Striatal and cerebellar vesicular acetylcholine transporter expression is disrupted in human DYT1 dystonia.

Early-onset torsion dystonia (TOR1A/DYT1) is a devastating hereditary motor disorder whose pathophysiology remains unclear. Studies in transgenic mice suggested abnormal cholinergic transmission in the putamen, but this has not yet been demonstrated in humans. The role of the cerebellum in the pathophysiology of the disease has also been highlighted but the involvement of the intrinsic cerebellar cholinergic system is unknown. In this study, cholinergic neurons were imaged using PET with 18F-fluoroethoxybenzovesamicol, a radioligand of the vesicular acetylcholine transporter (VAChT). Here, we found an age-related decrease in VAChT expression in the posterior putamen and caudate nucleus of DYT1 patients versus matched controls, with low expression in young but not in older patients. In the cerebellar vermis, VAChT expression was also significantly decreased in patients versus controls, but independently of age. Functional connectivity within the motor network studied in MRI and the interregional correlation of VAChT expression studied in PET were also altered in patients. These results show that the cholinergic system is disrupted in the brain of DYT1 patients and is modulated over time through plasticity or compensatory mechanisms.

Resting Heart Rate Predicts Depression and Cognition Early after Ischemic Stroke: A Pilot Study.

BACKGROUND: Early detection of poststroke depression (PSD) and cognitive impairment (PSCI) remains challenging. It is well documented that the function of autonomic nervous system is associated with depression and cognition. However, their relationship has never been investigated in the early poststroke phase. This pilot study aimed at determining whether resting heart rate (HR) parameters measured in early poststroke phase (1) are associated with early-phase measures of depression and cognition and (2) could be used as new tools for early objective prediction of PSD or PSCI, which could be applicable to patients unable to answer usual questionnaires. METHODS: Fifty-four patients with first-ever ischemic stroke, without cardiac arrhythmia, were assessed for resting HR and heart rate variability (HRV) within the first week after stroke and for depression and cognition during the first week and at 3 months after stroke. RESULTS: Multiple regression analyses controlled for age, gender, and stroke severity revealed that higher HR, lower HRV, and higher sympathovagal balance (low-frequency/high-frequency ratio of HRV) were associated with higher severity of depressive symptoms within the first week after stroke. Furthermore, higher sympathovagal balance in early phase predicted higher severity of depressive symptoms at the 3-month follow-up, whereas higher HR and lower HRV in early phase predicted lower global cognitive functioning at the 3-month follow-up. CONCLUSIONS: Resting HR measurements obtained in early poststroke phase could serve as an objective tool, applicable to patients unable to complete questionnaires, to help in the early prediction of PSD and PSCI.

Semantic retrieval over time in the aging brain: Structural evidence of hippocampal contribution.

This study investigates relationship between regional cerebral volumes and performances over time of a categorical fluency task, in a sample of older adults (n = 316). Using voxel-wise technique, the relationship between local grey matter volume and Isaacs Set Test (IST) scores at its early (first 15 sec) and late (last 15 sec) phase production was analyzed with a linear regression model adjusting for age, sex, educational level, ApoEɛ4 allele, handedness and Grey Matter atrophy. Lower early IST scores were associated with smaller volumes in bilateral inferior frontal gyri and in right thalamus, whereas lower late IST scores were associated to smaller left inferior parietal gyrus and left anterior hippocampus. An analysis based on automatic segmentation of hippocampus confirmed the latest relationship which cannot be attributed to the correlation of each variable with global cognitive impairment because it remained when MMSE was accounted for. We observed a switch from frontal to temporo-parietal regions as words retrieval become more difficult over time. Automatic speech production of the early phase of the category fluency task is dependent on executive networks integrity whereas controlled speech production of the late phase is dependent on memory networks integrity, including left hippocampus. These results are concordant with recent imaging studies expanding the implication of hippocampus to semantic memory performances and they underlie the need to consider verbal fluency task over time.

fMRI identifies the right inferior frontal cortex as the brain region where time interval processing is altered by negative emotional arousal.

The reason why human beings are inclined to overestimate the duration of highly arousing negative events remains enigmatic. The issue about what neurocognitive mechanisms and neural structures support the connection between time perception and emotion was addressed here by an event-related neuroimaging study involving a localizer task, followed by the main experiment. The localizer task, in which participants had to categorize either the duration or the average color of visual stimuli aimed at identifying the neural structures constitutive of a duration-specific network. The aim of the main experiment, in which participants had to categorize the presentation time of either neutral or emotionally negative visual stimuli, was to unmask which parts of the previously identified duration-specific network are sensitive to emotionally negative arousal. The duration-specific network that we uncovered from the localizer task comprised the cerebellum bilaterally as well as the orbitofrontal, the anterior cingulate, the anterior insular, and the inferior frontal cortices in the right hemisphere. Strikingly, the imaging data from the main experiment underscored that the right inferior frontal cortex (IFC) was the only region within the duration-specific network whose activity was increased in the face of emotionally negative pictures compared to neutral ones. Remarkably too, the extent of neural activation induced by emotionally negative pictures (compared to neutral ones) in this region correlated with a behavioral index reflecting the extent to which emotionally negative pictures were overestimated compared to neutral ones. The results are discussed in relation to recent models and studies suggesting that the right anterior insular cortex/IFC is of central importance in time perception.

Detection of Alzheimer's disease signature in MR images seven years before conversion to dementia: Toward an early individual prognosis.

Finding very early biomarkers of Alzheimer's Disease (AD) to aid in individual prognosis is of major interest to accelerate the development of new therapies. Among the potential biomarkers, neurodegeneration measurements from MRI are considered as good candidates but have so far not been effective at the early stages of the pathology. Our objective is to investigate the efficiency of a new MR-based hippocampal grading score to detect incident dementia in cognitively intact patients. This new score is based on a pattern recognition strategy, providing a grading measure that reflects the similarity of the anatomical patterns of the subject under study with dataset composed of healthy subjects and patients with AD. Hippocampal grading was evaluated on subjects from the Three-City cohort, with a followup period of 12 years. Experiments demonstrate that hippocampal grading yields prediction accuracy up to 72.5% (P < 0.0001) 7 years before conversion to AD, better than both hippocampal volume (58.1%, P = 0.04) and MMSE score (56.9%, P = 0.08). The area under the ROC curve (AUC) supports the efficiency of imaging biomarkers with a gain of 8.4 percentage points for hippocampal grade (73.0%) over hippocampal volume (64.6%). Adaptation of the proposed framework to clinical score estimation is also presented. Compared with previous studies investigating new biomarkers for AD prediction over much shorter periods, the very long followup of the Three-City cohort demonstrates the important clinical potential of the proposed imaging biomarker. The high accuracy obtained with this new imaging biomarker paves the way for computer-based prognostic aides to help the clinician identify cognitively intact subjects that are at high risk to develop AD.

Gray matter characteristics associated with trait anxiety in older adults are moderated by depression.

BACKGROUND: Structural gray matter characteristics of anxiety remain unclear. The aim of this study was to assess the influence of current depressive symptoms and history of depression on the gray matter characteristics of trait anxiety. METHODS: Structural magnetic resonance imaging (MRI) data from 393 individuals aged 65 years or older were used. Regions of interest (ROIs) included the amygdala, anterior cingulate cortex (ACC), insula, orbitofrontal cortex (OFC), and temporal cortex. Trait anxiety was measured by the State-Trait Anxiety Inventory (STAI). Depression and depressive symptoms were measured using DSM-IV criteria and the Center for Epidemiological Studies Depression Scale (CESD). RESULTS: After adjustments for sociodemographics and health-related variables, anxiety had a significant influence on the gray matter characteristics in all cortical ROIs. First, in participants without depression antecedents, higher trait anxiety was associated with a larger cortical thickness in all cortical ROIs. Second, in participants with a previous history of depression, higher trait anxiety was associated with a smaller cortical thickness in all cortical ROIs. CONCLUSIONS: These results suggest that anxiety is related to cortical thickness differently in healthy older adults and in older adults with psychiatric antecedents. Anxiety associated with thinner cortical areas could reflect symptoms of a specific type of depression or a vulnerability to develop depression.

Mediterranean diet and preserved brain structural connectivity in older subjects.

INTRODUCTION: The Mediterranean diet (MeDi) has been related to a lower risk of Alzheimer's disease; yet, the underlying mechanisms are unknown. We hypothesized that protection against neurodegeneration would translate into higher gray matter volumes, whereas a specific association with preserved white matter microstructure would suggest alternative mechanisms (e.g., vascular pathways). METHODS: We included 146 participants from the Bordeaux Three-City study nondemented when they completed a dietary questionnaire and who underwent a 3-T magnetic resonance imaging at an average of 9 years later, including diffusion tensor imaging. RESULTS: In multivariate voxel-by-voxel analyses, adherence to the MeDi was significantly associated with preserved white matter microstructure in extensive areas, a gain in structural connectivity that was related to strong cognitive benefits. In contrast, we found no relation with gray matter volumes. DISCUSSION: The MeDi appears to benefit brain health through preservation of structural connectivity. Potential mediation by a favorable impact on brain vasculature deserves further research.

Time course of brain volume changes in the preclinical phase of Alzheimer's disease.

BACKGROUND: Structural alterations of a large network characterize Alzheimer's disease (AD), but the time course of these changes remains unclear. The dynamic of these alterations was examined in the AD preclinical phase using data from the 10-year follow-up of a population-based cohort (Bordeaux-3City). METHODS: Participants received neuropsychological assessments every 2 years and two identical magnetic resonance imaging (MRI) exams at baseline and 4 years later. Twenty-five incident AD cases were compared with 319 subjects who remained free of dementia. Subjects were free of dementia at baseline and at follow-up MRI. Incident AD occurred after these time points. RESULTS: At baseline, incident AD already presented smaller volumes only in the left amygdalo-hippocampal complex. Moreover, a higher annual rate of atrophy of the temporoparietal cortices was observed in future AD subjects during the following 4 years. CONCLUSION: Incident AD cases present mediotemporal lesions up to 5 years before diagnosis. This neurodegenerative process seems to progressively reach the temporoparietal cortices in the AD preclinical phase.

Improvement of in vivo quantification of [123I]-Iodobenzovesamicol in single-photon emission computed tomography/computed tomography using anatomic image to brain atlas nonrigid registration.

Brain anatomy variability is a major problem in quantifying functional images in nuclear medicine, in particular relative to aging and neurodegenerative diseases. The aim of this study was to compare affine and elastic model-based methods for magnetic resonance imaging (MRI) to brain atlas registration and to assess their impact on the quantification of cholinergic neurotransmission. Patients with multiple system atrophy (MSA) and age-matched healthy subjects underwent an MRI and a single-photon emission computed tomographic (SPECT) examination using [123I]-iodobenzovesamicol (IBVM). Both affine and elastic methods were compared to register the subjects' MRI with the Montreal Neurological Institute brain atlas. Performance of the registration accuracy was quantitatively assessed and the impact on the IBVM quantification was studied. For both subject groups, elastic registration achieved better quantitative performance compared to the affine model. For patients suffering from neurogenerative disease, this study demonstrates the importance and relevance of MRI to atlas registration in quantification of neuronal integrity. In this context, in comparison with rigid registrations, an elastic model-based registration provides the best relocation of the brain structures to the atlas for accurately quantifying cholinergic neurotransmission.

Psychological and neuropsychological correlates of dependence-related behaviour in medication overuse headaches: a one year follow-up study.

BACKGROUND: Medication Overuse Headache (MOH) can be related in some patients to dependence-related behaviour characterised by craving, a deficit in controlling substance intake, which is associated to orbitofrontal cortex (OFC) dysfunction. The aim of this study was to explore the psychological correlates in MOH patients and the functioning of the OFC through neuropsychological assessment (Iowa Gambling Task: IGT) and to relate it to prognosis at a one year follow-up point. FINDINGS: Seventeen subjects suffering from probable MOH were included and compared to 19 migraineurs and to 17 controls. The results show significant between group differences for behavioural dependence, depression, anxiety, catastrophizing. There were no between group differences for impulsivity. Mean IGT score did not allow differentiation of MOH patients from the other groups, whereas the score was significantly different between opiate abusers and other medication abusers (45 +/-5.7 versus 57.1 +/-8.2, p = 0.019). Among the clinical variables rated at inclusion, the amount of acute headache medication taken per month was the only one predicting the prognosis (RR = 1.05, 95% CI = 1-1.06, p = 0.04). A slight increase in risk of relapse at 1 year was observed in patients with poorer IGT scores (RR = 0.92, 95% CI = 0.85-1, p = 0.05) and higher behavioural-dependence scores (RR = 1.07, 95% CI = 1-1.14, p = 0.05). None of the other psychological variables predicted relapse risk. CONCLUSIONS: These results must be interpreted with caution due to the low number of subjects. They showed a deficit in decision making processes in MOH patients who overuse medications containing psychoactive substances like opiates. Moreover dependence-related variables are related to the prognosis.

Subacute default mode network dysfunction in the prediction of post-stroke depression severity.

PURPOSE: To identify patterns of rest functional connectivity (FC) in the whole brain with the default mode network (DMN) soon after stroke and to explore the predictive accuracy of the strength of rest FC in specific areas on poststroke severity of depression and anxiety symptoms. MATERIALS AND METHODS: The protocol was accepted by the local ethics board, and all patients provided informed consent to participate. Resting-state functional magnetic resonance (MR) images were acquired 10 days after a first stroke in 24 patients without a history of psychiatric illness. Independent component analysis was used to isolate the DMN in each subject. Hamilton Depression Rating Scale (HDRS) 17 and Hamilton Anxiety Rating Scale (HARS) were recorded 10 days and 3 months after the stroke. Associations between severity of anxiety or depression symptoms and DMN functional connectivity were investigated with whole-brain analyses by using statistical parametric mapping software and were adjusted for age, sex, manual laterality, and National Institutes of Health Stroke Severity scores. Correlations were considered significant if P<.001, with a cluster size of more than 50 voxels. RESULTS: Ten days after stroke, anxiety severity was correlated with functional connectivity in the middle temporal cortex and the anterior midcingulate cortex, while at 3 months after stroke, a correlation was observed with the middle temporal cortex and the posterior cingulate cortex. Poststroke depressive symptom severity did not correlate with functional connectivity changes at 10-day follow-up, while the HDRS 17 score was correlated with functional connectivity in the left middle temporal cortex and precuneus at 3-month follow-up. CONCLUSION: These results suggest that a dysfunction of DMN functional connectivity involved in emotional control is associated with the severity of poststroke depression. Further studies are necessary to determine the mechanisms of this functional impairment.

Progressive supranuclear palsy: in vivo SPECT imaging of presynaptic vesicular acetylcholine transporter with [123I]-iodobenzovesamicol.

PURPOSE: To evaluate the integrity of brain cholinergic pathways in vivo in patients with progressive supranuclear palsy (PSP) by measuring the vesicular acetylcholine transporter expression at single photon emission computed tomography (SPECT) with [123I]-iodobenzovesamicol. MATERIALS AND METHODS: All participants provided informed written consent according to institutional human ethics committee guidelines. Ten patients with PSP and 12 healthy volunteers underwent dynamic [123I]-iodobenzovesamicol SPECT and magnetic resonance (MR) imaging. CT and MR images were used to register the dynamic SPECT image to the Montreal Neurologic Institute brain template, which includes the regions of interest of the striatum and the septo-hippocampal, innominato-cortical, and ponto-thalamic cholinergic pathways. For each region of interest, pharmacokinetic modeling of regional time activity curves was used to calculate [123I]-iodobenzovesamicol to vesicular acetylcholine transporter binding potential value, proportional to vesicular acetylcholine transporter expression. RESULTS: When compared with control participants, patients with PSP had binding potential values that were unchanged in the striatum and septohippocampal pathway, significantly lower in the anterior cingulate cortex (P=.017) in the innominatocortical pathway, and significantly decreased in the thalamus (P=.014) in the pontothalamic cholinergic pathway. In addition, binding potential values in the thalamus were positively correlated with those in the pedunculopontine nucleus (ρ=0.81, P<.004) and binding potential values in both the thalamus (ρ=-0.88, P<.001) and pedunculopontine nucleus (ρ=-0.80, P<.010) were inversely correlated with disease duration. CONCLUSION: Cholinergic pathways were differentially affected in the PSP group, with a significant alteration of pontothalamic pathways that increased with disease progression at both cell body and terminal levels, while the innominatocortical pathway was only mildly affected, and the septohippocampal pathway and the striatum were both preserved.

(99m)Tc-MAG3-aptamer for imaging human tumors associated with high level of matrix metalloprotease-9.

The human matrix metalloprotease 9 (hMMP-9) is involved in many physiological processes such as tissue remodeling. Its overexpression in tumors promotes the release of cancer cells thus contributing to tumor metastasis. It is a relevant marker of malignant tumors. We selected an RNA aptamer containing 2'-fluoro, pyrimidine ribonucleosides, that exhibits a strong affinity for hMMP-9 (K(d) = 20 nM) and that discriminates other human MMPs: no binding was detected to either hMMP-2 or -7. Investigating the binding properties of different MMP-9 aptamer variants by surface plasmon resonance allowed the determination of recognition elements. As a result, a truncated aptamer, 36 nucleotides long, was made fully resistant to nuclease following the substitution of every purine ribonucleoside residue by 2'-O-methyl analogues and was conjugated to S-acetylmercaptoacetyltriglycine for imaging purposes. The resulting modified aptamer retained the binding properties of the originally selected sequence. Following (99m)Tc labeling, this aptamer was used for ex vivo imaging slices of human brain tumors. We were able to specifically detect the presence of hMMP-9 in such tissues.

Health and aging in elderly farmers: the AMI cohort.

BACKGROUND: The health of the agricultural population has been previously explored, particularly in relation to the farming exposures and among professionally active individuals. However, few studies specifically focused on health and aging among elders retired from agriculture. Yet, this population faces the long-term effects of occupational exposures and multiple difficulties related to living and aging in rural area (limited access to shops, services, and practitioners). However, these difficulties may be counter-balanced by advantages related to healthier lifestyle, richer social support and better living environment. The general aim of the AMI cohort was to study health and aging in elderly farmers living in rural area through a multidisciplinary approach, with a main focus on dementia. METHODS/DESIGN: The study initially included 1 002 participants, randomly selected from the Farmer Health Insurance rolls. Selection criteria were: being 65 years and older; living in rural area in Gironde (South-Western France); being retired from agriculture after at least 20 years of activity and being affiliated to the Health Insurance under own name. The study started in 2007, with two follow-up visits over 5 years. Baseline visits were conducted at home by a neuropsychologist then by a geriatrician for all cases suspected of dementia, Parkinson's disease and depression (to confirm the diagnosis), and by a nurse for others. A large panel of data were collected through standardised questionnaires: complete neuropsychological assessment, material and social living environment, psychological transition to retirement, lifestyle (smoking, alcohol and diet), medications, disability in daily living, sensory impairments and some clinical measures (blood pressure, depression symptomatology, anxiety, visual test, anthropometry...). A blood sampling was performed with biological measurements and constitution of a biological bank, including DNA. Brain MRI were also performed on 316 of the participants. Finally, the three-year data on health-related reimbursements were extracted from the Health System database (medications, medical and paramedical consultations, biological examinations and medical devices), and the registered Long-Term Diseases (30 chronic diseases 100% covered by the Insurance System). DISCUSSION: AMI is the first French longitudinal study on health and aging set up in a population of elderly farmers living in rural area through a multidisciplinary approach.

Silicon-based chemistry: an original and efficient one-step approach to [18F]-nucleosides and [18F]-oligonucleotides for PET imaging.

Take it eaSi! Nucleosides, dinucleotides, and one oligonucleotide, all modified by click chemistry, have for the first time been directly and very efficiently labeled with (18)F by using a silicon-based, one-step approach that opens the way for the development of a new class of positron emission tomography (PET) tracers (see graphic).

Design, synthesis and biological evaluation of choline based SPECT imaging agent: Ga(III)-DO3A-EA-Choline.

The enhanced choline uptake and phosphorylation in tumor cells has motivated the development of radiolabeled choline derivatives as diagnostic markers for imaging cell membrane proliferation and noninvasive detection of prostate, brain and breast tumors. In the present work, we report a facile strategy for the synthesis of choline functionalized macrocyclic chelating agent (DO3A-EA-choline) and its radiocomplexation with (67)Ga for potential tumor imaging applications. The synthesis of the desired compound featured quaternization of N,N-dimethylaminoethanol with 1,2-dibromoethane followed by subsequent alkylation with trisubstituted cyclen (DO3A). All intermediates and final compounds have been fully characterized by spectroscopic techniques, namely, (1)H, (13)C NMR and mass spectroscopy. The compound has been successively labeled with (67)Ga-citrate in ammonium acetate buffer (pH 6.5) at 80 °C. MTT assays have been performed on the HEK cell line to determine the cytotoxicity of the compound. Cell uptake studies carried out on the U-87 MG cell line exhibited saturable binding of the radioconjugate in picomolar range with a K(d) value of 0.528 pM. The in vivo biodistribution and blood kinetics studies exhibited rapid clearance of the radiolabeled complex and excretion through the renal and hepatobiliary route. The present studies demonstrate the potential applications of (67)Ga-DO3A-EA-choline as a radiopharmaceutical for molecular imaging using ((67/68)Ga) SPECT and PET modalities.

Age-related change in episodic memory: role of functional and structural connectivity between the ventral posterior cingulate and the parietal cortex.

While the neural correlates of age-related episodic memory decline have been extensively studied, the precise involvement of the Posterior Cingulate Cortex (PCC) and posterior parietal cortex (the precuneus and the angular gyrus), remains unclear. The present study examined functional and structural neural correlates of age-related episodic memory change assessed over 12 years in 120 older adults (range 76-90 years). Episodic memory performance was measured using the Free and Cued Selective Reminding Test (FCSRT); functional connectivity metrics were computed from resting-state fMRI images and structural connectivity metrics were assessed through microstructural properties of reconstructed tract using a native space pipeline. We found that FCSRT change was significantly associated with the functional connectivity between the ventral PCC and three parietal regions, the ventral superior, the inferior part of the precuneus, and the rostro dorsal part of the angular gyrus. This association was independent of hippocampal volume. In addition, we found the that change in FCSRT scores was associated with fractional anisotropy of the tract connecting the ventral PCC and the ventral superior part of the precuneus. Change in episodic memory in aging was therefore related to a combination of high functional connectivity and low structural connectivity between the ventral PCC and the ventral superior part of the precuneus.

Free water: A marker of age-related modifications of the cingulum white matter and its association with cognitive decline.

Diffusion MRI is extensively used to investigate changes in white matter microstructure. However, diffusion measures within white matter tissue can be affected by partial volume effects due to cerebrospinal fluid and white matter hyperintensities, especially in the aging brain. In previous aging studies, the cingulum bundle that plays a central role in the architecture of the brain networks supporting cognitive functions has been associated with cognitive deficits. However, most of these studies did not consider the partial volume effects on diffusion measures. The aim of this study was to evaluate the effect of free water elimination on diffusion measures of the cingulum in a group of 68 healthy elderly individuals. We first determined the effect of free water elimination on conventional DTI measures and then examined the effect of free water elimination on verbal fluency performance over 12 years. The cingulum bundle was reconstructed with a tractography pipeline including a white matter hyperintensities mask to limit the negative impact of hyperintensities on fiber tracking algorithms. We observed that free water elimination increased the ability of conventional DTI measures to detect associations between tissue diffusion measures of the cingulum and changes in verbal fluency in older individuals. Moreover, free water content and mean diffusivity measured along the cingulum were independently associated with changes in verbal fluency. This suggests that both tissue modifications and an increase in interstitial isotropic water would contribute to cognitive decline. These observations reinforce the importance of using free water elimination when studying brain aging and indicate that free water itself could be a relevant marker for age-related cingulum white matter modifications and cognitive decline.

Changes Over Time of Diffusion MRI in the White Matter of Aging Brain, a Good Predictor of Verbal Recall.

Objective: Extensive research using water-diffusion MRI reported age-related modifications of cerebral White Matter (WM). Moreover, water-diffusion parameter modifications have been frequently associated with cognitive performances in the elderly sample, reinforcing the idea of aging inducing microstructural disconnection of the brain which in turn impacts cognition. However, only few studies really assessed over-time modifications of these parameters and their relationship with episodic memory outcome of elderly. Materials and Methods: One-hundred and thirty elderly subjects without dementia (74.1 ± 4.1 years; 47% female) were included in this study. Diffusion tensor imaging (DTI) was performed at two-time points (3.49 ± 0.68 years apart), allowing the assessment of changes in water-diffusion parameters over time using a specific longitudinal pipeline. White matter hyperintensity (WMH) burden and gray matter (GM) atrophy were also measured on FLAIR and T1-weighted sequences collected during these two MRI sessions. Free and cued verbal recall scores assessed at the last follow-up of the cohort were used as episodic memory outcome. Changes in water-diffusion parameters over time were included in serial linear regression models to predict retrieval or storage ability of elderly. Results: GM atrophy and an increase in mean diffusivity (MD) and WMH load between the two-time points were observed. The increase in MD was significantly correlated with WMH load and the different memory scores. In models accounting for the baseline cognitive score, GM atrophy, or WMH load, MD changes still significantly predict free verbal recall, and not total verbal recall, suggesting the specific association with the retrieval deficit in healthy aging. Conclusion: In elderly, microstructural WM changes are good predictors of lower free verbal recall performances. Moreover, this contribution is not only driven by WMH load increase. This last observation is in line with studies reporting early water-diffusion modification in WM tissue during aging, resulting lately in the appearance of WMH on conventional MRI.