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.

Polygenic risk for Alzheimer's disease is associated with neuroaxonal damage before onset of clinical symptoms.

INTRODUCTION: Establishing valid diagnostic strategies is a precondition for successful therapeutic intervention in Alzheimer's disease (AD). METHODS: One hundred forty-four healthy 75-year-old participants from the Vienna-Transdanube-Aging longitudinal cohort study were tested for neuroaxonal damage by single molecular array (Simoa) plasma neurofilament light chain (NfL) levels at baseline, 30, 60, and 90 months, and onset of AD dementia. Individual risk for sporadic AD was estimated by continuous shrinkage polygenic risk score (PRS-CS, genome-wide association study). RESULTS: Nineteen participants developed AD after a median of 60 months (interquartile range 30). In participants with AD, baseline NfL plasma levels correlated with PRS-CS (r = 0.75, p < 0.001; difference to controls: Fisher's r-to-z: z = 3.89, p < 0.001). PRS-CS combined with baseline plasma NfL predicted onset of AD (p < 0.01). DISCUSSION: Our data suggest that polygenic risk for AD and plasma NfL closely interact years before onset of clinical symptoms. Peripheral NfL may serve as a diagnostic measure supporting early therapeutic intervention and secondary prevention in AD.

[Dementia : current guidelines for clinical management]. / Démences : recommandations actuelles de prise en charge.

Dementia is an umbrella term used to describe a group of symptoms associated with a decline in cognitive abilities that are severe enough to interfere with daily functioning and independence. While Alzheimer's disease (AD) is the most frequent cause, dementia in old aged persons represents rather a syndrome caused by various underlying conditions and diseases. Successful treatment allows for the individual clinical picture, and should be aimed at helping the patient regarding his cognitive deficits, behavioral and psychiatric complaints, sleep disorders, as well as management of daily life. Recently published promising study results on the use of monoclonal antibody therapies in AD give reason to believe that treatments will be available soon that can modulate disease progression at the neurobiological level.

La démence est un terme générique utilisé pour décrire un groupe de symptômes associés à un déclin des capacités cognitives suffisamment grave pour interférer avec le fonctionnement quotidien. Bien que la maladie d'Alzheimer (MA) soit la cause la plus fréquente, la démence chez les personnes âgées représente plutôt un syndrome causé par diverses conditions et maladies sous-jacentes. Un traitement efficace tient compte du tableau clinique individuel et doit viser à surmonter les déficits cognitifs, comportementaux et psychiatriques, les troubles du sommeil, ainsi qu'à gérer la vie quotidienne. Les résultats prometteurs d'études récemment publiées sur l'utilisation de thérapies à base d'anticorps monoclonaux dans la MA laissent envisager la mise à disposition de traitements capables de moduler la progression au niveau neurobiologique.

[Hypoactive delirium]. / État confusionnel aigu hypoactif. Un diagnostic différentiel dans le traitement de la démence et de la dépression.

Delirium (or Acute Confusional State) refers to an acute alteration of attention, consciousness, and cognitive performance. Particularly the hypoactive subtype of delirium represents a diagnostic and clinical challenge. As symptoms of hypoactive delirium may overlap with the clinical picture present in dementia and depression, correct diagnostic differentiation can be challenging. In the absence of timely diagnosis and treatment, hypoactive delirium can last for several weeks. Apart from the health consequences for the patient, such a long course can stress caregivers and the family to their very limit. In this article, we will address the particularities of hypoactive delirium in hospital practice, the neurobiological bases of this disorder, the challenges it represents at the diagnostic level as well as its recommended management according to current literature.

L'état confusionnel aigu (ECA) correspond à une altération aiguë de l'attention et de la conscience ainsi que de la cognition. L'ECA hypoactif représente un défi pour l'équipe médico-soignante en ce qui concerne le diagnostic et la prise en charge. Par ailleurs, les symptômes de l'ECA hypoactif se recoupent le plus souvent avec ceux de la démence et la dépression, ce qui peut mener à une erreur diagnostique. Lorsqu'il se prolonge (plusieurs semaines), l'ECA hypoactif met les soignants et la famille du patient en grande difficulté. Dans cet article vont être abordés les particularités de l'ECA hypoactif dans la pratique en milieu hospitalier, ses bases neurobiologiques, les défis qu'il représente au niveau diagnostique ainsi que sa prise en charge selon les dernières données de la littérature.

Striatal Iron Deposition in Recreational MDMA (Ecstasy) Users.

BACKGROUND: The common club drug MDMA (also known as ecstasy) enhances mood, sensory perception, energy, sociability, and euphoria. While MDMA has been shown to produce neurotoxicity in animal models, research on its potential neurotoxic effects in humans is inconclusive and has focused primarily on the serotonin system. METHODS: We investigated 34 regular, largely pure MDMA users for signs of premature neurodegenerative processes in the form of increased iron load in comparison to a group of 36 age-, sex-, and education-matched MDMA-naïve control subjects. We used quantitative susceptibility mapping, a novel tool able to detect even small tissue (nonheme) iron accumulations. Cortical and relevant subcortical gray matter structures were grouped into 8 regions of interest and analyzed. RESULTS: Significantly increased iron deposition in the striatum was evident in the MDMA user group. The effect survived correction for multiple comparisons and remained after controlling for relevant confounding factors, including age, smoking, and stimulant co-use. Although no significant linear relationship between measurements of the amounts of MDMA intake (hair analysis and self-reports) and quantitative susceptibility mapping values was observed, increased striatal iron deposition might nevertheless point to MDMA-induced neurotoxic processes. Additional factors (hyperthermia and simultaneous co-use of other substances) that possibly amplify neurotoxic effects of MDMA during the state of acute intoxication are discussed. CONCLUSIONS: The demonstrated increased striatal iron accumulation may indicate that regular MDMA users have an increased risk potential for neurodegenerative diseases with progressing age.

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.

[Prevention of Alzheimer's disease : medical and lifestyle interventions]. / Prévention de la maladie d'Alzheimer : importance du mode de vie et interventions thérapeutiques précoces.

Progress in research methodology allows for better characterizing biological processes of brain aging, and therefore to detect dementia or Alzheimer's disease (AD) at a very early stage. Clinically, AD is characterized by progressive memory loss. Moreover, psychiatric symptoms such as anxiety, apathy or depression are frequently present, and may overlay cognitive dysfunction in early AD. There is a broad consensus in the research community that early stages of AD offer a promising window of opportunity for potential therapeutic intervention. Recent studies also suggest that a healthy and active lifestyle has a significant preventive effect. By supporting the patient in lifestyle and health management, the treating physician can make a relevant contribution to the prevention of AD.

Grâce aux progrès techniques, il est désormais possible de mieux comprendre les processus de vieillissement du cerveau et donc de détecter précocement les premiers stades de la maladie d'Alzheimer (MA). La MA se caractérise par une perte de mémoire progressive. Elle peut également se présenter sous la forme de symptômes psychiatriques tels que l'anxiété, l'apathie et la dépression. Le mélange de symptômes cognitifs et psychiatriques peut compliquer le diagnostic dans les premiers stades. Il existe un consensus sur le fait que les interventions thérapeutiques doivent avoir lieu le plus tôt possible. De nouvelles études suggèrent également qu'un mode de vie sain et actif a un effet préventif. En soutenant le patient dans la gestion de son mode de vie, le médecin traitant peut contribuer de manière significative à la prévention.

EEG-fMRI Signal Coupling Is Modulated in Subjects With Mild Cognitive Impairment and Amyloid Deposition.

Cognitive impairment indicates disturbed brain physiology which can be due to various mechanisms including Alzheimer's pathology. Combined functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) recordings (EEG-fMRI) can assess the interplay between complementary measures of brain activity and EEG changes to be localized to specific brain regions. We used a two-step approach, where we first examined changes related to a syndrome of mild cognitive impairment irrespective of pathology and then studied the specific impact of amyloid pathology. After detailed clinical and neuropsychological characterization as well as a positron emission tomography (PET) scans with the tracer 11-[C]-Pittsburgh Compound B to estimate cerebral amyloid deposition, 14 subjects with mild cognitive impairment (MCI) (mean age 75.6 SD: 8.9) according to standard criteria and 21 cognitively healthy controls (HCS) (mean age 71.8 SD: 4.2) were assessed with EEG-fMRI. Thalamo-cortical alpha-fMRI signal coupling was only observed in HCS. Additional EEG-fMRI signal coupling differences between HCS and MCI were observed in parts of the default mode network, salience network, fronto-parietal network, and thalamus. Individuals with significant cerebral amyloid deposition (amyloid-positive MCI and HCS combined compared to amyloid-negative HCS) displayed abnormal EEG-fMRI signal coupling in visual, fronto-parietal regions but also in the parahippocampus, brain stem, and cerebellum. This finding was paralleled by stronger absolute fMRI signal in the parahippocampus and weaker absolute fMRI signal in the inferior frontal gyrus in amyloid-positive subjects. We conclude that the thalamocortical coupling in the alpha band in HCS more closely reflects previous findings observed in younger adults, while in MCI there is a clearly aberrant coupling in several networks dominated by an anticorrelation in the posterior cingulate cortex. While these findings may broadly indicate physiological changes in MCI, amyloid pathology was specifically associated with abnormal fMRI signal responses and disrupted coupling between brain oscillations and fMRI signal responses, which especially involve core regions of memory: the hippocampus, para-hippocampus, and lateral prefrontal cortex.

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.

Differential Changes in Arteriolar Cerebral Blood Volume between Parkinson's Disease Patients with Normal and Impaired Cognition and Mild Cognitive Impairment (MCI) Patients without Movement Disorder - An Exploratory Study.

Cognitive impairment amongst Parkinson's disease (PD) patients is highly prevalent and associated with an increased risk of dementia. There is growing evidence that altered cerebrovascular functions contribute to cognitive impairment. Few studies have compared cerebrovascular changes in PD patients with normal and impaired cognition and those with mild-cognitive-impairment (MCI) without movement disorder. Here, we investigated arteriolar-cerebral-blood-volume (CBVa), an index reflecting the homeostasis of the most actively regulated segment in the microvasculature, using advanced MRI in various brain regions in PD and MCI patients and matched controls. Our goal is to find brain regions with altered CBVa that are specific to PD with normal and impaired cognition, and MCI-without-movement-disorder, respectively. In PD patients with normal cognition (n=10), CBVa was significantly decreased in the substantia nigra, caudate and putamen when compared to controls. In PD patients with impaired cognition (n=6), CBVa showed a decreasing trend in the substantia nigra, caudate and putamen, but was significantly increased in the presupplementary motor area and intracalcarine gyrus compared to controls. In MCI-patients-without-movement-disorder (n=18), CBVa was significantly increased in the caudate, putamen, hippocampus and lingual gyrus compared to controls. These findings provide important information for efforts towards developing biomarkers for the evaluation of potential risk of PD dementia (PDD) in PD patients. The current study is limited in sample size and therefore is exploratory in nature. The data from this pilot study will serve as the basis for power analysis for subsequent studies to further investigate and validate the current findings.

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.

Brain areas with normatively greater cerebral perfusion in early life may be more susceptible to beta amyloid deposition in late life.

BACKGROUND: The amyloid cascade hypothesis characterizes the stereotyped progression of pathological changes in Alzheimer's disease (AD) beginning with beta amyloid deposition, but does not address the reasons for amyloid deposition. Brain areas with relatively higher neuronal activity, metabolic demand, and production of reactive oxygen species in earlier life may have higher beta amyloid deposition in later life. The aim of this study was to investigate early life patterns of perfusion and late life patterns of amyloid deposition to determine the extent to which normative cerebral perfusion predisposes specific regions to future beta amyloid deposition. MATERIALS AND METHODS: One hundred twenty-eight healthy, older human subjects (age: 56-87 years old; 44% women) underwent positron emission tomography (PET) imaging with [11C]PiB for measures of amyloid burden. Cerebral perfusion maps derived from 47 healthy younger adults (age: 22-49; 47%) who had undergone single photon emission computed tomography (SPECT) imaging, were averaged to create a normative template, representative of young, healthy adults. Perfusion and amyloid measures were investigated in 31 cortical regions from the Hammers atlas. We examined the spatial relationship between normative perfusion patterns and amyloid pathophysiology. RESULTS: The pattern of increasing perfusion (temporal lobe < parietal lobe < frontal lobe < insula/cingulate gyrus < occipital lobe; F(4,26) = 7.8, p = 0.0003) in young, healthy adults was not exactly identical to but approximated the pattern of increasing amyloid burden (temporal lobe < occipital lobe < frontal lobe < parietal lobe < insula/cingulate gyrus; F(4,26) = 5.0, p = 0.004) in older adults. However, investigating subregions within cortical lobes provided consistent agreement between ranked normative perfusion patterns and expected Thal staging of amyloid progression in AD (Spearman r = 0.39, p = 0.03). CONCLUSION: Our findings suggest that brain areas with normatively greater perfusion may be more susceptible to amyloid deposition in later life, possibly due to higher metabolic demand, and associated levels of oxidative stress and inflammation.

The A/T/N model applied through imaging biomarkers in a memory clinic.

PURPOSE: The A/T/N model is a research framework proposed to investigate Alzheimer's disease (AD) pathological bases (i.e., amyloidosis A, neurofibrillary tangles T, and neurodegeneration N). The application of this system on clinical populations is still limited. The aim of the study is to evaluate the topography of T distribution by 18F-flortaucipir PET in relation to A and N and to describe the A/T/N status through imaging biomarkers in memory clinic patients. METHODS: Eighty-one patients with subjective and objective cognitive impairment were classified as A+/A- and N+/N- through amyloid PET and structural MRI. Tau deposition was compared across A/N subgroups at voxel level. T status was defined through a global cut point based on A/N subgroups and subjects were categorized following the A/T/N model. RESULTS: A+N+ and A+N- subgroups showed higher tau burden compared to A-N- group, with A+N- showing significant deposition limited to the medial and lateral temporal regions. Global cut point discriminated A+N+ and A+N- from A-N- subjects. On A/T/N classification, 23% of patients showed a negative biomarker profile, 58% fell within the Alzheimer's continuum, and 19% of the sample was characterized by non-AD pathologic change. CONCLUSION: Medial and lateral temporal regions represent a site of significant tau accumulation in A+ subjects and possibly a useful marker of early clinical changes. This is the first study in which the A/T/N model is applied using 18F-flortaucipir PET in a memory clinic population. The majority of patients showed a profile consistent with the Alzheimer's continuum, while a minor percentage showed a profile suggestive of possible other neurodegenerative diseases. These results support the applicability of the A/T/N model in clinical practice.

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.

Hybrid PET-MRI in Alzheimer's Disease Research.

Multiple factors, namely amyloid, tau, inflammation, metabolic, and perfusion changes, contribute to the cascade of neurodegeneration and functional decline occurring in Alzheimer's disease (AD). These molecular and cellular processes and related functional and morphological changes can be visualized in vivo by two imaging modalities, namely positron emission tomography (PET) and magnetic resonance imaging (MRI). These imaging biomarkers are now part of the diagnostic algorithm and of particular interest for patient stratification and targeted drug development.In this field the availability of hybrid PET/MR systems not only offers a comprehensive evaluation in a single imaging session, but also opens new possibilities for the integration of the two imaging information. Here, we cover the clinical protocols and practical details of FDG, amyloid, and tau PET/MR imaging as applied in our institutions.

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.

Brain amyloid burden and cerebrovascular disease are synergistically associated with neurometabolism in cognitively unimpaired older adults.

Alzheimer's disease (AD) is the most common cause of cognitive dysfunction in older adults. The pathological hallmarks of AD such as beta amyloid (Aß) aggregation and neurometabolic change, as indicated by altered myo-inositol (mI) and N-acetylaspartate (NAA) levels, typically precede the onset of cognitive dysfunction by years. Furthermore, cerebrovascular disease occurs early in AD, but the interplay between vascular and neurometabolic brain change is largely unknown. Thirty cognitively normal older adults (age = 70 ± 5.6 years, Mini-Mental State Examination = 29.2 ± 1) received 11-C-Pittsburgh Compound B positron emission tomography for estimating Aß-plaque density, 7 Tesla fluid-attenuated inversion recovery magnetic resonance imaging for quantifying white matter hyperintensity volume as a marker of small vessel cerebrovascular disease and high-resolution magnetic resonance spectroscopic imaging at 7 Tesla, based on free induction decay acquisition localized by outer volume suppression to investigate tissue-specific neurometabolism in the posterior cingulate and precuneus. Aß (ß = 0.45, p = 0.018) and white matter hyperintensities (ß = 0.40, p = 0.046) were independently and interactively (ß = -0.49, p = 0.026) associated with a higher ratio of mI over NAA (mI/NAA) in the posterior cingulate and precuneus gray matter but not in the white matter. Our data suggest that cerebrovascular disease and Aß burden are synergistically associated with AD-related gray matter neurometabolism in older adults.