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.

Imaging and cerebrospinal fluid biomarkers in the search for Alzheimer's disease mechanisms.

BACKGROUND: The pathophysiological process of Alzheimer's disease (AD) begins many years before the emergence of clinical symptoms (preclinical AD). A hypothetical biomarker progression in the pathogenesis of AD has been suggested, beginning with the deposition of amyloid-ß (Aß) and followed by increases in neurofibrillary tangles, synaptic loss, hippocampal atrophy, and lastly, cognitive impairment. OBJECTIVE: We explored the effect of several risk factors for AD on the pattern of AD biomarker expression in normal subjects. METHODS: AD biomarker evidence was examined at baseline in 96 cognitively normal elderly subjects with none or at least one of the following: ApoE4+ allele, a maternal history of AD (mFHx), sleep-disordered breathing (SDB), and longitudinal evidence of decline to mild cognitive impairment or AD (decliners) at follow-up. RESULTS: Decliners and ApoE4+ subjects presented with expected reduced cerebrospinal fluid Aß42, elevated P-tau and T-tau. In addition, decliners had fluorodeoxyglucose positron emission tomography hypometabolism in the medial temporal lobe. Individuals with mFHx demonstrated no Aß42 effect, but had elevations in P-tau and T-tau. SDB was found to be associated with elevated Aß42, P-tau and T-tau, as well as with reduced medial temporal lobe glucose metabolic rates. CONCLUSION: Our results indicate a heterogeneous biomarker expression, suggesting diversity of AD pathways in at-risk presymptomatic subjects.

Diagnostic criteria for apathy in clinical practice.

BACKGROUND: Apathy is an important and distressing behavioural symptom in Alzheimer's disease and in various neuropsychiatric disorders. Recently, diagnostic criteria for apathy have been proposed. OBJECTIVES: In groups of patients suffering from different neuropsychiatric diseases, (i) to estimate the prevalence of patients meeting the proposed diagnostic criteria; (ii) to estimate the concurrent validity of the criteria with the neuropsychiatric inventory (NPI) apathy item; (iii) to identify the most frequently met criteria or sub-criteria in each specific neuropsychiatric disease and (iv) to estimate the inter-observer reliability of the diagnostic criteria for apathy. METHODS: This cross-sectional, multicentric, observational study was performed on 306 patients. Each of the participating centres had to check the presence of apathy according to the diagnostic criteria for apathy in consecutive patients belonging to the following diagnoses list: Alzheimer disease (AD), mixed dementia, mild cognitive impairment (MCI), Parkinson's disease (PD), Schizophrenia (DSM-IV) and major depressive episode. In addition to the clinical interview, the assessment included the Mini Mental Score Examination (MMSE) and the NPI. At the end of the visit, clinicians were required to check the diagnostic criteria for apathy. RESULTS: Using the diagnostic criteria for apathy, the frequency of apathy was of 53% in the whole population, 55% in AD, 70% in mixed dementia, 43% in MCI, 27% in PD, 53% in schizophrenia and 94% in major depressive episode. In AD, mixed dementia, MCI and PD, the NPI apathy score was significantly higher for patient fulfilling the apathy criteria. Goal-directed cognitive activity (criteria B2-Cognition) was the most frequently observed domain followed by goal-directed behaviour (criteria B1-Behaviour) and emotion (criteria B3), respectively. Inter-rater reliability was high for the overall diagnostic (κ coefficient = 0.93; p = 0.0001) and for each criteria. CONCLUSION: This study is the first one to test the diagnostic criteria for apathy in clinical practice. Results make the diagnostic criteria useful for clinical practice and research.

The concept of FDG-PET endophenotype in Alzheimer's disease.

Often viewed as a potential tool for preclinical diagnosis in early asymptomatic stages of Alzheimer's disease (AD), the term "endophenotype" has acquired a recent popularity in the field. In this review, we analyze the construct of endophenotype-originally designed to discover genes, and examine the literature on potential endophenotypes for the late-onset form of AD (LOAD). We focus on the [18F]-fluoro-2-deoxyglucose (FDG) PET technique, which shows a characteristic pattern of hypometabolism in AD-related regions in asymptomatic carriers of the ApoE E4 allele and in children of AD mothers. We discuss the pathophysiological significance and the positive predictive accuracy of an FDG-endophenotype for LOAD in asymptomatic subjects, and discuss several applications of this endophenotype in the identification of both promoting and protective factors. Finally, we suggest that the term "endophenotype" should be reserved to the study of risk factors, and not to the preclinical diagnosis of LOAD.

Early detection of Alzheimer's disease with PET imaging.

Preclinical diagnosis of Alzheimer's disease (AD) is one of the major challenges for the prevention of AD. AD biomarkers are needed not only to reveal preclinical pathologic changes, but also to monitor progression and therapeutics. PET neuroimaging can reliably assess aspects of the molecular biology and neuropathology of AD. The aim of this article is to review the use of FDG-PET and amyloid PET imaging in the early detection of AD.

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

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

Evaluation of Early Dementia (Mild Cognitive Impairment).

Early diagnosis of Alzheimer disease (AD) is one of the major challenges for the prevention of this dementia. The pathologic lesions associated with AD develop many years before the clinical manifestations of the disease become evident, during a likely transitional period between normal aging and the appearance of first cognitive symptoms. AD biomarkers are needed not only to reveal these early pathologic changes but also to monitor progression in cognitive and behavioral decline and brain lesions. PET neuroimaging can reliably assess indirect and direct aspects of the molecular biology and neuropathology of AD. This article reviews the use of [18F] 2-fluoro-2-deoxy-D-glucose-PET and amyloid PET imaging in the early detection of AD.