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Objective: Cholinesterase inhibitors (CEIs) are prescribed for dementia to maintain or improve memory. Selective serotonin reuptake inhibitors (SSRIs) are also prescribed to manage psychiatric symptoms seen in dementia. What proportion of outpatients actually responds to these drugs is still unclear. Our objective was to investigate the responder rates of these medications in an outpatient setting using the electronic medical record (EMR).Methods: We used the Johns Hopkins EMR system to identify patients with dementia who were prescribed a CEI or SSRI for the first time between 2010 and 2021. Treatment effects were assessed through routinely documented clinical notes and free-text entries in which healthcare providers record clinical findings and impressions of patients. Responses were scored using a three-point Likert scale named the NOte-based evaluation method for Treatment Efficacy (NOTE) in addition to the Clinician’s Interview-Based Impression of Change Plus caregiver input (CIBIC-plus), a seven-point Likert scale used in clinical trials. To validate NOTE, the relationships between NOTE and CIBIC-plus and between NOTE and change in MMSE (Mini-Mental State Examination) before and after medication were examined. Inter-rater reliability was evaluated using Krippendorff’s alpha. The responder rates were calculated.Results: NOTE showed excellent inter-rater reliability and correlated well with CIBIC-plus and changes in MMSEs. Out of 115 CEI cases, 27.0% reported improvement and 34.8% reported stable symptoms in cognition; out of 225 SSRI cases, 69.3% reported an improvement in neuropsychiatric symptoms.Conclusion: NOTE showed high validity in measuring the pharmacotherapy effects based on unstructured clinical entries. Although our real-world observation included various types of dementia, the results were remarkably similar to what was reported in controlled clinical trials of Alzheimer’s disease and its related neuropsychiatric symptoms.

The blood–brain barrier (BBB) plays important roles in the maintenance of brain homeostasis. Its main role includes three kinds of functions: (1) to protect the central nervous system from blood-borne toxins and pathogens; (2) to regulate the exchange of substances between the brain parenchyma and capillaries; and (3) to clear metabolic waste and other neurotoxic compounds from the central nervous system into meningeal lymphatics and systemic circulation. Physiologically, the BBB belongs to the glymphatic system and the intramural periarterial drainage pathway, both of which are involved in clearing interstitial solutes such as β-amyloid proteins. Thus, the BBB is believed to contribute to preventing the onset and progression for Alzheimer’s disease. Measurements of BBB function are essential toward a better understanding of Alzheimer’s pathophysiology to establish novel imaging biomarkers and open new avenues of interventions for Alzheimer’s disease and related dementias. The visualization techniques for capillary, cerebrospinal, and interstitial fluid dynamics around the neurovascular unit in living human brains have been enthusiastically developed. The purpose of this review is to summarize recent BBB imaging developments using advanced magnetic resonance imaging technologies in relation to Alzheimer’s disease and related dementias. First, we give an overview of the relationship between Alzheimer’s pathophysiology and BBB dysfunction. Second, we provide a brief description about the principles of non-contrast agent-based and contrast agent-based BBB imaging methodologies. Third, we summarize previous studies that have reported the findings of each BBB imaging method in individuals with the Alzheimer’s disease continuum. Fourth, we introduce a wide range of Alzheimer’s pathophysiology in relation to BBB imaging technologies to advance our understanding of the fluid dynamics around the BBB in both clinical and preclinical settings. Finally, we discuss the challenges of BBB imaging techniques and suggest future directions toward clinically useful imaging biomarkers for Alzheimer’s disease and related dementias.

Alzheimer’s disease (AD) is the most common type of dementia and a distressing diagnosis for individuals and caregivers. Researchers and clinical trials have mainly focused on β-amyloid plaques, which are hypothesized to be one of the most important factors for neurodegeneration in AD. Meanwhile, recent clinicopathological and radiological studies have shown closer associations of tau pathology rather than β-amyloid pathology with the onset and progression of Alzheimer’s symptoms. Toward a biological definition of biomarker-based research framework for AD, the 2018 National Institute on Aging–Alzheimer’s Association working group has updated the ATN classification system for stratifying disease status in accordance with relevant pathological biomarker profiles, such as cerebral β-amyloid deposition, hyperphosphorylated tau, and neurodegeneration. In addition, altered iron metabolism has been considered to interact with abnormal proteins related to AD pathology thorough generating oxidative stress, as some prior histochemical and histopathological studies supported this iron-mediated pathomechanism. Quantitative susceptibility mapping (QSM) has recently become more popular as a non-invasive magnetic resonance technique to quantify local tissue susceptibility with high spatial resolution, which is sensitive to the presence of iron. The association of cerebral susceptibility values with other pathological biomarkers for AD has been investigated using various QSM techniques; however, direct evidence of these associations remains elusive. In this review, we first briefly describe the principles of QSM. Second, we focus on a large variety of QSM applications, ranging from common applications, such as cerebral iron deposition, to more recent applications, such as the assessment of impaired myelination, quantification of venous oxygen saturation, and measurement of blood– brain barrier function in clinical settings for AD. Third, we mention the relationships among QSM, established biomarkers, and cognitive performance in AD. Finally, we discuss the role of QSM as an imaging biomarker as well as the expectations and limitations of clinically useful diagnostic and therapeutic implications for AD.

Hypoxic–ischemic encephalopathy (HIE) is the most common cause of neonatal acquired brain injury. Although conventional MRI may predict neurodevelopmental outcomes, accurate prognostication remains difficult. As diffusion tensor imaging (DTI) may provide an additional diagnostic and prognostic value over conventional MRI, we aimed to develop a composite DTI (cDTI) score to relate to short-term neurological function. Sixty prospective neonates treated with therapeutic hypothermia (TH) for HIE were evaluated with DTI, with a voxel size of 1 × 1 × 2 mm. Fractional anisotropy (FA) and mean diffusivity (MD) from 100 neuroanatomical regions (FA/MD *100 = 200 DTI parameters in total) were quantified using an atlas-based image parcellation technique. A least absolute shrinkage and selection operator (LASSO) regression was applied to the DTI parameters to generate the cDTI score. Time to full oral nutrition [short-term oral feeding (STO) score] was used as a measure of short-term neurological function and was correlated with extracted DTI features. Seventeen DTI parameters were selected with LASSO and built into the final unbiased regression model. The selected factors included FA or MD values of the limbic structures, the corticospinal tract, and the frontotemporal cortices. While the cDTI score strongly correlated with the STO score (rho = 0.83, p = 2.8 × 10−16), it only weakly correlated with the Sarnat score (rho = 0.27, p = 0.035) and moderately with the NICHD-NRN neuroimaging score (rho = 0.43, p = 6.6 × 10−04). In contrast to the cDTI score, the NICHD-NRN score only moderately correlated with the STO score (rho = 0.37, p = 0.0037). Using a mixed-model analysis, interleukin-10 at admission to the NICU (p = 1.5 × 10−13) and tau protein at the end of TH/rewarming (p = 0.036) and after rewarming (p = 0.0015) were significantly associated with higher cDTI scores, suggesting that high cDTI scores were related to the intensity of the early inflammatory response and the severity of neuronal impairment after TH. In conclusion, a data-driven unbiased approach was applied to identify anatomical structures associated with some aspects of neurological function of HIE neonates after cooling and to build a cDTI score, which was correlated with the severity of short-term neurological functions.

Impaired expression of emotion through pitch, loudness, rate, and rhythm of speech (affective prosody) is common and disabling after right hemisphere (RH) stroke. These deficits impede all social interactions. Previous studies have identified cortical areas associated with impairments of expression, recognition, or repetition of affective prosody, but have not identified critical white matter tracts. We hypothesized that: (1) differences across patients in specific acoustic features correlate with listener judgment of affective prosody and (2) these differences are associated with infarcts of specific RH gray and white matter regions. To test these hypotheses, 41 acute ischemic RH stroke patients had MRI diffusion weighted imaging and described a picture. Affective prosody of picture descriptions was rated by 21 healthy volunteers. We identified percent damage (lesion load) to each of seven regions of interest previously associated with expression of affective prosody and two control areas that have been associated with recognition but not expression of prosody. We identified acoustic features that correlated with listener ratings of prosody (hereafter "prosody acoustic measures") with Spearman correlations and linear regression. We then identified demographic variables and brain regions where lesion load independently predicted the lowest quartile of each of the "prosody acoustic measures" using logistic regression. We found that listener ratings of prosody positively correlated with four acoustic measures. Furthermore, the lowest quartile of each of these four "prosody acoustic measures" was predicted by sex, age, lesion volume, and percent damage to the seven regions of interest. Lesion load in pars opercularis, supramarginal gyrus, or associated white matter tracts (and not control regions) predicted lowest quartile of the four "prosody acoustic measures" in logistic regression. Results indicate that listener perception of reduced affective prosody after RH stroke is due to reduction in specific acoustic features caused by infarct in right pars opercularis or supramarginal gyrus, or associated white matter tracts.