Clinical, imaging, and biomarker evidence of amyloid- and tau-related neurodegeneration in late-onset epilepsy of unknown etiology.

Accumulating evidence suggests amyloid and tau-related neurodegeneration may play a role in development of late-onset epilepsy of unknown etiology (LOEU). In this article, we review recent evidence that epilepsy may be an initial manifestation of an amyloidopathy or tauopathy that precedes development of Alzheimer's disease (AD). Patients with LOEU demonstrate an increased risk of cognitive decline, and patients with AD have increased prevalence of preceding epilepsy. Moreover, investigations of LOEU that use CSF biomarkers and imaging techniques have identified preclinical neurodegeneration with evidence of amyloid and tau deposition. Overall, findings to date suggest a relationship between acquired, non-lesional late-onset epilepsy and amyloid and tau-related neurodegeneration, which supports that preclinical or prodromal AD is a distinct etiology of late-onset epilepsy. We propose criteria for assessing elevated risk of developing dementia in patients with late-onset epilepsy utilizing clinical features, available imaging techniques, and biomarker measurements. Further research is needed to validate these criteria and assess optimal treatment strategies for patients with probable epileptic preclinical AD and epileptic prodromal AD.

Brain gray matter reduction and premature brain aging after breast cancer chemotherapy: a longitudinal multicenter data pooling analysis.

Brain gray matter (GM) reductions have been reported after breast cancer chemotherapy, typically in small and/or cross-sectional cohorts, most commonly using voxel-based morphometry (VBM). There has been little examination of approaches such as deformation-based morphometry (DBM), machine-learning-based brain aging metrics, or the relationship of clinical and demographic risk factors to GM reduction. This international data pooling study begins to address these questions. Participants included breast cancer patients treated with (CT+, n = 183) and without (CT-, n = 155) chemotherapy and noncancer controls (NC, n = 145), scanned pre- and post-chemotherapy or comparable intervals. VBM and DBM examined GM volume. Estimated brain aging was compared to chronological aging. Correlation analyses examined associations between VBM, DBM, and brain age, and between neuroimaging outcomes, baseline age, and time since chemotherapy completion. CT+ showed longitudinal GM volume reductions, primarily in frontal regions, with a broader spatial extent on DBM than VBM. CT- showed smaller clusters of GM reduction using both methods. Predicted brain aging was significantly greater in CT+ than NC, and older baseline age correlated with greater brain aging. Time since chemotherapy negatively correlated with brain aging and annual GM loss. This large-scale data pooling analysis confirmed findings of frontal lobe GM reduction after breast cancer chemotherapy. Milder changes were evident in patients not receiving chemotherapy. CT+ also demonstrated premature brain aging relative to NC, particularly at older age, but showed evidence for at least partial GM recovery over time. When validated in future studies, such knowledge could assist in weighing the risks and benefits of treatment strategies.

A minority of patients with functional seizures have abnormalities on neuroimaging.

OBJECTIVE: Functional seizures often are managed incorrectly as a diagnosis of exclusion. However, a significant minority of patients with functional seizures may have abnormalities on neuroimaging that typically are associated with epilepsy, leading to diagnostic confusion. We evaluated the rate of epilepsy-associated findings on MRI, FDG-PET, and CT in patients with functional seizures. METHODS: We studied radiologists' reports from neuroimages at our comprehensive epilepsy center from a consecutive series of patients diagnosed with functional seizures without comorbid epilepsy from 2006 to 2019. We summarized the MRI, FDG-PET, and CT results as follows: within normal limits, incidental findings, unrelated findings, non-specific abnormalities, post-operative study, epilepsy risk factors (ERF), borderline epilepsy-associated findings (EAF), and definitive EAF. RESULTS: Of the 256 MRIs, 23% demonstrated ERF (5%), borderline EAF (8%), or definitive EAF (10%). The most common EAF was hippocampal sclerosis, with the majority of borderline EAF comprising hippocampal atrophy without T2 hyperintensity or vice versa. Of the 87 FDG-PETs, 26% demonstrated borderline EAF (17%) or definitive EAF (8%). Epilepsy-associated findings primarily included focal hypometabolism, especially of the temporal lobes, with borderline findings including subtle or questionable hypometabolism. Of the 51 CTs, only 2% had definitive EAF. SIGNIFICANCE: This large case series provides further evidence that, while uncommon, EAF are seen in patients with functional seizures. A significant portion of these abnormal findings are borderline. The moderately high rate of these abnormalities may represent framing bias from the indication of the study being "seizures," the relative subtlety of EAF, or effects of antiseizure medications.

Optimizing Use of Neuroimaging Tools in Evaluation of Prodromal Alzheimer's Disease and Related Disorders.

Alzheimer's disease (AD) is the most common neurodegenerative disease and is characterized by preclinical, pre-dementia, and dementia phases. Progression of the disease leads to cognitive decline and is associated with loss of functional independence, personality changes, and behavioral disturbances. Current guidelines for AD diagnosis include the use of neuroimaging tools as biomarkers for identifying and monitoring pathological changes. Various imaging modalities, namely magnetic resonance imaging (MRI), fluorodeoxyglucose-positron emission tomography (FDG-PET) and PET with amyloid-beta tracers are available to facilitate early accurate diagnoses. Enhancing diagnosis in the early stages of the disease can allow for timely interventions that can delay progression of the disease. This paper will discuss the characteristic findings associated with each of the imaging tools for patients with AD, with a focus on FDG-PET due to its established accuracy in assisting with the differential diagnosis of dementia and discussion of other methods including MRI. Diagnostically-relevant features to aid clinicians in making a differential diagnosis will also be pointed out and multimodal imaging will be reviewed. We also discuss the role of quantification software in interpretation of brain imaging. Lastly, to guide evaluation of patients presenting with cognitive deficits, an algorithm for optimal integration of these imaging tools will be shared. Molecular imaging modalities used in dementia evaluations hold promise toward identifying AD-related pathology before symptoms are fully in evidence. The work describes state of the art functional and molecular imaging methods for AD. It will also overview a clinically applicable quantitative method for reproducible assessments of such scans in the early identification of AD.

Examining posttraumatic stress disorder as a key postinjury risk factor in OIF/OEF veterans with blast-induced mild traumatic brain injury.

OBJECTIVE: To explore the neuropsychological sequelae of blast-induced mild traumatic brain injury (mTBI) and posttraumatic stress disorder (PTSD), several neuropsychological tests and self-reported measures of cognitive and emotional functioning were administered to 138 Operation Iraqi Freedom (OIF)/Operation Enduring Freedom (OEF) veterans. We hypothesized that veterans affected by mTBI and PTSD would manifest differences in neuropsychological testing and self-report measures compared to a group of healthy veteran controls and to veterans with only PTSD. METHOD: Participants included 3 groups of veterans: (a) healthy controls (n = 43); (b) PTSD only (n = 48); and (c) comorbid blast-induced mTBI and PTSD (n = 47). An exploratory factor analysis (EFA) was used to extract a smaller number of latent dimensions for group comparison. RESULTS: The EFA supported an 8-factor model. A multivariate analysis of variance on the 8 factor scores demonstrated 3 significant factor mean differences: (a) perceived cognitive complications (PCC), (b) perceived emotional distress (PED), and (c) processing speed (PS). Post hoc analyses showed significant group mean difference in PS between the comorbid and the control groups. In addition, the comorbid group presented with the highest levels of PCC and PED. CONCLUSIONS: Results suggest that among OIF/OEF veterans with blast-induced mTBI, PTSD with its accompanying emotional distress may be a significant determinant of subjective sense of well-being both cognitively and emotionally. The objective discrepancy in PS between the comorbid group and the healthy controls also appears largely due to PTSD more so than the remote blast-induced mTBI, as the group mean difference in PS became negligible after controlling for PTSD levels. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Brain Metabolism During A Lower Extremity Voluntary Movement Task in Children With Spastic Cerebral Palsy.

Reduced selective voluntary motor control (SVMC) is a primary impairment due to corticospinal tract (CST) injury in spastic cerebral palsy (CP). There are few studies of brain metabolism in CP and none have examined brain metabolism during a motor task. Nine children with bilateral spastic CP [Age: 6-11 years, Gross Motor Function Classification System (GMFCS) Levels II-V] completed this study. SVMC was evaluated using Selective Control Assessment of the Lower Extremity (SCALE) ranging from 0 (absent) to 10 (normal). Brain metabolism was measured using positron emission tomography (PET) scanning in association with a selective ankle motor task. Whole brain activation maps as well as ROI averaged metabolic activity were correlated with SCALE scores. The contralateral sensorimotor and superior parietal cortex were positively correlated with SCALE scores (p < 0.0005). In contrast, a negative correlation of metabolic activity with SCALE was found in the cerebellum (p < 0.0005). Subsequent ROI analysis showed that both ipsilateral and contralateral cerebellar metabolism correlated with SCALE but the relationship for the ipsilateral cerebellum was stronger (R 2 = 0.80, p < 0.001 vs. R 2 = 0.46, p = 0.045). Decreased cortical and increased cerebellar activation in children with less SVMC may be related to task difficulty, activation of new motor learning paradigms in the cerebellum and potential engagement of alternative motor systems when CSTs are focally damaged. These results support SCALE as a clinical correlate of neurological impairment.

Long-Term Clinical and Neuronuclear Imaging Sequelae of Cancer Therapy, Trauma, and Brain Injury.

Neuronuclear imaging has been used for several decades in the study of primary neurodegenerative conditions, such as dementia and parkinsonian syndromes, both for research and for clinical purposes. There has been a relative paucity of applications of neuronuclear imaging to evaluate nonneurodegenerative conditions that can also have long-term effects on cognition and function. This article summarizes clinical and imaging aspects of 3 such conditions that have garnered considerable attention in recent years: cancer- and chemotherapy-related cognitive impairment, posttraumatic stress disorder, and traumatic brain injury. Further, we describe current research using neuroimaging tools aimed to better understand the relationships between the clinical presentations and brain structure and function in these conditions.

Changes in regional cerebral blood flow associated with a 45 day course of the ketogenic agent, caprylidene, in patients with mild to moderate Alzheimer's disease: Results of a randomized, double-blinded, pilot study.

BACKGROUND: Caprylidene is a ketogen that, when metabolized, produces the ketones beta-hydroxybutyrate and acetoacetate, which can cross the blood brain barrier. It has been hypothesized that ketone bodies can be used as an alternate energy source by neurons with impaired glucose utilization. Caprylidene has been shown to improve cognition in patients with mild-to-moderate Alzheimer's disease (AD) who lacked an AD-predisposing allele (ɛ4) of the gene for apolipoprotein E. In this pilot study, we examined the effects of caprylidene on regional cerebral blood flow (rCBF) in patients with mild to moderate AD. METHODS: Sixteen subjects with mild-to-moderate AD, based on NINCDS-ADRDA criteria, were enrolled in a double-blinded, placebo-controlled, randomized clinical trial. Fourteen subjects received treatment with caprylidene, and 2 subjects were given placebo. Subjects received 4 15O-water PET scans over the course of the study to assess rCBF: once before receiving a standard caprylidene or placebo dose and 90 min after the dose, on the first day and after 45 days of daily caprylidene or placebo consumption. The scans were examined by standardized volumes of interest (sVOI) and voxel-based statistical parametric mapping (spm) methods of analysis. RESULTS: Subjects lacking an ɛ4 allele had significantly elevated rCBF in the left superior lateral temporal cortex by sVOI analysis after adopting a caprylidene diet for 45 days (p = 0.04), which was further corroborated by spm. The anterior cerebellum, left inferior temporal cortex, and hypothalamus were also found by spm to be regions of long-term increase in rCBF in these subjects. In contrast, patients who possessed the ɛ4 allele did not display these changes in rCBF. CONCLUSION: Daily ingestion of caprylidene over 45 days was associated with increased blood flow in specific brain regions in patients lacking an apolipoprotein ɛ4 allele.

International Cognition and Cancer Task Force Recommendations for Neuroimaging Methods in the Study of Cognitive Impairment in Non-CNS Cancer Patients.

Cancer- and treatment-related cognitive changes have been a focus of increasing research since the early 1980s, with meta-analyses demonstrating poorer performance in cancer patients in cognitive domains including executive functions, processing speed, and memory. To facilitate collaborative efforts, in 2011 the International Cognition and Cancer Task Force (ICCTF) published consensus recommendations for core neuropsychological tests for studies of cancer populations. Over the past decade, studies have used neuroimaging techniques, including structural and functional magnetic resonance imaging (fMRI) and positron emission tomography, to examine the underlying brain basis for cancer- and treatment-related cognitive declines. As yet, however, there have been no consensus recommendations to guide researchers new to this field or to promote the ability to combine data sets. We first discuss important methodological issues with regard to neuroimaging study design, scanner considerations, and sequence selection, focusing on concerns relevant to cancer populations. We propose a minimum recommended set of sequences, including a high-resolution T1-weighted volume and a resting state fMRI scan. Additional advanced imaging sequences are discussed for consideration when feasible, including task-based fMRI and diffusion tensor imaging. Important image data processing and analytic considerations are also reviewed. These recommendations are offered to facilitate increased use of neuroimaging in studies of cancer- and treatment-related cognitive dysfunction. They are not intended to discourage investigator-initiated efforts to develop cutting-edge techniques, which will be helpful in advancing the state of the knowledge. Use of common imaging protocols will facilitate multicenter and data-pooling initiatives, which are needed to address critical mechanistic research questions.

Value of FDG-PET scans of non-demented patients in predicting rates of future cognitive and functional decline.

PURPOSE: The aim of this study was to examine the value of fluorodeoxyglucose (FDG) positron emission tomography (PET) in predicting subsequent rates of functional and cognitive decline among subjects considered cognitively normal (CN) or clinically diagnosed with mild cognitive impairment (MCI). METHODS: Analyses of 276 subjects, 92 CN subjects and 184 with MCI, who were enrolled in the Alzheimer's Disease Neuroimaging Initiative, were conducted. Functional decline was assessed using scores on the Functional Activities Questionnaire (FAQ) obtained over a period of 36 months, while cognitive decline was determined using the Alzheimer's disease Assessment Scale-Cognitive subscale (ADAS-Cog) and Mini-Mental State Examination (MMSE) scores. PET images were analyzed using clinically routine brain quantification software. A dementia prognosis index (DPI), derived from a ratio of uptake values in regions of interest known to be hypometabolic in Alzheimer's disease to regions known to be stable, was generated for each baseline FDG-PET scan. The DPI was correlated with change in scores on the neuropsychological examinations to examine the predictive value of baseline FDG-PET. RESULTS: DPI powerfully predicted rate of functional decline among MCI patients (t = 5.75, p < 1.0E-8) and pooled N + MCI patient groups (t = 7.02, p < 1.0E-11). Rate of cognitive decline on MMSE was also predicted by the DPI among MCI (t = 6.96, p < 1.0E-10) and pooled N + MCI (t = 8.78, p < 5.0E-16). Rate of cognitive decline on ADAS-cog was powerfully predicted by the DPI alone among N (p < 0.001), MCI (t = 6.46, p < 1.0E-9) and for pooled N + MCI (t = 8.85, p = 1.1E-16). CONCLUSIONS: These findings suggest that an index, derivable from automated regional analysis of brain PET scans, can be used to help predict rates of functional and cognitive deterioration in the years following baseline PET.

Examining the impact of grape consumption on brain metabolism and cognitive function in patients with mild decline in cognition: A double-blinded placebo controlled pilot study.

BACKGROUND: Natural compounds in grapes such as resveratrol are known for their antioxidant and anti-inflammatory properties. Some studies have shown a potential role for grapes or wine in slowing cognitive decline and other effects of aging. However, well-controlled experimental data obtained in human subjects are still in need of further development. Here we aimed to systematically assess effects of grapes on regional cerebral metabolism. METHODS: Ten subjects with mild decline in cognition (mean, 72.2±4.7years; 50% female) were included in this analysis. Participants were randomized into an active grape formulation arm or a placebo arm which consumed a formulation free of polyphenols for six months. Cognitive performance was measured through neuropsychological assessments performed at baseline and 6months after initiation of therapy. Changes in brain metabolism occurring with each therapy regimen were assessed by brain PET scans with the radiotracer [F-18] fluorodeoxyglucose (FDG), obtained during initial evaluation and 6months later. Standardized volumes of interest (sVOI) and statistical parametric mapping (SPM) methods were applied to FDG-PET scans to identify significant regional cerebral metabolic changes. RESULTS: In contrast to participants taking the active grape formulation, who displayed no significant decline in metabolism, the placebo arm underwent significant metabolic decline in sVOI's of the right posterior cingulate cortex (p=0.01), and left superior posterolateral temporal cortex (p=0.04). SPM analyses also found significant declines in the placebo group, particularly in left prefrontal, cingulate, and left superior posterolateral temporal cortex (p<0.01) with stable brain metabolism in the active formulation arm. No significant differences were seen in scores on the neuropsychological battery of tests between the two groups. However, metabolism in right superior parietal cortex and left inferior anterior temporal cortex was correlated with improvements in attention/working memory, as measured with WAIS-III Digital Span within the active formulation group (r=-0.69, p=0.04). CONCLUSIONS: The placebo arm had declines in regions of the brain known to be significantly affected in the early stages of Alzheimer's disease, while the active formulation group was spared such decline. This suggests a protective effect of grapes against early pathologic metabolic decline.

Critical review of the Appropriate Use Criteria for amyloid imaging: Effect on diagnosis and patient care.

INTRODUCTION: The utility of the Appropriate Use Criteria (AUC) for amyloid imaging is not established. METHODS: Fifty-three cognitively impaired patients with clinical F18-florbetapir imaging were classified as early and late onset, as well as AUC-consistent or AUC-inconsistent. Chi-square statistics and t test were used to compare demographic characteristics and clinical outcomes as appropriate. RESULTS: Early-onset patients were more likely to be amyloid positive. Change in diagnosis was more frequent in late-onset cases. Change in therapy was more common in early-onset cases. AUC-consistent and AUC-inconsistent cases had comparable rates of amyloid positivity. We saw no difference in the rate of treatment changes in the AUC-consistent group as opposed to the AUC-inconsistent group. DISCUSSION: The primary role of amyloid imaging in the early-onset group was to confirm the clinically suspected etiology, and in the late-onset group in detecting amyloid-negative cases. The rate of therapeutic changes was significantly greater in the early-onset cases.

Multimodal diagnosis of epilepsy using conditional dependence and multiple imputation.

The definitive diagnosis of the type of epilepsy, if it exists, in medication-resistant seizure disorder is based on the efficient combination of clinical information, long-term video-electroencephalography (EEG) and neuroimaging. Diagnoses are reached by a consensus panel that combines these diverse modalities using clinical wisdom and experience. Here we compare two methods of multimodal computer-aided diagnosis, vector concatenation (VC) and conditional dependence (CD), using clinical archive data from 645 patients with medication-resistant seizure disorder, confirmed by video-EEG. CD models the clinical decision process, whereas VC allows for statistical modeling of cross-modality interactions. Due to the nature of clinical data, not all information was available in all patients. To overcome this, we multiply-imputed the missing data. Using a C4.5 decision tree, single modality classifiers achieved 53.1%, 51.5% and 51.1% average accuracy for MRI, clinical information and FDG-PET, respectively, for the discrimination between non-epileptic seizures, temporal lobe epilepsy, other focal epilepsies and generalized-onset epilepsy (vs. chance, p<0.01). Using VC, the average accuracy was significantly lower (39.2%). In contrast, the CD classifier that classified with MRI then clinical information achieved an average accuracy of 58.7% (vs. VC, p<0.01). The decrease in accuracy of VC compared to the MRI classifier illustrates how the addition of more informative features does not improve performance monotonically. The superiority of conditional dependence over vector concatenation suggests that the structure imposed by conditional dependence improved our ability to model the underlying diagnostic trends in the multimodality data.

Cognitive function after the initiation of adjuvant endocrine therapy in early-stage breast cancer: an observational cohort study.

PURPOSE: This report examines cognitive complaints and neuropsychological (NP) testing outcomes in patients with early-stage breast cancer after the initiation of endocrine therapy (ET) to determine whether this therapy plays any role in post-treatment cognitive complaints. PATIENTS AND METHODS: One hundred seventy-three participants from the Mind Body Study (MBS) observational cohort provided data from self-report questionnaires and NP testing obtained at enrollment (T1, before initiation of ET), and 6 months later (T2). Bivariate analyses compared demographic and treatment variables, cognitive complaints, depressive symptoms, quality of life, and NP functioning between those who received ET versus not. Multivariable linear regression models examined predictors of cognitive complaints at T2, including selected demographic variables, depressive symptoms, ET use, and other medical variables, along with NP domains that were identified in bivariate analyses. RESULTS: Seventy percent of the 173 MBS participants initiated ET, evenly distributed between tamoxifen or aromatase inhibitors. ET-treated participants reported significantly increased language and communication (LC) cognitive complaints at T2 (P = .003), but no significant differences in NP test performance. Multivariable regression on LC at T2 found higher LC complaints significantly associated with T1 LC score (P < .001), ET at T2 (P = .004), interaction between ET and past hormone therapy (HT) (P < .001), and diminished improvement in NP psychomotor function (P = .05). Depressive symptoms were not significant (P = .10). CONCLUSION: Higher LC complaints are significantly associated with ET 6 months after starting treatment and reflect diminished improvements in some NP tests. Past HT is a significant predictor of higher LC complaints after initiation of ET.

Insulin resistance and medial prefrontal gyrus metabolism in women receiving hormone therapy.

Insulin resistance (IR) is a putative risk factor for cognitive decline and dementia, and has been shown to impede neuronal glucose metabolism in animal models. This post hoc study focused on metabolic changes in the medial prefrontal region, a brain region exhibiting decline years before documented cognitive changes, relative to high or low IR status in a cohort of postmenopausal women at risk for dementia who were randomized to continue or discontinue existing stable hormone therapy (HT) for 2 years. Subjects were dichotomized into high and low IR groups based on the homeostatic model assessment of insulin resistance, which was within clinically normal limits for the group as a whole at both baseline and 2-year follow-up. Results showed that high and low IR groups showed significant differences in metabolic decline of the medial prefrontal gyrus, regardless of HT randomization group. However, HT randomization was predictive of metabolic decline only in women with low HOMA (homeostatic assessment of insulin resistance). Performance in working memory was consistent with observed metabolic changes. These results suggest IR may be an independent moderator of regional metabolic changes, while protective metabolic effects of HT are most apparent in those at low-end range of IR. If replicated in future studies, these findings will help to better understand the interaction between putative risk and protective factors, and further delineate cohort postmenopausal women who may benefit from HT.

Treatment response evaluation using 18F-FDOPA PET in patients with recurrent malignant glioma on bevacizumab therapy.

PURPOSE: This study compares the value of 3,4-dihydroxy-6-[(18)F]-fluoro-l-phenylalanine ((18)F-FDOPA) positron emission tomography (PET) and MRI in assessing outcome during antiangiogenic treatment in patients with recurrent high-grade gliomas. EXPERIMENTAL DESIGN: Thirty patients were prospectively studied with (18)F-FDOPA PET scans immediately before, and two and six weeks after start of bevacizumab therapy. (18)F-FDOPA metabolic tumor volumes (MTV) as well as max and mean standardized uptake values (SUV) within this MTV were obtained. MRI treatment response was assessed at six weeks. The predictive ability of (18)F-FDOPA PET and MRI response assessment were evaluated with regard to progression-free survival (PFS) and overall survival (OS). RESULTS: A total of 30, 28, and 24 (18)F-FDOPA PET scans at baseline, two weeks, and six weeks, were available for analysis, respectively. (18)F-FDOPA PET SUVs as well as their changes through therapy were not predictive of outcome. However, MTV parameters such as MTV changes were highly prognostic. Interestingly, absolute MTV at the first follow up scan provides the most significant prediction for increased OS (P < 0.0001) as well as PFS (P = 0.001). This surprising result was scrutinized with cross-validation and simulation analysis. Responders based on (18)F-FDOPA PET data survived 3.5 times longer (12.1 months vs. 3.5 months, median OS, P < 0.001) than nonresponders (17 patients vs. 11 patients, respectively). In comparison, responders based on MRI data lived 1.5 times longer (11.4 months vs 7.7 months, P = 0.03) than nonresponders (22 patients vs. 7 patients, respectively). CONCLUSIONS: (18)F-FDOPA PET identifies treatment responders to antiangiogenic therapy as early as two weeks after treatment initiation.

Prospective randomized trial to assess effects of continuing hormone therapy on cerebral function in postmenopausal women at risk for dementia.

UNLABELLED: The objective of this study was to examine the effects of estrogen-based hormone therapy (HT) on regional cerebral metabolism in postmenopausal women (mean age = 58, SD = 5) at risk for development of dementia. The prospective clinical trial design included pre- and post-intervention neuroimaging of women randomized to continue (HT+) or discontinue (HT-) therapy following an average of 10 years of use. The primary outcome measure was change in brain metabolism during the subsequent two years, as assessed with fluorodeoxyglucose-18 positron emission tomography (FDG-PET). Longitudinal FDG-PET data were available for 45 study completers. Results showed that women randomized to continue HT experienced relative preservation of frontal and parietal cortical metabolism, compared with women randomized to discontinue HT. Women who discontinued 17-ß estradiol (17ßE)-based HT, as well as women who continued conjugated equine estrogen (CEE)-based HT, exhibited significant decline in metabolism of the precuneus/posterior cingulate cortical (PCC) area. Significant decline in PCC metabolism was additionally seen in women taking concurrent progestins (with either 17ßE or CEE). Together, these findings suggest that among postmenopausal subjects at risk for developing dementia, regional cerebral cortical metabolism is relatively preserved for at least two years in women randomized to continue HT, compared with women randomized to discontinue HT. In addition, continuing unopposed 17ßE therapy is associated specifically with preservation of metabolism in PCC, known to undergo the most significant decline in the earliest stages of Alzheimer's disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT00097058.

The effect of aromatase inhibition on the cognitive function of older patients with breast cancer.

INTRODUCTION: This study evaluated the association between aromatase inhibitor (AI) therapy and cognitive function (over a 6-month period) in a cohort of patients aged ≥ 60 years compared with an age-matched healthy control group, and it evaluated changes in regional cerebral metabolism as measured by positron emission tomography (PET) scans of the brain done in a subset of the patient cohort. PATIENTS AND METHODS: Thirty-five patients (32 evaluable) and 35 healthy controls were recruited to this study. Patients with breast cancer completed a neuropsychological battery, self-reported memory questionnaire, and geriatric assessment before initiation of AI therapy and again 6 months later. Age-matched healthy control participants completed the same assessments at the same time points as the patient group. RESULTS: No significant decline in cognitive function was seen among individuals receiving an AI from pretreatment to 6 months later compared with healthy controls. In the PET cohort over the same period, both standardized volume of interest and statistical parametric mapping analyses detected specific changes in metabolic activity between baseline and follow-up uniquely in the AI patients, most significantly in the medial temporal lobes. CONCLUSION: Although patients undergoing AI treatment had few changes in neuropsychological performance compared with healthy controls over a 6-month period, regionally specific changes in cerebral metabolic activity were identified during this interval in the patient group. Additional longitudinal follow-up is needed to understand the potential clinical implications of these findings.