Cause Of Neurodegeneration Research Articles

Early-Occurring Dendritic Spines Alterations in Mouse Models of Alzheimer's Disease Inform on Primary Causes of Neurodegeneration.

The consensus that synaptic failure is the earliest cause of cognitive deterioration in Alzheimer’s disease (AD) has initially led to investigate structural (dendritic spines) and physiological (LTP) synaptic dysfunctions in mouse models of AD with established cognitive alterations. The challenge is now to track down ultra-early alterations in spines to uncover causes rather than disease’s symptoms. This review article pinpoints dysregulations of the postsynaptic density (PSD) protein network which alter the morphology and function of spines in pre- and early- symptomatic hAPP mouse models of AD, and, hence, inform on primary causes of neurodegeneration.

Visual hallucinations in psychiatric, neurologic, and ophthalmologic disease.

Recent studies have increased our understanding of the biochemical and structural bases of visual hallucinations in patients with a variety of underlying causes. Visual hallucinations may be related to disruption of functional connectivity networks, with underlying biochemical dysfunction such as decreased in cholinergic activity. Structural abnormalities in primary and higher order visual processing areas also have been found in patients with visual hallucinations. The occurrence of visual hallucinations after vision loss, the Charles Bonnet syndrome, may have more functional similarity to psychiatric and neurodegenerative causes than previously suspected despite retained insight into the unreal nature of the phenomena. Visual hallucinations are common, and patients may not report them if specific inquiries are not made. Presence or absence of hallucinations may be of diagnostic and therapeutic importance, especially in patients with neurodegenerative conditions that have overlapping features. Treatment of visual hallucinations remains challenging and must be tailored to each patient based on the underlying cause and comorbid conditions.

Abstract P076: Cerebral Vascular Dysfunction Precedes Cognitive Impairment In Alzheimer’S Disease

Alzheimer’s disease (AD) is the most common form of dementia and is a major financial burden to the health care system. The prevailing view is that cholinergic deficiency, amyloid-beta (Aβ) accumulation, and Tau protein abnormalities are the primary underlying causes of neurodegeneration in AD, but unsuccessful clinical trials targeting these pathways have led the community to reconsider alternatives such as the vascular hypothesis. However, it is still uncertain whether cerebral vascular impairment is a cause or consequence of dementia in AD. Previous studies have demonstrated that a TgF344-AD model expressing mutant human amyloid precursor protein ( APP ) and presenilin 1 ( PS1 ) genes exhibits Aβ accumulation and cognition deficiency at 24 weeks of age. In the present study, we compared the myogenic response (MR) of the middle cerebral artery (MCA) and parenchymal arteriole (PA) in 8-, 16- and 24-week TgF344-AD and WT F344 rats. We first confirmed that TgF344-AD rats exhibited learning and memory dysfunction at 24-week of age, and they took 2-time longer to escape than WT rats using an eight-arm water maze. There was no difference in the MR of MCA and PA at 8 weeks of age in AD and WT rats. However, AD rats exhibited an impaired MR at 16-week of age as the inner diameter of the MCA of AD rats only decreased by 6.6 ± 1.7% vs. 10.7% ± 1.0% in WT rats when perfusion pressure was increased from 40 to 180 mmHg. The impaired MR was exacerbated in AD rats at 24-week of age. These findings suggest that impaired MR of cerebral vasculature precedes the development of a cognitive deficiency. Since the MR protects the cerebral microcirculation from elevations in pressure, an impaired MR and cerebral blood flow autoregulation could result in blood-brain barrier leakage that contributes to neurodegeneration and cognitive impairment. Our results provide novel insight in understanding the pathogenesis of AD, which will lay the foundation for the discovery of new biomarkers in AD.

Parkinson's: A Disease of Aberrant Vesicle Trafficking.

Parkinson's disease (PD) is a leading cause of neurodegeneration that is defined by the selective loss of dopaminergic neurons and the accumulation of protein aggregates called Lewy bodies (LBs). The unequivocal identification of Mendelian inherited mutations in 13 genes in PD has provided transforming insights into the pathogenesis of this disease. The mechanistic analysis of several PD genes, including α-synuclein (α-syn), leucine-rich repeat kinase 2 (LRRK2), PTEN-induced kinase 1 (PINK1), and Parkin, has revealed central roles for protein aggregation, mitochondrial damage, and defects in endolysosomal trafficking in PD neurodegeneration. In this review, we outline recent advances in our understanding of these gene pathways with a focus on the emergent role of Rab (Ras analog in brain) GTPases and vesicular trafficking as a common mechanism that underpins how mutations in PD genes lead to neuronal loss. These advances have led to previously distinct genes such as vacuolar protein-sorting-associated protein 35 (VPS35) and LRRK2 being implicated in a common signaling pathway. A greater understanding of these common nodes of vesicular trafficking will be crucial for linking other PD genes and improving patient stratification in clinical trials underway against α-syn and LRRK2 targets.

Neuroinflammation in dementia with Lewy bodies: a human post-mortem study

Dementia with Lewy bodies (DLB) is the second most common neurodegenerative cause of dementia, behind Alzheimer’s disease (AD). It is now established that cerebral inflammation has a key role in the aetiology and progression of AD, but this has yet to be confirmed in DLB. We aimed to determine the neuroinflammatory profile in the cerebral cortex of a large cohort of DLB cases. Thirty post-mortem confirmed DLB cases and twenty-nine matched controls were immunolabelled (Brodmann area 21) and quantified for: neuropathology—αSYN, Aβ, P-tau; microglial phenotype—Iba1, HLA-DR, CD68, FcƴR (CD64, CD32a, CD32b, CD16); presence of T lymphocytes—CD3; and anti-inflammatory markers—IL4R, CHI3L1. Status spongiosis, as a marker of neuropil degeneration, was quantified using Haematoxylin and Eosin staining. We found no significant difference between groups in protein load for Iba1, HLA-DR, CD68, CD64, CD32b, IL4R, or CHI3L1, despite increased neuropathology in DLB. CD32a load was significantly lower, and CD16 load higher, in DLB compared with controls. There was no difference in status spongiosis between groups. Significantly more DLB cases than controls showed T-lymphocyte recruitment. Overall, we conclude that microglial activation is not a prominent feature of DLB, and that this may be associated with the relatively modest neuropil degeneration observed in DLB. Our findings, based on the largest post-mortem cohort to date exploring neuroinflammation in DLB, demonstrate a dissociation between protein deposition, neurodegeneration and microglial activation. The relative preservation of cortical structures in DLB suggests the dementia could be more amenable to potential therapies.

Comparative analysis of brain pathology in heparan sulphate storing mucopolysaccharidoses

The cause of neurodegeneration in MPS mouse models is the focus of much debate and what the underlying cause of disease pathology in MPS mice is. The timing of development of pathology and when this can be reversed or impacted is the key to developing suitable therapies in MPS. This study is the first of its kind to correlate the biochemical changes with the functional outcome as assessed using non-invasive behaviour testing across multiple mucopolysaccharidosis (MPS) mouse models. In the MPS brain, the primary lysosomal enzyme dysfunction leads to accumulation of primary glycosaminoglycans (GAGs) with gangliosides (GM2 and GM3) being the major secondary storage products. With a focus on the neuropathology, a time course experiment was conducted in MPS I, MPS IIIA, MPS VII (severe and attenuated models) in order to understand the relative timing and level of GAG and ganglioside accumulation and how this correlates to behaviour deficits. Time course analysis from 1 to 6 months of age was conducted on brain samples to assess primary GAG (uronic acid), β-hexosaminidase enzyme activity and levels of GM2 and GM3 gangliosides. This was compared to a battery of non-invasive behaviour tests including open field, inverted grid, rotarod and water cross maze were assessed to determine effects on motor function, activity and learning ability. The results show that the GAG and ganglioside accumulation begins prior to the onset of detectable changes in learning ability and behaviour. Interestingly, the highest levels of GAG and ganglioside accumulation was observed in the MPS IIIA mouse despite having 3% residual enzyme activity. Deficits in motor function were clearly observed in the severe Gusmps/mps, which were significantly delayed in the attenuated Gustm(L175F)Sly model despite their minimal increase in detectable enzyme activity. This suggests that genotype and residual enzyme activity are not indicative of severity of disease pathology in MPS disease and there exists a window when there are considerable storage products without detectable functional deficits which may allow an alteration to occur with therapy.

Value of a Panel of 6 Serum Biomarkers to Differentiate Between Healthy Controls and Mild Cognitive Impairment Due to Alzheimer Disease.

There is considerable evidence suggesting that inflammatory responses may be involved in the neurodegenerative cascade of Alzheimer disease (AD). Blood-based biomarker analysis of inflammatory markers indicative of dementia could serve as a minimally invasive and easy-to-administer diagnostic tool in primary care. The authors quantified 6 markers (brain-derived neurotrophic factor, insulin-like growth factor 1, vascular endothelial growth factor, transforming growth factor-beta type 1, monocyte chemoattractant protein 1, and interleukin-18) in blood serum of 68 healthy blood donors (controls), 42 patients with AD at the dementia stage, 55 patients with AD at the stage of mild cognitive impairment (MCI-AD), and 25 patients with MCI non-AD. All patients have been fully characterized, including AD biomarker analyses in cerebrospinal fluid. Data were analyzed in an algorithm that was trained, validated, and then used for dichotomous classification of unknown data into data sets suspicious and not suspicious of AD. Using this algorithm, 47 of 55 MCI-AD (85.5%) and 20 of 25 MCI non-AD (80%) cases were classified as suspicious of AD. This panel of 6 markers in blood serum may indicate underlying neurodegenerative processes in patients with AD at the MCI stage. The authors assume that a deranged equilibrium of neuroprotective and inflammatory processes is an overall major cause for neurodegeneration and cognitive decline.

Assessment of Probiotics Mixture on Memory Function, Inflammation Markers, and Oxidative Stress in an Alzheimer's Disease Model of Rats.

Background:The most important cause of neurodegeneration in AD is associated with inflammation and oxidative stress. Probiotics are microorganisms that are believed to be beneficial to human and animals. Probiotics reduce oxidative stress and inflammation in some cases. Therefore, this study determined the effects of probiotics mixture on the biomarkers of oxidative stress and inflammation in an AD model of rats. Methods:In this study, 50 rats were allocated to five groups, namely control, sham, and AD groups with Aβ1-40 intra-hippocampal injection, as well as AD + rivastigmine and AD + probiotics groups with Aβ1-40 intra-hippocampal injection and 2 ml (1010 CFU) of probiotics (Lactobacillus reuteri, Lactobacillus rhamnosus, and Bifidobacterium infantis) orally once a day for 10 weeks. MWM was used to assess memory and learning. To detect Aβ plaque, Congo red staining was used. Oxidative stress was monitored by measuring the MDA level and SOD activity, and to assess inflammation markers (IL-1β and TNF-α) in the hippocampus, ELISA method was employed. Results:Spatial memory improved significantly in treatment group as measured by MWM. Probiotics administration reduced Aβ plaques in AD rats. MDA decreased and SOD increased in the treatment group. Besides, probiotics reduced IL-1β and TNF-α as inflammation markers in the AD model of rats. Conclusion:Our data revealed that probiotics are helpful in attenuating inflammation and oxidative stress in AD.

Cyclophilin D binds to the acidic C-terminus region of \u03b1-Synuclein and affects its aggregation characteristics

Cyclophilin D (CypD) is a peptidyl-prolyl isomerase expressed in the nucleus and transported into the mitochondria where it is best associated with the regulation of the mitochondrial permeability transition pore (MPTP). There are, however, other possible roles of CypD in the mitochondria which may or may not be linked with the MPTP. Alpha synuclein (αSyn) is shown here to interact directly with CypD via its acidic proline-rich C-terminus region and binding at the putative ligand binding pocket of CypD. The study shows that CypD binding with soluble αSyn prevents its aggregation. Furthermore, the addition of CypD to preformed αSyn fibrils leads to the disassembly of these fibrils. Enzymatically-compromised mutants of CypD show reduced abilities to dissociate αSyn aggregates, suggesting that fibril disassembly is linked to the increased rate of peptidyl-prolyl isomerisation catalysed by CypD. Protein aggregation in the mitochondria is increasingly seen as the cause of neurodegeneration. However, protein aggregation is a reversible process but disaggregation requires help from other proteins such as isomerases and chaperones. The results here demonstrate a possible mechanism by which CypD achieves this and suggest that disaggregation could be one of the many functions of this protein.

The Role of Mitochondria in Neurodegenerative Diseases: the Lesson from Alzheimer's Disease and Parkinson's Disease.

Although the pathogenesis of neurodegenerative diseases is still widely unclear, various mechanisms have been proposed and several pieces of evidence are supportive for an important role of mitochondrial dysfunction. The present review provides a comprehensive and up-to-date overview about the role of mitochondria in the two most common neurodegenerative disorders: Alzheimer's disease (AD) and Parkinson's disease (PD). Mitochondrial involvement in AD is supported by clinical features like reduced glucose and oxygen brain metabolism and by numerous microscopic and molecular findings, including altered mitochondrial morphology, impaired respiratory chain function, and altered mitochondrial DNA. Furthermore, amyloid pathology and mitochondrial dysfunction seem to be bi-directionally correlated. Mitochondria have an even more remarkable role in PD. Several hints show that respiratory chain activity, in particular complex I, is impaired in the disease. Mitochondrial DNA alterations, involving deletions, point mutations, depletion, and altered maintenance, have been described. Mutations in genes directly implicated in mitochondrial functioning (like Parkin and PINK1) are responsible for rare genetic forms of the disease. A close connection between alpha-synuclein accumulation and mitochondrial dysfunction has been observed. Finally, mitochondria are involved also in atypical parkinsonisms, in particular multiple system atrophy. The available knowledge is still not sufficient to clearly state whether mitochondrial dysfunction plays a primary role in the very initial stages of these diseases or is secondary to other phenomena. However, the presented data strongly support the hypothesis that whatever the initial cause of neurodegeneration is, mitochondrial impairment has a critical role in maintaining and fostering the neurodegenerative process.

Cerebral deficiency of vitamin B5 (d-pantothenic acid; pantothenate) as a potentially-reversible cause of neurodegeneration and dementia in sporadic Alzheimer’s disease

Alzheimer’s disease (AD) is the most common cause of age-related neurodegeneration and dementia, and there are no available treatments with proven disease-modifying actions. It is therefore appropriate to study hitherto-unknown aspects of brain structure/function in AD to seek alternative disease-related mechanisms that might be targeted by new therapeutic interventions with disease-modifying actions. During hypothesis-generating metabolomic studies of brain, we identified apparent differences in levels of vitamin B5 between AD cases and controls. We therefore developed a method based on gas chromatography-mass spectrometry by which we quantitated vitamin B5 concentrations in seven brain regions from nine AD cases and nine controls. We found that widespread, severe cerebral deficiency of vitamin B5 occurs in AD. This deficiency was worse in those regions known to undergo severe damage, including the hippocampus, entorhinal cortex, and middle temporal gyrus. Vitamin B5 is the obligate precursor of CoA/acetyl-CoA (acetyl-coenzyme A), which plays myriad key roles in the metabolism of all organs, including the brain. In brain, acetyl-CoA is the obligate precursor of the neurotransmitter acetylcholine, and the complex fatty-acyl groups that mediate the essential insulator role of myelin, both processes being defective in AD; moreover, the large cerebral vitamin B5 concentrations co-localize almost entirely to white matter. Vitamin B5 is well tolerated when administered orally to humans and other mammals. We conclude that cerebral vitamin B5 deficiency may well cause neurodegeneration and dementia in AD, which might be preventable or even reversible in its early stages, by treatment with suitable oral doses of vitamin B5.

Factors Related to Alzheimer’s Disease, Tau Pathology in Alzheimer’s Disease: Possible Treatments for Tau Pathology

The Tau protein is a microtubule-associated protein that acts as a three-dimensional “railroad tie” for the microtubule. Accumulation and Aggregation of the Tau is the pathogenesis of Alzheimer’s disease. Risk factors like ApoE risk alleles, changes in the endoplasmic reticulum, and Kinases and phosphatases dysregulation have identified as the most critical factors. In Tau pathology, the abnormal hyperphosphorylation of tau appears as its accumulation in the affected neurons in Alzheimer’s disease. Neurofibrillary Tangles has shown truncated tau in both Glu-391 and Asp-421. Truncated tau associated with apoptosis in cultured cells. All six molecules of tau are the hyperphosphorylated state in PHF. In AD, hyperphosphorylated tau is present as a cytosolic protein and PHF. Treatments related to tau pathology are under research. Tau phosphorylation inhibitors and Tau aggregation inhibitors tested in people with AD. In tau phosphorylation inhibitors, Lithium has multiple targets and inhibits GSK-3b, and in tau aggregation inhibitors, many drugs block aggregation of tau in cell-free conditions. Methylene blue has multiple targets; it slows disease progression. Tau pathology appears to be a primary cause of neurodegeneration in AD. Risk factors showed a relation between AD and Tau pathology clearly. Abnormal hyperphosphorylation of tau leads to AD, and truncated tau is the main finding in tau pathology. Tau phosphorylation inhibitors and Tau aggregation inhibitors are emerging treatments.

Learning from the Past: A Review of Clinical Trials Targeting Amyloid, Tau and Neuroinflammation in Alzheimer's Disease.

Alzheimer's Disease (AD) is the most common neurodegenerative disease and cause of dementia. Characterized by amyloid plaques and neurofibrillary tangles of hyperphosphorylated Tau, AD pathology has been intensively studied during the last century. After a long series of failed trials of drugs targeting amyloid or Tau deposits, currently, hope lies in the positive results of one Phase III trial, highly debated, and on other ongoing trials. In parallel, some approaches target neuroinflammation, another central feature of AD. Therapeutic strategies are initially evaluated on animal models, in which the various drugs have shown effects on the target (decreasing amyloid, Tau and neuroinflammation) and sometimes on cognitive impairment. However, it is important to keep in mind that rodent models have a less complex brain than humans and that the pathology is generally not fully represented. Although they are indispensable tools in the drug discovery process, results obtained from animal models must be viewed with caution. In this review, we focus on the current status of disease-modifying therapies targeting amyloid, Tau and neuroinflammation with particular attention on the discrepancy between positive preclinical results on animal models and failures in clinical trials.

The use of a pharmabiotic based on the Lactobacillus fermentum U-21 strain to modulate the neurodegenerative process in an experimental model of Parkinson disease

Introduction. Experimental and clinical studies have repeatedly shown the interplay between the intestinal microbiota properties and the nervous system, with a clear link established between changes in microbiota and the development of a neurodegenerative process. It is thought that inflammation and microbiota disturbances provoke the spread of pathological forms of a-synuclein in the nervous system, which is recognized as the main cause of neurodegeneration in Parkinson disease (PD). Aim of the study: to identify the effect of a pharmabiotic based on a Lactobacillus fermentum U-21 strain in Wistar rats with paraquat-induced parkinsonism. Materials and methods. Two groups of animals received intra-abdominal paraquat injections (8 doses of 10 mg/kg, every second day for 15 days) and then received orally either a 0.9% NaCl solution, or the U-21 preparation daily for 15 days. The control groups received 0.9% NaCl injections and either a U-21 preparation, or a 0.9% NaCl solution orally under the same regimen. Motor activity was tested in the open field and narrowing beam walking tests. Changes in tyrosine hydroxylase positive enteric plexus fibers and the in quantity of intestinal villi goblet cells were measured morphologically. Results. Paraquat administration led to a gradual animal death, however, administration of the U-21 increased their survival rate and preserved their motor activity at the level of the control rats. Oral administration of the pharmabiotic only did not alter the animals’ motor activity. Paraquat reduced density of the tyrosine hydroxylase positive fibers and increased the number of goblet cells, while the study drug partially diminished the changes induced by paraquat. Conclusion. The U-21 preparation demonstrated high biological activity in the neurotoxin-induced model of PD, which justifies further, extended studies of its effects.

The PERK-Dependent Molecular Mechanisms as a Novel Therapeutic Target for Neurodegenerative Diseases.

Higher prevalence of neurodegenerative diseases is strictly connected with progressive aging of the world population. Interestingly, a broad range of age-related, neurodegenerative diseases is characterized by a common pathological mechanism—accumulation of misfolded and unfolded proteins within the cells. Under certain circumstances, such protein aggregates may evoke endoplasmic reticulum (ER) stress conditions and subsequent activation of the unfolded protein response (UPR) signaling pathways via the protein kinase RNA-like endoplasmic reticulum kinase (PERK)-dependent manner. Under mild to moderate ER stress, UPR has a pro-adaptive role. However, severe or long-termed ER stress conditions directly evoke shift of the UPR toward its pro-apoptotic branch, which is considered to be a possible cause of neurodegeneration. To this day, there is no effective cure for Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), or prion disease. Currently available treatment approaches for these diseases are only symptomatic and cannot affect the disease progression. Treatment strategies, currently under detailed research, include inhibition of the PERK-dependent UPR signaling branches. The newest data have reported that the use of small-molecule inhibitors of the PERK-mediated signaling branches may contribute to the development of a novel, ground-breaking therapeutic approach for neurodegeneration. In this review, we critically describe all the aspects associated with such targeted therapy against neurodegenerative proteopathies.

The Machado-Joseph disease-associated form of ataxin-3 impacts dynamics of clathrin-coated pits.

Expansion above a certain threshold in the polyglutamine (polyQ) tract of ataxin-3 is the main cause of neurodegeneration in Machado-Joseph disease. Ataxin-3 contains an N-terminal catalytic domain, called Josephin domain, and a highly aggregation-prone C-terminal domain containing the polyQ tract. Recent work has shown that protein aggregation inhibits clathrin-mediated endocytosis (CME). However, the effects of polyQ expansion in ataxin-3 on CME have not been investigated. We hypothesize that the expansion of the polyQ tract in ataxin-3 could impact CME. Here, we report that both the wild-type and the expanded ataxin-3 reduce transferrin internalization and expanded ataxin-3 impacts dynamics of clathrin-coated pits (CCPs) by reducing CCP nucleation and increasing short-lived abortive CCPs. Since endocytosis plays a central role in regulating receptor uptake and cargo release, our work highlights a potential mechanism linking protein aggregation to cellular dysregulation.

Highly stabilized nanocrystals delivering Ginkgolide B in protecting against the Parkinson's disease.

As a major cause of neurodegeneration in the elderly, Parkinson's disease (PD) has attracted intense research attention. PD results from a decline in the numbers of dopaminergic neurons. Due to low levels of plasma exposure and the drug efflux properties of neuronal cells, orally delivering anti-PD drugs is challenging. Nanocrystals (NCs) can increase dissolution velocities and saturation solubility, improving oral bioavailability and brain uptake. In this study, Ginkgolide B (GB), a potent anti-Parkinsonism compound, was selected to verify the utility of NCs to effectively accumulate GB in both the blood and brain. Highly stabilized GB-NCs had small sizes, high rates of dissolution, enhanced cellular uptake and permeability. The GB-NCs could protect neurons against cytotoxicity induced by MPP+, and showed no toxicity in zebrafish. Fluorescent imaging in zebrafish indicated high levels of the NCs in both the gut and brain. When orally administrated to rats, the GB-NCs showed higher drug plasma levels and neuronal drug distributions when compared to control groups. Importantly, in MPTP-induced PD model, GB-NCs treatment resulted in improved behavior, reduced dopamine deficiency, and elevated dopamine metabolite levels. In summary, these highlight the fabrication of GB-NCs as effective drug carriers for the neuronal delivery of anti-PD therapies.

Direct prospective comparison of 18F-FDG PET and arterial spin labelling MR using simultaneous PET/MR in patients referred for diagnosis of dementia.

18F-FDG PET is routinely used as an imaging marker in the early and differential diagnosis of dementing disorders and has incremental value over the clinical neurological and neuropsychological evaluation. Perfusion MR imaging by means of arterial spin labelling (ASL) is an alternative modality to indirectly measure neuronal functioning and could be used as complement measurement in a single MR session in the workup of dementia. Using simultaneous PET-MR, we performed a direct head-to-head comparison between enhanced multiplane tagging ASL (eASL) and 18F-FDG PET in a true clinical context of subjects referred for suspicion of neurodegenerative dementia. Twenty-seven patients underwent a 20-min 18F-FDG PET/MR and simultaneously acquired eASL on a GE Signa PET/MR. Data were compared with 30 screened age- and gender-matched healthy controls. Both integral eASL and 18F-FDG datasets were analysed visually by two readers unaware of the final clinical diagnosis, either in normal/abnormal classes, or full differential diagnosis (normal, Alzheimer type dementia [AD], dementia with Lewy Bodies [LBD], frontotemporal dementia [FTD] or other). Reader confidence was assessed with a rating scale (range 1-4). Data were also analysed semiquantitatively by VOI and voxel-based analyses. The ground truth diagnosis for the patient group resulted in 14 patients with a neurodegenerative cognitive disorder (AD, FTD, LBD) and 13 patients with no arguments for an underlying neurodegenerative cause. Visual analysis resulted in equal specificity (0.70) for differentiating normal and abnormal cases between the two modalities, but in a higher sensitivity (0.93), confidence rating (0.64) and interobserver agreement for 18F-FDG PET compared with eASL. The same was true for assigning a specific differential diagnosis (sensitivity: and 0.39 for 18F-FDG PET and eASL, respectively). Semiquantitative analyses revealed prototypical patterns for AD and FTD, with both higher volumes of abnormality and intensity differences on 18F-FDG PET. In a direct head-to-head comparison on a simultaneous GE Signa PET/MR, 18F-FDG PET performed better compared with ASL in terms of sensitivity and reader confidence, as well as volume and intensity of abnormalities. However, using pure semiquantitative analysis, similar diagnostic accuracy between the two modalities was obtained. Therefore, ASL may still serve as complement to neuroreceptor or protein deposition PET studies when a single simultaneous investigation is warranted.

The Erythrocytic Hypothesis of Brain Energy Crisis in Sporadic Alzheimer Disease: Possible Consequences and Supporting Evidence.

Alzheimer’s disease (AD) is a fatal form of dementia of unknown etiology. Although amyloid plaque accumulation in the brain has been the subject of intensive research in disease pathogenesis and anti-amyloid drug development; the continued failures of the clinical trials suggest that amyloids are not a key cause of AD and new approaches to AD investigation and treatment are needed. We propose a new hypothesis of AD development based on metabolic abnormalities in circulating red blood cells (RBCs) that slow down oxygen release from RBCs into brain tissue which in turn leads to hypoxia-induced brain energy crisis; loss of neurons; and progressive atrophy preceding cognitive dysfunction. This review summarizes current evidence for the erythrocytic hypothesis of AD development and provides new insights into the causes of neurodegeneration offering an innovative way to diagnose and treat this systemic disease.

Effects of caloric restriction on retinal aging and neurodegeneration.

Glaucoma is the most common neurodegenerative cause of irreversible blindness worldwide. Restricted caloric regimens are an attractive approach for delaying the progression of neurodegenerative diseases. Here we review the current literature on the effects of caloric restriction on retinal neurons, under physiological and pathological conditions. We focused on autophagy as one of the mechanisms modulated by restricted caloric regimens and involved in the death of retinal ganglion cells (RGCs) over the course of glaucoma.