CONTINUUM Lifelong Learning in Neurology最新文献

Objective: Although Alzheimer disease (AD) is the most common neurodegenerative cause of dementia, neurologists must be aware of other etiologies that can mimic the amnestic-predominant syndrome and medial temporal brain involvement typically associated with AD. This article reviews recent updates surrounding limbic-predominant age-related transactive response DNA-binding protein 43 (TDP-43) encephalopathy (LATE), hippocampal sclerosis, and primary age-related tauopathy.

Latest developments: LATE neuropathologic change occurs in approximately 40% of autopsied older adults, including occurrences in isolation in some older individuals with amnestic cognitive impairment. LATE neuropathologic change is often, but not always, associated with hippocampal sclerosis (neuronal loss and gliosis in the hippocampus and associated structures) and frequently coexists with AD and other neurodegenerative pathologies. Although there is no direct clinical biomarker for TDP-43 pathology, recent studies suggest that a clinical diagnosis of LATE can be achieved through the integration of multiple data points. Primary age-related tauopathy refers to the pathologic finding (in some cognitively unimpaired older adults as well as some individuals with cognitive impairment) of medial temporal-predominant neurofibrillary tangles in the absence of amyloid-β (Aβ) plaques. Recent consensus frameworks have attempted to resolve ambiguities of nomenclature and diagnosis for these entities, and efforts toward in vivo biomarkers are ongoing.

Essential points: LATE, with or without hippocampal sclerosis, and primary age-related tauopathy belong in the differential diagnosis (along with AD, argyrophilic grain disease, and other disorders) for slowly progressive amnestic-predominant cognitive impairment, particularly in individuals older than 75 years. Accurate recognition of clinical and diagnostic test features supportive of these non-AD entities is vital to optimize patient counseling, therapeutic selection, and novel biomarker development.

Objective: Lewy body dementia (LBD) is an umbrella term describing two closely related conditions: Parkinson disease dementia (PDD) and dementia with Lewy bodies (DLB). LBD is the second most common cause of neurodegenerative dementia but is often underrecognized in clinical practice. This review covers the key epidemiologic, clinical, cognitive, behavioral, and biomarker features of LBD and discusses current treatment options.

Latest developments: Indicative biomarkers of LBD improve the ability to make a diagnosis and include single-photon emission computed tomography (SPECT) of the dopamine system (brain) and the noradrenergic system (cardiac), and polysomnography. α-Synuclein-specific biomarkers in spinal fluid, skin, plasma, and brain imaging are in active development with some available for clinical use. Prodromal stages of PDD and DLB have been contextualized, and diagnostic criteria have been published. An emerging theme is whether an integrated staging system focusing on protein aggregation, rather than clinical symptoms, may advance research efforts.

Essential points: LBD is a common cause of cognitive impairment in older adults but is often subject to significant delays in diagnosis and treatment, increasing the burden on patients and family care partners. Understanding key features of disease and the use of biomarkers will improve recognition. Earlier detection may also facilitate the development of new therapeutics and enrollment in clinical trials.

Objective: This article provides a comprehensive review of the distinct features of four atypical Alzheimer disease (AD) variants: dysexecutive AD, behavioral variant AD, posterior cortical atrophy, and the logopenic variant of primary progressive aphasia. It also elucidates their clinical presentations, underlying pathophysiologic pathways, diagnostic indicators, and management requirements.

Latest developments: Recent research has revealed that these atypical AD forms vary not only in clinical manifestations but in their functional neuroanatomy spanning a common pathophysiologic spectrum. Imaging techniques, such as MRI, fludeoxyglucose positron emission tomography (FDG-PET), and tau PET, have identified distinct abnormalities in specific brain regions associated with each variant. This same variability is less tightly coupled to amyloid imaging. Emerging diagnostic and therapeutic strategies should be tailored to each variant's unique features.

Essential points: Atypical forms of AD often present with symptoms that are predominantly nonmemory related, distinguishing them from the more common memory-centric presentation of the disease. Two distinct clinical and pathologic entities, dysexecutive AD and behavioral variant AD, have replaced the outdated term frontal AD. Posterior cortical atrophy is another variant that mainly affects higher-order visual functions, which can lead to misdiagnoses because of its atypical symptom profile. Logopenic primary progressive aphasia is marked by difficulties in word retrieval, a challenge that may not be readily apparent if the person compensates by using circumlocution. Modern diagnostic techniques, such as MRI, PET, and biomarker analysis, have proven crucial for the accurate diagnosis and differentiation of these atypical AD variants. In treating these forms, it is critical to use tailored therapeutic interventions that combine pharmacotherapy with nonpharmacologic strategies to effectively manage the disease.

Objective: Symptom-oriented treatment has been the mainstay of Alzheimer disease (AD) pharmacotherapy for decades. This article reviews the evidence basis for symptomatic treatments for AD and the emerging data on amyloid-lowering therapies with possible disease-slowing effects.

Latest development: Amyloid-lowering monoclonal antibody therapies entered clinical use in 2021. In July 2023, lecanemab became the first of these to gain full US Food and Drug Administration (FDA) approval and limited Medicare payment coverage. Donanemab gained similar approval status in July 2024. The approved agents remove amyloid plaque from the brain and appear to slow clinical disease progression but can produce significant adverse events known as amyloid-related imaging abnormalities with cerebral edema or effusion and with cerebral hemorrhages. Extensive safety monitoring is therefore required, including scheduled MRI scans. Also in 2023, brexpiprazole became the first agent specifically approved by the FDA for agitation associated with AD. Suvorexant, an orexin receptor antagonist, previously was approved for the treatment of insomnia in people with mild and moderate AD.

Essential points: There is robust evidence for the use of acetylcholinesterase inhibitors for patients with mild, moderate, and severe dementia due to AD, including outcomes beyond changes in cognitive screening test scores. More limited studies support the use of memantine in moderate and severe stages. These agents have a primary effect of delaying decline in cognition and function and postponing the emergence of adverse behaviors. Pharmacotherapy for behavioral and psychological symptoms is less predictable, and most clinical trials have had negative results. Anti-amyloid therapies provide the first FDA-approved option to alter AD pathology, but an understanding of overall utility and value to patients remains in its infancy.

Objective: This article reviews the current understanding of Alzheimer disease (AD), including the natural history, common risk factors, and expected progression of AD neuropathologic change so that neurologists can apply this knowledge to identify patients with symptoms, signs, and findings on common diagnostic tests consistent with AD.

Latest developments: The advent of potential disease-modifying therapies emphasizes the need to develop and deploy a practical and efficient approach to diagnose patients with cognitive impairment due to AD.

Essential points: The accumulation and spread of cerebral amyloid plaques and tau tangles in patients with AD leads to synaptic dysfunction, neuronal loss, and the eventual emergence and progression of cognitive impairment. A pragmatic and organized approach is needed to recognize patients with symptomatic AD in clinical practice, stage the level of impairment, confirm the clinical diagnosis, and apply this information to advance therapeutic decision making.