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.

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.

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.

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.

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.

Neuroimaging biomarkers and cognitive function in non-CNS cancer and its treatment: current status and recommendations for future research.

Cognitive changes in patients undergoing treatment for non-central nervous system (CNS) cancers have been recognized for several decades, yet the underlying mechanisms are not well understood. Structural, functional and molecular neuroimaging has the potential to help clarify the neural bases of these cognitive abnormalities. Structural magnetic resonance imaging (MRI), functional MRI (fMRI), diffusion tensor imaging (DTI), MR spectroscopy (MRS), and positron emission tomography (PET) have all been employed in the study of cognitive effects of cancer treatment, with most studies focusing on breast cancer and changes thought to be induced by chemotherapy. Articles in this special issue of Brain Imaging and Behavior are devoted to neuroimaging studies of cognitive changes in patients with non-CNS cancer and include comprehensive critical reviews and novel research findings. The broad conclusions that can be drawn from past studies and the present body of new research is that there are structural and functional changes associated with cancer and various treatments, particularly systemic cytotoxic chemotherapy, although some cognitive and fMRI studies have identified changes at pre-treatment baseline. Recommendations to accelerate progress include well-powered multicenter neuroimaging studies, a better standardized definition of the cognitive phenotype and extension to other cancers. A systems biology framework incorporating multimodality neuroimaging, genetics and other biomarkers will be highly informative regarding individual differences in risk and protective factors and disease- and treatment-related mechanisms. Studies of interventions targeting cognitive changes are also needed. These next steps are expected to identify novel protective strategies and facilitate a more personalized medicine for cancer patients.

FDG-PET in early AD diagnosis.

FDG-PET is a valuable tool that will continue to aid in identifying AD in its prodromal and early dementia stages, distinguishing it from other causes of dementia, and tracking progression of the disease. As brain FDG-PET scans and well-trained readers of these scans are becoming more widely available to clinicians who are becoming more informed about the role FDG-PET can play in early AD diagnosis, its use is expected to increase.

Cognitive complaints after breast cancer treatments: examining the relationship with neuropsychological test performance.

BACKGROUND: Cognitive complaints are reported frequently after breast cancer treatments. Their association with neuropsychological (NP) test performance is not well-established. METHODS: Early-stage, posttreatment breast cancer patients were enrolled in a prospective, longitudinal, cohort study prior to starting endocrine therapy. Evaluation included an NP test battery and self-report questionnaires assessing symptoms, including cognitive complaints. Multivariable regression models assessed associations among cognitive complaints, mood, treatment exposures, and NP test performance. RESULTS: One hundred eighty-nine breast cancer patients, aged 21-65 years, completed the evaluation; 23.3% endorsed higher memory complaints and 19.0% reported higher executive function complaints (>1 SD above the mean for healthy control sample). Regression modeling demonstrated a statistically significant association of higher memory complaints with combined chemotherapy and radiation treatments (P = .01), poorer NP verbal memory performance (P = .02), and higher depressive symptoms (P < .001), controlling for age and IQ. For executive functioning complaints, multivariable modeling controlling for age, IQ, and other confounds demonstrated statistically significant associations with better NP visual memory performance (P = .03) and higher depressive symptoms (P < .001), whereas combined chemotherapy and radiation treatment (P = .05) approached statistical significance. CONCLUSIONS: About one in five post-adjuvant treatment breast cancer patients had elevated memory and/or executive function complaints that were statistically significantly associated with domain-specific NP test performances and depressive symptoms; combined chemotherapy and radiation treatment was also statistically significantly associated with memory complaints. These results and other emerging studies suggest that subjective cognitive complaints in part reflect objective NP performance, although their etiology and biology appear to be multifactorial, motivating further transdisciplinary research.

Postmortem 3-D brain hemisphere cortical tau and amyloid-ß pathology mapping and quantification as a validation method of neuropathology imaging.

This work is aimed at correlating pre-mortem [18F]FDDNP positron emission tomography (PET) scan results in a patient with dementia with Lewy bodies (DLB), with cortical neuropathology distribution determined postmortem in three physical dimensions in whole brain coronal sections. Analysis of total amyloid-ß (Aß) distribution in frontal cortex and posterior cingulate gyrus confirmed its statistically significant correlation with cortical [18F]FDDNP PET binding values (distribution volume ratios, DVR) (p < 0.001, R = 0.97, R2 = 0.94). Neurofibrillary tangle (NFT) distribution correlated significantly with cortical [18F]FDDNP PET DVR in the temporal lobe (p < 0.001, R = 0.87, R2 = 0.76). Linear combination of Aß and NFT densities was highly predictive of [18F]FDDNP PET DVR through all analyzed regions of interest (p < 0.0001, R = 0.92, R2 = 0.85), and both densities contributed significantly to the model. Lewy bodies were present at a much lower level than either Aß or NFTs and did not significantly contribute to the in vivo signal. [18F]FDG PET scan results in this patient were consistent with the distinctive DLB pattern of hypometabolism. This work offers a mapping brain model applicable to all imaging probes for verification of imaging results with Aß and/or tau neuropathology brain distribution using immunohistochemistry, fluorescence microscopy, and autoradiography.

Neuronuclear imaging in the evaluation of dementia and mild decline in cognition.

Recently, the National Institute on Aging and the Alzheimer's Association identified specific structural and functional neuroimaging findings as valuable markers of biological processes occurring in the human brain, especially processes that herald impending dementia caused by Alzheimer's disease (AD) in its prodromal form. In particular, the imaging modalities of magnetic resonance imaging and positron emission tomography (PET) were singled out, along with certain biomarkers in cerebrospinal fluid, to serve this purpose. We review the clinical tests available for neuropsychologic evaluation and in cases when the differential diagnosis for the causes of cognitive impairment is difficult to make, we consider biomarkers, beginning with cerebrospinal fluid, for assessment of cognitive decline. For more direct information on dementia-related pathologic changes in brain tissue, structural features observed in magnetic resonance imaging scans are regarded. We next discuss the use of single-photon emission computed tomography for evaluating functional changes. Then, pertinent to the recent National Institute on Aging and the Alzheimer's Association's consensus statement on the diagnosis of prodromal AD, we focus on assessing the cerebral metabolic changes associated with neurodegenerative diseases that are identified with fluorodeoxyglucose PET, as well as consider the most appropriate roles for amyloid imaging based on recent studies examining the use of PET with tracers having higher retention in brain tissue-harboring plaques composed of insoluble beta-amyloid. We also consider the leading causes for the current underuse of neuronuclear imaging in evaluating patients with cognitive problems, along with strategies for combating them. Finally, we suggest an overall diagnostic algorithm to guide optimal use of all the neuroimaging tools in assessing patients with cognitive decline.