher than in the Normal group. Plasma B-12, MMA, Hcy, and prevalence of a normal values for these variables, were not significantly different among the cognitive function classes. We conclude that folate status is associated with dementia but that more research is needed on the relationship between vitaminB-12 status, Hcy and cognitive function to explore possible associations with these parameters.

Neuropathologic substrates of ischemic vascular dementia.

Ischemic vascular dementia (IVD) is a relatively uncommon entity, in the course of which multiple ischemic brain lesions result in progressive cognitive and memory impairment. Ischemic brain lesions may also aggravate the neuropsychologic deficit of Alzheimer disease (AD). In this review we summarize our experience based upon autopsy examination of the central nervous system in 20 patients (age range 68-92 years) enrolled in a longitudinal investigation of structural, neurochemical, functional neuroimaging, and neuropsychologic components of IVD, especially dementia associated with cerebral microvascular disease. While cystic infarcts were present in the CNS of 5 patients, the most commonly observed neuropathologic abnormalities were lacunar infarcts and microinfarcts--both types of lesion were encountered in over half of patients' brains. Evidence of (remote) hippocampal injury was found in 11/20 patients. Severe atherosclerosis and arterio/ arteriolosclerosis were both associated with the occurrence of multiple lacunar infarcts. Pronounced cerebral amyloid angiopathy (CAA) was noted in a single patient, who also showed other microscopic changes of severe AD. While fairly unusual as a nosologic entity, IVD appears to correlate with widespread small ischemic lesions distributed throughout the CNS. We furthermore propose an approach to quantifying the burden of ischemic vascular and parenchymal disease that may be associated with a dementia syndrome. A brief review of neuropathologic features of vascular dementia (both familial and sporadic) is presented.

Diminished glucose transport in Alzheimer's disease: dynamic PET studies.

Dynamic positron emission tomography with [18F]fluorodeoxyglucose was used in six patients with Alzheimer's disease (AD) and seven healthy age-matched control subjects to estimate the kinetic parameters K1*, k2*, and k3* that describe glucose transport and phosphorylation. A high-resolution tomograph was used to acquire brain uptake data in one tomographic plane, and a radial artery catheter connected to a plastic scintillator was used to acquire arterial input data. A nonlinear iterative least-squares fitting procedure that included terms for the vascular fraction and time delay to the peripheral sampling site was used to fit a three-compartment model to the brain data. Regions studied included frontal, temporal, occipital, and the entire cortex and subcortical white matter. The values obtained for the individual rate constants and regional CMRglc (rCMRglc; calculated using regional values of the rate constants) were higher than those reported previously. A significant (p less than 0.05) decrease was found in K1* in frontal and temporal cortex in the AD patients compared with the controls, with values of 0.157 and 0.161 ml/g/min in frontal and temporal cortex, respectively, of controls and 0.127 and 0.126 ml/g/min in frontal and temporal cortex of the AD patients. rCMRglc was also significantly (p less than 0.02) lower in the AD patients than controls in all cortical brain regions. Lower values of k3* were found in all brain regions in the AD patients, although these were not statistically significant. These findings provide evidence of an in vivo abnormality of forward glucose transport in AD.(ABSTRACT TRUNCATED AT 250 WORDS)

Cortical glucose metabolism in Parkinson's disease without dementia.

There have been several reports of decreased regional cerebral metabolic rates for glucose (rCMRglc) in Parkinson's disease (PD), although others find no differences between PD patients and controls. Differences in the cognitive status of the PD patients may account for some of these inconsistencies. We report the results of a PET study using 18F-fluorodeoxyglucose (FDG) to measure rCMRglc in eight nondemented PD patients, six of whom were receiving dopaminergic medications, and eight age-matched control subjects. We scanned one tomographic level through the temporal lobes that included both temporal neocortex and mesial temporal cortex, and one tomographic level through the basal ganglia that included frontal and parietal cortex. Previously determined rate constants and an operational equation were used to determine rCMRglc. On average, rCMRglc values were 23% below control values for all regions studied, with the greatest differences in posterior brain regions (visual association cortex, primary visual cortex, and parietal cortex) and thalamus. These results indicate that PD patients may show neocortical hypometabolism, especially in posterior brain regions, in the absence of any demonstrable cognitive deficits.

Reduced temporal lobe blood flow in Alzheimer's disease.

We used single photon emission computed tomography with the blood flow tracer [123I]N-isopropyl-p-iodoamphetamine (IMP) to study regional cerebral blood flow (rCBF) in 50 mildly and moderately demented Alzheimer's disease (AD) patients to evaluate rCBF as a function of disease severity. Relative rCBF (normalized to occipital cortex) was significantly lower than controls in temporal cortex for both mildly and moderately demented patients. Similar numbers of patients in both groups demonstrated perfusion abnormalities in temporal neocortex. Parietal cortex was more variably involved with greater numbers of moderately than mildly demented patients showing perfusion abnormalities. Relative rCBF in dirsolateral frontal cortex was reduced only in the moderately demented patients. Disease severity, as measured by the Mini Mental Status Examination, was associated with relative rCBF only in dorsolateral frontal and parietal cortex. These results suggest that the temporal lobes are the first neocortical regions affected by AD and that other cortical areas become involved as the disease progresses.

Cerebral glucose metabolism and memory in aged rhesus macaques.

Positron emission tomography and the glucose metabolic tracer [18F]fluorodeoxyglucose were used to evaluate the relationship between regional cerebral metabolic rates for glucose (rCMRglc), age, and performance on a delayed response (DR) test of memory in the aged monkey. Eleven aged animals, 21-26-years old, were included in the analysis. Regional CMRglc, normalized to values for the entire brain, were determined for the dorsal prefrontal cortex, orbitofrontal cortex, hippocampus, and temporal cortex. The aged animals exhibited significant DR deficits relative to a cohort of normal young monkeys. Variability in DR performance among the aged subjects was significantly correlated with relative hippocampal rCMRglc, and chronological age was a reliable predictor of orbitofrontal rCMRglc ratios. This pattern of results suggests that DR impairments in the aged monkey may partly reflect age-related dysfunction distributed among multiple limbic system structures that participate in normal learning and memory. Overall, the findings support the use of positron emission tomography in efforts to define the relationship between cognitive performance, age, and brain physiology in nonhuman primates.

Preliminary evidence that estrogen protects against age-related hippocampal atrophy.

Few studies have examined gender differences in hippocampal volumes, and the potential effect of estrogen on these measures has not been well studied. We used MRI to measure hippocampal volumes in elderly Mexican American men and women subjects in order to determine if there were gender differences and if estrogen replacement therapy (ERT) had an effect on hippocampal volume in postmenopausal women. MRI measures of hippocampal volumes (normalized to intracranial volume) were compared in 59 women and 38 men. Further comparisons were made between men subjects, women subjects taking ERT, and women subjects not taking ERT. There were no significant effects of gender on normalized hippocampal volumes. However, women subjects taking ERT had larger right hippocampal volumes than women subjects not taking ERT and larger anterior hippocampal volumes than men subjects and women subjects not taking ERT. These findings suggest a neuroprotective effect of estrogen.

PET studies of cerebral glucose metabolism in conscious rhesus macaques.

A growing body of evidence suggests that rhesus macaques may be a good model of human brain aging. We used positron emission tomography (PET) and 18F-fluorodeoxyglucose (FDG) to measure regional cerebral metabolic rates for glucose (rCMRglc) in young and aged rhesus macaques to determine if age-related decreases, such as those reported in humans, also occur in macaques. Whereas the aged animals had lower metabolic rates in every brain region studied, the largest differences were in left temporal cortex. The largest differences were also observed in left temporal cortex when relative rCMRglc values were used. Both rCMRglc and relative rCMRglc were marked by substantial individual variation within the aged group. This variation may parallel the variation observed in behavioral studies. Future studies that include both PET and behavioral measures should help determine if there is a relationship between age-related changes in rCMRglc and behavior.

Human corpus callosum in aging and Alzheimer's disease: a magnetic resonance imaging study.

The involvement of the corpus callosum in aging and Alzheimer's disease (AD) is not clear. We measured cross sectional areas of the entire corpus callosum (CC), as well as the front 20% (genu), middle 60% (body), and posterior 20% (splenium) of the structure from a midsagittal MRI slice in AD patients (N = 20), and young (N = 16) and old (N = 13) control subjects. We found that mean CC area in young controls was 570 +/- 107 mm2. Aging did not significantly affect the mean area of the CC (562 +/- 98 mm2). A small, significant reduction was seen in AD in comparison to the young control group (480 +/- 133 mm2). However, AD is accompanied by a large and statistically significant reduction in the genu area in comparison to both young and old control subjects. A trend toward an age-dependent reduction in the body area is also accentuated in AD patients who showed significantly smaller callosal bodies than young controls. We conclude that selective changes within corpus callosum accompany aging and AD pathology.

Comparison of methods for measuring longitudinal brain change in cognitive impairment and dementia.

PURPOSE: The goal of this project was to compare MRI measures of hippocampal, entorhinal cortex (ERC), and whole brain longitudinal change in cognitively normal elderly controls (C), non-demented subjects with cognitive impairment (CI), and demented (D) subjects. METHODS: 16 C, 6 CI, and 7 D subjects of comparable age were studied with MRI twice, at least 1 year apart. Longitudinal change in total brain size was measured by several methods, including computerized segmentation, non-linear warping, and change in the fluid/tissue boundaries between cerebrospinal fluid (CSF) and brain. Change in hippocampal volume was measured by semi-automated methods, and ERC volumes were manually measured. RESULTS: The annual rate of atrophy was greater in D versus C and D versus CI for cortical gray matter (cGM) (P=0.009 and 0.002), hippocampus (P=0.0001 and 0.002), and for the change in the fluid/tissue boundary (P=0.03 and 0.03). The annual rate of atrophy of ERC was greater in both CI and D versus C (P=0.01 and 0.0002). No significant differences between groups were found using non-linear warping. CONCLUSIONS: In CI, the greatest annual rates of atrophy were in ERC, while in D the greatest annual rates of atrophy were in hippocampus and cortex. Progressive ERC atrophy was observed with a greater degree of cognitive impairment, while hippocampal and cortical atrophy were only observed in demented subjects.

Differences in lateral hemispheric asymmetries of glucose utilization between early- and late-onset Alzheimer-type dementia.

Positron emission tomography with [18F]fluorodeoxyglucose revealed greater right than left hemispheric impairment of cortical glucose metabolism in patients with probable Alzheimer's disease who were younger than 65 but not in those over 65. This asymmetry was related to poor visuospatial performance.

Temporal lobe perfusion on single photon emission computed tomography predicts the rate of cognitive decline in Alzheimer's disease.

OBJECTIVE: To examine the ability of relative regional cerebral blood flow as measured by single photon emission computed tomography to predict longitudinal course of cognitive decline in Alzheimer's disease. DESIGN: Single photon emission computed tomography using the blood flow tracer 123I-N-isopropyl-p-iodoamphetamine was performed at initial evaluation and was used to predict the rate of cognitive decline over a follow-up period from 1 to 4 years. SETTING: Outpatient university dementia clinic and center for functional imaging. PARTICIPANTS: Twenty-nine patients met National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria for probably or possible AD. RESULTS: Temporal lobe regional cerebral blood flow ratio at initial evaluation correlated with rate of decline in Mini-Mental State Examination over the longitudinal follow-up. Temporal regional cerebral blood flow ratio also predicted rate of decline of specific memory measures on the California Verbal Learning Test. Neither parietal nor frontal ratios predicted rate of cognitive decline. Dorsolateral frontal hypoperfusion was associated with the emergence of perseverative behaviors over time. Age, prior dementia duration, estimated prior rate of decline, and initial severity did not predict rate of cognitive decline. CONCLUSION: Results suggest that regional perfusion on single photon emission computed tomography may predict cognitive decline in Alzheimer's disease better than these demographic and course variables.

The diagnosis of dementia with single photon emission computed tomography.

Single photon emission computed tomography is a practical modality for the study of physiologic cerebral activity in vivo. We utilized single photon emission computed tomography and N-isopropyl-p-iodoamphetamine iodine 123 to evaluate regional cerebral blood flow in nine patients with Alzheimer's disease (AD), five healthy elderly control subjects, and two patients with multi-infarct dementia. We found that all subjects with AD demonstrated flow deficits in temporoparietal cortex bilaterally, and that the ratio of activity in bilateral temporoparietal cortex to activity in the whole slice allowed the differentiation of all patients with AD from both the controls and from the patients with multi-infarct dementia. Furthermore, this ratio showed a strong correlation with disease severity in the AD group. Single photon emission computed tomography appears to be useful in the differential diagnosis of dementia and reflects clinical features of the disease.

The effects of age on rate of progression of Alzheimer disease and dementia with associated cerebrovascular disease.

BACKGROUND: Relatively little is known about how cerebrovascular disease affects progression of dementia. Previous studies have found no differences in progression of Alzheimer disease and vascular dementia, but these studies have not specifically examined age effects. OBJECTIVE: To test whether the rate of cognitive decline is different in Alzheimer disease compared with dementia with associated cerebrovascular disease in clinical and autopsy patient series. PATIENTS AND METHODS: We studied the longitudinal course of cognitive function as measured by the Mini-Mental State Examination (MMSE) in patients with clinically and neuropathologically diagnosed conditions evaluated through a university Alzheimer disease center. Clinical patients were grouped according to possible Alzheimer disease without stroke (n = 37), probable Alzheimer disease without stroke (n = 181), and dementia with stroke (n = 50). Autopsy cases were categorized into Alzheimer disease (n = 78) and dementia with vascular disease (n = 13). Data were analyzed using random-effects modeling of longitudinal change. RESULTS: There was a significant interaction between age and diagnosis in determining rate of change on the MMSE scores for both the clinical and autopsy samples. Rate of change decreased slightly with advancing age for Alzheimer disease groups, but increased with age for dementia with cerebrovascular disease groups. CONCLUSIONS: Dementia with cerebrovascular disease declined faster in patients 80 years and older compared with Alzheimer disease without associated cerebrovascular pathological conditions, but showed slower decline in patients younger than 80 years. This effect most likely reflects combined Alzheimer and vascular pathological conditions in older patients with cerebrovascular disease.

Cognitive correlates of regional cerebral blood flow in Alzheimer's disease.

OBJECTIVE: To study the relationship between relative regional cerebral blood flow (rCBF) and performance on a variety of neuropsychological tests in a group of subjects with Alzheimer's disease. DESIGN: Analysis of the relationship between relative rCBF and neuropsychological performance using stepwise multiple regressions and Pearson Product-Moment Correlation coefficients. SETTING: University dementia clinic and research laboratory. PARTICIPANTS: Twelve mildly demented patients with Alzheimer's disease (Mini-Mental State examination [MMSE] scores, 24 to 29; age, 56 to 78 years); 38 moderately demented patients with Alzheimer's disease (MMSE scores, 0 to 23; age, 59 to 86 years); and eight normal control subjects (MMSE scores, 27 to 30; age, 61 to 79 years). MAIN OUTCOME MEASURES: Single photon emission computed tomography and the blood flow tracer N-isopropyl-p-iodoamphetamine iodine 123 were used to measure relative rCBF. Cognitive performance was assessed by grouping neuropsychological tests into clusters reflecting frontal lobe abilities, perseveration, memory, and visuoconstructive abilities. RESULTS: While MMSE score was a significant (P < .05) predictor of visuoconstruction, frontal lobe, and memory cluster scores, relative rCBF was a weaker predictor of neuropsychological performance, with only right orbitofrontal relative rCBF emerging as a significant (P < .05) predictor of the frontal cluster score and right parietal relative rCBF as a significant (P < .05) predictor of the visuoconstruction cluster score. CONCLUSIONS: These results support our a priori grouping of neuropsychological tests into frontal and visuoconstruction clusters and suggest that these two clusters are good measures of frontal and parietal lobe function, respectively.

Alzheimer's disease. Age at onset and single-photon emission computed tomographic patterns of regional cerebral blood flow.

We performed this study to determine whether early- and late-onset Alzheimer's disease differ physiologically. Ten patients with a presenile (before 65 years old) onset of the disease and 16 with senile onset of the disease were evaluated clinically and neuropsychologically and studied with single photon emission computed tomography using the blood flow tracer [123I]N-isopropyl-p-iodoamphetamine. Although the presenile subjects had more severe neuropsychological abnormalities in all realms of cognitive function, including language, and showed greater reductions in regional blood flow than the older patients, they were also more severely demented, thus complicating interpretation of the results. Two indexes of cerebral perfusion, a ratio of regional flow compared with occipital flow and a left-right asymmetry index, demonstrated relative left frontal hypoperfusion in presenile- but not senile-onset patients and did not appear to be an artifact of the severity differences. Although no asymmetry of cognitive function was noted, the perfusion asymmetry provides biological evidence for an alteration in left-hemisphere function in patients with the early onset of Alzheimer's disease.