Biology subjects

Geldmacher, D. S.

Publications and source records attributed to Geldmacher, D. S..

3 recordsLinked to original sources

bioRxiv2023

"Surviving and Thriving": Evidence for Cortical GABA Stabilization in Cognitively-Intact Oldest-Old Adults

Cortical GABA levels are reduced in older age; age-related differences in GABA may be associated with age-related cognitive change. The nature of age-related GABA differences in the highest-functioning stratum of the oldest-old (85+) population is not yet known. We extend our previously-reported Individual Participant Data Meta-Analysis of GABA levels (Porges et al., 2021) across the lifespan with four novel datasets sampling the cognitively-intact oldest-old. The slope of age-related GABA differences in cognitively-intact oldest-old adults flattens after roughly age 80. We interpret these findings as an effect of survivorship: inclusion in the study required intact cognition, and too great a reduction of GABA levels may not be compatible with neurophysiological function needed for intact cognition. This work contributes to a growing body of evidence suggesting that successful cognitive aging may require intact GABAergic function, as well as further characterizing successful aging amongst oldest-old adults.

neuroscience↗

bioRxiv2022

Larger and more dentated hippocampal structure is associated with better memory in the oldest-old.

Episodic memory is widely recognized as a critically important aspect of cognition that is often impacted by cognitive and brain aging. Prior work has shown that episodic memory is related to the presence of teeth-like folds on the dentate gyrus, called dentation. We hypothesized that episodic memory performance relates to overall hippocampal structure (i.e., dentation and volume) in an oldest-old cohort. We used data from the McKnight Brain Aging Registry, which consisted of cognitively healthy 85+-year-old adults. We conducted a canonical correlation analysis on 111 participants between a set of episodic memory tests and a set of characterizations of hippocampal structure. The analysis yielded a strong canonical correlation between episodic memory and hippocampal structure (r = 0.491, p = <0.001). The results suggest there is a connection between hippocampal morphology and function in the oldest-old. Our findings suggest that dentation may play an important role in relation to the individual differences observed in episodic memory performance among the oldest old and that hippocampal structure supports healthy cognitive aging. HighlightsO_LIWe characterized hippocampal dentation in a healthy oldest-old sample. C_LIO_LIHippocampal structure is related to episodic memory in healthy oldest-old adults. C_LIO_LIMemory functioning is related to both hippocampal volume and dentation. C_LI

neuroscience↗

bioRxiv2019

Genome sequencing for early-onset dementia: high diagnostic yield and frequent observation of multiple contributory alleles

We assessed the utility of genome sequencing for early-onset dementia. Participants were selected from a memory disorders clinic. Genome sequencing was performed along with C9orf72 repeat expansion testing. All returned sequencing results were Sanger validated clinically. Prior clinical diagnoses included Alzheimers disease, frontotemporal dementia, and unspecified dementia. The mean age-of-onset was 54 (41-76). 50% of patients had a strong family history, 37.5% had some, and 12.5% had no known family history. Nine of 32 patients (28%) had a variant defined as pathogenic or likely pathogenic (P/LP) by American College of Medical Genetics standards, including variants in APP, C9orf72, CSF1R, and MAPT. Nine patients (including three with P/LP variants) harbored established risk alleles with moderate penetrance (odds ratios of about 2-5) in ABCA7, AKAP9, GBA, PLD3, SORL1, and TREM2. All six patients harboring these moderate penetrance variants but not P/LP variants also had one or two APOE {varepsilon}4 alleles. One patient had two APOE {varepsilon}4 alleles with no other established contributors. In total, 16 patients (50%) harbored one or more genetic variants likely to explain symptoms. We identified variants of uncertain significance (VUSs) in ABI3, ADAM10, ARSA, GRID2IP, MME, NOTCH3, PLCD1, PSEN1, TM2D3, TNK1, TTC3, and VPS13C, also often along with other variants. In summary, genome sequencing for early-onset dementia demonstrated high utility, with particular advantages where targeted testing may fail such as atypical variant-disease associations or presence of multiple moderate impact alleles. One or more established contributory alleles is often present in early-onset dementia, supporting an oligogenic model.

neuroscience↗