2 Minute Medicine Rewind July 5, 2021

Accuracy of tau positron emission tomography as a prognostic marker in preclinical and prodromal Alzheimer disease

1. Tau PET predicted cognitive change and effect sizes were greater than amyloid PET and MRI.

2. MRI mediated the association between tau PET and cognition among Alzheimer’s and amyloid-positive MCI groups.

Evidence Rating Level: 2 (Good)

Alzheimer’s disease (AD) is generally defined by tau pathology and amyloid-beta deposition. However, prognosis in the form of accurately predicting rate of cognitive decline remains elusive. This prognostic study of eight cohorts from the U.S., Sweden, and South Korea examined prognostic accuracy of baseline fluorine 18 (¹⁸F)-flortaucipir and [¹⁸F]RO948 (tau) positron emission tomography (PET) among those with AD. Further, this study compared prognostic ability of tau PET with MRI and amyloid PET biomarkers. A total of 1,431 participants (M [SD] age = 71.2 [8.8] years, 47.5% female) were included in this study. Approximately 47% were cognitively unimpaired (37.6% amyloid-beta-positive, 31% had MCI (61.2% amyloid-beta-positive), and 22% had AD (100% amyloid-beta-positive). Among the amyloid-beta-positive MCI group, tau PET predicted changes in cognition and demonstrated stronger effect sizes compared to amyloid PET and MRI cortical thickness (R² = 0.35 [tau PET] vs 0.17 [amyloid PET] vs 0.24 [MRI], p<.001). The amyloid-beta-positive cognitively unimpaired group exhibited similar characteristics (R² = 0.16 [tau PET] vs 0.08 [amyloid PET] vs 0.08 [MRI], p<.001). For the amyloid-beta-positive MCI (13.6%, 95% CI 0.0 to 28.0% of total effect) and AD (33.4%, 95% CI 15.5 to 60.0% of total effect) groups, MRI mediated the observed association between cognition and tau PET. However, MRI did not mediate this association among the amyloid-beta-positive cognitively unimpaired group (p = 0.71). Age modified the association between baseline tau PET and cognitive decline (t = -2.28, p = 0.02) but sex and APOE genotype did not. Overall, this study demonstrated the prognostic capabilities of tau PET and the potential benefits over MRI and amyloid PET. With increased interest in amyloid PET to detect AD pathology, this study broadens our understanding of the importance prognostics in clinical care.

Association between a common, benign genotype and unnecessary bone marrow biopsies among African American patients

1. Approximately 97% of Black individuals undergoing bone marrow biopsy (BMB) for isolated low white blood cell (WBC) count had the benign rs2814778-CC genotype.

2. Of those with the CC genotype undergoing a BMB for WBC count, 97% had normal hematologic results.

Evidence Rating Level: 2 (Good)

The rs2814778-CC genotype, found in approximately 67% of Black individuals, is benign but lowers total white blood cell (WBC) count. Low WBC counts can result in a bone marrow biopsy (BMB). This retrospective genetic association study investigated Black participants under 90 years of age who underwent a BMB at Mount Sinai Health System, Vanderbilt University Medical Center, or Children’s Hospital of Philadelphia from January 1998 to December 2020. The primary outcome was the proportion of participants with the benign genotype who underwent a BMB for low WBC count with a subsequent normal biopsy compared to those with the CC genotype who underwent a BMB for other reasons. A total of 399 participants (M [SD] age = 41.8 [22.5] years, 59% female) underwent a BMB, 69% of whom had the benign CC genotype. In total, 9% had histories of isolated low WBC counts and 91% had other histories beyond WBC counts. Among those with a history of isolated low WBC count, 97% had the benign genotype compared to only 67% of those without a history of low WBC count. Further, 97% of those with the CC genotype, 97% had normal hematologic results when receiving a BMB for WBC count compared to only 55% among those receiving a BMB for other indications (p<0.001). Overall, this study suggests that genotyping could prevent unnecessary BMB among Black individuals who are more likely to carry the benign rs2814778-CC genotype.

Prevalence and course of depression during the first year after mild to moderate stroke

1. Approximately 35.3% of patients who experienced a mild or moderate stroke were found to have depression three months following the stroke.

2. Depressive symptoms persist beyond six months post-stroke in individuals with more severe symptoms.

Evidence Rating Level: 2 (Good)

Nearly one-third of patients experiencing a stroke develop depression following the incident, resulting in diminished functional abilities and overall well-being. For this reason, screening for depression is an important component of post-stroke care. This population-based longitudinal cohort study investigated both prevalence and course of depression in the first year following mild and moderate stroke. A total of 648 participants (M age = 65.6 years, 49.4% female, 56.7% Mexican American) were included from the Brain Attack Surveillance in Corpus Christi project (2014-2016). Each participant had experienced a mild to moderate ischemic stroke or intracerebral hemorrhage and at least one depression evaluation at three, six, or twelve months following the stroke. The eight-item Patient Health Questionnaire was completed between the three- and twelve-month time points. At three months, the prevalence of depression was 35.3%. There was a decrease at six months to 24.9%, and a stable prevalence of 25.7% at twelve months. Of those experiencing depression at three or six months, approximately half had improved symptoms by their subsequent assessment. Most participants with mild or no symptoms of depression were stable along this course throughout the study, while those with severe symptoms were more likely to continue experiencing these symptoms after six months, compared to at three months. Overall, this study demonstrated that depression is a common phenomenon following mild or moderate stroke. Further, more significant depressive symptoms persist beyond six months, suggesting the need for ongoing screening and care.

Plasma IL-12/IFN-γ axis predicts cognitive trajectories in cognitively unimpaired older adults

1. In the context of elevated amyloid-beta, IL-12p70 was associated with slower cognitive decline.

2. IFN-γ was associated with slower cognitive decline irrespective of amyloid-beta deposition.

Evidence Rating Level: 2 (Good)

It is currently understood that immune dysregulation, as well as premature immunosenescence and cytokine levels, impact the neurodegenerative process. Less understood, however, is the predictive value of cytokine levels in the context of cognitive trajectories in cognitively unimpaired individuals. This is particularly important among those who are amyloid-beta- (Aβ) positive. This longitudinal study assessed baseline plasma for nine cytokines of 298 cognitively unimpaired older adults (50 to 90 years old) to determine whether or not these biomarkers were associated with cognitive decline and Aβ deposition. Cytokine levels were also compared to Aβ and tau PET as well as neurodegeneration. Eligible participants had a score of 27 or greater on the age- and education-adjusted Mini Mental Status Examination and scored with the normatively average range on several other neuropsychological measures. Those with unstable medical or psychiatric conditions, as well as those with a stroke history, were excluded. Elevated IL-12p70 was found to be associated with slower cognitive decline in the context of increased Aβ (false discovery rate [FDR] = 0.0023). Conversely, IFN-γ was associated with cognitive decline irrespective of Aβ findings (FDR = 0.013). Elevated IL-12p70 was also associated with reduced neurodegeneration and tau protein in those with elevated Aβ. Overall, this study demonstrates the role of immune dysregulation in neurodegeneration, such that certain cytokines may serve a protective role in slowing cognitive decline in those with and without elevated Aβ.

Bidirectional relationship between subjective age and frailty: A prospective cohort study

1. Individuals who reported feeling older than their chronological ages were significantly more likely to be frail or pre-frail than those who felt younger or the same age.

Evidence Rating Level: 2 (Good)

Frailty is associated with age, biological processes, health status, and a range of other factors. Similarly, subjective age is also dependent on these variables and defined as the age one experiences themselves as being. The relationship between subjective age and frailty is poorly understood. This prospective cohort study of 2,592 community-dwelling older adults (M [SD] age = 75.2 [6.8] years, 58% female, 76% White) from the National Health and Aging Trends Study sought to examine this relationship. Frailty was quantified through five phenotypic criteria: exhaustion, unintentional weight loss, low physical activity, slow gait, weak grip strength. The following categories were then used to define the number of criteria met: robust (0), pre-frailty (1-2), frailty (≥3). Subjective age was determined by self-report and was a response to the age that the participants feel most of the time. These categories comprised 45%, 46%, and 9% of participants, respectively. Approximately 77% of participants felt younger than their chronological age while 18% felt the same age and 5% felt older. Feeling older than one’s chronological age was predictive of a higher likelihood of frailty and pre-frailty (OR = 1.93, 95% CI 1.45 to 2.56). Overall, this study suggests that those whose subjective ages exceed their chronological ages are more likely to be frail or pre-frail. These findings could be used to develop brief screeners that could indicate frailty level and risk of negative outcomes as a result.

Image: PD

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