Baseline Findings of PreventE4: A Double-Blind Placebo Controlled Clinical Trial Testing High Dose DHA in APOE4 Carriers before the Onset of Dementia.

INTRODUCTION: Lower blood levels of the omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) are correlated with worse cognitive functions, particularly among APOE ε4 carriers. Whether DHA supplementation in APOE ε4 carriers with limited DHA consumption and dementia risk factors can delay or slow down disease progression when started before the onset of clinical dementia is not known. METHODS: PreventE4 is a double-blind, single site, randomized, placebo-controlled trial in cognitively unimpaired individuals with limited omega-3 consumption and dementia risk factors (n=368). Its objectives are to determine (1) whether carrying the APOE ε4 allele is associated with lower delivery of DHA to the brain; and (2) whether high dose DHA supplementation affects brain imaging biomarkers of AD and cognitive function. RESULTS: 365 cognitively unimpaired individuals between 55 and 80 (mean age 66) were randomized to 2 grams of DHA per day or identically appearing placebo for a period of 2 years. Half the participants were asked to complete lumbar punctures at baseline and 6-month visits to obtain cerebrospinal fluid (CSF). The primary trial outcome measure is the change in CSF DHA to arachidonic acid ratio after 6 months of the intervention (n=181). Secondary trial outcomes include the change in functional and structural connectivity using resting state functional MRI at 24 months (n=365). Exploratory outcomes include the change in Repeatable Battery of the Assessment of Neuropsychological Status at 24 months (n=365). CONCLUSIONS: Findings from PreventE4 will clarify the brain delivery of DHA in individuals carrying the APOE ε4 allele with implications for dementia prevention strategies. Trial was registered as NCT03613844.

Urine dicarboxylic acids change in pre-symptomatic Alzheimer's disease and reflect loss of energy capacity and hippocampal volume.

Non-invasive biomarkers will enable widespread screening and early diagnosis of Alzheimer's disease (AD). We hypothesized that the considerable loss of brain tissue in AD will result in detection of brain lipid components in urine, and that these will change in concert with CSF and brain biomarkers of AD. We examined urine dicarboxylic acids (DCA) of carbon length 3-10 to reflect products of oxidative damage and energy generation or balance that may account for changes in brain function in AD. Mean C4-C5 DCAs were lower and mean C7-C10 DCAs were higher in the urine from AD compared to cognitively healthy (CH) individuals. Moreover, mean C4-C5 DCAs were lower and mean C7-C9 were higher in urine from CH individuals with abnormal compared to normal CSF amyloid and Tau levels; i.e., the apparent urine changes in AD also appeared to be present in CH individuals that have CSF risk factors of early AD pathology. In examining the relationship between urine DCAs and AD biomarkers, we found short chain DCAs positively correlated with CSF Aß42, while C7-C10 DCAs negatively correlated with CSF Aß42 and positively correlated with CSF Tau levels. Furthermore, we found a negative correlation of C7-C10 DCAs with hippocampal volume (p < 0.01), which was not found in the occipital volume. Urine measures of DCAs have an 82% ability to predict cognitively healthy participants with normal CSF amyloid/Tau. These data suggest that urine measures of increased lipoxidation and dysfunctional energy balance reflect early AD pathology from brain and CSF biomarkers. Measures of urine DCAs may contribute to personalized healthcare by indicating AD pathology and may be utilized to explore population wellness or monitor the efficacy of therapies in clinical trials.

Review: Vascular dementia: clinicopathologic and genetic considerations.

The incidence and severity of cerebrovascular disease (CVD) increase with advancing age, as does the risk of developing Alzheimer's disease (AD). Not surprisingly, heterogeneous forms of CVD may coexist with AD changes in the 'ageing brain'. These include angiopathies (affecting both large and small arteries) that result from 'classical' risk factors (hypertension, smoking and diabetes) and others (cerebral amyloid angiopathy) that are biochemically closely linked to AD. The morphologic consequences of these various vascular diseases are infarcts and/or haemorrhages of varying sizes within the brain, which lead to neurocognitive decline that may mimic AD - though the vascular abnormalities are usually detectable by neuroimaging. More subtle effects of CVD may include neuroinflammation and biochemical 'lesions' that have no reliable morphologic correlate and thus escape the attention of even an experienced Neuropathologist. The pathogenesis of hippocampal injury resembling ischaemic change - commonly seen in the brains of geriatric subjects - remains controversial. In recent years, genetically determined forms of microangiopathy (e.g. CADASIL, CARASIL, Trex1-related microangiopathies, CARASAL, familial forms of cerebral amyloid angiopathy or CAA) have provided interesting cellular and molecular clues to the pathogenesis of sporadic microvascular disease such as arteriolosclerosis and AD-related CAA.

Particulate air pollutants, APOE alleles and their contributions to cognitive impairment in older women and to amyloidogenesis in experimental models.

Exposure to particulate matter (PM) in the ambient air and its interactions with APOE alleles may contribute to the acceleration of brain aging and the pathogenesis of Alzheimer's disease (AD). Neurodegenerative effects of particulate air pollutants were examined in a US-wide cohort of older women from the Women's Health Initiative Memory Study (WHIMS) and in experimental mouse models. Residing in places with fine PM exceeding EPA standards increased the risks for global cognitive decline and all-cause dementia respectively by 81 and 92%, with stronger adverse effects in APOE ɛ4/4 carriers. Female EFAD transgenic mice (5xFAD+/-/human APOE ɛ3 or ɛ4+/+) with 225 h exposure to urban nanosized PM (nPM) over 15 weeks showed increased cerebral ß-amyloid by thioflavin S for fibrillary amyloid and by immunocytochemistry for Aß deposits, both exacerbated by APOE ɛ4. Moreover, nPM exposure increased Aß oligomers, caused selective atrophy of hippocampal CA1 neurites, and decreased the glutamate GluR1 subunit. Wildtype C57BL/6 female mice also showed nPM-induced CA1 atrophy and GluR1 decrease. In vitro nPM exposure of neuroblastoma cells (N2a-APP/swe) increased the pro-amyloidogenic processing of the amyloid precursor protein (APP). We suggest that airborne PM exposure promotes pathological brain aging in older women, with potentially a greater impact in ɛ4 carriers. The underlying mechanisms may involve increased cerebral Aß production and selective changes in hippocampal CA1 neurons and glutamate receptor subunits.

Granulation of anaerobic sludge in the sulfate-reducing up-flow sludge bed (SRUSB) of SANI(®) process.

This study reports on anaerobic sludge granulation in a laboratory-scale sulfate-reducing up-flow sludge bed (SRUSB) in a novel sulfate reduction, autotrophic denitrification and nitrification integrated (SANI(®)) process for treatment of saline sewage. Granulation occurred in 30 d and reached full development in 90 d. The sulfate-reducing granules grew up to around 1 mm after 90 d with 21 mL/g SVI5 (sludge volume index measured after 5 min) and the biomass concentration reached 29 g/L after 4 months' operation. The reactor removed 89% chemical oxygen demand (COD) and reduced 75% sulfate within 1 h of hydraulic retention time, under a COD loading rate of up to 6.4 kg COD/(m(3) · d).

Industrial flue gas desulfurization waste may offer an opportunity to facilitate SANI® application for significant sludge minimization in freshwater wastewater treatment.

This paper reports an exploratory study on the use of a sulfite-rich industrial effluent to enable the integration of a sulfite-sulfide-sulfate cycle to the conventional carbon and nitrogen cycles in wastewater treatment to achieve sludge minimization through the non-sludge-producing Sulfate reduction, Autotrophic denitrification and Nitrification Integrated (SANI) process. A laboratory-scale sulfite reduction reactor was set up for treating sulfite-rich synthetic wastewater simulating the wastewater from industrial flue gas desulfurization (FGD) units. The results indicated that the sulfite reduction reactor can be started up within 11 d, which was much faster than that using sulfate. Thiosulfate was found to be the major sulfite reduction intermediate, accounting for about 30% of the total reduced sulfur in the reactor effluent, which may enable additional footprint reduction of the autotrophic denitrification reactor in the SANI process. This study indicated that it was possible to make use of the FGD effluent for applying the FGD-SANI process in treating freshwater-based sewage.

Walking stabilizes cognitive functioning in Alzheimer's disease (AD) across one year.

AD is a public health epidemic, which seriously impacts cognition, mood and daily activities; however, one type of activity, exercise, has been shown to alter these states. Accordingly, we sought to investigate the relationship between exercise and mood, in early-stage AD patients (N=104) from California, over a 1-year period. Patients completed the Mini-Mental State Examination (MMSE), Geriatric Depression Scale (GDS), and Blessed-Roth Dementia Rating Scale (BRDRS), while their caregivers completed the Yale Physical Activity Survey (YALE), Profile of Mood States (POMS), the Neuropsychiatric Inventory (NPI) and Functional Abilities Questionnaire (FAQ). Approximately half of the participants were female, from a variety of ethnic groups (Caucasian=69.8%; Latino/Hispanic Americans=20.1%). Our results demonstrated that the patients spent little time engaged in physical activity in general, their overall activity levels decreased over time, and this was paired with a change in global cognition (e.g., MMSE total score) and affect/mood (e.g., POMS score). Patients were parsed into Active and Sedentary groups based on their Yale profiles, with Active participants engaged in walking activities, weekly, over 1 year. Here, Sedentary patients had a significant decline in MMSE scores, while the Active patients had an attenuation in global cognitive decline. Importantly, among the Active AD patients, those individuals who engaged in walking for more than 2 h/week had a significant improvement in MMSE scores. Structured clinical trials which seek to increase the amount of time AD patients were engaged in walking activities and evaluate the nature and scope of beneficial effects in the brain are warranted.

Weight change associated with corticosteroid therapy in adolescents with systemic lupus erythematosus.

UNLABELLED: Physical appearance is very important to adolescents and weight gain secondary to corticosteroid (CS) treatment may have a direct impact on adolescent development. Understanding weight gain in adolescents with SLE who are being treated with CS will help clinicians develop strategies for prevention of nonadherence, obesity and eating disorders in this population. METHODS: Patients aged 11-18 years old with newly diagnosed SLE between January,1995 and December, 2006 were identified through the Rheumatology database at the Sickkids hospital, Canada. All charts were reviewed. Patients were categorized based on final BMI status as normal, overweight and obese. Risk factors for being obese were examined by logistic regression model analysis. RESULTS: Of 236 patients, 78% fulfilled the criteria. 85% were female with mean age at onset of diagnosis was 14 ± 1.7 years. Mean duration of CS treatment was 50 ± 31 months and mean cumulative CS dosage was 34.11 ± 32.7 g of prednisone. At baseline, 10% had BMI >25 kg/m(2) while at the end of the study, 20% were overweight and 10.4% were obese. In addition, 61% gained <10 kg while 15% gained ≥20 kg. Initial BMI was a significant predictors for final BMI (OR = 27.59, 95%CI = 6.04-126.09, p < .001) while male (OR = 8.50, 95%CI = 2.95-24.5, p < 0.000) and cumulative CS dosage (OR = 1.53, 95%CI = 1.05-2.23, p < .05) were the significant predictors for weight gain >10 kg. Duration of CS treatment did not correlate with obesity. CONCLUSION: Although a significant number of patients became overweight or obese after being treated with CS, most gained <10 kg. Obesity secondary to CS treatment in SLE patients was significantly correlated with baseline BMI, gender and cumulative CS dosage.

Is it feasible to discuss an advance directive with a Chinese patient with advanced malignancy? A prospective cohort study.

OBJECTIVES: Advance directives have been implemented for years in western countries, but the concept is new to Asian cultures. According to traditional Chinese culture, family members usually play a decisive role in a patient's treatment plan. Thus it may be hard to implement an advance directive despite its importance to the treatment of patients. The objectives of this study were to assess the feasibility of advance directive engagement and to explore significant contributing factors to achieving such a goal. DESIGN: Prospective cohort study. SETTING: Palliative Care Unit of Clinical Oncology, Tuen Mun Hospital, Hong Kong. PATIENTS: The subjects of the investigation were adult patients diagnosed to have advanced malignancy and newly referred to the hospice service from 24 April 2009 to 30 July 2009. Data were collected from nursing assessment forms, locally designed advance directive forms, a checklist completed by oncologists, and details available in the electronic hospital record. RESULTS: Of the 191 eligible patients, 120 (63%) had the advance directive, whereas 71 (37%) did not. In the Cox regression model, the patient having insight of a poor prognosis was the most significant factor facilitating advance directive engagement (P=0.001). Any family objection in the discussion of advance directives was also an important factor, though it did not reach statistical significance (P=0.082). Other factors like age, gender, education, religion, financial status, living environment, understanding the diagnosis, bereavement experience, type of cancer, nature of illness, courses of chemotherapy or radiotherapy received, main caregiver, in-house supporter, nurse-led clinic attendance, clinical psychologist consultation, and in-patient hospice nurse coordinator interview were all statistically insignificant. CONCLUSIONS: Our study demonstrated that it was feasible to discuss an advance directive with Chinese patients with advanced malignancy. When patients have insight about their poor prognosis and family members have no objection, it may be appropriate to discuss an advance directive.

Phosphorus release and uptake during start-up of a covered and non-aerated sequencing batch reactor with separate feeding of VFA and sulfate.

This study explored a sulfur cycle-associated biological phosphorus (P) removal process in a covered and non-aerated sequencing batch reactor (SBR) fed with volatile fatty acid (VFA) and sulfate separately. During the 60-day start-up, both phosphate release and uptake rates increased, while poly-phosphate cyclically increased and decreased accordingly. The P-release and P-uptake rates were associated with VFA uptake and sulfate reduction. The average ratio of potassium to phosphate during the P-uptake and P-release was also determined to be 0.29-0.31 mol K/mol P, which is close to a reported value (0.33) for biological phosphorus removal. All this evidence confirmed there was biological P removal in this reactor, in which metabolism could be different from conventional biological P removal.

Integration of seawater and grey water reuse to maximize alternative water resource for coastal areas: the case of the Hong Kong International Airport.

Development, population growth and climate change have pressurized water stress in the world. Being an urbanized coastal city, Hong Kong has adopted a dual water supply system since the 1950s for seawater toilet flushing for 80% of its 7 million inhabitants. Despite its success in saving 750,000 m(3)/day of freshwater, the saline sewage (consisting of about 20-30% of seawater) appears to have sacrificed the urban water cycle in terms of wastewater reuse and recycling. Can seawater toilet flushing be applied without affecting the urban water cycle with respect to sustainable water resource management? To address this issue, we examined the entire urban water cycle and developed an innovative water resource management system by integrating freshwater, seawater and reclaimed grey water into a sustainable, low-freshwater demand, low-energy consumption, and low-cost triple water supply (TWS) system. The applicability of this novel system has been demonstrated at the Hong Kong International Airport which reduced 52% of its freshwater demand.

Beyond-limit light focusing in the intermediate zone.

We experimentally verify that a new nanolens of a designed plasmonic aperture can focus visible light to a single line with its width smaller than the limit of half the wavelength in the intermediate zone. The experimental measurement indicates that while the near field plays a role to increase the spot size in the near zone, it is negligible at the beyond-limit focused region; i.e., the focused light is dominated by the radiative fields. The image taken by the optical microscope shows that the fields focused have propagated to the far zone. Besides being of academic interest, the nanolens capable in achieving a lower diffraction limit in the intermediate zone is important for application possibilities.

MRI shows more severe hippocampal atrophy and shape deformation in hippocampal sclerosis than in Alzheimer's disease.

While hippocampal atrophy is a key feature of both hippocampal sclerosis (HS) and Alzheimer's disease (AD), the pathology underlying this finding differs in these two conditions. In AD, atrophy is due primarily to loss of neurons and neuronal volume as a result of neurofibrillary tangle formation. While the etiology of HS is unknown, neuron loss in the hippocampus is severe to complete. We compared hippocampal volume and deformations from premortem MRI in 43 neuropathologically diagnosed cases of HS, AD, and normal controls (NC) selected from a longitudinal study of subcortical ischemic vascular disease (IVD Program Project). HS cases (n = 11) showed loss of neurons throughout the rostral-caudal extent of the hippocampus in one or both hemispheres. AD cases (n = 24) met NIA-Reagan criteria for high likelihood of AD. Normal control cases (n = 8) were cognitively intact and showed no significant AD or hippocampal pathology. The mean hippocampal volumes were significantly lower in HS versus AD groups (P < .001). Mean shape deformations in the CA1 and subiculum differed significantly between HS versus AD, HS versus NC, and AD versus NC (P < .0001). Additional study is needed to determine whether these differences will be meaningful for clinical diagnosis of individual cases.

An inverse association of cardiovascular risk and frontal lobe glucose metabolism.

OBJECTIVE: To investigate associations between vascular risk profile and cerebral glucose metabolism. METHODS: Subjects ranged from normal to having dementia (age >55 years) and underwent neuropsychological testing, MRI, and FDG PET scanning (n = 58). The Framingham Cardiovascular Risk Profile (FCRP) and its individual components were used as covariates in regression analyses with each PET scan using SPM2. RESULTS: Analyses revealed broad areas of the frontal lobe in which higher FCRP was associated with lower normalized glucose metabolism including the superior medial frontal, superior frontal and superior orbital frontal cortex and the ventrolateral prefrontal cortex. Significant associations were predominately found in the left hemisphere. Independent component analyses revealed interesting regions but further confirm the relevance of the integrative measure of coronary risk. CONCLUSIONS: Although the mechanism of this association bears further investigation, this finding provides further evidence that vascular risk factors have malignant effects on the brain, particularly in the prefrontal cortex.

Epigenetic-mediated dysfunction of the bone morphogenetic protein pathway inhibits differentiation of glioblastoma-initiating cells.

Despite similarities between tumor-initiating cells with stem-like properties (TICs) and normal neural stem cells, we hypothesized that there may be differences in their differentiation potentials. We now demonstrate that both bone morphogenetic protein (BMP)-mediated and ciliary neurotrophic factor (CNTF)-mediated Jak/STAT-dependent astroglial differentiation is impaired due to EZH2-dependent epigenetic silencing of BMP receptor 1B (BMPR1B) in a subset of glioblastoma TICs. Forced expression of BMPR1B either by transgene expression or demethylation of the promoter restores their differentiation capabilities and induces loss of their tumorigenicity. We propose that deregulation of the BMP developmental pathway in a subset of glioblastoma TICs contributes to their tumorigenicity both by desensitizing TICs to normal differentiation cues and by converting otherwise cytostatic signals to proproliferative signals.

Co-registration of In-Vivo Human MRI Brain Images to Postmortem Histological Microscopic Images.

Certain features such as small vascular lesions seen in human MRI are detected reliably only in postmortem histological samples by microscopic imaging. Co-registration of these microscopically detected features to their corresponding locations in the in-vivo images would be of great benefit to understanding the MRI signatures of specific diseases. Using non-linear Polynomial transformation, we report a method to co-register in-vivo MRIs to microscopic images of histological samples drawn off the postmortem brain. The approach utilizes digital photographs of postmortem slices as an intermediate reference to co-register the MRIs to microscopy. The overall procedure is challenging due to gross structural deformations in the postmortem brain during extraction and subsequent distortions in the histological preparations. Hemispheres of the brain were co-registered separately to mitigate these effects. Approaches relying on matching single-slices, multiple-slices and entire volumes in conjunction with different similarity measures suggested that using four slices at a time in combination with two sequential measures, Pearson correlation coefficient followed by mutual information, produced the best MRI-postmortem co-registration according to a voxel mismatch count. The accuracy of the overall registration was evaluated by measuring the 3D Euclidean distance between the locations of microscopically identified lesions on postmortem slices and their MRI-postmortem co-registered locations. The results show a mean 3D displacement of 5.1 ± 2.0 mm between the in-vivo MRI and microscopically determined locations for 21 vascular lesions in 11 subjects.

Amyloid imaging in distinguishing atypical prion disease from Alzheimer disease.

OBJECTIVE: To compare the in vivo uptake of two amyloid-binding PET agents, PIB and FDDNP, in human subjects with a prion protein (PrP) gene (PRNP) mutation that produces a clinical syndrome similar to Alzheimer disease (AD). BACKGROUND: Amyloid imaging with specific PET ligands offers great promise for early detection and differential diagnosis of AD. Genetic forms of prion disease can present with clinical features that resemble AD, and at autopsy may show deposition of mutant PrP-amyloid. FDDNP binds to PrP-amyloid in postmortem human specimens, but has not been reported in vivo in prion disease. The ability of PIB to bind PrP-amyloid is not known. METHODS: Two brothers with a 6 octapeptide repeat insertion mutation (6-OPRI) in the PRNP gene underwent clinical, structural MRI, and FDG-PET evaluations. One brother received a PIB-PET evaluation, while the other received an FDDNP-PET scan. PET results were compared with five normal subjects and five individuals with AD scanned with either agent. RESULTS: PIB uptake was similar to controls in one brother, while FDDNP uptake was intermediate between AD and controls in the other brother. CONCLUSIONS: Different amyloid-binding agents may have differential sensitivity to prion-related brain pathology. A combination of amyloid imaging agents may be useful in the diagnosis of early-onset dementia.

Diffusion tensor imaging of cingulum fibers in mild cognitive impairment and Alzheimer disease.

BACKGROUND: Neuroimaging in mild cognitive impairment (MCI) and Alzheimer disease (AD) generally shows medial temporal lobe atrophy and diminished glucose metabolism and cerebral blood flow in the posterior cingulate gyrus. However, it is unclear whether these abnormalities also impact the cingulum fibers, which connect the medial temporal lobe and the posterior cingulate regions. OBJECTIVE: To use diffusion tensor imaging (DTI), by measuring fractional anisotropy (FA), to test 1) if MCI and AD are associated with DTI abnormalities in the parahippocampal and posterior cingulate regions of the cingulum fibers; 2) if white matter abnormalities extend to the neocortical fiber connections in the corpus callosum (CC); 3) if DTI improves accuracy to separate AD and MCI from healthy aging vs structural MRI. METHODS: DTI and structural MRI were preformed on 17 patients with AD, 17 with MCI, and 18 cognitively normal (CN) subjects. RESULTS: FA of the cingulum fibers was significantly reduced in MCI, and even more in AD. FA was also significantly reduced in the splenium of the CC in AD, but not in MCI. Adding DTI to hippocampal volume significantly improved the accuracy to separate MCI and AD from CN. CONCLUSION: Assessment of the cingulum fibers using diffusion tensor imaging may aid early diagnosis of Alzheimer disease.

Longitudinal volumetric MRI change and rate of cognitive decline.

OBJECTIVE: To examine how baseline and change of volumetric MRI relate to cognitive decline in older individuals. BACKGROUND: Memory is associated with hippocampal integrity, whereas executive function has been linked to impaired frontal lobe function. Previous studies have shown that hippocampal and cortical atrophy are more strongly related to cognition than are measures of subcortical cerebrovascular disease (CVD). The authors hypothesized that memory (MEM) decline would be related to change in hippocampal volume (HC), whereas decline in executive function (EXEC) would be related to change of cortical gray matter volume (CGM) and measures of subcortical CVD. METHODS: Subjects from a multicenter study (n = 103) included cognitively normal, mildly impaired, and demented cases with and without subcortical lacunes. All had longitudinal cognitive evaluation (mean = 4.8 years) and two or more MRI scans at least one year apart (mean = 3.4 years). MRI measures included HC, CGM, total lacune volume (LAC), and white matter hyperintensity volume (WMH). Random effects modeling of longitudinal data assessed effects of MRI baseline and MRI change on baseline and change of psychometrically matched measures of MEM and EXEC. RESULTS: Change in MEM was related to HC baseline and HC change. Change in EXEC was related to baseline CGM and to change in CGM, HC, and LAC. Results were unchanged when demented cases were excluded. WMH was not associated with change in MEM or EXEC independent of HC, CGM, and LAC. CONCLUSION: Hippocampal volume was the primary determinant of memory decline, whereas executive function (EXEC) decline was related to multiple brain components. Results support a hypothesis that MEM decline is strongly influenced by Alzheimer disease (AD), whereas EXEC decline may be complexly determined by cerebrovascular disease and AD.

Reduced medial temporal lobe N-acetylaspartate in cognitively impaired but nondemented patients.

BACKGROUND: N-acetylaspartate (NAA) in the medial temporal lobe (MTL) and parietal lobe gray matter (GM) is diminished in Alzheimer disease (AD). Because NAA is considered a marker of neuronal integrity, reduced medial temporal and parietal lobe NAA could be an early indication of dementia-related pathology in elderly individuals. OBJECTIVES: 1) To determine whether cognitively impaired but nondemented (CIND) elderly individuals exhibit a similar pattern of reduced medial temporal and parietal lobe NAA as AD patients. 2) To compare regional NAA patterns, hippocampal and neocortical gray matter (GM) volumes in CIND patients who remained cognitively stable and those who became demented over 3.6 years of follow-up. 3) To examine the relationship between memory performance, medial temporal lobe NAA, and hippocampal volume. METHODS: Seventeen CIND, 24 AD, and 24 cognitively normal subjects were studied using MRSI and MRI. RESULTS: Relative to controls, CIND patients had reduced MTL NAA (19 to 21%, p = 0.005), hippocampal (11 to 14%, p < or = 0.04), and neocortical GM (5%, p = 0.05) volumes. CIND patients who later became demented had less MTL NAA (26%, p = 0.01), hippocampal (17 to 23%, p < or = 0.05), and neocortical GM (13%, p = 0.02) volumes than controls, but there were no significant differences between stable CIND patients and controls. MTL NAA in combination with hippocampal volume improved discrimination of CIND and controls over hippocampal volume alone. In AD and CIND patients, decreased MTL NAA correlated significantly with impaired memory performance. CONCLUSION: Reduced medial temporal lobe N-acetylaspartate, together with reduced hippocampal and neocortical gray matter volumes, may be early indications of dementia-related pathology in subjects at high risk for developing dementia.