综述:阿尔茨海默病的神经影像学研究进展

阿尔茨海默病(Alzheimer's disease,AD)是以记忆和其他高级认知功能下降为特征的神经退行性疾病．早期的神经影像学研究通常是探索AD患者局部脑区的结构和功能变化．随着多模态神经影像技术和人脑连接组学研究方法的发展,研究者已经能够考察AD患者脑结构和功能连接通路．采用这些方法,最近的研究已经发现,AD患者脑网络的连接强度、网络效率、模块化组织和核心脑区连接的下降,并发现这些变化与患者的记忆评分等密切相关．这些新方法和新技术的出现不仅提供了新颖的观点来解释AD病的脑区失连接病理生理机制,而且发现的AD异常脑连接模式可能作为敏感特征应用于AD早期辅助诊断的影像标记物研究．特别重要的是,研究表明,在AD患者脑神经网络出现的异常连接模式,在AD前期即轻度认知障碍期患者中也已出现,表明了将AD影像学研究的重点前移到AD前期这一可治疗阶段的重要性和迫切性．     

Amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD)

There is increasing clinical, imaging and neurophatological evidence that amyotrophic lateral sclerosis (ALS) represents a multisystem neurodegenerative disease. Neurodegeneration is not restricted to motor neurons, but also includes parts of the brain other than the motor cortex, especially the prefrontal and/or anterior temporal lobe, that contribute to the clinical syndrome. In some cases an evident dementia that resembles frontotemporal degeneration (FTD) was observed. It is now suggested that ALS and FTD are closely related conditions with overlapping clinical, pathological, radiological, and genetic characteristics. The presence of a frontal dementia in ALS has also crucial practical consequences for management of the patients, whose disorder requires critical life decisions for enteral nutrition and respiratory complications. It is our intent to provide a brief overview of the relationships between ALS and FTD.     

Processing of neuropeptide Y, galanin, and somatostatin in the cerebrospinal fluid of patients with Alzheimer’s disease and frontotemporal dementia

Alzheimer's disease (AD) and frontotemporal dementia (FTD) are two prevalent neurodegenerative disorders for which the causes are unknown, except in rare familial cases. Several changes in neuropeptide levels as measured by radioimmunoassay (RIA) have been observed in these illnesses. Somatostatin (SOM) levels in cerebrospinal fluid (CSF) are consistently decreased in AD and FTD. Neuropeptide Y (NPY) levels are decreased in AD, but normal in FTD. Galanin (GAL) levels increase with the duration of illness in AD patients. The majority of studies of neuropeptides in CSF have not been verified by HPLC. The observed decrease in a neuropeptide level as measured by RIA may therefore reflect an altered synthesis or extracellular processing, resulting in neuropeptide fragments that may or may not be detected by RIA. Matrix-assisted laser desorption time-of-flight mass spectrometry (MALDI-MS) has been shown to be a powerful technique in the analysis of biological materials without any pre-treatment, by detecting peptides and proteins at a specific mass-to-charge (m/z) ratio. We studied the processing of the neuropeptides NPY, NPY, SOM and GAL in the cerebrospinal fluid of patients with AD (n = 3), FTD (n = 3) and controls (n = 2) using MALDI-MS. We found that considerable inter-individual variability exists in the rate of neuropeptide metabolism in CSF, as well as the number of peptide fragments formed. Certain patients showed differences in the processing of specific neuropeptides, relative to other patients and controls. This analysis of the metabolic processing of neuropeptides in CSF yielded a large amount of data for each individual studied. Further studies are required to determine the changes in neuropeptide processing that can be associated with AD and FTD. With further investigations using MALDI-MS analysis, it may be possible to identify a neuropeptide fragment or processing enzyme that can be correlated to these disease states.     

“Ik kan mijn acceptgiro niet meer invullen”

Visual problems occur frequently in elderly patients and are often caused by ophthalmological problems. In this clinical lesson we show that visual problems can also be caused by posterior cortical atrophy (PCA). PCA is a clinico-radiological syndrome that is often caused by Alzheimer’s disease and other neurodegenerative diseases as Lewy body dementia and corticobasal degeneration. It is characterized by progressive decline in visual information processing. In addition, there is relative retention of memory and language in early stages. Brain imaging shows atrophy of the posterior brain areas.     

Molecular mechanisms for Alzheimer's disease: implications for neuroimaging and therapeutics

Alzheimer's disease is a progressive neurodegenerative disorder characterised by the gradual onset of dementia. The pathological hallmarks of the disease are beta-amyloid (Abeta) plaques, neurofibrillary tangles, synaptic loss and reactive gliosis. The current therapeutic effort is directed towards developing drugs that reduce Abeta burden or toxicity by inhibiting secretase cleavage, Abeta aggregation, Abeta toxicity, Abeta metal interactions or by promoting Abeta clearance. A number of clinical trials are currently in progress based on these different therapeutic strategies and they should indicate which, if any, of these approaches will be efficacious. Current diagnosis of Alzheimer's disease is made by clinical, neuropsychologic and neuroimaging assessments. Routine structural neuroimaging evaluation with computed tomography and magnetic resonance imaging is based on non-specific features such as atrophy, a late feature in the progression of the disease, hence the crucial importance of developing new approaches for early and specific recognition at the prodromal stages of Alzheimer's disease. Functional neuroimaging techniques such as functional magnetic resonance imaging, magnetic resonance spectroscopy, positron emission tomography and single photon emission computed tomography, possibly in conjunction with other related Abeta biomarkers in plasma and CSF, could prove to be valuable in the differential diagnosis of Alzheimer's disease, as well as in assessing prognosis. With the advent of new therapeutic strategies there is increasing interest in the development of magnetic resonance imaging contrast agents and positron emission tomography and single photon emission computed tomography radioligands that will permit the assessment of Abeta burden in vivo.     

FTD and ALS: genetic ties that bind

Curiously, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), seemingly disparate neurodegenerative disorders, can be inherited together. Two groups (DeJesus-Hernandez et?al. and Renton et?al.) show that the long sought after ALS/FTD mutation on chromosomal region 9p is a hexanucleotide expansion in C90RF72. These studies, plus a study on X-linked ALS/FTD, provide molecular starting points for identifying pathways that link ALS and FTD pathogenesis.     

Imagerie moléculaire de la maladie de Parkinson : données actuelles

During the last years, knowledge and concepts concerning Parkinson's disease and other parkinsonian syndromes have progressed: a concept of network pathology with different clinical presentations and evolutions, involving several neurotransmission pathways succeeeded the single dopaminergic lesion concept. Imaging also changed with the development of MRI. In this context, the aim of this work is to bring up-to-date methodology and clinical contribution of dopaminergic neuron imaging. Nigrostriatal neuron imaging (dopamine transporter imaging) contributes to diagnosis of Parkinson's disease and Lewy body dementia. Dopamine receptor imaging mainly helps in differential diagnosis of parkinsonian syndromes (Parkinson's disease and Parkinson plus syndromes). The ongoing development of dopaminergic, cholinergic, serotoninergic tracers and the recent emergence of amyloid plaques and neurofibrillary tangles imaging open perspectives for molecular imaging and care of neurodegenerative diseases.     

Dysregulated molecular pathways in amyotrophic lateral sclerosis–frontotemporal dementia spectrum disorder

Frontotemporal dementia (FTD), the second most common form of dementia in people under 65 years of age, is characterized by progressive atrophy of the frontal and/or temporal lobes. FTD overlaps extensively with the motor neuron disease amyotrophic lateral sclerosis (ALS), especially at the genetic level. Both FTD and ALS can be caused by many mutations in the same set of genes; the most prevalent of these mutations is a GGGGCC repeat expansion in the first intron of C9ORF72. As shown by recent intensive studies, some key cellular pathways are dysregulated in the ALS‐FTD spectrum disorder, including autophagy, nucleocytoplasmic transport, DNA damage repair, pre‐mRNA splicing, stress granule dynamics, and others. These exciting advances reveal the complexity of the pathogenic mechanisms of FTD and ALS and suggest promising molecular targets for future therapeutic interventions in these devastating disorders.     

Implications of Microglia in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders with clear similarities regarding their clinical, genetic and pathological features. Both are progressive, lethal disorders, with no current curative treatment available. Several genes that correlated with ALS and FTD are implicated in the same molecular pathways. Strikingly, many of these genes are not exclusively expressed in neurons, but also in glial cells, suggesting a multicellular pathogenesis. Moreover, chronic inflammation is a common feature observed in ALS and FTD, indicating an essential role of microglia, the resident immune cells of the central nervous system, in disease development and progression. In this review, we will provide a comprehensive overview of the implications of microglia in ALS and FTD. Specifically, we will focus on the role of impaired phagocytosis and increased inflammatory responses and their impact on microglial function. Several genes associated with the disorders can directly be linked to microglial activation, phagocytosis and neuroinflammation. Other genes associated with the disorders are implicated in biological pathways involved in protein degradation and autophagy. In general such mutations have been shown to cause abnormal protein accumulation and impaired autophagy. These impairments have previously been linked to affect the innate immune system in the central nervous system through inappropriate activation of microglia and neuroinflammation, highlighted in this review. Although it has been well established that microglia play essential roles in neurodegenerative disorders, the precise underlying mechanisms remain to be elucidated.     

Extracellular Tau Levels Are Influenced by Variability in Tau That Is Associated with Tauopathies

Tauopathies are a class of neurodegenerative diseases marked by intracellular aggregates of hyperphosphorylated Tau. These diseases may occur by sporadic mechanisms in which genetic variants represent risk factors for disease, as is the case in Alzheimer disease (AD). In AD, cerebrospinal fluid (CSF) levels of soluble Tau/pTau-181 are higher in cases compared with controls. A subset of frontotemporal dementia (FTD) cases occur by a familial mechanism in which MAPT, the gene that encodes Tau, mutations are dominantly inherited. In symptomatic FTD patients expressing a MAPT mutation, CSF Tau levels are slightly elevated but are significantly lower than in AD patients. We sought to model CSF Tau changes by measuring extracellular Tau in cultured cells. Full-length, monomeric extracellular total Tau and pTau-181 were detectable in human neuroblastoma cells expressing endogenous Tau, in human non-neuronal cells overexpressing wild-type Tau, and in mouse cortical neurons. Tau isoforms influence the rate of Tau release, whereby the N terminus (exons 2/3) and microtubule binding repeat length contribute to Tau release from the cell. Compared with cells overexpressing wild-type Tau, cells overexpressing FTD-associated MAPT mutations produce significantly less extracellular total Tau without altering intracellular total Tau levels. This study demonstrates that cells actively release Tau in the absence of disease or toxicity, and Tau release is modified by changes in the Tau protein that are associated with tauopathies.     

L’imagerie TEP-traceurs des plaques amyloïdes : le point de vue du clinicien

The purpose of this article is to summarize the main elements of clinician point of view concerning the contribution of amyloid neuroimaging in the diagnostic approach of the Alzheimer's disease. The main pathological characteristics of the Alzheimer's disease are established by two types of protein aggregates: the extracellular plaques (containing Aβ aggregates) and neurofibrillary tangles (composed of aggregates of tau-protein). At present, the use of biomarkers is more and more included in the diagnostic approach of Alzheimer's disease. The possibility to highlight in vivo cortical amyloid deposits through the amyloid neuroimaging can allow the realization of an earlier diagnosis. However, the amyloid imaging is a “physiopathological” biomarker and is not correlated with the clinical evaluation. It is still difficult to differentiate the Alzheimer's disease of the other neurodegenerative diseases.     

Evidence of social understanding impairment in patients with amyotrophic lateral sclerosis

The present study aims at clarifying the nature of the Theory of Mind (ToM) deficits associated with Amyotrophic Lateral Sclerosis (ALS). ToM is the ability to attribute mental states such as intentions and beliefs to others in order to understand and predict their behaviour and to behave accordingly. Several neuroimaging studies reported the prefrontal cortices as the brain region underlying a key ToM ability, i.e. the comprehension of social intentions. Dysfunction of the prefrontal cortices in patients with ALS has been indicated by a range of neuroimaging studies. The frontal syndrome that appears to characterize up to 50% of ALS has been noted to be similar to the profile that characterizes patients with frontotemporal dementia (FTD), a neurodegenerative condition characterised by ToM deficits. In the present paper, we hypothesize that the performance of patients with ALS is significantly worse than healthy controls' performance on tasks requiring the comprehension of social contexts, whereas patients' performance is comparable to healthy controls' performance on tasks not requiring the comprehension of social contexts. To this end, we tested 15 patients with ALS with an experimental protocol that distinguishes between private (non-social) intentions and social intentions. The pattern of results followed the experimental hypothesis: the performance of patients with ALS and healthy controls significantly differed on the comprehension of social context only, with an impairment in patients with ALS. Single case analysis confirmed the findings at an individual level. The present study is the first which has examined and compared the understanding of social and non-social contexts in patients with ALS and shown a specific and selective deficit in the former only. The current findings further support the notion of a continuum of cognitive dysfunction ranging from ALS to FTD, with parallel cognitive profiles in both disorders.     

The impact of histone post-translational modifications in neurodegenerative diseases

Every year, neurodegenerative disorders take more than 5000 lives in the US alone. Cures have not yet been found for many of the multitude of neuropathies. The majority of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Parkinson's disease (PD) cases have no known genetic basis. Thus, it is evident that contemporary genetic approaches have failed to explain the etiology or etiologies of ALS/FTD and PD. Recent investigations have explored the potential role of epigenetic mechanisms in disease development. Epigenetics comprises heritable changes in gene utilization that are not derived from changes in the genome. A main epigenetic mechanism involves the post-translational modification of histones. Increased knowledge of the epigenomic landscape of neurodegenerative diseases would not only further our understanding of the disease pathologies, but also lead to the development of treatments able to halt their progress. Here, we review recent advances on the association of histone post-translational modifications with ALS, FTD, PD and several ataxias.     

Familial frontotemporal dementia with neuronal intranuclear inclusions is not a polyglutamine expansion disease

Background  

Many cases of frontotemporal dementia (FTD) are familial, often with an autosomal dominant pattern of inheritance. Some are due to a mutation in the tau- encoding gene, on chromosome 17, and show an accumulation of abnormal tau in brain tissue (FTDP-17T). Most of the remaining familial cases do not exhibit tau pathology, but display neuropathology similar to patients with dementia and motor neuron disease, characterized by the presence of ubiquitin-immunoreactive (ub-ir), dystrophic neurites and neuronal cytoplasmic inclusions in the neocortex and hippocampus (FTLD-U). Recently, we described a subset of patients with familial FTD with autopsy-proven FTLD-U pathology and with the additional finding of ub-ir neuronal intranuclear inclusions (NII). NII are a characteristic feature of several other neurodegenerative conditions for which the genetic basis is abnormal expansion of a polyglutamine-encoding trinucleotide repeat region. The genetic basis of familial FTLD-U is currently not known, however the presence of NII suggests that a subset of cases may represent a polyglutamine expansion disease.     

The ART of Loss: Aβ Imaging in the Evaluation of Alzheimer’s Disease and other Dementias

Molecular neuroimaging based on annihilation radiation tomographic (ART) techniques such as positron emission tomography (PET), in conjunction with related biomarkers in plasma and cerebrospinal fluid (CSF), are proving valuable in the early and differential diagnosis of Alzheimer's disease (AD). With the advent of new therapeutic strategies aimed at reducing beta-amyloid (Abeta) burden in the brain to potentially prevent or delay functional and irreversible cognitive loss, there is increased interest in developing agents that allow assessment of Abeta burden in vivo. Abeta burden as assessed by molecular imaging matches histopathological reports of Abeta plaque distribution in aging and dementia and appears more accurate than FDG for the diagnosis of AD. Abeta imaging is also a very powerful tool in the differential diagnosis of AD from fronto-temporal dementia (FTD). Although Abeta burden as assessed by PET does not correlate with measures of cognitive decline in AD, it does correlate with memory impairment and rate of memory decline in mild cognitive impairment (MCI) and healthy older subjects. Approximately 30% of asymptomatic controls present cortical (11)C-PiB retention. These observations suggest that Abeta deposition is not part of normal ageing, supporting the hypothesis that Abeta deposition occurs well before the onset of symptoms and is likely to represent preclinical AD. Further longitudinal observations are required to confirm this hypothesis and to better elucidate the role of Abeta deposition in the course of Alzheimer's disease.     

Imagerie moléculaire dans les démences

Nuclear neuroimaging, with single photon emission computed tomography (SPECT) or with positron emission tomography (PET), allows study of functional and neurochemical aspects of human brain. It provides in vivo informations about pathophysiology in dementia. The routinely available tracers are perfusional tracers (^99mTc-HMPAO/GE Healthcare and ^99mTc-ECD/BMS). In June 2006, a new indication for the DaTSCAN^® (GE Healthcare) has been adopted. DaTSCAN^® could now be used to help differentiate probable dementia with Lewy bodies from Alzheimer's disease. Since a few years, there have been tremendous efforts expended to develop specific radioligands for several neurochemical systems and for imaging of beta-amyloid plaques. The aim of this paper is to review the most common radiotracers for SPECT and PET brain imaging in dementia and to focus on the new tracers.     

VCP disease associated with myopathy, Paget disease of bone and frontotemporal dementia: review of a unique disorder

Inclusion body myopathy (IBM) associated with Paget disease of the bone (PDB) and frontotemporal dementia (FTD) (now called IBMPFD), is a progressive autosomal dominant disorder that was recently identified as being caused by mutations in the VCP (p97 or CDC48) gene which plays a key role in the ubiquitin-proteasome dependent degradation of cytosolic proteins and in the retro translocation of misfolded proteins from the endoplasmic reticulum into the cytoplasm. Approximately 90% of the affected persons in the study have myopathy or muscle weakness particularly of the shoulder and hip girdles, which can lead to loss of walking ability and even death by complications of respiratory and cardiac failure. About half of affected study participants have Paget disease of bone characterized by abnormal rates of bone growth that can result in bone pain, enlargement and fractures. Findings of premature FTD affecting behavior and personality are seen in a third of affected individuals. Within 20 IBMPFD families whose data was analyzed for this study, ten missense mutations have been identified, the majority of which are located in the N-terminal ubiquitin binding domain. Inclusions seen in the muscle, brain and heart in VCP disease contain ubiquitin, beta amyloid and TDP-43, also seen in other neurodegenerative disorders thus implicating common pathways in their pathogenesis.     

Neurochemical approaches of cerebrospinal fluid diagnostics in neurodegenerative diseases

Alzheimer's disease (AD), Parkinson's disease dementia (PDD)/Lewy-body disease (DLB), and frontotemporal dementia (FTD) are the major causes of memory impairment and dementia. As new therapeutic agents are visible for the different diseases, there is an ultimate need for an early and an early differential diagnosis. Since cerebrospinal fluid (CSF) is in direct contact with the central nervous system (CNS), potentially promising biomarkers might be seen there first. In principle, two research approaches can be considered for the laboratory diagnosis of dementias: (i) the direct detection of disease specific protein like Abeta-peptide-oligomers in AD or alpha-synuclein-aggregates in DLB and (ii) the detection of surrogate markers that show an altered pattern of expression in early stages of the disease or are used in the differential diagnosis of other dementias and thus enable an exclusion diagnosis. Especially Abeta-peptides and tau-protein measurements seem to employ a combination of these approaches. Until now it was shown that a combined determination of just these few markers (tau-proteins and Abeta-peptides) is already sufficient to achieve a high degree of diagnostic certainty in the diagnosis of AD. However although these markers seem to correlate with neuropathological changes and memory disturbances, these markers are not specific for a single form of dementia and further research is necessary to improve especially the early differential diagnosis of dementias.