神经退行性疾病是由神经元的病理死亡引起的 - 每种疾病都由影响不同类别的神经元和神经回路的特征模式定义。建立了某些神经退行性疾病的原因，特别是由特定DNA异常引起的原因。但是，神经退行性疾病的更常见，零星形式的病因仍然是神秘的。对于几乎所有此类疾病，寻找预防或停止变性的方法是正在进行。

A better understanding of how and why each disease progresses is necessary both for developing potential treatment strategies and for monitoring the effectiveness of interventions during clinical trials. Below are some of the main techniques deployed to study these debilitating and increasingly common diseases.

Human studies

Post-mortem brain tissue

Detailed histological examination of post-mortem brains remains the gold standard for assessing the neuropathological extent of a disease. Schemes for analyzing microscopic and macroscopic features to divide disease progression into well-defined stages have been developed for each major condition. For example, Braak staging is used for both阿尔茨海默氏病（ad）和Parkinson’s Disease(PD) and Vonsattel and colleagues established five grades of亨廷顿氏病(HD) neuropathology.

Comparing the extent of pathology to clinical records of people’s symptoms is an important application of these data. Such analyses can, however, reveal variable relationships between the brain structure and clinical signs. For example, Vonsattel et al noted, in their original report, that five people with clinically manifest HD had no discernible structural abnormalities , whereas people with pronounced广告orPDpathology can display a wide range of symptoms.

Staging is an essential component of studies seeking to identify contributors to disease biology in post-mortem human brains. Such studies useimmunohistochemistryandin situ杂交查看疾病标志物和感兴趣的分子，以了解其表达和分布如何变化。大多数疾病以疾病特异性蛋白的积累为特征，但也存在与细胞应激，细胞死亡和炎症有关的泛症过程。此类研究的另一个重要工具是染色技术，用于标记即将垂死或指示机制的细胞染色技术。cell death。

Post-mortem tissue can also be used for large-scale analyses of gene expression or protein abundance using contemporarygeneticorproteomic分析方法。

Living brains

In contrast to post-mortem studies that provide a single, final snapshot of a brain in time, clinical and basic researchers need methods for tracking the real-time progression of neurodegenerative diseases in living people.

最好的 biomarkers will correlate with disease progression strongly enough to provide diagnostic and prognostic information. However, methods not sensitive enough at an individual level to inform clinical decisions can still be useful for research purposes. And biomarker monitoring in individual patients is an increasingly vital element of clinical trials. Additionally, the possibility of identifying biomarkers indicating that an asymptomatic person is in the prodromal stage of a disease would facilitate the testing of 早期干预措施 。

神经影像学

Magnetic resonance imaging (MRI) can reveal both structural changes to the brain as neurodegeneration progresses and changes in function. Individual diseases are associated with specific patterns of atrophy that can be monitored using MRI. For example, shrinkage of striatal regions is a biomarker of HD progression ，而电机系统中的各种节点在自然历史上的大小降低 运动神经元疾病 (MND). Diffusion tensor imaging (DTI) is a variant of MRI that is useful for studying white matter changes.

Functional MRI also plays an essential role in tracking disease-associated changes in neurophysiology and how they develop over time. For example, AD is robustly associated with 脑血流减少 to temporal and frontal cortices and this can be used to distinguish AD from other causes of dementia.

PET成像为监测神经退行性疾病提供了特殊的优势，因为它允许对活体大脑中特定分子的标记和可视化。例如，与淀粉样肽和TAU结合的放射性标记的分子用于成像这些分子在中的积累和分布 广告 ，，，，while there are a range of ligands that bind to components of the dopaminergic system used to look at dopaminergic neuronal loss and its consequences in PD 。

神经影像学可以与临床测试一起使用，以将结构和功能性大脑变化与症状变化相关联。此外，可以将PET和MRI方法合并，以将分子变化与萎缩或血流变化相关联。

Other biomarkers

In addition to directly imaging the brain – which is expensive and not widely available – basic researchers and clinicians agree that more accurate and easy-to-monitor biomarkers are needed for tracking disease progression.

Electrophysiological techniques – such as EEG, MEG and nerve conduction studies – can aid in tracking neurophysiological changes, such as changes in communication between brain regions or outputs to muscles, with 高时间分辨率 。

还花了很多努力来识别与疾病状况相关的生物流体分子。因此，血液，尿液和脑脊液（CSF）是信息代谢物或其他生物分子的潜在来源。举个例子， 在高清 ，，，，CSF levels of neurofilament light protein correlate with disease progression and can distinguish premanifest from manifest disease in carriers of pathogenic mutations, and CSF levels of mutant huntingtin protein are also useful. In AD ，，，，serum neurofilament light protein might covary with pathology. Ongoing research in 广告 ，，，， PD and MND all aims to establish better biomarkers for these conditions.

Genetics

Certain neurodegenerative disorders are always the direct result of genetic abnormalities. HD, for example, follows pathogenic expansion of a sequence of CAG repeats in the huntingtin gene, whereas spinal muscular atrophy (SMA) comes in various forms, each associated with different genetic lesions.

For more common, neurodegenerative disorders there are often inherited subtypes of disease – which can be clinically indistinguishable from sporadic forms – that arise from specific genetic mutations. Hence, early onset Alzheimer’s can result from mutations in the amyloid precursor protein or presenilin 1 or 2 genes. And mutations in superoxide dismutase 1 cause a familial form of MND.

但是，通常，特定基因突变与疾病发生率之间的关系较不直接。相反，基因变异可以被视为疾病进展的疾病或调节剂的危险因素。

无论哪种方式，定义在不断填充的粒度上定义神经退行性疾病风险的遗传结构仍然是一种积极的追求。研究涉及基因的生物学，其改变的蛋白质产物以及这些影响的系统应使人们更好地了解疾病病理生理学。尽管事实证明，这种目标被证明是令人沮丧的，这是迄今为止（迄今为止）的例证 amyloid hypothesis of AD to yield effective interventions.

模型系统

为了进行人们不允许的侵入性机械研究，神经科学家长期以来一直在寻求开发模型系统，以概括人类神经退行性条件的关键特征。拥有有效的模型系统 - 无论是in vivo动物模型或in vitrosystems – permits investigations of pathogenesis and pathophysiology, electrophysiological investigations of how neuronal loss affects network function, and early stage screening of compounds that might halt degeneration or otherwise protect or restore brain function.

动物模型

在早期的几十年中，基于选择性靶向特定神经元种群的神经毒素的动物模型占主导地位。一个突出的例子是 MPTP model of Parkinsonism 。最近，研究人员偏爱基于遗传学的模型，认为这种模型更好地模仿了人类场景。

在人类种群中发现的致病突变可以尽可能忠实地引入小鼠或其他动物及其作用研究中。但是，这种情况并不像研究人员希望或预测的那样直接，因为这些突变是引起疾病的突变，并不总是导致疾病状态 动物 。Consequently, disease-associated genes may need to be overexpressed in animal models or manipulated in ways not seen in human populations to induce similar 情况 。

这 validity of any model ，，，，therefore, needs to be carefully assessed. These models do nevertheless provide invaluable opportunities for testing potential therapies, such as the development of antisense molecules for HD 。

Human tissue models

An emerging alternative to animal models of neurodegenerative disease is the use of brain cells derived from human-derived induced pluripotent stem cells (iPSC). Such cells can be grown in monolayers or used to form three-dimensional brain organoids. Briefly, fibroblasts taken from human subjects are reprogrammed into iPSCs and these, in turn, are transformed into neurons or other cell types. Such cells are then capable of self-organizing into three-dimensional structures which develop certain characteristics of brain tissue.

可以从任何人类手中获取开胃细胞，从而使研究人员可以根据他们希望如何进行实验选择患者和对照。也就是说，可以根据他们的疾病表型或感兴趣的基因型选择受试者，并且可以对控制年龄匹配，也可以是控制遗传因素的家庭成员。

Such research is at an early stage, but initial results suggest promise for enabling researchers to investigate core aspects of disease biology in not just human tissue, but tissue derived from people affected by the disease in question. For example ，，，，the consequences of manipulating the AD risk gene APOE4 in iPSC-derived neurons, glia and organoids all showed specific disease-related phenotypes.

Neuroinflammation

尽管每种神经退行性状况都有其自身的病因和神经元丧失的定义模式，但近年来，人们对对该作用的作用激增了 免疫系统 ，，，， 自噬 and 炎 in neurodegeneration. In particular, the contribution microglia make to degeneration has attracted attention 。Studying inflammation and microglia can involve staining of post-mortem tissue, neuroimaging 方法，甚至做 microglia-like cells from iPSCs 并与它们一起播种脑器官。