Behavioral and psychological symptoms of dementia (BPSD) afflict the vast majority of patients with dementia, especially those with Alzheimer’s disease (AD). In clinical settings, patients with BPSD most often do not present with just one symptom. Rather, clusters of symptoms commonly co-occur and can, thus, be grouped into behavioral domains that may ultimately be the result of disruptions in overarching neural circuits. One major BPSD domain routinely identified across patients with AD is the hyperactivity–impulsivity–irritiability–disinhibition–aggression–agitation (HIDA) domain. The HIDA domain represents one of the most difficult sets of symptoms to manage in AD and accounts for much of the burden for caregivers and hospital staff. Although many studies recommend non-pharmacological treatments for HIDA domain symptoms as first-line, they demonstrate little consensus as to what these treatments should be and are often difficult to implement clinically. Certain symptoms within the HIDA domain also do not respond adequately to these treatments, putting patients at risk and necessitating adjunct pharmacological intervention. In this review, we summarize the current literature regarding non-pharmacological and pharmacological interventions for the HIDA domain and provide suggestions for improving treatment. As epigenetic changes due to both aging and AD cause dysfunction in drug-targeted receptors, we propose that HIDA domain treatments could be enhanced by adjunct strategies that modify these epigenetic alterations and, thus, increase efficacy and reduce side effects. To improve the implementation of non-pharmacological approaches in clinical settings, we suggest that issues regarding inadequate resources and guidance for implementation should be addressed. Finally, we propose that increased monitoring of symptom and treatment progression via novel sensor technology and the “DICE” (describe, investigate, create, and evaluate) approach may enhance both pharmacological and non-pharmacological interventions for the HIDA domain.

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The TDP-43 type C pathologic form of frontotemporal lobar degeneration (FTLD-TDP-type C) is characterized by the presence of immunoreactive TDP-43 short and long dystrophic neurites (DNs), neuronal cytoplasmic inclusions (NCIs), neuronal loss and gliosis (NL/G), and the absence of neuronal intranuclear inclusions (NIIs). FTLD-TDP-type C cases are commonly associated with the semantic variant of primary progressive aphasia (PPA-S) or behavioral variant frontotemporal dementia (bvFTD). Here, we provide detailed characterization of regional distributions of pathologic TDP-43 and NL/G in cortical and subcortical regions in 10 FTLD-TDP-type C cases and investigate the relationship between inclusions and NL/G. Specimens were obtained from the first 10 FTLD-TDP-type C cases accessioned from the Northwestern Alzheimer’s Disease Research Center (PPA-S, N = 7; bvFTD, N = 3). A total of 42 cortical (majority bilateral) and subcortical regions were immunostained with a phosphorylated TDP-43 antibody and/or stained with hematoxylin-eosin. Regions were evaluated for atrophy, and for long DNs, short DNs, NCIs, and NL/G using a semiquantitative 5-point scale. We calculated a “neuron-to-inclusion” score (TDP-C mean score—NL/G mean score) for each region per case to assess the relationship between TDP-type C inclusions and NL/G. PPA cases demonstrated leftward asymmetry of cortical atrophy consistent with the aphasic phenotype. We also observed abundant inclusions and neurodegeneration in both cortical and subcortical regions, with certain subcortical regions emerging as particularly vulnerable to DNs (e.g. amygdala, caudate, and putamen). Interestingly, linear mixed models showed that regions with lowest type C pathology had high neuronal dropout, and conversely, regions with abundant pathology displayed relatively preserved neuronal densities (p < 0.05). This inverse relationship between the extent of TDP-positive inclusions and neuronal loss may reflect a process whereby inclusions disappear as their associated neurons are lost. Together, these findings offer insight into the putative substrates of neurodegeneration in unique dementia syndromes.

Alzheimer's Disease (AD) is a devastating neurodegenerative disorder currently affecting 45 million people worldwide, ranking as the 6 th highest cause of death. Throughout the development and progression of AD, over 90% of patients display behavioral and psychological symptoms of dementia (BPSD), with some of these symptoms occurring before memory deficits and therefore serving as potential early predictors of AD-related cognitive decline. However, the biochemical links between AD and BPSD are not known. In this study, we explored the molecular interactions between AD and BPSD using protein-protein interaction (PPI) networks built from OMIM (Online Mendelian Inheritance in Man) genes that were related to AD and two distinct BPSD domains, the Affective Domain and the Hyperactivity, Impulsivity, Disinhibition, and Aggression (HIDA) Domain. Our results yielded 8 unique proteins for the Affective Domain (RHOA, GRB2, PIK3R1, HSPA4, HSP90AA1, GSK3beta, PRKCZ, and FYN), 5 unique proteins for the HIDA Domain (LRP1, EGFR, YWHAB, SUMO1, and EGR1), and 6 shared proteins between both BPSD domains (APP, UBC, ELAV1, YWHAZ, YWHAE, and SRC) and AD. These proteins might suggest specific targets and pathways that are involved in the pathogenesis of these BPSD domains in AD.

Average aging is associated with a gradual decline of memory capacity. SuperAgers are humans ≥80 years of age who show exceptional episodic memory at least as good as individuals 20–30 years their junior. This study investigated whether neuronal integrity in the entorhinal cortex (ERC), an area critical for memory and selectively vulnerable to neurofibrillary degeneration, differentiated SuperAgers from cognitively healthy younger individuals, cognitively average peers (“Normal Elderly”), and individuals with amnestic mild cognitive impairment. Postmortem sections of the ERC were stained with cresyl violet to visualize neurons and immunostained with mouse monoclonal antibody PHF-1 to visualize neurofibrillary tangles. The cross-sectional area (i.e., size) of layer II and layer III/V ERC neurons were quantified. Two-thirds of total participants were female. Unbiased stereology was used to quantitate tangles in a subgroup of SuperAgers and Normal Elderly. Linear mixed-effect models were used to determine differences across groups. Quantitative measurements found that the soma size of layer II ERC neurons in postmortem brain specimens were significantly larger in SuperAgers compared with all groups (p< 0.05)—including younger individuals 20–30 years their junior (p< 0.005). SuperAgers had significantly fewer stereologically quantified Alzheimer's disease-related neurofibrillary tangles in layer II ERC than Normal Elderly (p< 0.05). This difference in tangle burden in layer II between SuperAgers and Normal Elderly suggests that tangle-bearing neurons may be prone to shrinkage during aging. The finding that SuperAgers show ERC layer II neurons that are substantially larger even compared with individuals 20–30 years younger is remarkable, suggesting that layer II ERC integrity is a biological substrate of exceptional memory in old age.SIGNIFICANCE STATEMENTAverage aging is associated with a gradual decline of memory. Previous research shows that an area critical for memory, the entorhinal cortex (ERC), is susceptible to the early formation of Alzheimer's disease neuropathology, even during average (or typical) trajectories of aging. The Northwestern University SuperAging Research Program studies unique individuals known as SuperAgers, individuals ≥80 years old who show exceptional memory that is at least as good as individuals 20–30 years their junior. In this study, we show that SuperAgers harbor larger, healthier neurons in the ERC compared with their cognitively average same-aged peers, those with amnestic mild cognitive impairment, and – remarkably – even compared with individuals 20–30 years younger. We conclude that larger ERC neurons are a biological signature of the SuperAging trajectory.