Nutrient patterns and brain biomarkers of Alzheimer's disease in cognitively normal individuals.

OBJECTIVES: Epidemiological evidence linking diet, one of the most important modifiable lifestyle factors, and risk of Alzheimer's disease (AD) is rapidly increasing. However, there is little or no evidence for a direct association between dietary nutrients and brain biomarkers of AD. This study identifies nutrient patterns associated with major brain AD biomarkers in a cohort of clinically and cognitively normal (NL) individuals at risk for AD. DESIGN: Cross-sectional study. SETTING: Manhattan (broader area). PARTICIPANTS: Fifty-two NL individuals (age 54+12 y, 70% women, Clinical Dementia Rating=0, MMSE>27, neuropsychological test performance within norms by age and education) with complete dietary information and cross-sectional, 3D T1-weighted Magnetic Resonance Imaging (MRI; gray matter volumes, GMV, a marker of brain atrophy), 11C-Pittsburgh compound-B (PiB; a marker of fibrillar amyloid-ß, Aß) and 18F-fluorodeoxyglucose (FDG; a marker of glucose metabolism, METglc) Positron Emission Tomography (PET) scans were examined. MEASUREMENTS: Dietary intake of 35 nutrients associated with cognitive function and AD was assessed using the Harvard/Willet Food Frequency Questionnaire. Principal component analysis was used to generate nutrient patterns (NP) from the full nutrient panel. Statistical parametric mapping and voxel based morphometry were used to assess the associations of the identified NPs with AD biomarkers. RESULTS: None of the participants were diabetics, smokers, or met criteria for obesity. Five NPs were identified: NP1 was characterized by most B-vitamins and several minerals [VitB and Minerals]; NP2 by monounsaturated and polyunsaturated fats, including ω-3 and ω-6 PUFA, and vitamin E [VitE and PUFA]; NP3 by vitamin A, vitamin C, carotenoids and dietary fibers [Anti-oxidants and Fibers]; NP4 by vitamin B12, vitamin D and zinc [VitB12 and D]; NP5 by saturated, trans-saturated fats, cholesterol and sodium [Fats]. Voxel-based analysis showed that NP4 scores [VitB12 and D] were positively associated with METglc and GMV, and negatively associated with PiB retention in AD-vulnerable regions (p<0.001). In addition, both METglc and GMV were positively associated with NP2 scores [VitE and PUFA], and negatively associated with NP5 scores [Fats] (p<0.001), and METglc was positively associated with higher NP3 scores [Anti-oxidants and Fibers] (p<0.001). Adjusting for age, gender, ethnicity, education, caloric intake, BMI, alcohol consumption, family history and Apolipoprotein E (APOE) status did not attenuate these relationships. The identified 'AD-protective' nutrient combination was associated with higher intake of fresh fruit and vegetables, whole grains, fish and low-fat dairies, and lower intake of sweets, fried potatoes, high-fat dairies, processed meat and butter. CONCLUSION: Specific dietary NPs are associated with brain biomarkers of AD in NL individuals, suggesting that dietary interventions may play a role in the prevention of AD by modulating AD-risk through its effects on Aß and associated neuronal impairment.

Mediterranean Diet and Magnetic Resonance Imaging-Assessed Brain Atrophy in Cognitively Normal Individuals at Risk for Alzheimer's Disease.

OBJECTIVES: Epidemiological evidence linking diet, one of the most important modifiable environmental factors, and risk of Alzheimer's disease (AD) is rapidly increasing. Several studies have shown that higher adherence to a Mediterranean diet (MeDi) is associated with reduced risk of AD. This study examines the associations between high vs. lower adherence to a MeDi and structural MRI-based brain atrophy in key regions for AD in cognitively normal (NL) individuals with and without risk factors for AD. DESIGN: Cross-sectional study. SETTING: Manhattan (broader area). PARTICIPANTS: Fifty-two NL individuals (age 54+12 y, 70% women) with complete dietary information and cross-sectional, 3D T1-weighted MRI scans were examined. MEASUREMENTS: Subjects were dichotomized into those showing higher vs. lower adherences to the MeDi using published protocols. Estimates of cortical thickness for entorhinal cortex (EC), inferior parietal lobe, middle temporal gyrus, orbitofrontal cortex (OFC) and posterior cingulate cortex (PCC) were obtained by use of automated segmentation tools (FreeSurfer). Multivariate general linear models and linear regressions assessed the associations of MeDi with MRI measures. RESULTS: Of the 52 participants, 20 (39%) showed higher MeDi adherence (MeDi+) and 32 (61%) showed lower adherence (MeDi-). Groups were comparable for clinical, neuropsychological measures, presence of a family history of AD (FH), and frequency of Apolipoprotein E (APOE) ε4 genotype. With and without controlling for age and total intracranial volume, MeDi+ subjects showed greater thickness of AD-vulnerable ROIs as compared to MeDi- subjects (Wilk's Lambda p=0.026). Group differences were most pronounced in OFC (p=0.001), EC (p=0.03) and PCC (p=0.04) of the left hemisphere. Adjusting for gender, education, FH, APOE status, BMI, insulin resistance scores and presence of hypertension did not attenuate the relationship. CONCLUSION: NL individuals showing lower adherence to the MeDi had cortical thinning in the same brain regions as clinical AD patients compared to those showing higher adherence. These data indicate that the MeDi may have a protective effect against tissue loss, and suggest that dietary interventions may play a role in the prevention of AD.

Systematic differences between lean and obese adolescents in brain spin-lattice relaxation time: a quantitative study.

BACKGROUND AND PURPOSE: Emerging evidence suggests that obese adolescents show changes in brain structure compared with lean adolescents. In addition, obesity impacts body development during adolescence. We tested a hypothesis that T1, a marker of brain maturation, can show brain differences associated with obesity. MATERIALS AND METHODS: Adolescents similar in sex, family income, and school grade were recruited by using strict entry criteria. We measured brain T1 in 48 obese and 31 lean adolescents by quantitative MR imaging at 1.5T. We combined MPRAGE and inversion-recovery sequences with normalization to standard space and automated skull stripping to obtain T1 maps with a symmetric voxel volume of 1 mm(3). RESULTS: Sex, income, triglycerides, total cholesterol, and fasting glucose did not differ between groups, but obese adolescents had significantly lower HDL, higher LDL, and higher fasting insulin levels than lean adolescents. Intracranial vault volume did not differ between groups, but obese adolescents had smaller intracranial vault-adjusted brain parenchymal volumes. Obese adolescents had 4 clusters (>100 contiguous voxels) of T1 relaxation that were significantly different (P < .005) from those in lean adolescents. Three of these clusters had longer T1s in obese adolescents (in the orbitofrontal and parietal regions), and 1 cluster had shorter T1s, compared with lean adolescents. CONCLUSIONS: Our results suggest that obesity may have a significant impact on brain development, especially in the frontal and parietal lobes. It is unclear if these changes persist into adulthood or whether they indicate that obese subjects follow a different developmental trajectory during adolescence.

Preliminary evidence for brain complications in obese adolescents with type 2 diabetes mellitus.

AIMS/HYPOTHESIS: Central nervous system abnormalities, including cognitive and brain impairments, have been documented in adults with type 2 diabetes who also have multiple co-morbid disorders that could contribute to these observations. Assessing adolescents with type 2 diabetes will allow the evaluation of whether diabetes per se may adversely affect brain function and structure years before clinically significant vascular disease develops. METHODS: Eighteen obese adolescents with type 2 diabetes and 18 obese controls without evidence of marked insulin resistance, matched on age, sex, school grade, ethnicity, socioeconomic status, body mass index and waist circumference, completed MRI and neuropsychological evaluations. RESULTS: Adolescents with type 2 diabetes performed consistently worse in all cognitive domains assessed, with the difference reaching statistical significance for estimated intellectual functioning, verbal memory and psychomotor efficiency. There were statistical trends for executive function, reading and spelling. MRI-based automated brain structural analyses revealed both reduced white matter volume and enlarged cerebrospinal fluid space in the whole brain and the frontal lobe in particular, but there was no obvious grey matter volume reduction. In addition, assessments using diffusion tensor imaging revealed reduced white and grey matter microstructural integrity. CONCLUSIONS/INTERPRETATION: This is the first report documenting possible brain abnormalities among obese adolescents with type 2 diabetes relative to obese adolescent controls. These abnormalities are not likely to result from education or socioeconomic bias and may result from a combination of subtle vascular changes, glucose and lipid metabolism abnormalities and subtle differences in adiposity in the absence of clinically significant vascular disease. Future efforts are needed to elucidate the underlying pathophysiological mechanisms.

Longitudinal CSF isoprostane and MRI atrophy in the progression to AD.

Very little data exist to evaluate the value of longitudinal CSF biological markers for Alzheimer's disease (AD). Most studies indicate that tau and amyloid beta markers do not reflect disease progression. We now report on a longitudinal, three-time point, CSF Isoprostane (IsoP) and quantitative MRI study that examined 11 normal elderly (NL) volunteers and 6 Mild Cognitive Impairment (MCI) patients. After 4 years, all 6 MCI patients declined to AD and 2 of the NL subjects declined to MCI. At baseline and longitudinally, the MCI patients showed reduced delayed memory, increased IsoP levels, and reduced medial temporal lobe gray matter concentrations as compared to NL. A group comprised of all decliners to AD or to MCI (n = 8) was distinguished at baseline from the stable NL controls (n = 9) by IsoP with 100% accuracy.Moreover, both at baseline and longitudinally, the IsoP measures significantly improved the diagnostic and predictive outcomes of conventional memory testing and quantitative MRI measurements. These data indicate that IsoP is potentially useful for both the early detection of AD-related pathology and for monitoring the course of AD.

Reduced hippocampal metabolism in MCI and AD: automated FDG-PET image analysis.

BACKGROUND: To facilitate image analysis, most recent 2-[18F]fluoro-2-deoxy-d-glucose PET (FDG-PET) studies of glucose metabolism (MRglc) have used automated voxel-based analysis (VBA) procedures but paradoxically none reports hippocampus MRglc reductions in mild cognitive impairment (MCI) or Alzheimer disease (AD). Only a few studies, those using regions of interest (ROIs), report hippocampal reductions. The authors created an automated and anatomically valid mask technique to sample the hippocampus on PET (HipMask). METHODS: Hippocampal ROIs drawn on the MRI of 48 subjects (20 healthy elderly [NL], 16 MCI, and 12 AD) were used to develop the HipMask. The HipMask technique was applied in an FDG-PET study of NL (n = 11), MCI (n = 13), and AD (n = 12), and compared to both MRI-guided ROIs and VBA methods. RESULTS: HipMask and ROI hippocampal sampling produced significant and equivalent MRglc reductions for contrasts between MCI and AD relative to NL. The VBA showed typical cortical effects but failed to show hippocampal MRglc reductions in either clinical group. Hippocampal MRglc was the only discriminator of NL vs MCI (78% accuracy) and added to the cortical MRglc in classifying NL vs AD and MCI vs AD. CONCLUSIONS: The new HipMask technique provides accurate and rapid assessment of the hippocampus on PET without the use of regions of interest. Hippocampal glucose metabolism reductions are found in both mild cognitive impairment and Alzheimer disease and contribute to their diagnostic classification. These results suggest re-examination of prior voxel-based analysis 2-[18F]fluoro-2-deoxy-d-glucose PET studies that failed to report hippocampal effects.

Atrophy rate in medial temporal lobe during progression of Alzheimer disease.

OBJECTIVE: To establish the progression of brain atrophy rates in patients with a known date of onset of Alzheimer disease (AD). METHODS: Each of 18 subjects had two high-resolution T1-weighted three-dimensional MRI examinations. The two MRIs were coregistered and the annual rate of brain tissue atrophy was derived both for the entire brain and regionally for the left and right medial temporal lobe (MTL). Time since onset (TSO) of AD, defined as the interval between the date of onset and the midpoint of MRI dates, ranged from -2.9 to 4.2 years. RESULTS: In patients with AD, TSO was a correlate of the atrophy rate for both the left MTL (R2 = 0.58, p = 0.001) and right MTL (R2 = 0.30, p = 0.03). When serial measurements were applied to a control group of 21 cognitively normal elderly subjects, MTL atrophy rate classified the group membership (AD vs normal cognition) with an accuracy of 92.3%. CONCLUSION: Increased annual atrophy rate in the medial temporal lobe is a potential diagnostic marker of the progression of Alzheimer disease.

In vitro susceptibility of 10 clinical isolates of SARS coronavirus to selected antiviral compounds.

Effective antiviral agents are urgently needed to combat the possible return of severe acute respiratory syndrome (SARS). Commercial antiviral agents and pure chemical compounds extracted from traditional Chinese medicinal herbs were screened against 10 clinical isolates of SARS coronavirus by neutralisation tests with confirmation by plaque reduction assays. Interferon-beta-1a, leukocytic interferon-alpha, ribavirin, lopinavir, rimantadine, baicalin and glycyrrhizin showed antiviral activity. The two interferons were only active if the cell lines were pre-incubated with the drugs 16 h before viral inoculation. Results were confirmed by plaque reduction assays. Antiviral activity varied with the use of different cell lines. Checkerboard assays for synergy were performed showing combinations of interferon beta-1a or leukocytic interferon-alpha with ribavirin are synergistic. Since the clinical and toxicity profiles of these agents are well known, they should be considered either singly or in combination for prophylaxis or treatment of SARS in randomised placebo controlled trials in future epidemics.

Use of linearity of the Sokoloff model to improve performance of non-linear search.

The three-parameter Sokoloff equation is used to measure the rates of glucose consumption in the brain in vivo. This equation depends linearly on one of its parameters, k1, which is responsible for the glucose transport from plasma to tissue. By equating to zero the first derivative of the minimization function with respect to k1, it is possible to express this parameter as a function of the other two and reduce the non-linear search from three to two dimensions. This approach was examined by the Nelder-Mead simplex method and the Levenberg-Marquardt algorithm. In both cases the process of convergence was more robust and required fewer iterations to achieve a given accuracy than the direct three-parameter non-linear search.

Hippocampal formation glucose metabolism and volume losses in MCI and AD.

We used MRI volume sampling with coregistered and atrophy corrected FDG-PET scans to test three hypotheses: 1) hippocampal formation measures are superior to temporal neocortical measures in the discrimination of normal (NL) and mild cognitive impairment (MCI); 2) neocortical measures are most useful in the separation of Alzheimer disease (AD) from NL or MCI; 3) measures of PET glucose metabolism (MRglu) have greater diagnostic sensitivity than MRI volume. Three groups of age, education, and gender matched NL, MCI, and AD subjects were studied. The results supported the hypotheses: 1) entorhinal cortex MRglu and hippocampal volume were most accurate in classifying NL and MCI; 2) both imaging modalities identified the temporal neocortex as best separating MCI and AD, whereas widespread changes accurately classified NL and AD; 3) In most between group comparisons regional MRglu measures were diagnostically superior to volume measures. These cross-sectional data show that in MCI hippocampal formation changes exist without significant neocortical changes. Neocortical changes best characterize AD. In both MCI and AD, metabolism reductions exceed volume losses.

Peak velocities of visually and nonvisually guided saccades in smooth-pursuit and saccadic tasks.

Smooth pursuit typically includes corrective catch-up saccades, but may also include such intrusive saccades away from the target as anticipatory or large overshooting saccades. We sought to differentiate catch-up from anticipatory and overshooting saccades by their peak velocities, to see whether the higher velocities of visually rather than nonvisually guided saccades in saccadic tasks may be found also in saccades in pursuit. In experiment 1, 12 subjects showed catch-up, anticipatory, and overshooting saccades to comprise 70.4% of all saccades in pursuit of periodic, 30 degrees/s constant-velocity targets. Catch-up saccades were faster than the others. Saccadic tasks were run as well, on 19 subjects, including the 12 whose pursuit data were analyzed, with target-onset, target-remaining (saccade to the remaining target when the other three extinguish), and antisaccade tasks. For 17 of the 19 subjects, antisaccade velocities were lower than for either target-onset or target-remaining tasks. Velocities for the target-remaining task were near those for target onset, indicating that target presence, not its onset, defines visually guided saccades. Error and reaction-time data suggest greater cognitive difficulty for target remaining than for target onset, so that the cognitive difficulty of typical nonvisually guided saccade tasks is not sufficient to produce their lowered velocity. To produce reliably, in each subject, catch-up and anticipatory saccades with comparable amplitude distributions, nine new subjects were asked in experiment 2 to make intentional catch-up and anticipatory saccades in pursuit, and were presented with embedded target jumps to elicit catch-up saccades, all with periodic target trajectories of 15 degrees/s and 30 degrees/s. Velocities of intentional anticipatory saccades were lower than velocities of intentional catch-up saccades, while velocities of intentional and embedded catch-up saccades were similar. Target-onset and remembered-target saccadic tasks were run, showing the expected higher velocity for the target-onset task in each subject. Both experiments demonstrate higher peak velocities for catch-up saccades than for anticipatory saccades, suggesting that cortical structures preferentially involved in nonvisually guided saccades may initiate the anticipatory and overshooting saccades in pursuit.

Square-root relations between main saccadic parameters.

PURPOSE: To derive and evaluate two equations in which saccade duration and peak velocity are proportional to the square root of saccade amplitude. METHODS: A population of horizontal visually guided saccades in a range of amplitudes from 1.5 degrees to 30 degrees was recorded by means of electro-oculography in eight normal adult subjects. The peak velocity-amplitude data of this population were fitted to four models: inverse linear, exponential, power law, and square root. To approximate the duration-amplitude relation, the square root was tested against the linear and power law models. For each model, the best-fit values of its parameters were estimated by the method of least squares. RESULTS: When the entire population was used, all tested models displayed comparable goodness of fit, but when different subranges of this population were used, only the square root equations appeared to be robust and acceptably accurate. CONCLUSIONS: In a restricted range of saccade amplitudes from 1.5 degrees to 30 degrees, the square root model has some advantages over the others commonly used: to express peak velocity and duration as functions of amplitude, it requires the estimation of only two parameters, whereas the others require four. Because of its robustness, this model can be used to evaluate populations of saccadic eye movements with different ranges of amplitudes. The two parameters of the model equations allow a simple and clear physical interpretation.

Predictive human pursuit and "orbital goal" of microstimulated smooth eye movements.

1. Anticipatory saccades in smooth pursuit move the point of gaze from near the moving target to well ahead of it, interrupting accurate smooth pursuit. Their effects on the pursuit process were studied in 22 normal human subjects. We presented horizontal periodic target trajectories of 30 degrees amplitude and 30 degrees/s constant velocity or 0.4 Hz sinusoidal velocity in 40-s trials. Saccades and surrounding smooth eye movement (SEM) segments were marked and classified by computer. 2. Anticipatory saccades were often followed by slowed SEM that tended to intercept the target at the endpoint of its trajectory. This was seen in the distribution of projections of the initial 60 ms of postsaccadic SEM to the time of the trajectory endpoint. Magnitude of this SEM tended to follow a function of the time and location of the endpoint of the anticipatory saccade, decreasing as the anticipatory saccades landed closer to the trajectory endpoint. 3. The time and location of the target trajectory endpoint seemed to be the goal for this SEM. We believe this to demonstrate the predictive use of the period and amplitude of the trajectory in smooth pursuit, apart from the instantaneous velocity match of the target. 4. Gottlieb and coworkers in the frontal eye field and Ron and Robinson in the cerebellum produced SEMs in the monkey by microstimulation. At some sites in both structures, direction and velocity of the SEMs depended on the initial position of the eye in that the elicited SEMs appeared to be converging toward a common point, or "orbital goal", and the SEM velocity diminished as the gaze neared that goal.2+ Both our SEM after anticipatory saccades and microstimulated SEM in the monkey slowed as the initial position was brought closer to the inferred orbital goal. This similarity suggests that the goal-directed SEM sites in the monkey might be part of a mechanism for predictive pursuit.

Anticipatory saccades in smooth pursuit: task effects and pursuit vector after saccades.

The dramatic improvement in smooth pursuit performance seen while analyzing the pursuit target has been ascribed to attention enhancement. With a periodic constant velocity target trajectory we ran a concurrent listening condition instead, to see if this mild distraction would degrade performance. Performance improved somewhat with the listening task, suggesting that displacing attentional effort from pursuit accuracy, rather than increasing it, brings better pursuit performance. Catch-up saccades were evenly distributed across tracking, listening, and target analysis conditions, but anticipatory and overshooting saccades were almost eliminated with target analysis. Thus the poor pursuit seems to have been caused by anticipatory and overshooting saccades, produced erroneously in the attempt to perform purposive smooth pursuit. Pursuit velocity immediately following anticipatory saccades was reduced such that the target would catch up with the point of gaze when it reached the endpoint of its trajectory, indicating a predictive goal other than instantaneous target foveation and velocity match.

Age-related changes in brain: II. Positron emission tomography of frontal and temporal lobe glucose metabolism in normal subjects.

While many neuropsychological studies have demonstrated age-related performance alterations in tests thought to reflect frontal and temporal lobe function, there is little direct observation and comparison of these hypothesized brain changes in vivo. The cerebral glucose metabolism of frontal, temporal, and cerebellar regions was examined in 40 young (mean = 27.5 +/- 4.9) and 31 elderly (mean = 67.6 +/- 8.8) normal males using PET-FDG. Univariate analysis showed age-related metabolic reductions in all frontal and temporal lobe regions. The reductions ranged from 13%-24% with the greatest changes in the frontal lobes. Multiple regression analyses showed a stronger age relationship with frontal lobe than with temporal lobe metabolism. The dorsal lateral frontal lobe was the region that appears to change most within the frontal lobes. Examination of the temporal lobe showed that age contributed equally to the metabolic variance of both the lateral temporal lobe and hippocampus. These results suggest that age-related metabolic changes exist in both frontal and temporal lobes and that the frontal lobe change is greater.

Principal axes and surface fitting methods for three-dimensional image registration.

We evaluated the effect of the image acquisition parameters on the accuracy of the principal axes and surface-fitting techniques for three-dimensional image registration. Using two types of phantom objects, MR brain image and a mathematically defined ellipsoid, we simulated pairs of scans with known acquisition parameters, including longitudinal coverage, magnitude of mis-registration, number of sections and section thickness. Both methods are sensitive to the systematic deformation of contours. The principal axes method is also sensitive to incomplete scan coverage and to the x-axis and y-axis misangulation. Both methods are insensitive to the number of sections, section thickness and the number of points per section. Surface fitting performed well without user supervision. There is no need for routine inclusion of the scaling factors as search parameters. The results confirm the feasibility of three-dimensional multimodality registration of brain scans with accuracy 1-2 mm, with surface fitting being the method of choice.

Saccades in pursuit eye tracking reflect motor attention processes.

A dysfunction of pursuit eye tracking in psychiatric patients has been well documented, but its cause has not. Recent speculation implicates a pathological disinhibition of saccades in these patients. However, great variability in tracking performance was found among nine normal subjects, and tracking quality improved in each when asked to perform a simple analysis of the tracking target: saccade counts and amplitudes decreased, as did a root-mean-square (RMS) error measure of overall tracking performance. This improvement was as great at the end as at the beginning of the analysis condition, suggesting that the improvement is not due to increased attention to a novel task, but rather is the preferred mode of tracking automatically, while attending to target analysis. The anticipatory, purposive saccades produced in attending to the act of tracking thus can be studied as involuntary attention effects reflecting frontal lobe function, and used for diagnostic classification of attentional dysfunction.

A comparison of the effects of atenolol and metoprolol on attention.

Additional side-effects of two beta-blockers, atenolol (hydrophilic) and metoprolol (lipophilic), were measured in 18 normal male volunteers in a randomized double-blind placebo-controlled crossover study. A saccadic eye movement reaction time (RT) task, a manual RT version of the Stroop Colour-Word Task, the Span of Apprehension Task, and the Continuous Performance Task were presented on a graphics display screen. Standard cognitive effects were replicated on all measures. Atenolol was noticeably, but not significantly, superior to metoprolol in visual alerting and in angular breadth of visual information processing, both with saccadic RT.