Limbic-predominant age-related TDP-43 encephalopathy (LATE) is a recently recognized neurodegenerative dementia in the most elderly individuals, characterized by accumulation of TDP-43 protein aggregates in limbic and medial temporal lobe structures. This is clinically important pathology as it often mimics Alzheimer’s disease (AD) and is now understood to be a common contributor to cognitive decline in the “oldest-old”. Pathologically, LATE is distinguished from AD by TDP-43-positive neuronal inclusions (rather than amyloid plaques and neurofibrillary tangles), typically affecting the amygdala, hippocampus, and other limbic regions, often accompanied by hippocampal sclerosis. Clinically, LATE presents with a gradually progressive amnestic dementia syndrome similar to AD which complicates diagnosis. Currently, there are no established antemortem biomarkers for LATE, and definitive diagnosis relies on postmortem confirmation. However, an AD-like dementia with negative amyloid and tau biomarkers in a patient of advanced age is suggestive of LATE. No disease-modifying treatment exists at this time, however multiple therapeutic strategies are under investigation, including immunotherapies targeting pathological TDP-43, small molecules that enhance TDP-43 clearance, and gene or antisense approaches to mitigate TDP-43 toxicity. Continued research is critical to develop effective biomarkers and therapies for this prevalent but under-recognized TDP-43 proteinopathy.
Zachary R. Grese, E. Tunc, George T. Grossberg· Discover Neuroscience· 0 citations
OBJECTIVES
Agitation is a common and distressing phenomenon across neurocognitive disorders (NCD). It is linked to decreased quality of life of the person with NCD, cognitive and functional decline, increased health-care utilization and institutionalization rates, and substantial burden for family carers and care professionals. Its management is particularly challenging. The objective of this International Psychogeriatric Association's (IPA) task force was to synthesize recent advances in nomenclature and assessment, epidemiology, progression, etiology, detection, impact, approaches to managing agitation; and to make recommendations to guide IPA's next 10-year strategy.
METHODS
A multidisciplinary expert workgroup met multiple times virtually and during the 2024 IPA Congress in person to discuss the current scientific and clinical practice landscape for agitation in NCD. The group integrated evidence about validated behavioral measures, biomarkers, digital monitoring, psychosocial and environmental interventions, and pharmacological options.
RESULTS
Agitation is attributed to disruptions in fronto-limbic circuitry with contributions from neuroimmune dysregulation, neurotransmitter alterations, and mitochondrial dysfunction, and various psychosocial and environmental factors. Psychosocial and environmental strategies can reduce agitation, though magnitude and durability of responses vary. Pharmacological options can have short-term benefits but carry risks that require strict patient selection, counseling, monitoring and medication stewardship. Approved medications based on controlled clinical trials remain limited.
CONCLUSION
Care and support in agitation in NCD should involve the implementation of person-centered, rights-based psychosocial and environmental approaches, with time-limited pharmacological adjuncts as second-line. Key evidence gaps include head-to-head and longer-term trials, active safety surveillance, validated agitation measures, and equity-focused implementation across settings and cultures.
D. Gerritsen, Maarten Van Den Bossche, A. Atri et al.· International Psychogeriatri...· 0 citations
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