Reduced glucose uptake and Aß in brain regions with hyperintensities in connected white matter.

Interstitial concentration of amyloid beta (Aß) is positively related to synaptic activity in animal experiments. In humans, Aß deposition in Alzheimer's disease overlaps with cortical regions highly active earlier in life. White matter lesions (WML) disrupt connections between gray matter (GM) regions which in turn changes their activation patterns. Here, we tested if WML are related to Aß accumulation (measured with PiB-PET) and glucose uptake (measured with FDG-PET) in connected GM. WML masks from 72 cognitively normal (age 61.7 ± 9.6 years, 71% women) individuals were obtained from T2-FLAIR. MRI and PET images were normalized into common space, segmented and parcellated into gray matter (GM) regions. The effects of WML on connected GM regions were assessed using the Change in Connectivity (ChaCo) score. Defined for each GM region, ChaCo is the percentage of WM tracts connecting to that region that pass through the WML mask. The regional relationship between ChaCo, glucose uptake and Aß was explored via linear regression. Subcortical regions of the bilateral caudate, putamen, calcarine, insula, thalamus and anterior cingulum had WM connections with the most lesions, followed by frontal, occipital, temporal, parietal and cerebellar regions. Regional analysis revealed that GM with more lesions in connecting WM and thus impaired connectivity had lower FDG-PET (r = 0.20, p<0.05 corrected) and lower PiB uptake (r = 0.28, p<0.05 corrected). Regional regression also revealed that both ChaCo (ß = 0.045) and FDG-PET (ß = 0.089) were significant predictors of PiB. In conclusion, brain regions with more lesions in connecting WM had lower glucose metabolism and lower Aß deposition.

Assessment of change in prostate volume and shape following surgical resection through co-registration of in-vivo MRI and fresh specimen ex-vivo MRI.

AIM: To compare the size and shape of the prostate between in-vivo and fresh ex-vivo magnetic resonance imaging (MRI), in order to quantify alterations in the prostate resulting from surgical resection. MATERIAL AND METHOD: Ten patients who had undergone 3 T prostate MRI using a phased-array coil and who were scheduled for prostatectomy were included in this prospective study. The ex-vivo specimen underwent MRI prior to formalin fixation or any other histopathological processing. Prostate volume in vivo and ex vivo was assessed using planimetry. Prostate shape was assessed by calculating ratios between the diameters of the prostate in all three dimensions. RESULTS: Mean prostate volume was significantly smaller ex vivo than in vivo (39.7 ± 18.6 versus 50.8 ± 26.8 cm(3); p = 0.008), with an average change in volume of -19.5%. The right-to-left (RL)/anteroposterior (AP) ratio of the prostate, representing the shape of the prostate within its axial plane, was significantly larger ex vivo than in vivo (1.33 ± 0.14 versus 1.21 ± 0.12; p = 0.015), with an average percent change in RL/AP ratio of the prostate of +12.2%. There was no significant difference between in-vivo and ex-vivo acquisitions in terms of craniocaudal (CC)/AP (p = 0.963, median change = -2.1%) or RL/CC (p = 0.265, median change = +1.3%) ratios. CONCLUSION: The observed volume and shape change following resection has not previously been assessed by comparison of in-vivo and fresh ex-vivo MRI and likely represents loss of vascularity and of connective tissue attachments in the ex-vivo state. These findings have implications for co-registration platforms under development to facilitate improved understanding of the accuracy of MRI in spatial localization of prostate tumours.

Preliminary experience with a novel method of three-dimensional co-registration of prostate cancer digital histology and in vivo multiparametric MRI.

AIM: To assess a novel method of three-dimensional (3D) co-registration of prostate cancer digital histology and in-vivo multiparametric magnetic resonance imaging (mpMRI) image sets for clinical usefulness. MATERIAL AND METHODS: A software platform was developed to achieve 3D co-registration. This software was prospectively applied to three patients who underwent radical prostatectomy. Data comprised in-vivo mpMRI [T2-weighted, dynamic contrast-enhanced weighted images (DCE); apparent diffusion coefficient (ADC)], ex-vivo T2-weighted imaging, 3D-rebuilt pathological specimen, and digital histology. Internal landmarks from zonal anatomy served as reference points for assessing co-registration accuracy and precision. RESULTS: Applying a method of deformable transformation based on 22 internal landmarks, a 1.6 mm accuracy was reached to align T2-weighted images and the 3D-rebuilt pathological specimen, an improvement over rigid transformation of 32% (p = 0.003). The 22 zonal anatomy landmarks were more accurately mapped using deformable transformation than rigid transformation (p = 0.0008). An automatic method based on mutual information, enabled automation of the process and to include perfusion and diffusion MRI images. Evaluation of co-registration accuracy using the volume overlap index (Dice index) met clinically relevant requirements, ranging from 0.81-0.96 for sequences tested. Ex-vivo images of the specimen did not significantly improve co-registration accuracy. CONCLUSION: This preliminary analysis suggests that deformable transformation based on zonal anatomy landmarks is accurate in the co-registration of mpMRI and histology. Including diffusion and perfusion sequences in the same 3D space as histology is essential further clinical information. The ability to localize cancer in 3D space may improve targeting for image-guided biopsy, focal therapy, and disease quantification in surveillance protocols.

Choroid Plexus Calcification Correlates with Cortical Microglial Activation in Humans: A Multimodal PET, CT, MRI Study.

BACKGROUND AND PURPOSE: The choroid plexus (CP) within the brain ventricles is well-known to produce cerebrospinal fluid (CSF). Recently, the CP has been recognized as critical in modulating inflammation. MRI-measured CP enlargement has been reported in neuroinflammatory disorders like MS as well as with aging and neurodegeneration. The basis of MRI-measured CP enlargement is unknown. On the basis of tissue studies demonstrating CP calcification as a common pathology associated with aging and disease, we hypothesized that previously unmeasured CP calcification contributes to MRI-measured CP volume and may be more specifically associated with neuroinflammation. MATERIALS AND METHODS: We analyzed 60 subjects (43 healthy controls and 17 subjects with Parkinson's disease) who underwent PET/CT using 11C-PK11195, a radiotracer sensitive to the translocator protein expressed by activated microglia. Cortical inflammation was quantified as nondisplaceable binding potential. Choroid plexus calcium was measured via manual tracing on low-dose CT acquired with PET and automatically using a new CT/MRI method. Linear regression assessed the contribution of choroid plexus calcium, age, diagnosis, sex, overall volume of the choroid plexus, and ventricle volume to cortical inflammation. RESULTS: Fully automated choroid plexus calcium quantification was accurate (intraclass correlation coefficient with manual tracing = .98). Subject age and choroid plexus calcium were the only significant predictors of neuroinflammation. CONCLUSIONS: Choroid plexus calcification can be accurately and automatically quantified using low-dose CT and MRI. Choroid plexus calcification-but not choroid plexus volume-predicted cortical inflammation. Previously unmeasured choroid plexus calcium may explain recent reports of choroid plexus enlargement in human inflammatory and other diseases. Choroid plexus calcification may be a specific and relatively easily acquired biomarker for neuroinflammation and choroid plexus pathology in humans.

A new method to analyze dGEMRIC measurements in femoroacetabular impingement: preliminary validation against arthroscopic findings.

OBJECTIVE: To validate a new method to analyze delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) measurements in the hip for early assessment of cartilage defects in femoroacetabular impingement (FAI). METHODS: We performed a retrospective review of 10 hips in 10 FAI patients, who underwent hip arthroscopy. T1-weighted images and dGEMRIC T(1) maps were acquired at 1.5 T on coronal planes, including the anterior-superior, superior, posterior-superior hip cartilage. For all slices, a region of interest (ROI) was defined over the central portion of the femoral cartilage, assumed to be healthy, and T1 values (x) were transformed to standard scores (z) using z = (x -µ)/σ, where µ and σ are the average and standard deviation of T1 in the femoral ROI. Diagnostic performance of the resulting standardized dGEMRIC maps was evaluated against intraoperative findings and compared with that of a previously proposed dGEMRIC analysis as well as morphologic assessment. RESULTS: Assuming z = -2 or z = -3 as the threshold between normal and degenerated cartilage, sensitivity, specificity and accuracy were 88%, 51% and 62%, and 71%, 63% and 65%, respectively. By using T1 = 500 ms as single threshold for all dGEMRIC T1 maps, these values became 47%, 58% and 55%, whereas they were 47%, 79% and 70% for morphologic evaluation. CONCLUSIONS: Standardized dGEMRIC can increase the sensitivity in detecting abnormal cartilage in FAI and has the potential to improve the clinical interpretation of dGEMRIC measurements in FAI, by removing the effect of inter- and intra-patient T1 variability.

Preliminary Findings Associate Hippocampal 1H-MR Spectroscopic Metabolite Concentrations with Psychotic and Manic Symptoms in Patients with Schizophrenia.

BACKGROUND AND PURPOSE: Previous hippocampal proton MR spectroscopic imaging distinguished patients with schizophrenia from controls by elevated Cr levels and significantly more variable NAA and Cho concentrations. This goal of this study was to ascertain whether this metabolic variability is associated with clinical features of the syndrome, possibly reflecting heterogeneous hippocampal pathologies and perhaps variability in its "positive" (psychotic) and "negative" (social and emotional deficits) symptoms. MATERIALS AND METHODS: In a sample of 15 patients with schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, we examined the association of NAA and Cho levels with research diagnostic interviews and clinical symptom ratings of the patients. Metabolite concentrations were previously obtained with 3D proton MR spectroscopic imaging at 3T, a technique that facilitates complete coverage of this small, irregularly shaped, bilateral, temporal lobe structure. RESULTS: The patient cohort comprised 8 men and 7 women (mean age, 39.1 [SD, 10.8] years, with a mean disease duration of 17.2 [SD, 10.8] years. Despite the relatively modest cohort size, we found the following: 1) Elevated Cho levels predict the positive (psychotic, r = 0.590, P = .021) and manic (r = 0.686, P = .005) symptom severity; and 2) lower NAA levels trend toward negative symptoms (r = 0.484, P = .08). No clinical symptoms were associated with Cr level or hippocampal volume (all, P ≥ .055). CONCLUSIONS: These preliminary findings suggest that NAA and Cho variations reflect different pathophysiologic processes, consistent with microgliosis/astrogliosis and/or lower vitality (reduced NAA) and demyelination (elevated Cho). In particular, the active state-related symptoms, including psychosis and mania, were associated with demyelination. Consequently, their deviations from the means of healthy controls may be a marker that may benefit precision medicine in selection and monitoring of schizophrenia treatment.

MR spectroscopy indicates diffuse multiple sclerosis activity during remission.

OBJECTIVE: To test the hypothesis that diffuse abnormalities precede axonal damage and atrophy in the MRI normal-appearing tissue of relapsing-remitting (RR) multiple sclerosis (MS) patients, and that these processes continue during clinical remission. METHODS: Twenty-one recently diagnosed mildly disabled (mean disease duration 2.3 years, mean Expanded Disability Status Scale score of 1.4) RR MS patients and 15 healthy matched controls were scanned with MRI and proton MR spectroscopic imaging ((1)H-MRSI) at 3 T. Metabolite concentrations: N-acetylaspartate (NAA) for neuronal integrity; choline (Cho) for membrane turnover rate; creatine (Cr) and myo-inositol (mI) for glial status were obtained in a 360 cm(3) volume of interest (VOI) with 3D multivoxel (1)H-MRSI. They were converted into absolute amounts using phantom replacement and normalised into absolute concentrations by dividing by the VOI tissue volume fraction obtained from MRI segmentation. RESULTS: The patients' mean VOI tissue volume fraction, 0.92 and NAA concentration, 9.6 mM, were not different from controls' 0.94 and 9.6 mM. In contrast, the patients' mean Cr, Cho and mI levels 7.7, 1.9 and 4.1 mM were 9%, 14% and 20%, higher than the controls' 7.1, 1.6 and 3.4 mM (p = 0.0097, 0.003 and 0.0023). CONCLUSIONS: The absence of early tissue atrophy and apparent axonal dysfunction (NAA loss) in these RR MS patients suggests that both are preceded by diffuse glial proliferation (astrogliosis), as well as possible inflammation, demyelination and remyelination reflected by elevated mI, Cho and Cr, even during clinical remission and despite immunomodulatory treatment.

Imaging and CSF studies in the preclinical diagnosis of Alzheimer's disease.

It is widely believed that the path to early and effective treatment for Alzheimer's disease (AD) requires the development of early diagnostic markers that are both sensitive and specific. To this aim, using longitudinal study designs, we and others have examined magnetic resonance imaging (MRI), 2-fluoro-2-deoxy-d-glucose-positron emission tomography (FDG/PET), and cerebrospinal fluid (CSF) biomarkers in cognitively normal elderly (NL) subjects and in patients with mild cognitive impairment (MCI). Such investigations have led to the often replicated findings that structural evidence of hippocampal atrophy as determined by MRI, as well as metabolic evidence from FDG-PET scan of hippocampal damage, predicts the conversion from MCI to AD. In this article we present a growing body of evidence of even earlier diagnosis. Brain pathology can be detected in NL subjects and used to predict future transition to MCI. This prediction is enabled by examinations revealing reduced glucose metabolism in the hippocampal formation (hippocampus and entorhinal cortex [EC]) as well as by the rate of medial temporal lobe atrophy as determined by MRI. However, neither regional atrophy nor glucose metabolism reductions are specific for AD. These measures provide secondary not primary evidence for AD. Consequently, we will also summarize recent efforts to improve the diagnostic specificity by combining imaging with CSF biomarkers and most recently by evaluating amyloid imaging using PET. We conclude that the combined use of conventional imaging, that is MRI or FDG-PET, with selected CSF biomarkers incrementally contributes to the early and specific diagnosis of AD. Moreover, selected combinations of imaging and CSF biomarkers measures are of importance in monitoring the course of AD and thus relevant to evaluating clinical trials.

Proton MR spectroscopy and MRI-volumetry in mild traumatic brain injury.

BACKGROUND AND PURPOSE: More than 85% of brain traumas are classified as "mild"; MR imaging findings are minimal if any and do not correspond to clinical symptoms. Our goal, therefore, was to quantify the global decline of the neuronal marker N-acetylaspartate (NAA), as well as gray (GM) and white matter (WM) atrophy after mild traumatic brain injury (mTBI). MATERIALS AND METHODS: Twenty patients (11 male, 9 female; age range, 19-57 years; median, 35 years) with mTBI (Glasgow Coma Scale score 13-15 with loss of consciousness for at least 30 seconds) and 19 age- and sex-matched control subjects were studied. Seven patients were studied within 9 days of TBI; the other 13 ranged from 1.2 months to 31.5 years (average and median of 4.6 and 1.7 years, respectively) after injury. Whole-brain NAA (WBNAA) concentration was obtained in all subjects with nonlocalizing proton MR spectroscopy. Brain volume and GM and WM fractions were segmented from T1-weighted MR imaging and normalized to the total intracranial volume, suitable for intersubject comparisons. The data were analyzed with least squares regression. RESULTS: Patients with mTBI exhibited, on average, a 12% WBNAA deficit that increased with age, compared with the control subjects (p<.05). Adjusted for age effects, patients also suffered both global atrophy (-1.09%/year; P=.029) and GM atrophy (-0.89%/year; P=.042). Patients with and without visible MR imaging pathology, typically punctate foci of suspected shearing injury, were indistinguishable in both atrophy and WBNAA. CONCLUSION: WBNAA detected neuronal/axonal injury beyond the minimal focal MR-visible lesions in mTBI. Combined with GM atrophy, the findings may provide further, noninvasive insight into the nature and progression of mTBI.

Lumbar Puncture Test in Normal Pressure Hydrocephalus: Does the Volume of CSF Removed Affect the Response to Tap?

BACKGROUND AND PURPOSE: There is limited evidence to support the use of high-volume lumbar taps over lower-volume taps in the diagnosis of normal pressure hydrocephalus. The purpose of this study is to detect whether the volume of CSF removed from patients undergoing high-volume diagnostic lumbar tap test for normal pressure hydrocephalus is significantly associated with post-lumbar tap gait performance. MATERIALS AND METHODS: This retrospective study included 249 consecutive patients who underwent evaluation for normal pressure hydrocephalus. The patients were analyzed both in their entirety and as subgroups that showed robust response to the lumbar tap test. The volume of CSF removed was treated as both a continuous variable and a discrete variable. Statistical tests were repeated with log-normalized volumes. RESULTS: This study found no evidence of a relationship between the volume of CSF removed during the lumbar tap test and subsequent gait test performance in the patient population (Pearson coefficient r = 0.049-0.129). Log normalization of the volume of CSF removed and controlling for age and sex failed to yield a significant relationship. Subgroup analyses focusing on patients who showed greater than 20% improvement in any of the gait end points or who were deemed sufficiently responsive clinically to warrant surgery also yielded no significant relationships between the volume of CSF removed and gait outcomes, but there were preliminary findings that patients who underwent tap with larger-gauge needles had better postprocedure ambulation among patients who showed greater than 20% improvement in immediate time score (P = .04, n = 62). CONCLUSIONS: We found no evidence to support that a higher volume of CSF removal impacts gait testing, suggesting that a high volume of CSF removal may not be necessary in a diagnostic lumbar tap test.

Longitudinal CSF and MRI biomarkers improve the diagnosis of mild cognitive impairment.

The diagnosis of Alzheimer's disease (AD) in patients with mild cognitive impairment (MCI) is limited because it is based on non-specific behavioral and neuroimaging findings. The lesions of Alzheimer's disease: amyloid beta (Abeta) deposits, tau pathology and cellular oxidative damage, affect the hippocampus in the earlier stages causing memory impairment. In a 2-year longitudinal study of MCI patients and normal controls, we examined the hypothesis that cerebrospinal fluid (CSF) markers for these pathological features improve the diagnostic accuracy over memory and magnetic resonance imaging (MRI)-hippocampal volume evaluations. Relative to control, MCI patients showed decreased memory and hippocampal volumes and elevated CSF levels of hyperphosphorylated tau and isoprostane. These two CSF measures consistently improved the diagnostic accuracy over the memory measures and the isoprostane measure incremented the accuracy of the hippocampal volume achieving overall diagnostic accuracies of about 90%. Among MCI patients, over 2 years, longitudinal hippocampal volume losses were closely associated with increasing hyperphosphorylated tau and decreasing amyloid beta-42 levels. These results demonstrate that CSF biomarkers for AD contribute to the characterization of MCI.

Protruding aortic atheromas predict stroke in elderly patients undergoing cardiopulmonary bypass: experience with intraoperative transesophageal echocardiography.

Protruding atheromas of the aortic arch identified by transesophageal echocardiography have been implicated as a cause of stroke in elderly patients. One hundred thirty patients greater than or equal to 65 years of age were studied with intraoperative transesophageal echocardiography to detect aortic arch protruding atheromas and determine if these patients were at higher risk for perioperative stroke. Protruding atheromas were identified in 23 (18%) of 130 patients. In 19 (83%) of these 23 patients, palpation of the aortic arch at operation did not identify significant abnormalities. Five patients (4%) had perioperative stroke. Logistic regression identified aortic arch atheroma as the only historical or procedural variable that was predictive of stroke (odds ratio 5.8, 95% confidence interval 1.2 to 27.9, p less than 0.03). A history of peripheral or cerebrovascular disease, presence of aortic calcification, cardiac risk factors, age and duration of cardiopulmonary bypass did not predict stroke. In contrast, patients with protruding atheromas with mobile components were at highest risk. There were 3 (25%) of 12 patients with a mobile atheroma who had a stroke versus 2 (2%) of 118 patients without a mobile atheroma (chi-square = 10.3, p = 0.001). Displacement and detachment of the frail, protruding atherosclerotic material by aortic arch cannulation or by the high pressure jet emanating from the cannula tip may play an important role in the creation of embolization and stroke.

Volumetric measure of the frontal and temporal lobe regions in schizophrenia: relationship to negative symptoms.

BACKGROUND: Previous research has provided evidence for brain abnormalities in schizophrenia, but their relationship to specific clinical symptoms and syndromes remains unclear. METHODS: With an all-male demographically similar sample of 53 schizophrenic patients and 29 normal control subjects, cerebral gray and white matter volumes (adjusted for intracranial volume and age were determined for regions in the prefrontal lobe and in the superficial and mesial temporal lobe using T1-weighted magnetic resonance imaging with 2.8-mm coronal slices. RESULTS: As a group, schizophrenic patients had wide-spread bilateral decrements in gray matter in the pre-frontal (7.4%) and temporal lobe regions (8.9%), but not in white matter in these regions. In the temporal lobe, gray matter reductions were found bilaterally in the superior temporal gyrus (6.0%), but not in the hippocampus and parahippocampus. While there were no overall group differences in white matter volumes, widespread decrements in prefrontal white matter in schizophrenic patients (n = 53) were related to higher levels of negative symptoms (partial r[49] = -0.42, P = .002), as measured by the Scale for the Assessment of Negative Symptoms. A post hoc analysis revealed that schizophrenic patients with high negative symptoms had generalized prefrontal white matter reductions (11.4%) that were most severe in the orbitofrontal subregion (15.1%). CONCLUSIONS: These results suggest that gray matter deficits may be a fairly common structural abnormality of schizophrenia, whereas reductions in prefrontal white matter may be associated with schizophrenic negative symptoms.

Cortisol reduces hippocampal glucose metabolism in normal elderly, but not in Alzheimer's disease.

Glucocorticoids are known to play a role in the regulation of peripheral glucose mobilization and metabolism. Although several animal studies have shown that hippocampal glucose metabolism is reduced acutely and chronically by the action of corticosterone and that excess glucocorticoids are harmful to hippocampal neurons, little is known about the central effects of glucocorticoids in the human. In this study we examined the brain glucose utilization (CMRglu) response to hydrocortisone (cortisol) in seven normal elderly and eight Alzheimer's disease (AD) patients. On 2 separate days, immediately after the administration of a bolus of either 35 mg hydrocortisone or placebo, we administered 2-deoxy-2-[18F]fluoro-D-glucose. After a 35-min radiotracer uptake period, positron emission tomography (PET) images were collected. PET CMRglu images were analyzed using two methods: an image transformation that allowed analyses across cases on a voxel by voxel basis, and an anatomically based region of interest method that used coregistered magnetic resonance imaging scans. Both image analysis methods yielded similar results, identifying relative to placebo, a specific hippocampal CMRglu reduction in response to the hydrocortisone challenge that was restricted to the normal group. The region of interest technique showed CMRglu reductions of 16% and 12% in the right and left hippocampi, respectively. Blood collected during the PET scans showed, for the normal group, a rise in plasma glucose levels, starting approximately 25 min after hydrocortisone administration. The AD group did not show this effect. Baseline cortisol was elevated in the AD group, but the clearance of hydrocortisone was not different between the groups. In conclusion, these data show that among normal individuals in the presence of a pharmacological dose of cortisol, the glucose utilization of the hippocampus is specifically reduced, and serum glucose levels increase. Based in part on other studies, we offer the interpretation that glucocorticoid-mediated regulation of glucose transport is altered in AD, and this may underlie both the hippocampal insensitivity to cortisol and the failure in these patients to mount a peripheral glucose response. As our findings could reflect an altered state of the AD patients, we interpret our results as preliminary with respect to evidence for metabolic abnormalities in AD. The results suggest the continued study of the hydrocortisone challenge as a test of hippocampal responsivity.

Atrophy of the medial occipitotemporal, inferior, and middle temporal gyri in non-demented elderly predict decline to Alzheimer's disease.

Our goal was to ascertain, among normal elderly and individuals with mild cognitive impairment, which temporal lobe neocortical regions predicted decline to dementia of the Alzheimer's type (DAT). Individuals received an MRI at baseline and a clinical and cognitive evaluation at baseline and follow-up. By using the baseline MRI we assessed the anatomical subdivisions of the temporal lobe: anteromedial temporal lobe (hippocampus and parahippocampal gyrus), medial occipitotemporal (fusiform) gyrus, middle and inferior temporal gyri, and superior temporal gyrus. We studied two groups of carefully screened age- and education-matched elderly individuals: 26 normal elderly (NL) and 20 individuals with mild cognitive impairment (MCI). Fourteen individuals (12 from the MCI group and two from the NL group) declined to DAT within the 3.2-year follow-up interval. We used logistic regression analyses to ascertain whether the baseline brain volumes were useful predictors of decline to DAT at follow-up after accounting for age, gender, individual differences in brain size, and other variables known to predict DAT. After accounting for age, gender, and head size, adding the volume of the anteromedial temporal lobe (the aggregate of hippocampus and parahippocampal gyrus) and an index of global atrophy raised the accuracy of overall classification to 80.4%. However, the ability to detect those individuals who declined (sensitivity) was low at 57%. When baseline medial occipitotemporal and the combined middle and inferior temporal gyri were added to the logistic model, the overall classification accuracy reached 95.6% and, most importantly, the sensitivity rose to 92.8%. These data indicate that the medial occipitotemporal and the combined middle and inferior temporal gyri may be the first temporal lobe neocortical sites affected in AD; atrophy in these areas may herald the presence of future AD among nondemented individuals. No other clinical baseline variables examined predicted decline with sensitivities above 71%. The apolipoprotein APOE epsilon4 genotype was not associated with decline.

Specific hippocampal volume reductions in individuals at risk for Alzheimer's disease.

Our goal was to ascertain the involvement of the temporal lobe in the preclinical (not yet diagnosable) stages of dementia of the Alzheimer's type (DAT) by using MRI-derived volumes. We assessed anatomical subdivisions of the temporal lobe on three groups of carefully screened age- and education-matched elderly individuals: 27 normal elderly (NL), 22 individuals with minimal cognitive impairment (MCI), who did not fulfill DAT criteria but were regarded at high risk for future DAT, and 27 DAT individuals. We found hippocampal volume reductions of 14% for the MCI and 22% for the DAT group compared to the NL group. Utilizing regression analyses and after accounting for gender head size-age, generalized atrophy (CSF), and other temporal lobe subvolumes, the hippocampal volume separated NL from MCI individuals, correctly classifying 74%. For NL and MCI groups combined the hippocampal volume was the only temporal lobe subvolume related to delayed recall memory performance. When contrasting MCI and DAT individuals, the fusiform gyrus volume uniquely improved the ability of the hippocampal volume to separate MCI from DAT individuals from 74 to 80%. Our cross-sectional data suggest that, within the temporal lobe, specific hippocampal volume reductions separated the group at risk for DAT from the normal group. By the time impairments are sufficient to allow a diagnosis of DAT to be made, in addition to the medial temporal lobe volume reductions, the lateral temporal lobe is also showing volume reductions, most saliently involving the fusiform gyrus.

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.

Frequency of hippocampal formation atrophy in normal aging and Alzheimer's disease.

We used CT and MR to examine the frequency of occurrence of hippocampal formation atrophy (HA) in a research clinic population of 130 normal elderly, 72 nondemented patients with very mild memory and cognitive impairments (MCI), 73 mild Alzheimer's disease (AD) patients, and 130 patients with moderate to severe AD. HA was found in 29% of the normal elderly group and its frequency of occurrence was strongly related to increasing age. For normal elderly 60-75 years of age, 15% had HA: the proportion rose to 48% in subjects 76-90 years of age. Among the three groups of impaired patients, the frequencies of HA ranged from 78% in the MCI patients to 96% in the advanced AD group. Unlike the normal elderly group, the percentages were not related to age. In both the normal elderly group and MCI group disproportionately more males than females had HA. After controlling for learning and the effects of generalized brain changes as reflected in ventricular size, only in the normal group was HA associated with reduced delayed verbal recall performance. Follow-up examinations for 15 individuals with baseline HA. 4 who at entry were MCI and 11 probable AD, yielded clinical and neuropathologic diagnoses of AD in all cases. The results of the present study indicate that hippocampal formation atrophy is associated with memory and cognitive impairments. Further longitudinal and neuropathologic work is required to validate the relationship between hippocampal formation atrophy and AD.