Alzheimer-type Neurodegeneration Research Articles

Comorbidity of cerebral amyloid angiopathy and Alzheimer's disease. Clinical case analysis

The development of cognitive impairment in old age is often caused by overlapping neurodegenerative and cerebrovascular changes which have a mutually aggravating clinical effect. In recent years, the problem of cerebral amyloid angiopathy (CAA), which is one of the variants of such an interaction, has gained importance. Despite the frequent occurrence of this pathology in the elderly, a unified approach to the treatment of these patients has not yet been developed, especially taking into account the frequent combination with other nosological forms. CAA is a disease associated with both Alzheimer's type neurodegeneration and cerebrovascular pathology. The article presents a clinical case illustrating this situation and discusses the diagnostic algorithm in detail. The characteristics of the pathogenesis and clinical manifestations of CAA and the link between neurodegenerative and cerebrovascular pathologies are discussed.

Vitamin D, a Secosteroid Hormone and Its Multifunctional Receptor, Vitamin D Receptor, in Alzheimer's Type Neurodegeneration.

Vitamin D is a secosteroid hormone exerting neurosteroid-like properties. Its well-known nuclear hormone receptor, and recently proposed as a mitochondrial transcription factor, vitamin D receptor, acts for its primary functions. The second receptor is an endoplasmic reticulum protein, protein disulfide isomerase A3 (PDIA3), suggested to act as a rapid response. Vitamin D has effects on various systems, particularly through calcium metabolism. Among them, the nervous system has an important place in the context of our subject. Recent studies have shown that vitamin D and its receptors have numerous effects on the nervous system. Neurodegeneration is a long-term process. Throughout a human life span, so is vitamin D deficiency. Our previous studies and others have suggested that the out-come of long-term vitamin D deficiency (hypovitaminosis D or inefficient utilization of vitamin D), may lead neurons to be vulnerable to aging and neurodegeneration. We suggest that keeping vitamin D levels at adequate levels at all stages of life, considering new approaches such as agonists that can activate vitamin D receptors, and utilizing other derivatives produced in the synthesis process with UVB are crucial when considering vitamin D-based intervention studies. Given most aspects of vitamin D, this review outlines how vitamin D and its receptors work and are involved in neurodegeneration, emphasizing Alzheimer's disease.

Arc/Arg3.1 expression in the brain tissues during the learning process in Alzheimer's disease animal models

Introduction. Arc/Arg3.1 is a common marker of neuronal activation for learning and memorizing. Some experimental data show the Arc/Arg3.1 expression in the post-mitotic neurons of the neurogenic niches. At the same time, we still have to understand the importance of such an expression for neurogenesis induced by the learning or memorizing processes, in health and in disease.
 Objective: to evaluate the changes in Arc/Arg3.1 expression in the post-mitotic neurons and to assess the proliferative activity of the neurogenic niche cells in Alzheimer's disease animal models.
 Materials and methods. We divided the C57Bl/6В mice into 2 groups: experimental (n = 15) and control (n = 15). The experimental group were injected with the amyloid- oligomers 2535 in their CA1 hippocampal region while the control mice received normal saline injections in the same region. Passive Avoidance Test (PAT) was used to assess the cognitive functions from the day 9 after the intervention. One hour after each test session we collected the samples of brain tissues to immunohistochemically assess them for the Arc/Arg3.1 expression and PCNA cell proliferation marker.
 Results. At day 11 the count of Arc/Arg3.1+NeuN+ cells in the subgranular zone had significantly increased. In animal neurodegeneration models the 1st and 2nd PAT sessions were associated with a significant increase in Arc/Arg3.1+NeuN+ cells, although by the day 11 their count significantly decreased. The count of Arc/Arg3.1+ cells in the subventricular and subgranular zones had increased after the 3rd PAT session in the control group while in Alzheimer's disease animal models this was observed only after the 2nd PAT session. Preserved Arc/Arg3.1 expression in the subventricular zone is associated with the increased PCNA cell prolifera- tion marker expression. At the same time, the toxic effect of the amyloid- oligomers suppressed the cells' proliferative activity in the subgranular zone at day 9.
 Conclusions. Despite the toxic effect of the amyloid- oligomers 2535, the post-mitotic neurons of the neurogenic niches retained the ability to express Arc/Arg3.1 in vivo. The obtained results show a transient increase in sensitivity of the post-mitotic neurons of the neurogenic niches for the learning stimuli in the early stages of the Alzheimer-type neurodegeneration.

The Neurotoxic Effect of β-Amyloid Is Accompanied by Changes in the Mitochondrial Dynamics and Autophagy in Neurons and Brain Endothelial Cells in the Experimental Model of Alzheimer's Disease.

A comparative assessment of the expression of the mitochondrial fission marker Drp1 and the autophagy marker LC3 in neurons and endothelial cells in the hippocampus and entorhinal cortex during progression of cognitive deficit was performed in animals with intrahippocampal administration of β-amyloid. In both brain regions, the expression of Drp1 and LC3 in neuronal and endothelial cells was enhanced. The peak of cognitive impairment corresponded to the maximum expression of Drp1 and LC3 in hippocampal neurons and was preceded by an increase in the number of Drp1+ and LC3+ endothelial cells in this brain region. These data attests to a possible role of aberrant mitochondrial dynamics and autophagy of endothelial cells in the impairment of brain plasticity in the Alzheimer's type neurodegeneration.

Expression of NLRP3 Inflammasomes in Neurogenic Niche Contributes to the Effect of Spatial Learning in Physiological Conditions but Not in Alzheimer’s Type Neurodegeneration

A common feature of neurodegenerative disorders, in particular Alzheimer's disease (AD), is a chronic neuroinflammation associated with aberrant neuroplasticity. Development of neuroinflammation affects efficacy of stem and progenitor cells proliferation, differentiation, migration, and integration of newborn cells into neural circuitry. However, precise mechanisms of neurogenesis alterations in neuroinflammation are not clear yet. It is well established that expression of NLRP3 inflammasomes in glial cells marks neuroinflammatory events, but less is known about contribution of NLRP3 to deregulation of neurogenesis within neurogenic niches and whether neural stem cells (NSCs), neural progenitor cells (NPCs) or immature neuroblasts may express inflammasomes in (patho)physiological conditions. Thus, we studied alterations of neurogenesis in rats with the AD model (intra-hippocampal injection of Aβ1-42). We found that in Aβ-affected brain, number of CD133+ cells was elevated after spatial training in the Morris water maze. The number of PSA-NCAM+ neuroblasts diminished by Aβ injection was completely restored by subsequent spatial learning. Spatial training leads to elevated expression of NLRP3 inflammasomes in the SGZ (subgranular zones): CD133+ and PSA-NCAM+ cells started to express NLRP3 in sham-operated, but not AD rats. Taken together, our data suggest that expression of NLRP3 inflammasomes in CD133+ and PSA-NCAM+ cells may contribute to stimulation of adult neurogenesis in physiological conditions, whereas Alzheimer's type neurodegeneration abolishes stimuli-induced overexpression of NLRP3 within the SGZ neurogenic niche.

Synthetic fragment (60–76) of RAGE improves brain mitochondria function in olfactory bulbectomized mice

The receptor for advanced glycation end products (RAGE) is considered to contribute to the pathogenesis of Alzheimer's disease (AD), mediating amyloid beta (Aβ) accumulation, mitochondrial damage, and neuroinflammation. Previously, we have synthesized small peptides corresponding to the fragments (60–76) (P1) and (60–62) (P2) of the RAGE extracellular domain, and have shown that administration of P1 fragment but not P2 results in restoration of the spatial memory and decreases the brain Aβ (1–40) level in olfactory bulbectomized (OBX) mice demonstrating main features of Alzheimer's type neurodegeneration. In the present study, we have investigated the supposed mechanism of the therapeutic efficacy of P1 RAGE fragment and compared it to P2 short fragment. We have found that P1 restored activities of the respiratory chain in the Complexes I and IV in both cortical and hippocampal mitochondria of the OBX mice while P2 had no effect. Besides, fluorescein-labeled analog Flu-P1 bound to Aβ (1–40) and Aβ (1–42) with high affinity (Kd in the nanomolar range) whereas Flu-P2 revealed low affinity with tenfold higher Kd value for Aβ (1–40) and did not bind to Aβ (1–42). However, neither of the peptides had a notable impact on inflammation, estimated as mRNA expression of proinflammatory cytokines in the brain tissues of OBX mice. Taken together, our results suggest that direct Aβ-P1 interaction is one of the molecular events mediating the protection of the mitochondria in OBX animals from Aβ toxic effect. The RAGE fragment P1 would be the soluble decoy for Aβs and serve as a promising therapeutic agent against neurodegeneration accompanied by mitochondrial dysfunction.

Effect of Transplantation of Neural Stem and Progenitor Cells on Memory in Animals with Alzheimer's Type Neurodegeneration.

The effects of systemic and intracerebral transplantation of human fetal neural stem and progenitor cells were studied on the model of olfactory bulbectomy in mice with developing signs of sporadic Alzheimer's disease. It was found that transplantation of these cells at certain stages of disease development contributed to improvement of spatial memory and preservation of hippocampal neurons in these animals.

Pericytes in Alzheimer's Disease: Novel Clues to Cerebral Amyloid Angiopathy Pathogenesis.

Pericytes in the central nervous system attract growing attention of neurobiologists because of obvious opportunities to use them as target cells in numerous brain diseases. Functional activity of pericytes includes control of integrity of the endothelial cell layer, regeneration of vascular cells, and regulation of microcirculation. Pericytes are well integrated in the so-called neurovascular unit (NVU) serving as a platform for effective communications of neurons, astrocytes, endothelial cells, and pericytes. Contribution of pericytes to the establishment and maintaining the structural and functional integrity of blood-brain barrier is confirmed in numerous experimental and clinical studies. The review covers current understandings on the role of pericytes in molecular pathogenesis of NVU/BBB dysfunction in Alzheimer's disease with the special focus on the development of cerebral amyloid angiopathy, deregulation of cerebral angiogenesis, and progression of BBB breakdown seen in Alzheimer's type neurodegeneration.

Choroid Plexus Blood-CSF Barrier: Major Player in Brain Disease Modeling and Neuromedicine

The choroid plexus (CP) of the blood-cerebrospinal fluid barrier (BCSFB) impacts CSF homeostasis, brain diseases, and neuromedical translation. CP executes neuroendocrine, excretory, and neuroimmune actions. BCSFB diversely manages brain-spinal cord fluid environments, giving rise to a wide pathophysiology spectrum. Newly-discovered choroidal phenomena include integration of circadian clock signals, immune interaction with gut microbiotica, and expression of receptors to taste CSF composition. BCSFB tight junctions and transcellular mechanisms differ from blood-brain barrier (BBB) counterparts, variably regulating pathogen and leukocyte access to the CSF-brain nexus. This review highlights microbial agents, substrates and autoantigens using CP epithelial membranes to penetrate CSF and periventricular regions. Lipopolysaccharide (LPS) is analyzed as a barrier-damaging agent and neuroinflammation promoter. Transducing LPS- and toll-like receptor activity produce CP-CSF cytokines in sickness behavior and virulent sepsis-associated encephalopathy. Agents/systems that counter oxidative activity such as matrix metalloproteinase 8 inhibitors and Nrf2 activators (bile acids and isothiocyanates) show promise as neural and CP protectants. One review theme emphasizes CP’s preponderant role in initiating central diseases, and their remediation. In view of BCSFB permeability alterations and epithelial transformation, we discuss systemic lupus erythematosus, N-methyl D-aspartate-associated autoencephalitis, helicobacter disruption of BCSFB, toll-like receptor 2 stimulation in CP (neuroinflammation), the CP gateway for trypanosomes, and APOE-linked cholesterol transport into CSF. Another section treats concurrent involvement of BCSFB-BBB alterations in helminthic meningitis, forebrain ischemia, acute hyperthermia, leptin resistance/obesity, diabetes mellitus, and Alzheimer-type neurodegeneration. Barrier impairment is analyzed by injury type, time course, therapeutic strategies, and translational neuromedicine principles. The restorative power of BCSFB-transported growth factors, hormones and medicinal agents is emphasized for strengthening CP-CSF homeostatic mechanisms in seizures, stroke and Parkinsonism. A worthy therapeutic aim is to attenuate CNS disorders triggered by BCSFB malfunction, using CSF-delivered therapeutic agents for promoting neural viability.

A comparison of the neuropsychological profiles of people living in squalor without hoarding to those living in squalor associated with hoarding.

Squalor affects 1 in 1000 older people and is regarded as a secondary condition to other primary disorders such as dementia, intellectual impairment and alcohol abuse. Squalor frequently is associated with hoarding behaviour. We compared the neuropsychological profile of people living in squalor associated with hoarding to those presenting with squalor only. This study is a retrospective case series of hospital inpatient and community healthcare services of 69 people living in squalor (49 from aged care, 16 from aged psychiatry, 3 from acute medical and 1 from a memory clinic). Forty per cent had co-morbid hoarding behaviours. The main outcomes were neuropsychologists' opinions of domain-specific cognitive impairment. The squalor-hoarding group (M age 75.8, SD = 6.9,) was significantly older (p < 0.05) than the squalor-only group (M age 69.9 years, SD = 13.1), significantly more likely to have vascular or Alzheimer's type neurodegeneration (p < 0.05) and significantly less likely to have alcohol-related impairment (p < 0.05). Chi-square analyses revealed significantly greater rates of impairment for the squalor-only group (p < 0.05) in visuospatial reasoning, abstraction, planning, organisation, problem solving and mental flexibility, compared with the squalor-hoarding group. Logistic regression analysis indicated that impaired mental flexibility was a significant predictor and strongly indicated squalor only (odds ratio = 0.07; 95% confidence interval: 0.01-0.82). Preliminary evidence suggests that squalor associated with hoarding may have distinct neuropsychological features compared against squalor only. Future work should be conducted using a larger sample and a common neuropsychological battery to better understand the deficits associated with hoarding-related squalor. Copyright © 2016 John Wiley & Sons, Ltd.

New azepino[4,3-b]indole derivatives as nanomolar selective inhibitors of human butyrylcholinesterase showing protective effects against NMDA-induced neurotoxicity

Several 6-substituted 3,4,5,6-tetrahydroazepino[4,3-b]indol-1(2H)-one (THAI) derivatives were synthesized and evaluated for their activity as cholinesterase (ChE) inhibitors. The most potent inhibitors were identified among 6-(2-phenylethyl)-THAI derivatives, and in particular compounds 12b and 12d proved to be very active against human BChE (IC50 = 13 and 1.8 nM, respectively), with 1000-fold selectivity over AChE. Structure-activity relationships highlighted critical features (e.g., ring fusion [4,3-b], integrity of the lactam CONH function) and favorable physicochemical properties of the 6-(2-phenylethyl) group (i.e., optimal position, size and lipophilicity of phenyl substituents). The effects of a number of compounds against NMDA-induced SH-SY5Y neuronal cell injury were also evaluated. Treatment with 12b increased cell viability in SH-SY5Y cells pretreated with 250 μM NMDA, with significant effects (P < 0.05) at concentrations between 0.5 and 5 μM. These findings suggest that THAI can be used as a scaffold for developing new drug leads for the treatment of Alzheimer-type neurodegeneration syndrome.

Oxidative damage and the pathogenesis of menopause related disturbances and diseases.

The postmenopausal phase of life is frequently associated in women with subjective symptoms (e.g. vasomotor) and real diseases (atherosclerosis with coronary ischemia, osteoporosis, Alzheimer-type neurodegeneration, urogenital dystrophy), which together determine the post-menopausal syndrome. Observations that oxidative damage by reactive oxygen/nitrogen species in experimental models can contribute to the pathogenesis of these disturbances stimulated research on the relationships between menopause, its endocrine deficiency, oxidative balance and the "wellness" in postmenopausal life. The connection among these events is probably due to the loss of protective actions exerted by estrogens during the fertile life. Most recent studies have revealed that estrogens exert an antioxidant action not by direct chemical neutralization of reactants as it was expected until recently but by modulating the expression of antioxidant enzymes that control levels of biological reducing agents. Also nutritional antioxidants apparently act by a similar mechanism. From this perspective it is conceivable that a cumulative control of body oxidant challenges and biological defenses could help in monitoring between "normal" and "pathological" menopause. However, as clinical studies failed to confirm this scenario in vivo, we have decided to review the existing literature to understand the causes of this discrepancy and whether this was due to methodologic reasons or to real failure of the basic hypothesis.

The effects of two polymorphisms on p21cip1 function and their association with Alzheimer's disease in a population of European descent.

With the exception of ApoE4, genome-wide association studies have failed to identify strong genetic risk factors for late-onset Alzheimer’s disease, despite strong evidence of heritability, suggesting that many low penetrance genes may be involved. Additionally, the nature of the identified genetic risk factors and their relation to disease pathology is also largely obscure. Previous studies have found that a cancer-associated variant of the cell cycle inhibitor gene p21cip1 is associated with increased risk of Alzheimer’s disease. The aim of this study was to confirm this association and to elucidate the effects of the variant on protein function and Alzheimer-type pathology. We examined the association of the p21cip1 variant with Alzheimer’s disease and Parkinson’s disease with dementia. The genotyping studies were performed on 719 participants of the Oxford Project to Investigate Memory and Ageing, 225 participants of a Parkinson’s disease DNA bank, and 477 participants of the Human Random Control collection available from the European Collection of Cell Cultures. The post mortem studies were carried out on 190 participants. In the in-vitro study, human embryonic kidney cells were transfected with either the common or rare p21cip1 variant; and cytometry was used to assess cell cycle kinetics, p21cip1 protein expression and sub-cellular localisation. The variant was associated with an increased risk of Alzheimer’s disease, and Parkinson’s disease with dementia, relative to age matched controls. Furthermore, the variant was associated with an earlier age of onset of Alzheimer’s disease, and a more severe phenotype, with a primary influence on the accumulation of tangle pathology. In the in-vitro study, we found that the SNPs reduced the cell cycle inhibitory and anti-apoptotic activity of p21cip1. The results suggest that the cancer-associated variant of p21cip1 may contribute to the loss of cell cycle control in neurons that may lead to Alzheimer-type neurodegeneration.

Therapeutic Effect of Mesenchymal Multipotent Stromal Cells on Memory in Animals with Alzheimer-Type Neurodegeneration

Transplantation of human mesenchymal multipotent stromal cells improved spatial memory in bulbectomized mice with Alzheimer-type neurodegeneration. The positive effect was observed in 1 month after intracerebral transplantation and in 3 months after systemic injection of mesenchymal multipotent stromal cells. No cases of malignant transformation were noted. These findings indicate prospects of using mesenchymal multipotent stromal cells for the therapy of Alzheimer disease and the possibility of their systemic administration for attaining the therapeutic effect.

Possible Influence of a Non-Synonymous Polymorphism Located in the NGF Precursor on Susceptibility to Late-Onset Alzheimer's Disease and Mild Cognitive Impairment

The complex network of neurotrophic factors is supposed to play a role in neurodegeneration, but the effect of variations in their coding genes on susceptibility to sporadic Alzheimer's disease is not established. The mature form of nerve growth factor (NGF) derives from a precursor, proNGF, which was recently discovered to exert crucial functions in brain. We designed a case-control association study to test the hypothesis as to whether polymorphisms located in the proNGF genomic region influence the liability to Alzheimer's disease and its prodromal form, mild cognitive impairment. Three independent case-control samples, with individuals aged >60 years, were collected in Italian Alzheimer Units. One polymorphism located in the proNGF region, rs6330, demonstrated a minor allele frequency >5% and was used in the association study. The minor allele of rs6330 was more frequent in patients from the three sample series as compared to respective normal controls. Multivariate logistic regression showed a significant association under the dominant model in one cohort (OR 1.83, 95% CI 1.00-3.54) and in the pooled case-control sample (OR 1.47, 95% CI 1.03-2.08). These findings further suggest that proNGF may play a role in Alzheimer-type neurodegeneration and that genetic variations in the NGF locus may influence the occurrence of sporadic, late-onset Alzheimer's disease.

One Year Follow up in Ischemic Brain Injury and the Role of Alzheimer Factors

Ongoing interest in brain ischemia research has provided data showing that ischemia may be involved in the pathogenesis of Alzheimer disease. Brain ischemia in the rat produces a stereotyped pattern of selective neuronal degeneration, which mimics early Alzheimer disease pathology. The objective of this study was to further develop and characterize cardiac arrest model in rats, which provides practical way to analyze Alzheimer-type neurodegeneration. Rats were made ischemic by cardiac arrest. Blood-brain barrier (BBB) insufficiency, accumulation of different parts of amyloid precursor protein (APP) and platelets inside and outside BBB vessels were investigated in ischemic brain up to 1-year survival. Ischemic brain tissue demonstrated haphazard BBB changes. Toxic fragments of APP deposits were associated with the BBB vessels. Moreover our study revealed platelet aggregates in- and outside BBB vessels. Toxic parts of APP and platelet aggregates correlated very well with BBB permeability. Progressive injury of the ischemic brain parenchyma may be caused not only by a degeneration of neurons destroyed during ischemia but also by chronic damage in BBB. Chronic ischemic BBB insufficiency with accumulation of toxic components of APP in the brain tissue perivascular space, may gradually over a lifetime, progress to brain atrophy and to full blown Alzheimer-type pathology.

A specific relationship between hippocampal CA1 subfield atrophy and episodic memory encoding in amnestic mild cognitive impairment

uptake ratios were calculated within a ROI including frontal, temporoparietal, and retrosplenial cortices (FLR-ROI), using the cerebellum as reference region. Based on a FLR-threshold of 1.15, subjects were divided into PIBpositive (+) and -negative (-). Three age-matched groups were studied: A) 12 PIB(-) cognitively normal elderly controls, B) 12 PIB(+) cognitively normal elderly controls and C) 13 PIB(+) MCI-patients. Voxel-based and ROI-based statistical analyses were performed. The overlap between hypometabolism andWBC-abnormalities inMCI was used to define a ROI to extract values for correlation analysis between different modalities. Results: Group comparison between MCI and PIB(-) controls revealed significant hypometabolism and regionally overlapping WBC-reductions in MCI in posterior cingulate cortex/precuneus (typical cortical hubs, see figure 1). PIB-FLR values were negatively correlated with FDG-values (r 1⁄4 -0.67) and WBC-values (r 1⁄4 -0.42) and a linear positive correlation was found between FDG and WBC-values (r 1⁄4 0.51) across the entire population (groups A, B and C). These results survived correction for age and grey matter density.Conclusions: These results indicate that disruption of functional connectivity and hypometabolism may represent early functional consequences of emerging molecular Alzheimer-pathology, evolving prior to clinical onset of dementia. The spatial overlap between hypometabolism and disruption of connectivity in cortical hubs points to a particular susceptibility of these regions to early Alzheimer-type neurodegeneration and may reflect a link between synaptic dysfunction and functional disconnection.

Extended results of the Alzheimer's disease anti‐inflammatory prevention trial

Epidemiologic evidence suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) delay onset of Alzheimer's dementia (AD), but randomized trials show no benefit from NSAIDs in patients with symptomatic AD. The Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT) randomized 2,528 elderly persons to naproxen or celecoxib versus placebo for 2 years (standard deviation = 11 months) before treatments were terminated. During the treatment interval, 32 cases of AD revealed increased rates in both NSAID-assigned groups. We continued the double-masked ADAPT protocol for 2 additional years to investigate incidence of AD (primary outcome). We then collected cerebrospinal fluid (CSF) from 117 volunteer participants to assess their ratio of CSF tau to Aβ(1-42.) Including 40 new events observed during follow-up of 2,071 randomized individuals (92% of participants at treatment cessation), there were 72 AD cases. Overall, NSAID-related harm was no longer evident, but secondary analyses showed that increased risk remained notable in the first 2.5 years of observations, especially in 54 persons enrolled with cognitive impairment--no dementia (CIND). These same analyses showed later reduction in AD incidence among asymptomatic enrollees who were given naproxen. CSF biomarker assays suggested that the latter result reflected reduced Alzheimer-type neurodegeneration. These data suggest a revision of the original ADAPT hypothesis that NSAIDs reduce AD risk, as follows: NSAIDs have an adverse effect in later stages of AD pathogenesis, whereas asymptomatic individuals treated with conventional NSAIDs such as naproxen experience reduced AD incidence, but only after 2 to 3 years. Thus, treatment effects differ at various stages of disease. This hypothesis is consistent with data from both trials and epidemiological studies.

A specific relationship between hippocampal CA1 subfield atrophy and episodic memory encoding in amnestic mild cognitive impairment

uptake ratios were calculated within a ROI including frontal, temporoparietal, and retrosplenial cortices (FLR-ROI), using the cerebellum as reference region. Based on a FLR-threshold of 1.15, subjects were divided into PIBpositive (+) and -negative (-). Three age-matched groups were studied: A) 12 PIB(-) cognitively normal elderly controls, B) 12 PIB(+) cognitively normal elderly controls and C) 13 PIB(+) MCI-patients. Voxel-based and ROI-based statistical analyses were performed. The overlap between hypometabolism andWBC-abnormalities inMCI was used to define a ROI to extract values for correlation analysis between different modalities. Results: Group comparison between MCI and PIB(-) controls revealed significant hypometabolism and regionally overlapping WBC-reductions in MCI in posterior cingulate cortex/precuneus (typical cortical hubs, see figure 1). PIB-FLR values were negatively correlated with FDG-values (r 1⁄4 -0.67) and WBC-values (r 1⁄4 -0.42) and a linear positive correlation was found between FDG and WBC-values (r 1⁄4 0.51) across the entire population (groups A, B and C). These results survived correction for age and grey matter density.Conclusions: These results indicate that disruption of functional connectivity and hypometabolism may represent early functional consequences of emerging molecular Alzheimer-pathology, evolving prior to clinical onset of dementia. The spatial overlap between hypometabolism and disruption of connectivity in cortical hubs points to a particular susceptibility of these regions to early Alzheimer-type neurodegeneration and may reflect a link between synaptic dysfunction and functional disconnection.

Neuronal dysfunction and disconnection of cortical hubs in non-demented subjects with elevated amyloid burden

Disruption of functional connectivity between brain regions may represent an early functional consequence of β-amyloid pathology prior to clinical Alzheimer's disease. We aimed to investigate if non-demented older individuals with increased amyloid burden demonstrate disruptions of functional whole-brain connectivity in cortical hubs (brain regions typically highly connected to multiple other brain areas) and if these disruptions are associated with neuronal dysfunction as measured with fluorodeoxyglucose-positron emission tomography. In healthy subjects without cognitive symptoms and patients with mild cognitive impairment, we used positron emission tomography to assess amyloid burden and cerebral glucose metabolism, structural magnetic resonance imaging to quantify atrophy and novel resting state functional magnetic resonance imaging processing methods to calculate whole-brain connectivity. Significant disruptions of whole-brain connectivity were found in amyloid-positive patients with mild cognitive impairment in typical cortical hubs (posterior cingulate cortex/precuneus), strongly overlapping with regional hypometabolism. Subtle connectivity disruptions and hypometabolism were already present in amyloid-positive asymptomatic subjects. Voxel-based morphometry measures indicate that these findings were not solely a consequence of regional atrophy. Whole-brain connectivity values and metabolism showed a positive correlation with each other and a negative correlation with amyloid burden. These results indicate that disruption of functional connectivity and hypometabolism may represent early functional consequences of emerging molecular Alzheimer's disease pathology, evolving prior to clinical onset of dementia. The spatial overlap between hypometabolism and disruption of connectivity in cortical hubs points to a particular susceptibility of these regions to early Alzheimer's-type neurodegeneration and may reflect a link between synaptic dysfunction and functional disconnection.