BBA - Molecular Basis of Disease (v.1822, #3)

In this review focus is on structural imaging in the Alzheimer's disease (AD) pre-states, particularly cognitively normal (CN) persons at future dementia risk. Findings in mild cognitive impairment (MCI) are described here only for comparison with CN. Cited literature evidence and commentary address issues of structural imaging alterations in CN that precede MCI and AD, regional patterns of such alterations, and the time relationship between structural imaging alterations and the appearance of symptoms of AD, issues relevant to the conduct of future AD prevention trials. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.► This review focuses on MRI imaging in normal subjects before symptoms of dementia. ► Structural MRI changes are found in normal persons at risk of Alzheimer's disease. ► These findings are important for the prevention of dementia.
Keywords: Review; Mild cognitive impairment; Alzheimer's disease; Magnetic resonance imaging; Morphometry; Normal aging;

Structural brain imaging in frontotemporal dementia by Jonathan D. Rohrer (325-332).
Frontotemporal dementia (FTD) is the second commonest young-onset neurodegenerative dementia. The canonical clinical syndromes are a behavioural variant (bvFTD) and two language variants (progressive nonfluent aphasia, PNFA, and semantic dementia, SD) although there is overlap with motor neurone disease and the atypical parkinsonian disorders corticobasal syndrome (CBS) and progressive supranuclear palsy syndrome (PSPS). Characteristic patterns of atrophy or hypometabolism are described in each of the variants but in reality imaging studies are rather heterogeneous. This review attempts to address four key questions in the neuroimaging of FTD: 1) what are the early imaging features of the different FTD syndromes (and how do these change as the disease progresses); 2) what do studies of presymptomatic genetic cases of FTD tell us about the very early stages of the disease; 3) can neuroimaging help to differentiate the different FTD syndromes; and 4) can neuroimaging help to differentiate FTD from other neurodegenerative diseases? This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.► This paper examines the use of neuroimaging in frontotemporal dementia (FTD). ► Characteristic patterns of atrophy are described at a group level in each subtype. ► Studies of presymptomatic genetic cases provide a window to early imaging changes. ► Imaging can help to differentiate FTD subtypes and FTD from AD at a group level.
Keywords: Frontotemporal dementia; Frontotemporal lobar degeneration; Primary progressive aphasia; Neuroimaging; MRI;

Insulin is differentially related to cognitive decline and atrophy in Alzheimer's disease and aging by Jeffrey M. Burns; Robyn A. Honea; Eric D. Vidoni; Lewis J. Hutfles; William M. Brooks; Russell H. Swerdlow (333-339).
We assessed the relationship of insulin resistance with cognitive decline and brain atrophy over two years in early Alzheimer's disease (AD, n = 48) and nondemented controls (n = 61). Intravenous glucose tolerance tests were conducted at baseline to determine insulin area-under-the-curve (AUC). A standard battery of cognitive tasks and MRI were conducted at baseline and 2-year follow-up. In nondemented controls, higher baseline insulin AUC was associated with 2-year decline in global cognitive performance (beta = − 0.36, p = 0.005). In early AD, however, higher insulin AUC was associated with less decline in global cognitive performance (beta = 0.26, p = 0.06), slower global brain atrophy (beta = 0.40, p = 0.01) and less regional atrophy in the bilateral hippocampi and cingulate cortices. While insulin resistance is associated with cognitive decline in nondemented aging, higher peripheral insulin may have AD-specific benefits or insulin signaling may be affected by systemic physiologic changes associated with AD. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.► Peripheral insulin, cognitive change, and brain atrophy in aging and Alzheimer's. ► Higher insulin in aging is associated with greater 2-year decline in cognition. ► Higher insulin in AD is associated with less cognitive decline and brain atrophy.
Keywords: Alzheimer disease; Insulin; Brain atrophy; Cognitive decline; Glucose tolerance test;

Dementia: Alzheimer pathology and vascular factors: From mutually exclusive to interaction by Anouk G.W. van Norden; Ewoud J. van Dijk; Karlijn F. de Laat; Philip Scheltens; Marcel G.M. OldeRikkert; F.E. de Leeuw (340-349).
Alzheimer's disease (AD) is the most common type of dementia. Both its incidence and prevalence are expected to increase exponentially as populations' age worldwide. Despite impressive efforts of research worldwide, neither cure nor effective preventive strategy is available for this devastating disease. Currently there are several hypotheses on what causes AD, with the amyloid hypothesis being the most investigated and accepted hypothesis over the past 20 years. However the exact role of amyloid-β in the onset and progression of AD is not yet fully understood, and even the validity of the amyloid hypothesis itself is still being discussed. This debate is fuelled by the vascular hypothesis, as increasing epidemiological, neuroimaging, pathological, pharmacotherapeutic and clinical studies suggest that vascular pathology plays a key role in the onset and progression of AD. We here will discuss arguments in favor and limitations of both hypotheses within the framework of available literature, but also provide arguments for convergence of both hypotheses.Finally we propose approaches that may aid in unraveling the etiology and treatment of AD. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.► Alzheimer's disease is caused by a mixture of interacting risk factors. ► Amyloid-β accumulation and vascular damage are the most frequent risk factors. ► The interaction of Aβ and vascular damage is a double hit on cognitive function. ► Etiological research needs a large, well-defined study population with long follow up. ► Influence of risk factors varies over time with potential therapeutic consequences.
Keywords: Amyloid; Vascular; Dementia; Alzheimer's disease; Imaging;

Iron participates in a wide array of cellular functions and is essential for normal neural development and physiology. However, if inappropriately managed, the transition metal is capable of generating neurotoxic reactive oxygen species. A number of hereditary conditions perturb body iron homeostasis and some, collectively referred to as neurodegeneration with brain iron accumulation (NBIA), promote pathological deposition of the metal predominantly or exclusively within the central nervous system (CNS). In this article, we discuss seven NBIA disorders with emphasis on the clinical syndromes and neuroimaging. The latter primarily entails magnetic resonance scanning using iron-sensitive sequences. The conditions considered are Friedreich ataxia (FA), pantothenate kinase 2-associated neurodegeneration (PKAN), PLA2G6-associated neurodegeneration (PLAN), FA2H-associated neurodegeneration (FAHN), Kufor-Rakeb disease (KRD), aceruloplasminemia, and neuroferritinopathy. An approach to differential diagnosis and the status of iron chelation therapy for several of these entities are presented. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.► Iron is vital to life but may generate neurotoxic reactive oxygen species if inappropriately handled. ► A group of heritable disorders are collectively known as neurodegeneration with brain iron accumulation (NBIA). ► Known NBIA conditions include PKAN, PLAN, FAHN, KRD, aceruloplasminemia and neuroferritinopathy. ► Friedreich ataxia (FA), although not classically an NBIA, also features excessive brain iron deposition. ► Diagnosis of NBIA considers inheritance patterns, clinical syndromes, genetic testing and iron-sensitive neuroimaging.
Keywords: Ferritin; Iron; Neurodegeneration with brain iron accumulation (NBIA); Magnetic resonance imaging (MRI); Neuroimaging; Syndromes;

Aging is associated with appearance of white matter hyperintensities (WMH) on MRI scans. Vascular risk and inflammation, which increase with age, may contribute to white matter deterioration and proliferation of WMH. We investigated whether circulating biomarkers and genetic variants associated with elevated vascular risk and inflammation are associated with WMH volume in healthy adults (144 volunteers, 44–77 years of age). We examined association of WMH volume with age, sex, hypertension, circulating levels of total plasma homocysteine (tHcy), cholesterol (low-density lipoprotein), and C-reactive protein (CRP), and four polymorphisms related to vascular risk and inflammation: Apolipoprotein ε (ApoE ε2,3,4), Angiotensin-Converting Enzyme insertion/deletion (ACE I/D), methylenetetrahydrofolate reductase (MTHFR) C677T, C-reactive protein (CRP)-286C>A>T, and interleukin-1β (IL-1β) C-511T. We found that larger WMH volume was associated with advanced age, hypertension, and elevated levels of homocysteine and CRP but not with low-density lipoprotein levels. Homozygotes for IL-1β-511T allele and carriers of CRP-286T allele that are associated with increased inflammatory response had larger WMH than the other allelic combinations. Carriers of the APOE ε2 allele had larger frontal WMH than ε3 homozygotes and ε4 carriers did. Thus, in healthy adults, who are free of neurological and vascular disease, genetic variants that promote inflammation and elevated levels of vascular risk biomarkers can contribute to brain abnormalities. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.► Question: Do vascular risk and inflammation biomarkers/polymorphisms predict WMH? ► WMH volume is associated with age, hypertension, and homocysteine and CRP levels. ► IL-1β-511T homozygotes and CRP-286T carriers have enlarged WMH. ► ApoE ε2 carriers had larger frontal WMH than ε3 homozygotes, and ε4 carriers.
Keywords: Brain; Aging; CRP; Interleukin; Homocysteine; Frontal lobe; ApoE; MTHFR; ACE;

PET amyloid-beta imaging in preclinical Alzheimer's disease by Andrei G. Vlassenko; Tammie L.S. Benzinger; John C. Morris (370-379).
Alzheimer's disease (AD) is the leading cause of dementia, accounting for 60–70% of all cases [Hebert et al., 2003, ]. The need for effective therapies for AD is great. Current approaches, including cholinesterase inhibitors and N-methyl-d-aspartate (NMDA) receptor antagonists, are symptomatic treatments for AD but do not prevent disease progression. Many diagnostic and therapeutic approaches to AD are currently changing due to the knowledge that underlying pathology starts 10 to 20 years before clinical signs of dementia appear [Holtzman et al., 2011, ]. New therapies which focus on prevention or delay of the onset or cognitive symptoms are needed. Recent advances in the identification of AD biomarkers now make it possible to detect AD pathology in the preclinical stage of the disease, in cognitively normal (CN) individuals; this biomarker data should be used in the selection of high-risk populations for clinical trials. In vivo visualization of AD neuropathology and biological, biochemical or physiological confirmation of the effects of treatment likely will substantially improve development of novel pharmaceuticals. Positron emission tomography (PET) is the leading neuroimaging tool to detect and provide quantitative measures of AD amyloid pathology in vivo at the early stages and follow its course longitudinally. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.
Keywords: Amyloid; Alzheimer disease; PET; PIB; Neuroimaging;

The use of PIB-PET as a dual pathological and functional biomarker in AD by Anton Forsberg; Henry Engler; Gunnar Blomquist; Bengt Långström; Agneta Nordberg (380-385).
Amyloid imaging with positron emission tomography (PET) is presently used in Alzheimer's disease (AD) research. In this study we investigated the possibility to use early frames (ePIB) of the PIB scans as a rough index of CBF by comparing normalised early PIB values with cerebral glucose metabolism (rCMRglc). PIB-PET and FDG-PET were performed in 37 AD patients, 21 subjects with mild cognitive impairment (MCI) and 6 healthy controls (HC). The patients were divided based on their PIB retention (amyloid load) as either PIB positive (PIB+) or PIB negative (PIB−). Data of the unidirectional influx K 1 from a subset of the subjects including 7 AD patients and 3 HC was used for correlative analysis. Data was analysed using regions of interest (ROI) analysis. A strong, positive correlation was observed across brain regions between K 1 and ePIB (r = 0.70; p  ≤ 0.001). The ePIB values were significantly lower in the posterior cingulate (p  ≤ 0.001) and the parietal cortices (p  = 0.002) in PIB+ subjects compared to PIB−, although the group difference were stronger for rCMRglc in cortical areas (p  ≤ 0.001). Strong positive correlations between ePIB and rCMRglc were observed in all cortical regions analysed, especially in the posterior cingulate and parietal cortices (p  ≤ 0.001). A single dynamic PIB-PET scan may provide information about pathological and functional changes (amyloidosis and impaired blood flow). This might be important for diagnosis of AD, enrichment of patients in clinical trials and evaluation of treatment effects. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.► A strong, positive correlation was observed across brain regions between K 1 and ePIB. ► The ePIB values were lower in posterior cingulate, parietal cortices in PIB+ subjects compared to PIB. ► Strong positive correlations between ePIB and rCMRglc. ► A single dynamic PIB-PET scan may provide information about pathological and functional changes.
Keywords: PIB; Positron emission tomography (PET); Alzheimer's disease (AD); Cerebral blood flow; Cerebral glucose metabolism; Mild Cognitive Impairment (MCI);

Diffusion tensor imaging of cerebral white matter integrity in cognitive aging by David J. Madden; Ilana J. Bennett; Agnieszka Burzynska; Guy G. Potter; Nan-kuei Chen; Allen W. Song (386-400).
In this article we review recent research on diffusion tensor imaging (DTI) of white matter (WM) integrity and the implications for age-related differences in cognition. Neurobiological mechanisms defined from DTI analyses suggest that a primary dimension of age-related decline in WM is a decline in the structural integrity of myelin, particularly in brain regions that myelinate later developmentally. Research integrating behavioral measures with DTI indicates that WM integrity supports the communication among cortical networks, particularly those involving executive function, perceptual speed, and memory (i.e., fluid cognition). In the absence of significant disease, age shares a substantial portion of the variance associated with the relation between WM integrity and fluid cognition. Current data are consistent with one model in which age-related decline in WM integrity contributes to a decreased efficiency of communication among networks for fluid cognitive abilities. Neurocognitive disorders for which older adults are at risk, such as depression, further modulate the relation between WM and cognition, in ways that are not as yet entirely clear. Developments in DTI technology are providing a new insight into both the neurobiological mechanisms of aging WM and the potential contribution of DTI to understanding functional measures of brain activity. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.► We review diffusion tensor imaging (DTI) of white matter (WM) integrity in aging. ► Even without disease, age-related decline occurs in both cognition and WM integrity. ► Age-related decline in WM integrity interrupts communication among brain networks. ► Disconnection of brain network may contribute to normal cognitive decline with age.
Keywords: Magnetic resonance imaging; Brain; Behavior; Adult development; Neuroaxonal damage;

Diffusion tensor imaging and cognition in cerebral small vessel disease by Anouk G.W. van Norden; Karlijn F. de Laat; Ewoud J. van Dijk; Inge W.M. van Uden; Lucas J.B. van Oudheusden; Rob A.R. Gons; David G. Norris; Marcel P. Zwiers; Frank-Erik de Leeuw (401-407).
Cerebral small vessel disease (SVD) is very common in elderly and related to cognition, although this relation is weak. This might be because the underlying pathology of white matter lesions (WML) is diverse and cannot be properly appreciated with conventional FLAIR MRI. In addition, conventional MRI is not sensitive to early loss of microstructural integrity of the normal appearing white matter (NAWM), which might be an important factor. Diffusion tensor imaging (DTI) provides alternative information on microstructural white matter integrity and we have used this to investigate the relation between white matter integrity, in both WML and NAWM, and cognition among elderly with cerebral SVD.The RUN DMC study is a prospective cohort study among 503 independently living, non-demented elderly with cerebral SVD aged between 50 and 85 years. All subjects underwent MRI and DTI scanning. WML were segmented manually. We measured mean diffusivity (MD) and fractional anisotropy (FA), as assessed by DTI in both WML and NAWM.Inverse relations were found between MD in the WML and NAWM and global cognitive function (β = −.11, p < 0.05; β = −.18, p < 0.001), psychomotor speed (β = −.15, p < 0.01; β = −.18, p < 0.001), concept shifting (β = −.11, p < 0.05; β = −.10, p < 0.05) and attention (β = −.12, p < 0.05; β = −.15, p < 0.001). The relation between DTI parameters in both WML and NAWM and cognitive performance was most pronounced in subjects with severe WML.DTI parameters in both WML and NAWM correlate with cognitive performance, independent of SVD. DTI may be a promising tool in exploring the mechanisms of cognitive decline and could function as a surrogate marker for disease progression in therapeutic trials.This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.► Conventional MRI is not sensitive to loss of white matter microstructural integrity. ► DTI provides alternative information on microstructural white matter integrity. ► DTI parameters in WML and NAWM are related to cognition independent of SVD. ► DTI may be a promising tool in exploring the mechanisms of cognitive decline in SVD. ► The NAWM is not as ‘normal’ as it looks like.
Keywords: Cerebral small vessel disease; Diffusion tensor imaging (DTI); Cognitive performance; White matter structural integrity; White matter lesion; Normal appearing white matter;

Aging is associated with declining cognitive performance as well as structural changes in brain gray and white matter (WM). The WM deterioration contributes to a disconnection among distributed brain networks and may thus mediate age-related cognitive decline. The present diffusion tensor imaging (DTI) study investigated age-related differences in WM microstructure and their relation to cognition (episodic memory, visuospatial processing, fluency, and speed) in a large group of healthy subjects (n = 287) covering 6 decades of the human life span. Age related decreases in fractional anisotropy (FA) and increases in mean diffusivity (MD) were observed across the entire WM skeleton as well as in specific WM tracts, supporting the WM degeneration hypothesis. The anterior section of the corpus callosum was more susceptible to aging compared to the posterior section, lending support to the anterior–posterior gradient of WM integrity in the corpus callosum. Finally, and of critical interest, WM integrity differences were found to mediate age-related reductions in processing speed but no significant mediation was found for episodic memory, visuospatial ability, or fluency. These findings suggest that compromised WM integrity is not a major contributing factor to declining cognitive performance in normal aging. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.► We report causal role of WM integrity in age-related differences in processing speed. ► Age related decreases in FA and increases in MD were observed. ► The anterior section of the corpus callosum was more susceptible to aging. ► Compromised WM integrity is not a major contributing factor to declining cognitive performance in normal aging.
Keywords: White matter; Cognition; Aging; Mediation; DTI;

White matter integrity and vulnerability to Alzheimer's disease: Preliminary findings and future directions by Brian T. Gold; Nathan F. Johnson; David K. Powell; Charles D. Smith (416-422).
Neuroimaging biomarkers that precede cognitive decline have the potential to aid early diagnosis of Alzheimer's disease (AD). A body of diffusion tensor imaging (DTI) work has demonstrated declines in white matter (WM) microstructure in AD and its typical prodromal state, amnestic mild cognitive impairment. The present review summarizes recent evidence suggesting that WM integrity declines are present in individuals at high AD-risk, prior to cognitive decline. The available data suggest that AD-risk is associated with WM integrity declines in a subset of tracts showing decline in symptomatic AD. Specifically, AD-risk has been associated with WM integrity declines in tracts that connect gray matter structures associated with memory function. These tracts include parahippocampal WM, the cingulum, the inferior fronto-occipital fasciculus, and the splenium of the corpus callosum. Preliminary evidence suggests that some AD-risk declines are characterized by increases of radial diffusivity, raising the possibility that a myelin-related pathology may contribute to AD onset. These findings justify future research aimed at a more complete understanding of the neurobiological bases of DTI-based declines in AD. With continued refinement of imaging methods, DTI holds promise as a method to aid identification of presymptomatic AD. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.► Review focuses on diffusion tensor imaging (DTI) studies of normal subjects before symptoms of Alzheimer’s disease (AD). ► Summarizes risk factors of AD, and DTI methodology. ► Summarizes evidence that white matter (WM) integrity changes are present in normal persons at high-AD risk. ► These findings have the potential to aid early diagnosis of AD. ► Future research should determine if DTI changes reflect classic AD pathologies, or other WM pathologies.
Keywords: DTI; Diffusion tensor imaging; APOE; Presymptomatic; Alzheimer's; Alzheimer's risk;

Selective changes in white matter integrity in MCI and older adults with cognitive complaints by Yang Wang; John D. West; Laura A. Flashman; Heather A. Wishart; Robert B. Santulli; Laura A. Rabin; Nadia Pare; Konstantinos Arfanakis; Andrew J. Saykin (423-430).
White matter changes measured using diffusion tensor imaging have been reported in Alzheimer's disease and amnestic mild cognitive impairment, but changes in earlier pre-mild cognitive impairment stages have not been fully investigated.In a cross-sectional analysis, older adults with mild cognitive impairment (n = 28), older adults with cognitive complaints but without psychometric impairment (n = 29) and healthy controls (n = 35) were compared. Measures included whole-brain diffusion tensor imaging, T1-weighted structural magnetic resonance imaging, and neuropsychological assessment. Diffusion images were analyzed using Tract-Based Spatial Statistics. Voxel-wise fractional anisotropy and mean, axial, and radial diffusivities were assessed and compared between groups. Significant tract clusters were extracted in order to perform further region of interest comparisons. Brain volume was estimated using FreeSurfer based on T1 structural images.The mild cognitive impairment group showed lower fractional anisotropy and higher radial diffusivity than controls in bilateral parahippocampal white matter. When comparing extracted diffusivity measurements from bilateral parahippocampal white matter clusters, the cognitive complaint group had values that were intermediate to the mild cognitive impairment and healthy control groups. Group difference in diffusion tensor imaging measures remained significant after controlling for hippocampal atrophy. Across the entire sample, diffusion tensor imaging indices in parahippocampal white matter were correlated with memory function.These findings are consistent with previous results showing changes in parahippocampal white matter in Alzheimer's disease and mild cognitive impairment compared to controls. The intermediate pattern found in the cognitive complaint group suggests the potential of diffusion tensor imaging to contribute to earlier detection of neurodegenerative changes during prodromal stages. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.► MCI patients show abnormalities in parahippocampal white matter (WM) tracts. ► Elders with cognitive complaints show intermediate changes relative to MCI and controls. ► Alteration in WM in prodromal AD is independent of gray matter degeneration.
Keywords: Alzheimer's disease; Diffusion tensor imaging; Mild cognitive impairment; Hippocampus; Memory; Diffusivity;

Imaging the default mode network in aging and dementia by Anne Hafkemeijer; Jeroen van der Grond; Serge A.R.B. Rombouts (431-441).
Although in the last decade brain activation in healthy aging and dementia was mainly studied using task-activation fMRI, there is increasing interest in task-induced decreases in brain activity, termed deactivations. These deactivations occur in the so-called default mode network (DMN). In parallel a growing number of studies focused on spontaneous, ongoing ‘baseline’ activity in the DMN. These resting state fMRI studies explored the functional connectivity in the DMN. Here we review whether normal aging and dementia affect task-induced deactivation and functional connectivity in the DMN. The majority of studies show a decreased DMN functional connectivity and task-induced DMN deactivations along a continuum from normal aging to mild cognitive impairment and to Alzheimer's disease (AD). Even subjects at risk for developing AD, either in terms of having amyloid plaques or carrying the APOE4 allele, showed disruptions in the DMN. While fMRI is a useful tool for detecting changes in DMN functional connectivity and deactivation, more work needs to be conducted to conclude whether these measures will become useful as a clinical diagnostic tool in AD. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.► Aging and dementia: altered deactivation in the brain's default mode network (DMN). ► Altered (mostly decreased) functional connectivity in the DMN in aging and dementia. ► Subjects at risk for dementia: altered deactivation and functional connectivity. ► DMN fMRI is relevant for studying (early) AD and for monitoring progression.
Keywords: Aging; Dementia; Default mode network; fMRI; Functional connectivity; Deactivation;

Functional magnetic resonance imaging of semantic memory as a presymptomatic biomarker of Alzheimer's disease risk by Michael A. Sugarman; John L. Woodard; Kristy A. Nielson; Michael Seidenberg; J. Carson Smith; Sally Durgerian; Stephen M. Rao (442-456).
Extensive research efforts have been directed toward strategies for predicting risk of developing Alzheimer's disease (AD) prior to the appearance of observable symptoms. Existing approaches for early detection of AD vary in terms of their efficacy, invasiveness, and ease of implementation. Several non-invasive magnetic resonance imaging strategies have been developed for predicting decline in cognitively healthy older adults. This review will survey a number of studies, beginning with the development of a famous name discrimination task used to identify neural regions that participate in semantic memory retrieval and to test predictions of several key theories of the role of the hippocampus in memory. This task has revealed medial temporal and neocortical contributions to recent and remote memory retrieval, and it has been used to demonstrate compensatory neural recruitment in older adults, apolipoprotein E ε4 carriers, and amnestic mild cognitive impairment patients. Recently, we have also found that the famous name discrimination task provides predictive value for forecasting episodic memory decline among asymptomatic older adults. Other studies investigating the predictive value of semantic memory tasks will also be presented. We suggest several advantages associated with the use of semantic processing tasks, particularly those based on person identification, in comparison to episodic memory tasks to study AD risk. Future directions for research and potential clinical uses of semantic memory paradigms are also discussed. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.► Person identity presents an opportunity to study semantic memories of different ages. ► Semantic processing tasks may function as an fMRI biomarker for cognitive decline. ► Semantic tasks present advantages over episodic tasks for studying aging and AD risk. ► Optimal prediction of risk may include a combination of variables.
Keywords: fMRI; Semantic memory; Person identification; Alzheimer's disease; Cognitive decline; Prediction;

Empirical derivation of the reference region for computing diagnostic sensitive 18fluorodeoxyglucose ratios in Alzheimer's disease based on the ADNI sample by Jerod M. Rasmussen; Anita Lakatos; Theo G.M. van Erp; Frithjof Kruggel; David B. Keator; James T. Fallon; Fabio Macciardi; Steven G. Potkin (457-466).
Careful selection of the reference region for non-quantitative positron emission tomography (PET) analyses is critically important for Region of Interest (ROI) data analyses. We introduce an empirical method of deriving the most suitable reference region for computing neurodegeneration sensitive 18fluorodeoxyglucose (FDG) PET ratios based on the dataset collected by the Alzheimer's Disease Neuroimaging Initiative (ADNI) study. Candidate reference regions are selected based on a heat map of the difference in coefficients of variation (COVs) of FDG ratios over time for each of the Automatic Anatomical Labeling (AAL) atlas regions normalized by all other AAL regions. Visual inspection of the heat map suggests that the portion of the cerebellum and vermis superior to the horizontal fissure is the most sensitive reference region. Analyses of FDG ratio data show increases in significance on the order of ten-fold when using the superior portion of the cerebellum as compared with the traditionally used full cerebellum. The approach to reference region selection in this paper can be generalized to other radiopharmaceuticals and radioligands as well as to other disorders where brain changes over time are hypothesized and longitudinal data is available. Based on the empirical evidence presented in this study, we demonstrate the usefulness of the COV heat map method and conclude that intensity normalization based on the superior portion of the cerebellum may be most sensitive to measuring change when performing longitudinal analyses of FDG-PET ratios as well as group comparisons in Alzheimer's disease. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.Display Omitted► This study investigates reference region selection in quantifying Alzheimer's disease using 18fluorodeoxyglucose PET. ► A novel approach using coefficients of variation and emphasizing a longitudinal design was used. ► Superior portion of the cerebellum was shown to be stable over time. ► Superior portion of the cerebellum was found to be the most sensitive to detecting changes over time. ► Superior portion of the cerebellum was identified as the most effective region for detecting group differences.
Keywords: PET; FDG; Ratio; ADNI; Reference; Normalization;

Exploring the neural basis of cognitive reserve in aging by Jason Steffener; Yaakov Stern (467-473).
The concept of reserve arose from the mismatch between the extent of brain changes or pathology and the clinical manifestations of these brain changes. The cognitive reserve hypothesis posits that individual differences in the flexibility and adaptability of brain networks underlying cognitive function may allow some people to cope better with brain changes than others. Although there is ample epidemiologic evidence for cognitive reserve, the neural substrate of reserve is still a topic of ongoing research. Here we review some representative studies from our group that exemplify possibilities for the neural substrate of reserve including neural reserve, neural compensation, and generalized cognitive reserve networks. We also present a schematic overview of our ongoing research in this area. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.►Reserve addresses discontinuities between brain change and its clinical consequences. ►Cognitive reserve refers to the flexibility or efficiency of cognitive networks. ►The neural implementation of cognitive reserve is a topic of research. ►Our current research strategy for investigating cognitive reserve is presented.
Keywords: Aging; fMRI; Cognition;

The influence of exercise on brain aging and dementia by Nicola T. Lautenschlager; Kay Cox; Elizabeth V. Cyarto (474-481).
Physical activity has been recognized as an important protective factor reducing disability and mortality and therefore it is focus of many health promotion activities at all ages. More recently a growing body of literature is focusing whether physical activity could also have a positive impact on brain aging with exploring healthy brain aging as well as on cognitive impairment and dementia. An increasing number of prospective studies and randomized controlled trials involving humans take place both with older adults with normal cognition as well as with mild cognitive impairment or dementia. However, the body of evidence is still sparse and many methodological issues make comparisons across studies challenging. Increasingly research into underlying mechanisms in relation to physical activity and brain aging identify biomarker candidates with especially neuroimaging measurements being more used in trials with humans. Whilst the evidence base is slowly growing more detailed research is needed to address methodological issues to finally achieve clinical relevance. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.► Physical activity has many health benefits. ► Recently there has been a research focus on investigating the association between physical activity and brain aging. ► Neuroimaging methods are now more often used for clinical trials. ► The evidence is still limited in regards to whether physical activity might be protective for cognitive decline and dementia. ► More studies and trials are needed with high-quality methodology.
Keywords: Physical activity; Exercise; Cognition; Cognitive impairment; Dementia; Alzheimer's disease;

Leisure activities, cognition and dementia by Hui-Xin Wang; Weili Xu; Jin-Jing Pei (482-491).
Accumulated evidence shows that leisure activities have a positive impact on cognitive function and dementia. This review aimed to systematically summarize the current evidence on this topic taking into account the limitations of the studies and biological plausibility for the underlying mechanisms linking cognition, dementia and leisure activities, with special attention on mental, physical and social activities. We included only longitudinal studies, with a follow-up time of at least 2 years, published in English from 1991 to March 2011 on leisure activities and cognition (n = 29) or dementia (n = 23) and provided some evidence from intervention studies on the topic. A protective effect of mental activity on cognitive function has been consistently reported in both observational and interventional studies. The association of mental activity with the risk of dementia was robust in observational studies but inconsistent in clinical trials. The protective effect of physical activity on the risk of cognitive decline and dementia has been reported in most observational studies, but has been less evident in interventional studies. Current evidence concerning the beneficial effect of other types of leisure activities on the risk of dementia is still limited and results are inconsistent. For future studies it is imperative that the assessment of leisure activities is standardized, for example, the frequency, intensity, duration and the type of activity; and also that the cognitive test batteries and the definition of cognitive decline are harmonized/standardized. Further, well designed studies with long follow-up times are necessary. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.► We summarized the evidence of the influence of leisure activities on dementia risk. ► Mental activity may protect against dementia and cognitive decline. ► The beneficial effect of physical activity on dementia risk needs to be confirmed. ► The protective role of other types of leisure activities to date is insufficient.
Keywords: Cognitive function; Dementia; Leisure activity; Mental activity; Physical activity; Social activity;