伴有痴呆的神经变性疾病

痴呆是由脑部疾病所致的综合征,通常具有慢性或进行性的性质。临床上呈现多种高级神经功能紊乱,包括记忆、思维、定向、理解、计算、语言、学习和判断功能低下,但是意识清楚。过去献曾强调必须持续6个月以上才能诊断为痴呆,目前不能过分强调此点。因为,有些伴有痴呆的变性疾病整个病程不到6个月。我国急性发病的Creutzfeldt—Jakob病就是如此。     

Developing Therapeutic Antibodies for Neurodegenerative Disease

The central nervous system has been considered off-limits to antibody therapeutics. However, recent advances in preclinical and clinical drug development suggest that antibodies can cross the blood–brain barrier in limited quantities and act centrally to mediate their effects. In particular, immunotherapy for Alzheimer’s disease has shown that targeting beta amyloid with antibodies can reduce pathology in both mouse models and the human brain, with strong evidence supporting a central mechanism of action. These findings have fueled substantial efforts to raise antibodies against other central nervous system targets, particularly neurodegenerative targets, such as tau, beta-secretase, and alpha-synuclein. Nevertheless, it is also apparent that antibody penetration across the blood–brain barrier is limited, with an estimated 0.1–0.2 % of circulating antibodies found in brain at steady-state concentrations. Thus, technologies designed to improve antibody uptake in brain are receiving increased attention and are likely going to represent the future of antibody therapy for neurologic diseases, if proven safe and effective. Herein we review briefly the progress and limitations of traditional antibody drug development for neurodegenerative diseases, with a focus on passive immunotherapy. We also take a more in-depth look at new technologies for improved delivery of antibodies to the brain.     

Repeat-Associated Non-AUG Translation and Its Impact in Neurodegenerative Disease

Nucleotide repeat expansions underlie numerous human neurological disorders. Repeats can trigger toxicity through multiple pathogenic mechanisms, including RNA gain-of-function, protein gain-of-function, and protein loss-of-function pathways. Traditionally, inference of the underlying pathogenic mechanism derives from the repeat location, with dominantly inherited repeats within transcribed noncoding sequences eliciting toxicity predominantly as RNA via sequestration of specific RNA binding proteins. However, recent findings question this assumption and suggest that repeats outside of annotated open reading frames may also trigger toxicity through a novel form of protein translational initiation known as repeat-associated non-AUG (RAN) translation. To date, RAN translation has been implicated in 4 nucleotide repeat expansion disorders: spinocerebellar ataxia type 8; myotonic dystrophy type 1 with CTG?CAG repeats; C9orf72 amyotrophic lateral sclerosis/frontotemporal dementia with GGGGCC?GGCCCC repeats; and fragile X-associated tremor/ataxia syndrome with CGG repeats. RAN translation contributes to hallmark pathological characteristics in these disorders by producing homopolymeric or dipeptide repeat proteins. Here, we review what is known about RAN translation, with an emphasis on how differences in both repeat sequence and context may confer different requirements for unconventional initiation. We then discuss how this new mechanism of translational initiation might function in normal physiology and lay out a roadmap for addressing the numerous questions that remain.     

Dissolving the Complex Role Aggregation Plays in Neurodegenerative Disease

Prominent neuropathological hallmarks of many adult-onset neurodegenerative diseases include the deposition and accumulation of misfolded proteins or conformers; however, their role in pathogenesis has remained unclear. This is in part due to the deceptive simplicity of the question and our limited understanding of how protein homeostasis is maintained in the compartmentalized cells of the central nervous system, especially in the context of the adult brain. Building on studies from simple cell-based systems and invertebrate animals, we recently identified a protein central to the specific and selective turnover of aggregated proteins in the adult brain, the autophagy-linked FYVE protein (Alfy)/Wdfy3. Depletion of Alfy levels in a mouse model of Huntington's disease showed that it accelerated the accumulation of the aggregated mutant huntingtin protein, as well as the onset of behavioral deficits. Although the motor dysfunction was accelerated in the model, this was in the absence of increasing overt cell loss, implicating protein aggregates as a modifier of circuit dysfunction rather than driving degeneration per se. We discuss these findings in the context of what is known about protein accumulation and how we can use proteins such as Alfy to determine if protein accumulation is a shared pathogenic event across different adult-onset diseases. © 2021 International Parkinson and Movement Disorder Society     

Atlas-Based Anatomic Labeling in Neurodegenerative Disease via Structure-Driven Atlas Warping

A new method is presented for the automated anatomic labeling and comparative morphometric analysis of brain magnetic resonance imaging, warping a prelabeled atlas into congruence with the subject anatomy. The strategy emphasizes anatomically meaningful atlas deformations in the presence of strong degeneration and substantial morphologic differences, for example, cases with high levels of atrophy. The atlas deformation is not driven by image intensity similarities but by continuous anatomic correspondence maps, derived from individual presegmented brain structures. Automatically generated correspondence maps provide large sets of fiducials, driving a warp with many thousand degrees of freedom. Validation included a scan-rescan study and anatomically relevant self-validation in multiple sclerosis patients with substantial cortical and subcortical degeneration. The mean coefficient of variation in the scan-rescan study was 1.4%, with no significant difference in precision between normal and neurodegenerative anatomies. The self-validation demonstrated good structural overlap, with substantial improvement over established methods, such as Talairach spatial normalization.     

Mapping Brain Metals to Evaluate Therapies for Neurodegenerative Disease

The brain is rich in metals and has a high metabolic rate, making it acutely vulnerable to the toxic effects of endogenously produced free radicals. The abundant metals, iron and copper, transfer single electrons as they cycle between their reduced (Fe²⁺, Cu¹⁺) and oxidized (Fe³⁺, Cu²⁺) states making them powerful catalysts of reactive oxygen species (ROS) production. Even redox inert zinc, if present in excess, can trigger ROS production indirectly by altering mitochondrial function. While metal chelators seem to improve the clinical outcome of several neurodegenerative diseases, their mechanisms of action remain obscure and the effects of long‐term use are largely unknown. Most chelators are not specific to a single metal and could alter the distribution of multiple metals in the brain, leading to unexpected consequences over the long‐term. We show here how X‐ray fluorescence will be a valuable tool to examine the effect of chelators on the distribution and amount of metals in the brain.     

Estimating Premorbid IQ in the Prodromal Phase of a Neurodegenerative Disease

Estimates of premorbid intellect are often used in neuropsychological assessment to make inferences about cognitive decline. To optimize the method of controlling for premorbid intellect in assessments of prodromal neurodegenerative disease, we examined performance on the American National Adult Reading Test (ANART; administered during Years 1 and 3) and the two-subtest version of the Wechsler Abbreviated Scale of Intelligence (WASI; administered in Years 2 and 4) in an ongoing prospective longitudinal study of 371 participants with prodromal Huntington disease and 51 participants with normal CAG repeats. Although both measures performed similarly, the ANART demonstrated slightly lower variability in performance over a 2-year period and had slightly higher test–retest reliability than the WASI.     

Late Diagnosis of Neurodegenerative Disease in Children: Anosognosia by Proxy

Anosognosia is a term now generally defined as a failure to recognize the existence of disease processes, particularly those with a neurological basis. Denial of illness has been recognized in a large number of disorders, and is generally thought to have not only a central nervous system basis, but to also be influenced by the psychological processes of denial. This disorder has been reported in the adult population, and there are initial suggestions that it exists in children/adolescents.We propose to extend the concept of anosognosia to the caregivers of children who suffer significant dementia, and extended degeneration in neuro-psychological and neurological functioning. We term this syndrome anosognosia by proxy. Three case examples are presented in which parents, teachers, and health care professionals observed extended deterioration in a child/adolescent’s level of functioning prior to seeking appropriate diagnostic evaluations. Possible explanations for this process are advanced, including a combination of insidious onset coupled with the intimate nature of the child/parent relationship. The need for professional, teacher, and parent education on the nature of childhood degenerative neurological disorders is emphasized.     

A Neurodegenerative Disease Sleep Questionnaire: Principal component analysis in Parkinson's disease

Sleep disturbances are common in many neurodegenerative diseases and may include altered sleep duration, fragmented sleep, nocturia, excessive daytime sleepiness, and vivid dreaming experiences, with occasional parasomnias. Although representing the “gold standard,” polysomnography is not always cost-effective or available for measuring sleep disturbance, particularly for screening. Although numerous sleep-related questionnaires exist, many focus on a specific sleep disturbance (e.g., restless legs, REM Behavior Disorder) and do not capture efficiently the variety of sleep issues experienced by such patients. We administered the 12-item Neurodegenerative Disease Sleep Questionnaire (NDSQ) and the Epworth Sleepiness Scale to 145 idiopathic Parkinson's disease patients. Principal component analysis using eigenvalues greater than 1 suggested five separate components: sleep quality (e.g., sleep fragmentation), nocturia, vivid dreams/nightmares, restless legs symptoms, and sleep-disordered breathing. These results demonstrate construct validity of our sleep questionnaire and suggest that the NDSQ may be a useful screening tool for sleep disturbances in at least some types of neurodegenerative disorders.     

Transplanted Neurons Alter the Course of Neurodegenerative Disease in Lurcher Mutant Mice

Embryonic cerebellar, neocortical, and striatal tissues derived from NSE-LacZ transgenic mice were transplanted into the right cerebellar hemisphere of 8- to 10-day-oldLurcheror wild-type mice. Host mice survived for 30–90 days and the transplanted tissue was examined by light microscopy using Nissl staining, X-gal histochemistry, and immunohistochemistry for calcium binding protein and glutamic acid decarboxylase. Transplantation of cerebellar tissue, but not neocortical or striatal progenitors, resulted in robust infiltration of the lurcher mutant host cerebellar cortex by transgenic Purkinje neurons. Deep to the infiltrated molecular layer, the host granular layer was thicker and denser than the mutant granular layer, but transgenic cells did not contribute to the spared granular layer. The host inferior olivary complex consistently exhibited a noticeable bilateral asymmetry in Nissl-stained sections. A quantitative analysis of the olivary complex was performed in 10 90-day-old host mice. The results indicate that the left inferior olivary complex of 90-day-old host mice contained more neurons than the right inferior olive of the host mice and contained more neurons than was observed in 90-day-oldLurchercontrol mice. Analysis by olivary subdivision indicates that increased neuron numbers were present in all subdivisions of the host left inferior olive. These studies confirm the specific attractive effect of the mutant cerebellar cortex on transplanted Purkinje neuron progenitors and indicate that neural transplants may survive the neurodegenerative period to interact with developing host neural systems. The unilateral rescue of Lurcher inferior olivary neurons in cerebellar transplant hosts indicates that transplanted neurons may interact with diseased host neural circuits to reduce transneuronal degeneration in the course of a neurodegenerative disease.