To determine whether the DCTclock can detect differences across groups of patients seen in the memory clinic for suspected dementia.
Patients (
= 123) were classified into the following groups: ...cognitively normal (CN), subtle cognitive impairment (SbCI), amnestic cognitive impairment (aMCI), and mixed/dysexecutive cognitive impairment (mx/dysMCI). Nine outcome variables included a combined command/copy total score and four command and four copy indices measuring drawing efficiency, simple/complex motor operations, information processing speed, and spatial reasoning.
Total combined command/copy score distinguished between groups in all comparisons with medium to large effects. The mx/dysMCI group had the lowest total combined command/copy scores out of all groups. The mx/dysMCI group scored lower than the CN group on all command indices (
< .050, all analyses); and lower than the SbCI group on drawing efficiency (
= .011). The aMCI group scored lower than the CN group on spatial reasoning (
= .019). Smaller effect sizes were obtained for the four copy indices.
These results suggest that DCTclock command/copy parameters can dissociate CN, SbCI, and MCI subtypes. The larger effect sizes for command clock indices suggest these metrics are sensitive in detecting early cognitive decline. Additional research with a larger sample is warranted.
The last decade has seen a substantial increase in research focused on the identification, development, and validation of diagnostic and prognostic retinal biomarkers for Alzheimer's disease (AD). ...Sensitive retinal biomarkers may be advantageous because they are cost and time efficient, non‐invasive, and present a minimal degree of patient risk and a high degree of accessibility. Much of the work in this area thus far has focused on distinguishing between symptomatic AD and/or mild cognitive impairment (MCI) and cognitively normal older adults. Minimal work has been done on the detection of preclinical AD, the earliest stage of AD pathogenesis characterized by the accumulation of cerebral amyloid absent clinical symptoms of MCI or dementia. The following review examines retinal structural changes, proteinopathies, and vascular alterations that have been proposed as potential AD biomarkers, with a focus on studies examining the earliest stages of disease pathogenesis. In addition, we present recommendations for future research to move beyond the discovery phase and toward validation of AD risk biomarkers that could potentially be used as a first step in a multistep screening process for AD risk detection.
Both estrous cycle and sex affect the numbers and types of neuronal and glial profiles containing the classical estrogen receptors α and β, and synaptic levels in the rodent dorsal hippocampus. Here, ...we examined whether the membrane estrogen receptor, G-protein-coupled estrogen receptor 1 (GPER1), is anatomically positioned in the dorsal hippocampus of mice to regulate synaptic plasticity. By light microscopy, GPER1-immunoreactivity (IR) was most noticeable in the pyramidal cell layer and interspersed interneurons, especially those in the hilus of the dentate gyrus. Diffuse GPER1-IR was found in all lamina but was most dense in stratum lucidum of CA3. Ultrastructural analysis revealed discrete extranuclear GPER1-IR affiliated with the plasma membrane and endoplasmic reticulum of neuronal perikarya and dendritic shafts, synaptic specializations in dendritic spines, and clusters of vesicles in axon terminals. Moreover, GPER1-IR was found in unmyelinated axons and glial profiles. Overall, the types and amounts of GPER1-labeled profiles were similar between males and females; however, in females elevated estrogen levels generally increased axonal labeling. Some estradiol-induced changes observed in previous studies were replicated by the GPER agonist G1: G1 increased PSD95-IR in strata oriens, lucidum, and radiatum of CA3 in ovariectomized mice 6 h after administration. In contrast, estradiol but not G1 increased Akt phosphorylation levels. Instead, GPER1 actions in the synapse may be due to interactions with synaptic scaffolding proteins, such as SAP97. These results suggest that although estrogen's actions via GPER1 may converge on the same synaptic elements, different pathways are used to achieve these actions.
The estrogen 17β-estradiol (E2) modulates dendritic spine plasticity in the cornu ammonis 1 (CA1) region of the hippocampus, and GPR30 (G-protein coupled estrogen receptor 1 (GPER1)) is an ...estrogen-sensitive G-protein-coupled receptor (GPCR) that is expressed in the mammalian brain and in specific subregions that are responsive to E2, including the hippocampus. The subcellular localization of hippocampal GPR30, however, remains unclear. Here, we demonstrate that GPR30 immunoreactivity is detected in dendritic spines of rat CA1 hippocampal neurons in vivo and that GPR30 protein can be found in rat brain synaptosomes. GPR30 immunoreactivity is identified at the post-synaptic density (PSD) and in the adjacent peri-synaptic zone, and GPR30 can associate with the spine scaffolding protein PSD-95 both in vitro and in vivo. This PSD-95 binding capacity of GPR30 is specific and determined by the receptor C-terminal tail that is both necessary and sufficient for PSD-95 interaction. The interaction with PSD-95 functions to increase GPR30 protein levels residing at the plasma membrane surface. GPR30 associates with the N-terminal tandem pair of PDZ domains in PSD-95, suggesting that PSD-95 may be involved in clustering GPR30 with other receptors in the hippocampus. We demonstrate that GPR30 has the potential to associate with additional post-synaptic GPCRs, including the membrane progestin receptor, the corticotropin releasing hormone receptor, and the 5HT1a serotonin receptor. These data demonstrate that GPR30 is well positioned in the dendritic spine compartment to integrate E2 sensitivity directly onto multiple inputs on synaptic activity and might begin to provide a molecular explanation as to how E2 modulates dendritic spine plasticity.
Background: Estrogen modulates synaptic plasticity in the hippocampus.
Results: GPR30 (an estrogen-sensitive GPCR) localizes to dendritic spines, interacts with PSD-95, and can associate with other GPCRs. PSD-95 increases GPR30 membrane levels.
Conclusion: GPR30 localization to dendritic spines would allow for estrogen modulation at synapses.
Significance: This is the first report to demonstrate a GPR30 association with other post-synaptic proteins.
The retinal neurovascular unit consists of blood vessel endothelial cells, pericytes, neurons, astrocytes, and Müller cells that form the inner retinal blood barrier. A peripheral capillary free zone ...(pCFZ) represents the distance that oxygen and nutrients must diffuse to reach the neural retina, and serves as a metric of retinal tissue oxygenation. The pCFZs are formed based on oxygen saturation in the retinal arterioles and venules. Because retinal arterioles contain a larger concentration of oxygenated blood than venules, there is a reduced need for capillaries to exist closely to arterioles compared to venules. Therefore, in a healthy individual, larger periarteriole CFZs are expected compared to perivenule CFZs. With normal aging, there is atrophy of the inner retinal neurons, and consequently reduced extraction of oxygen and nutrients from the retinal vessels (i.e., increased oxygen saturation). Therefore, we hypothesized that the peripheral CFZ will remodel with normal aging. Using Optical Coherence Tomography Angiography, we showed that the pCFZs do remodel in normal aging with large (perivenule: η
= 0.56) and moderate (periarteriole: η
= 0.12) effect sizes, opening the possibility that such changes may be further increased by neurodegenerative diseases that adversely impact the health of the retinal neural cell layers.
Introduction
Understanding the associations among depression, subjective cognitive decline, and prodromal Alzheimer's disease (AD) has important implications for both depression and dementia ...screening in older adults. The Geriatric Depression Scale (GDS) is a depression screening tool for older adults that queries memory concerns. To determine whether depression symptoms on the GDS (15‐item version), including self‐reported memory problems, differ by levels of brain amyloid beta (Aβ), a pathological hallmark of early stage AD, we investigated potential measurement bias with regard to Aβ level. We also examined measurement bias attributable to level of cognitive functioning and sex as positive controls.
Methods
We examined 3961 cognitively normal older adults from the A4/LEARN Study. We used the MIMIC (multiple indicators, multiple causes) approach to detect measurement bias.
Results
We found measurement bias with small‐to‐moderate range effect sizes in several GDS‐15 items with respect to Aβ level, cognitive functioning, and sex. There was negligible impact of measurement bias attributable to Aβ level on overall depressive symptom level.
Discussion
GDS‐15 item responses are sensitive to Aβ burden, cognitive functioning, and sex over and above what would be expected given the effect of those factors on depressive symptom severity overall. However, these direct effects for GDS item measurement bias are of small magnitude and do not appreciably impact the validity of inferences about depression based on the GDS‐15.
Background
Sensitive and non‐invasive methods of screening for early‐stage Alzheimer’s disease (AD) are urgently needed. Digital assessment tools have the potential to improve the efficiency of ...cognitive screening for older adults in both clinical and research settings. The Linus Health DCTclock uses a digital pen to capture traditional clock drawing test performance and advanced analytics to evaluate the drawing process for indicators of cognitive difficulty.
Method
We compared the DCTclock to the Montreal Cognitive Assessment (MoCA), a standard cognitive screening test, in a sample of older adults (total N = 60) with normal cognition (n = 30) or a clinical diagnosis of mild cognitive impairment (MCI) or AD (n = 30) and investigated which measure is more accurate in predicting cerebral amyloid (Aβ) PET status in a subset of 32 participants with PET imaging data.
Result
MoCA total score was moderately correlated with DCTclock total score (r = 0.61, p < 0.01), as well as various DCTclock composite sub‐scores. ROC analysis indicated that the MoCA had superior accuracy in differentiating between cognitively impaired and unimpaired participants (AUC = 0.98) relative to the DCTclock (AUC = 0.82). ROC analysis also indicated that the MoCA had superior accuracy in differentiating elevated versus non‐elevated Aβ PET status (AUC = 0.76) relative to the DCTclock (AUC = 0.60). A composite of the MoCA and DCTclock total scores did not improve accuracy over the MoCA alone (AUC = 0.71)
Conclusion
Overall, these preliminary results suggest that the MoCA is a superior cognitive screening tool and may also be useful for detecting AD associated neuropathology.
Studies have shown apolipoprotein E (APOE) genotype disclosure to be safe and well-tolerated in cognitively unimpaired (CU) older adults. This study aimed to examine the effect of the disclosure ...process on decisions about future directives and health behaviors in community-dwelling CU older adults from the Butler Alzheimer's Prevention Registry (BAPR).
CU APOE E4 non-carriers (n = 106) and carriers (n = 80) aged 58-78 completed in-person psychological readiness screening to undergo APOE disclosure. Follow-up assessments were completed online 3 days, 6 weeks, and 6 months post-disclosure. The primary outcomes were future directives, dietary habits, and physical activity scores.
Disclosure was associated with decision making on future directives in E4 carriers (
= 3.59,
= .01) at 6 months compared to baseline, but not non-carriers. Family history of memory impairment, SCD endorsement, and education consistently predicted scores on future directives. A significant interaction between E4+ and SCD endorsement on future directive scores was noted (OR = 163.06, 9.5-2,799.8). E4 + carrier status was associated with physical activity (
= 60,148,
= .005) but not dietary habits scores.
Our findings indicate that disclosure led to a change in future directives but not protective health behaviors, specifically in E4 carriers. Future work will explore whether pairing disclosure with education about the role of lifestyle factors in AD risk and providing guidelines on making risk-lowering lifestyle modifications as an intervention approach leads to positive change.
Introduction
The early detection of cognitive impairment is one of the most important challenges in Alzheimer's disease (AD) research. The use of brief, short‐term repeated test sessions via mobile ...app has demonstrated similar or better reliability and validity compared to standard in‐clinic assessments in adult samples. The present study examined adherence, acceptability, and reliability for a remote, app‐based cognitive screening protocol in healthy older adults.
Methods
Cognitively unimpaired older adults (N = 52, ages 60–80) completed three brief cognitive testing sessions per day within morning, afternoon, and evening time windows, for 8 consecutive days using a mobile app‐based cognitive testing platform. Cognitive tasks assessed visual working memory, processing speed, and episodic memory.
Results
Participants completed an average of 93% (M = 22.3 sessions, standard deviation = 10.2) of the 24 assigned sessions within 8 to 9 days. Average daily adherence ranged from 95% of sessions completed on day 2 to 88% of sessions completed on day 8. There was a statistically significant effect of session time on adherence between the morning and afternoon sessions only F (1, 51) = 9.15, P = .004, η p 2 = 0.152, with fewer afternoon sessions completed on average. The within‐person reliabilities of average scores, aggregated across all 24 sessions, were exceptionally high, ranging from 0.89 to 0.97. Performance on the episodic memory task was positively and significantly associated with total score and word list recall score on the Telephone Interview for Cognitive Status. In an exit survey, 65% of participants reported that they “definitely” would complete the sessions again.
Discussion
These findings suggests that remote, mobile app–based cognitive testing in short bursts is both highly feasible and reliable in a motivated sample of cognitively normal older adults. Limitations include the limited diversity and generalizability of the sample; this was a largely White, highly educated, and motivated sample self‐selected for AD research.
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