Gray matter gamma-hydroxy-butyric acid and glutamate reflect beta-amyloid burden at old age.

Gamma-hydroxy-butyric acid (GABA) and glutamate are neurotransmitters with essential importance for cognitive processing. Here, we investigate relationships between GABA, glutamate, and brain ß-amyloid (Aß) burden before clinical manifestation of Alzheimer's disease (AD). Thirty cognitively healthy adults (age 69.9 ± 6 years) received high-resolution atlas-based 1H-magnetic resonance spectroscopic imaging (MRSI) at ultra-high magnetic field strength of 7 Tesla for gray matter-specific assessment of GABA and glutamate. We assessed Aß burden with positron emission tomography and risk factors for AD. Higher gray matter GABA and glutamate related to higher Aß-burden (ß = 0.60, p < 0.05; ß = 0.64, p < 0.02), with positive effect modification by apolipoprotein-E-epsilon-4-allele (APOE4) (p = 0.01-0.03). GABA and glutamate negatively related to longitudinal change in verbal episodic memory performance (ß = -0.48; p = 0.02; ß = -0.50; p = 0.01). In vivo measures of GABA and glutamate reflect early AD pathology at old age, in an APOE4-dependent manner. GABA and glutamate may represent promising biomarkers and potential targets for early therapeutic intervention and prevention. Highlights: Gray matter-specific metabolic imaging with high-resolution atlas-based MRSI at 7 Tesla.Higher GABA and glutamate relate to ß-amyloid burden, in an APOE4-dependent manner.Gray matter GABA and glutamate identify older adults with high risk of future AD.GABA and glutamate might reflect altered synaptic and neuronal activity at early AD.

ATN profile classification across two independent prospective cohorts.

Background: The ATN model represents a research framework used to describe in subjects the presence or absence of Alzheimer's disease (AD) pathology through biomarkers. The aim of this study was to describe the prevalence of different ATN profiles using quantitative imaging biomarkers in two independent cohorts, and to evaluate the pertinence of ATN biomarkers to identify comparable populations across independent cohorts. Methods: A total of 172 subjects from the Geneva Memory Clinic and 113 volunteers from a study on healthy aging at the University Hospital of Zurich underwent amyloid (A) and tau (T) PET, as well as T1-weigthed MRI scans using site-specific protocols. Subjects were classified by cognition (cognitively unimpaired, CU, or impaired, CI) based on clinical assessment by experts. Amyloid data converted into the standardized centiloid scale, tau PET data normalized to cerebellar uptake, and hippocampal volume expressed as a ratio over total intracranial volume ratio were considered as biomarkers for A, T, and neurodegeneration (N), respectively. Positivity for each biomarker was defined based on previously published thresholds. Subjects were then classified according to the ATN model. Differences among profiles were tested using Kruskal-Wallis ANOVA, and between cohorts using Wilcoxon tests. Results: Twenty-nine percent of subjects from the Geneva cohorts were classified with a normal (A-T-N-) profile, while the Zurich cohort included 64% of subjects in the same category. Meanwhile, 63% of the Geneva and 16% of the Zurich cohort were classified within the AD continuum (being A+ regardless of other biomarkers' statuses). Within cohorts, ATN profiles were significantly different for age and mini-mental state examination scores, but not for years of education. Age was not significantly different between cohorts. In general, imaging A and T biomarkers were significantly different between cohorts, but they were no longer significantly different when stratifying the cohorts by ATN profile. N was not significantly different between cohorts. Conclusion: Stratifying subjects into ATN profiles provides comparable groups of subjects even when individual recruitment followed different criteria.

Patterns of amyloid accumulation in amyloid-negative cases.

Amyloid staging models showed that regional abnormality occurs before global positivity. Several studies assumed that the trajectory of amyloid spread is homogeneous, but clinical evidence suggests that it is highly heterogeneous. We tested whether different amyloid-ß (Aß) patterns exist by applying clustering on negative scans and investigating their demographics, clinical, cognitive, and biomarkers correlates, and cognitive trajectories. 151 individuals from Geneva and Zurich cohorts with T1-MRI, negative Aß positron emission tomography (PET,centiloid<12) and clinical assessment were included. N=123 underwent tau PET, and N=65 follow-up neuropsychological assessment. We performed k-means clustering using 33 Aß regional Standardized Uptake Vales ratio. Demographics, clinical, cognitive, and biomarkers differences were investigated. Longitudinal cognitive changes by baseline cluster status were estimated using a linear mixed model. The cluster analysis identified two clusters: temporal predominant (TP) and cingulate predominant (CP). TP tau deposition was higher than CP. A trend for a higher cognitive decline in TP compared to CP was observed. This study suggests the existence of two Aß deposition patterns in the earliest phases of Aß accumulation, differently prone to tau pathology and cognitive decline.

Lifestyle Affects Amyloid Burden and Cognition Differently in Men and Women.

OBJECTIVE: Evidence on associations of lifestyle factors with Alzheimer's pathology and cognition are ambiguous, potentially because they rarely addressed inter-relationships of factors and sex effects. While considering these aspects, we examined the relationships of lifestyle factors with brain amyloid burden and cognition. METHODS: We studied 178 cognitively normal individuals (women, 49%; 65.0 [7.6] years) and 54 individuals with mild cognitive impairment (women, 35%; 71.3 [8.3] years) enrolled in a prospective study of volunteers who completed 18 F-Flutemetamol amyloid positron emission tomography. Using structural equation modeling, we examined associations between latent constructs representing metabolic/vascular risk, physical activity, and cognitive activity with global amyloid burden and cognitive performance. Furthermore, we investigated the influence of sex in this model. RESULTS: Overall, higher cognitive activity was associated with better cognitive performance and higher physical activity was associated with lower amyloid burden. The latter association was weakened to a nonsignificant level after excluding multivariate outliers. Examination of the moderating effect of sex in the model revealed an inverse association of metabolic/vascular risk with cognition in men, whereas in women metabolic/vascular risk trended toward increased amyloid burden. Furthermore, a significant inverse association between physical activity and amyloid burden was found only in men. Inheritance of an APOE4 allele was associated with higher amyloid burden only in women. INTERPRETATION: Sex modifies effects of certain lifestyle-related factors on amyloid burden and cognition. Notably, our results suggest that the negative impact of metabolic/vascular risk influences the risk of cognitive decline and Alzheimer's disease through distinct paths in women and men. ANN NEUROL 2022;92:451-463.

Low Subicular Volume as an Indicator of Dementia-Risk Susceptibility in Old Age.

Introduction: Hippocampal atrophy is an established Alzheimer's Disease (AD) biomarker. Volume loss in specific subregions as measurable with ultra-high field magnetic resonance imaging (MRI) may reflect earliest pathological alterations. Methods: Data from positron emission tomography (PET) for estimation of cortical amyloid ß (Aß) and high-resolution 7 Tesla T1 MRI for assessment of hippocampal subfield volumes were analyzed in 61 non-demented elderly individuals who were divided into risk-categories as defined by high levels of cortical Aß and low performance in standardized episodic memory tasks. Results: High cortical Aß and low episodic memory interactively predicted subicular volume [F(3,57) = 5.90, p = 0.018]. The combination of high cortical Aß and low episodic memory was associated with significantly lower subicular volumes, when compared to participants with high episodic memory (p = 0.004). Discussion: Our results suggest that low subicular volume is linked to established indicators of AD risk, such as increased cortical Aß and low episodic memory. Our data support subicular volume as a marker of dementia-risk susceptibility in old-aged non-demented persons.

Early termination of pivotal trials in Alzheimer's disease-Preserving optimal value for participants and science.

Participants in Alzheimer's disease late-phase clinical trials are frequently confronted with a situation of early termination. We discuss measures to protect the perceived value of study participation and to maximize the scientific value under such circumstances. A communication strategy should ensure that trial participants maintain a positive relationship with the research team and have their informational needs optimally met. Measures to maximize the scientific value may include data/sample sharing, strategies for personalized medicine, as well as scientific follow-up. Critical for the success of such a concept are networks of excellence, extending models of existing initiatives like Global Alzheimer's Platform Foundation Network (GAP-Net). These networks could fundamentally strengthen the role of clinical investigators if they decide on their involvement in trials based upon their estimation of the scientific value and benefit for the participants, actively contribute to scientific analyses, and mediate optimal communication among the relevant trial stakeholders.

Physical activity is associated with lower cerebral beta-amyloid and cognitive function benefits from lifetime experience-a study in exceptional aging.

BACKGROUND: Exceptional agers (85+ years) are characterized by preserved cognition presumably due to high cognitive reserve. In the current study, we examined whether personality, risk and protective factors for dementia as well as quality of life are associated with core features of Alzheimer's disease (amyloid-deposition and hippocampal volume) as well as cognition in exceptional aging. METHODS: We studied 49 exceptional agers (average 87.8 years, range 84-94 years), with preserved activities of daily living and absence of dementia. All participants received a detailed clinical and neuropsychological examination. We used established questionnaires to measure lifetime experience, personality, recent physical and cognitive activity as well as quality of life. Cerebral amyloid-deposition was estimated by 18-[F]-Flutemetamol-PET and manual hippocampal volumetry was performed on 3D T1 MRI images. RESULTS: In this sample of exceptional agers with preserved activities of daily living, we found intact cognitive performance in the subjects with the highest amyloid-load in the brain, but a lower quality of life with respect to autonomy as well as higher neuroticism. Higher self-reported physical activity in the last twelve months went with a lower amyloid load. Higher self-reported leisure-time/ not work-related activity went with better executive functioning at older age. CONCLUSION: Even in exceptional aging, high amyloid load may subtly influence personality and quality of life. Our findings support a close relationship between high physical activity and low amyloid-deposition and underscore the importance of extracurricular activities for executive functions. As executive functions are known to be a central resource for everyday functioning in fostering extracurricular activities may be effective in delaying the onset of dementia.

Reduced uptake of [11C]-ABP688, a PET tracer for metabolic glutamate receptor 5 in hippocampus and amygdala in Alzheimer's dementia.

INTRODUCTION: Metabotropic glutamate receptors play a critical role in the pathogenesis of Alzheimer's disease due to their involvement in processes of memory formation, neuroplasticity, and synaptotoxity. The objective of the current study was to study mGluR5 availability measured by [11 C]-ABP688 (ABP) in patients with clinically diagnosed Alzheimer's dementia (AD). METHODS: A bolus-infusion protocol of [11 C]-ABP688 was applied in 9 subjects with AD and 10 cognitively healthy controls (Controls) to derive distribution volume estimates of mGluR5. Furthermore, we also estimated cerebral perfusion by averaging early frame signal of initial ABP bolus injection. RESULTS: Subjects with Alzheimer's dementia (mean age: 77.3/SD 5.7) were older than controls (mean age: 68.5/SD: 9.6) and scored lower on the MMSE (22.1/SD2.7 vs. 29.0/SD0.8). There were no overall differences in ABP signal. However, distribution volume ratio (DVR) for ABP was reduced in the bilateral hippocampus (AD: 1.34/SD: 0.40 vs. Control: 1.84/SD:0.31, p = .007) and the bilateral amygdala (AD:1.86/SD:0.26 vs. Control:2.33/SD:0.37 p = .006) in AD patients compared to controls. Estimate of cerebral blood flow was reduced in the bilateral hippocampus in AD (AD:0.75/SD:0.10 vs. Control:0.86/SD:0.09 p = .02). CONCLUSION: Our findings demonstrate reduced mGluR5 binding in the hippocampus and amygdala in Alzheimer's dementia. Whether this is due to synaptic loss and/or consecutive reduction of potential binding sites or reflects disease inherent mechanisms remains to be elucidated in future studies.

Functional Brain Network Connectivity Patterns Associated With Normal Cognition at Old-Age, Local ß-amyloid, Tau, and APOE4.

Background: Integrity of functional brain networks is closely associated with maintained cognitive performance at old age. Consistently, both carrier status of Apolipoprotein E ε4 allele (APOE4), and age-related aggregation of Alzheimer's disease (AD) pathology result in altered brain network connectivity. The posterior cingulate and precuneus (PCP) is a node of particular interest due to its role in crucial memory processes. Moreover, the PCP is subject to the early aggregation of AD pathology. The current study aimed at characterizing brain network properties associated with unimpaired cognition in old aged adults. To determine the effects of age-related brain change and genetic risk for AD, pathological proteins ß-amyloid and tau were measured by Positron-emission tomography (PET), PCP connectivity as a proxy of cognitive network integrity, and genetic risk by APOE4 carrier status. Methods: Fifty-seven cognitively unimpaired old-aged adults (MMSE = 29.20 ± 1.11; 73 ± 8.32 years) were administered 11C Pittsburgh Compound B and 18F Flutemetamol PET for assessing ß-amyloid, and 18F AV-1451 PET for tau. Individual functional connectivity seed maps of the PCP were obtained by resting-state multiband BOLD functional MRI at 3-Tesla for increased temporal resolution. Voxelwise correlations between functional connectivity, ß-amyloid- and tau-PET were explored by Biological Parametric Mapping (BPM). Results: Local ß-amyloid was associated with increased connectivity in frontal and parietal regions of the brain. Tau was linked to increased connectivity in more spatially distributed clusters in frontal, parietal, occipital, temporal, and cerebellar regions. A positive interaction was observable for APOE4 carrier status and functional connectivity with brain regions characterized by increased local ß-amyloid and tau tracer retention. Conclusions: Our data suggest an association between spatially differing connectivity systems and local ß-amyloid, and tau aggregates in cognitively normal, old-aged adults, which is moderated by APOE4. Additional longitudinal studies may determine protective connectivity patterns associated with healthy aging trajectories of AD-pathology aggregation.

APOE4 moderates effects of cortical iron on synchronized default mode network activity in cognitively healthy old-aged adults.

INTRODUCTION: Apolipoprotein E ε4 (APOE4)-related genetic risk for sporadic Alzheimer's disease is associated with an early impairment of cognitive brain networks. The current study determines relationships between APOE4 carrier status, cortical iron, and cortical network-functionality. METHODS: Sixty-nine cognitively healthy old-aged individuals (mean age [SD] 66.1 [± 7.2] years; Mini-Mental State Exam [MMSE] 29.3 ± 1.1) were genotyped for APOE4 carrier-status and received 3 Tesla magnetic resonance imaging (MRI) for blood oxygen level-dependent functional magnetic resonance imaging (MRI) at rest, three-dimensional (3D)-gradient echo (six echoes) for cortical gray-matter, non-heme iron by quantitative susceptibility mapping, and 18F-flutemetamol positron emission tomography for amyloid-ß. RESULTS: A spatial pattern consistent with the default mode network (DMN) could be identified by independent component analysis. DMN activity was enhanced in APOE4 carriers and related to cortical iron burden. APOE4 and cortical iron synergistically interacted with DMN activity. Secondary analysis revealed a positive, APOE4 associated, relationship between cortical iron and DMN connectivity. DISCUSSION: Our findings suggest that APOE4 moderates effects of iron on brain functionality prior to manifestation of cognitive impairment.

Increased cerebral blood volume in small arterial vessels is a correlate of amyloid-ß-related cognitive decline.

The protracted accumulation of amyloid-ß (Aß) is a major pathologic hallmark of Alzheimer's disease and may trigger secondary pathological processes that include neurovascular damage. This study was aimed at investigating long-term effects of Aß burden on cerebral blood volume of arterioles and pial arteries (CBVa), possibly present before manifestation of dementia. Aß burden was assessed by 11C Pittsburgh compound-B positron emission tomography in 22 controls and 18 persons with mild cognitive impairment (MCI), [ages: 75(±6) years]. After 2 years, inflow-based vascular space occupancy at ultra-high field strength of 7-Tesla was administered for measuring CBVa, and neuropsychological testing for cognitive decline. Crushing gradients were incorporated during MR-imaging to suppress signals from fast-flowing blood in large arteries, and thereby sensitize inflow-based vascular space occupancy to CBVa in pial arteries and arterioles. CBVa was significantly elevated in MCI compared to cognitively normal controls and regional CBVa related to local Aß deposition. For both MCI and controls, Aß burden and follow-up CBVa in several brain regions synergistically predicted cognitive decline over 2 years. Orbitofrontal CBVa was positively associated with apolipoprotein E e4 carrier status. Increased CBVa may reflect long-term effects of region-specific pathology associated with Aß deposition. Additional studies are needed to clarify the role of the arteriolar system and the potential of CBVa as a biomarker for Aß-related vascular downstream pathology.

Oxidative stress and altered mitochondrial protein expression in the absence of amyloid-ß and tau pathology in iPSC-derived neurons from sporadic Alzheimer's disease patients.

Mitochondrial dysfunction is a prominent feature of Alzheimer's disease (AD) and increased production of reactive oxygen species (ROS) has been described in postmortem brain samples and animal models. However, these observations were made at a late stage of disease and the inability to examine an early, presymptomatic phase in human neurons impeded our understanding of cause or consequence of mitochondrial dysfunction in AD. We used human induced pluripotent stem cell-derived neuronal cells (iN cells) from sporadic AD (SAD) patients and healthy control subjects (HCS) to show aberrant mitochondrial function in patient-derived cells. We observed that neuronal cultures from some patients produced more ROS and displayed higher levels of DNA damage. Furthermore, patient-derived cells showed increased levels of oxidative phosphorylation chain complexes, whereas mitochondrial fission and fusion proteins were not affected. Surprisingly, these effects neither correlated with Aß nor phosphorylated and total tau levels. Synaptic protein levels were also unaffected in SAD iN cells. The results of this study give new insights into constitutional metabolic changes in neurons from subjects prone to develop Alzheimer's pathology. They suggest that increased ROS production may have an integral role in the development of sporadic AD prior to the appearance of amyloid and tau pathology.

Low cortical iron and high entorhinal cortex volume promote cognitive functioning in the oldest-old.

The aging brain is characterized by an increased presence of neurodegenerative and vascular pathologies. However, there is substantial variation regarding the relationship between an individual's pathological burden and resulting cognitive impairment. To identify correlates of preserved cognitive functioning at highest age, the relationship between ß-amyloid plaque load, presence of small vessel cerebrovascular disease (SVCD), iron-burden, and brain atrophy was investigated. Eighty cognitively unimpaired participants (44 oldest-old, aged 85-96 years; 36 younger-old, aged 55-80 years) were scanned by integrated positron emission tomography-magnetic resonance imaging for assessing beta regional amyloid plaque load (18F-flutemetamol), white matter hyperintensities as an indicator of SVCD (fluid-attenuated inversion recovery-magnetic resonance imaging), and iron load (quantitative susceptibility mapping). For the oldest-old group, lower cortical volume, increased ß-amyloid plaque load, prevalence of SVCD, and lower cognitive performance in the normal range were found. However, compared to normal-old, cortical iron burden was lower in the oldest-old. Moreover, only in the oldest-old, entorhinal cortex volume positively correlated with ß-amyloid plaque load. Our data thus indicate that the co-occurrence of aging-associated neuropathologies with reduced quantitative susceptibility mapping measures of cortical iron load constitutes a lower vulnerability to cognitive loss.

Changes of Functional and Directed Resting-State Connectivity Are Associated with Neuronal Oscillations, ApoE Genotype and Amyloid Deposition in Mild Cognitive Impairment.

The assessment of effects associated with cognitive impairment using electroencephalography (EEG) power mapping allows the visualization of frequency-band specific local changes in oscillatory activity. In contrast, measures of coherence and dynamic source synchronization allow for the study of functional and effective connectivity, respectively. Yet, these measures have rarely been assessed in parallel in the context of mild cognitive impairment (MCI) and furthermore it has not been examined if they are related to risk factors of Alzheimer's disease (AD) such as amyloid deposition and apolipoprotein ε4 (ApoE) allele occurrence. Here, we investigated functional and directed connectivities with Renormalized Partial Directed Coherence (RPDC) in 17 healthy controls (HC) and 17 participants with MCI. Participants underwent ApoE-genotyping and Pittsburgh compound B positron emission tomography (PiB-PET) to assess amyloid deposition. We observed lower spectral source power in MCI in the alpha and beta bands. Coherence was stronger in HC than MCI across different neuronal sources in the delta, theta, alpha, beta and gamma bands. The directed coherence analysis indicated lower information flow between fronto-temporal (including the hippocampus) sources and unidirectional connectivity in MCI. In MCI, alpha and beta RPDC showed an inverse correlation to age and gender; global amyloid deposition was inversely correlated to alpha coherence, RPDC and beta and gamma coherence. Furthermore, the ApoE status was negatively correlated to alpha coherence and RPDC, beta RPDC and gamma coherence. A classification analysis of cognitive state revealed the highest accuracy using EEG power, coherence and RPDC as input. For this small but statistically robust (Bayesian power analyses) sample, our results suggest that resting EEG related functional and directed connectivities are sensitive to the cognitive state and are linked to ApoE and amyloid burden.

Memory performance-related dynamic brain connectivity indicates pathological burden and genetic risk for Alzheimer's disease.

BACKGROUND: The incidence of Alzheimer's disease (AD) strongly relates to advanced age and progressive deposition of cerebral amyloid-beta (Aß), hyperphosphorylated tau, and iron. The purpose of this study was to investigate the relationship between cerebral dynamic functional connectivity and variability of long-term cognitive performance in healthy, elderly subjects, allowing for local pathology and genetic risk. METHODS: Thirty seven participants (mean (SD) age 74 (6.0) years, Mini-Mental State Examination 29.0 (1.2)) were dichotomized based on repeated neuropsychological test performance within 2 years. Cerebral Aß was measured by 11C Pittsburgh Compound-B positron emission tomography, and iron by quantitative susceptibility mapping magnetic resonance imaging (MRI) at an ultra-high field strength of 7 Tesla (7T). Dynamic functional connectivity patterns were investigated by resting-state functional MRI at 7T and tested for interactive effects with genetic AD risk (apolipoprotein E (ApoE)-ε4 carrier status). RESULTS: A relationship between low episodic memory and a lower expression of anterior-posterior connectivity was seen (F(9,27) = 3.23, p < 0.008), moderated by ApoE-ε4 (F(9,27) = 2.22, p < 0.005). Inherent node-strength was related to local iron (F(5,30) = 13.2; p < 0.022). CONCLUSION: Our data indicate that altered dynamic anterior-posterior brain connectivity is a characteristic of low memory performance in the subclinical range and genetic risk for AD in the elderly. As the observed altered brain network properties are associated with increased local iron, our findings may reflect secondary neuronal changes due to pathologic processes including oxidative stress.

Subcortical Shape Changes, Hippocampal Atrophy and Cortical Thinning in Future Alzheimer's Disease Patients.

Efficacy of future treatments depends on biomarkers identifying patients with mild cognitive impairment at highest risk for transitioning to Alzheimer's disease. Here, we applied recently developed analysis techniques to investigate cross-sectional differences in subcortical shape and volume alterations in patients with stable mild cognitive impairment (MCI) (n = 23, age range 59-82, 47.8% female), future converters at baseline (n = 10, age range 66-84, 90% female) and at time of conversion (age range 68-87) compared to group-wise age and gender matched healthy control subjects (n = 23, age range 61-81, 47.8% female; n = 10, age range 66-82, 80% female; n = 10, age range 68-82, 70% female). Additionally, we studied cortical thinning and global and local measures of hippocampal atrophy as known key imaging markers for Alzheimer's disease. Apart from bilateral striatal volume reductions, no morphometric alterations were found in cognitively stable patients. In contrast, we identified shape alterations in striatal and thalamic regions in future converters at baseline and at time of conversion. These shape alterations were paralleled by Alzheimer's disease like patterns of left hemispheric morphometric changes (cortical thinning in medial temporal regions, hippocampal total and subfield atrophy) in future converters at baseline with progression to similar right hemispheric alterations at time of conversion. Additionally, receiver operating characteristic curve analysis indicated that subcortical shape alterations may outperform hippocampal volume in identifying future converters at baseline. These results further confirm the key role of early cortical thinning and hippocampal atrophy in the early detection of Alzheimer's disease. But first and foremost, and by distinguishing future converters but not patients with stable cognitive abilities from cognitively normal subjects, our results support the value of early subcortical shape alterations and reduced hippocampal subfield volumes as potential markers for the early detection of Alzheimer's disease.

Hippocampal shape alterations are associated with regional Aß load in cognitively normal elderly individuals.

Aß deposition is a driving force of Alzheimer's disease pathology and can be detected early by amyloid positron emission tomography. Identifying presymptomatic structural brain changes associated with Aß deposition might lead to a better understanding of its consequences and provide early diagnostic information. In this respect we analyzed measures of cortical thickness and subcortical volumes along with hippocampal, thalamic and striatal shape and surface area by applying novel analysis strategies for structural magnetic resonance imaging. We included 69 cognitively normal elderly subjects after careful clinical and neuropsychological workup. Standardized uptake value ratios (cerebellar reference) for uptake of 11-C-Pittsburgh Compound B (PiB) were calculated from positron emission tomographic data for a cortical measurement and for bilateral hippocampus, thalamus and striatum. Associations to shape, surface area, volume and cortical thickness were tested using regression models that included significant predictors as covariates. Left anterior hippocampal shape was associated with regional PiB uptake (P < 0.05, FDR corrected), whereas volumes of the hippocampi and their subregions were not associated with cortical or regional PiB uptake (all P > 0.05, FDR corrected). Within the entorhinal cortical region of both hemispheres, thickness was negatively associated with cortical PiB uptake (P < 0.05, FDR corrected). Hence, localized shape measures and cortical thickness may be potential biomarkers of presymptomatic Alzheimer's disease.

Low episodic memory performance in cognitively normal elderly subjects is associated with increased posterior cingulate gray matter N-acetylaspartate: a 1H MRSI study at 7 Tesla.

Low episodic memory performance characterizes elderly subjects at increased risk for Alzheimer's disease (AD) and may reflect neuronal dysfunction within the posterior cingulate cortex and precuneus (PCP) region. To investigate a potential association between cerebral neurometabolism and low episodic memory in the absence of cognitive impairment, tissue-specific magnetic resonance spectroscopic imaging at ultrahigh field strength of 7 Tesla was used to investigate the PCP region in a healthy elderly study population (n = 30, age 70 ± 5.7 years, Mini-Mental State Examination 29.4 ± 4.1). The Verbal Learning and Memory Test (VLMT) was administered as part of a neuropsychological battery for assessment of episodic memory performance. Significant differences between PCP gray and white matter could be observed for glutamate-glutamine (p = 0.001), choline (p = 0.01), and myo-inositol (p = 0.02). Low Verbal Learning and Memory Test performance was associated with high N-acetylaspartate in PCP gray matter (p = 0.01) but not in PCP white matter. Our data suggest that subtle decreases in episodic memory performance in the elderly may be associated with increased levels of N-acetylaspartate as a reflection of increased mitochondrial energy capacity in PCP gray matter.

Volumetric and shape analysis of the thalamus and striatum in amnestic mild cognitive impairment.

Alterations in brain structures, including progressive neurodegeneration, are a hallmark in patients with Alzheimer's disease (AD). However, pathological mechanisms, such as the accumulation of amyloid and the proliferation of tau, are thought to begin years, even decades, before the initial clinical manifestations of AD. In this study, we compare the brain anatomy of amnestic mild cognitive impairment patients (aMCI, n = 16) to healthy subjects (CS, n = 22) using cortical thickness, subcortical volume, and shape analysis, which we believe to be complimentary to volumetric measures. We were able to replicate "classical" cortical thickness alterations in aMCI in the hippocampus, amygdala, putamen, insula, and inferior temporal regions. Additionally, aMCI showed significant thalamic and striatal shape differences. We observed higher global amyloid deposition in aMCI, a significant correlation between striatal displacement and global amyloid, and an inverse correlation between executive function and right-hemispheric thalamic displacement. In contrast, no volumetric differences were detected in thalamic, striatal, and hippocampal regions. Our results provide new evidence for early subcortical neuroanatomical changes in patients with aMCI, which are linked to cognitive abilities and amyloid deposition. Hence, shape analysis may aid in the identification of structural biomarkers for identifying individuals at highest risk of conversion to AD.

Arterial spin labeling imaging reveals widespread and Aß-independent reductions in cerebral blood flow in elderly apolipoprotein epsilon-4 carriers.

Changes in cerebral blood flow are an essential feature of Alzheimer's disease and have been linked to apolipoprotein E-genotype and cerebral amyloid-deposition. These factors could be interdependent or influence cerebral blood flow via different mechanisms. We examined apolipoprotein E-genotype, amyloid beta-deposition, and cerebral blood flow in amnestic mild cognitive impairment using pseudo-continuous arterial spin labeling MRI in 27 cognitively normal elderly and 16 amnestic mild cognitive impairment participants. Subjects underwent Pittsburgh Compound B (PiB) positron emission tomography and apolipoprotein E-genotyping. Global cerebral blood flow was lower in apolipoprotein E ɛ4-allele carriers (apolipoprotein E4+) than in apolipoprotein E4- across all subjects (including cognitively normal participants) and within the group of cognitively normal elderly. Global cerebral blood flow was lower in subjects with mild cognitive impairment compared with cognitively normal. Subjects with elevated cerebral amyloid-deposition (PiB+) showed a trend for lower global cerebral blood flow. Apolipoprotein E-status exerted the strongest effect on global cerebral blood flow. Regional analysis indicated that local cerebral blood flow reductions were more widespread for the contrasts apolipoprotein E4+ versus apolipoprotein E4- compared with the contrasts PiB+ versus PiB- or mild cognitive impairment versus cognitively normal. These findings suggest that apolipoprotein E-genotype exerts its impact on cerebral blood flow at least partly independently from amyloid beta-deposition, suggesting that apolipoprotein E also contributes to cerebral blood flow changes outside the context of Alzheimer's disease.