Four Recent Research Studies in Geriatric Psychiatry
Pitt Psychiatry investigators have recently published research studies on mental health in late life in Alzheimer’s & Dementia, Nature Communications, and Neuropsychopharmacology. Below is a summary of original research on amyloid beta accumulation, neuroinflammation, neurodegeneration, and severe worry in older adults.
Altered glymphatic-related fluid dynamics are increasingly recognized as a feature of Alzheimer's disease. A group of investigators generalized an established diffusion imaging framework to quantify periventricular diffusivity, hypothesizing that fast diffusion signals in the periventricular region can reflect amyloid beta (Aβ) deposition across the Alzheimer's disease continuum.
They found that lower periventricular diffusivity was extensively associated with greater Aβ burden, neurodegeneration, cognitive impairment, and clinical severity in a clinical cohort. Importantly, the relationship between periventricular diffusivity and Aβ burden was significantly modulated by apolipoprotein E (APOE) ε4 status; APOE ε4 carriers exhibited a replicable stronger negative association. Baseline periventricular diffusivity also predicted longitudinal cognitive decline.
Chen CL, Son SJ, Schweitzer N, Jin H, Li J, Wang L, Yang S, Hong CH, Roh HW, Park B, Choi JW, AN YS, Seo SW, Cho YH, Hong S, Nam YJ, Minhas DS, Laymon CM, Stetten GD, Tudorascu DL, Aizenstein HJ, Wu M, Mayo Clinic Study of Aging.
Alzheimer's & Dementia. 2025; 21:e70659. https://doi.org/10.1002/alz.70659
Amyloid Beta and Tau Are Associated with the Dual Effect of Neuroinflammation on Neurodegeneration
In Alzheimer’s disease research, open questions remain regarding the impact of neuroinflammation on Alzheimer's-related neurodegeneration. Some research has suggested that neuroinflammation indicates increased likelihood of neurodegeneration, others indicate a protective effect. Scientists conducted a study in which participants underwent positron emission tomography (PET) for amyloid beta (Aβ), tau, and translocator protein (a proxy of neuroinflammation) to test the hypothesis that Aβ and tau are associated with the dual effect of neuroinflammation on neurodegeneration across the Alzheimer’s disease continuum. They found that Aβ- and tau-associated neuroinflammation are related to two waves of deleterious effects on Alzheimer’s-related neurodegeneration.
Povala G, Bellaver B, De Bastiani MA, Ferrari-Souza JP, Aguzzoli CS, Leffa DT, Ferreira PCL, Lussier FZ, Rocha A, Zalzale H, Soares C, Bauer-Negrini G, Therriault J, Rahmouni N, Stevenson J, Servaes S, Tissot C, Zatt B, Karikari TK, Ikonomovic MD, Villemagne VL, Gauthier S, Zimmer ER, Tudorascu DL, Benedet AL, Rosa-Neto P, Pascoal TA.
Alzheimer's & Dementia. 2025; 21:e70746. https://doi.org/10.1002/alz.70746
CSF Total Tau as a Proxy of Synaptic Degeneration
Cerebrospinal fluid total tau is considered a biomarker of neuronal degeneration alongside brain atrophy and fluid neurofilament light chain protein in biomarker models of Alzheimer’s disease. However, previous studies show that cerebrospinal fluid total tau correlates strongly with synaptic dysfunction/degeneration biomarkers like neurogranin and synaptosomal-associated protein 25.
Investigators compared the association between cerebrospinal fluid total tau and synaptic degeneration and axonal/neuronal degeneration biomarkers in cognitively unimpaired and impaired individuals. They found a stronger correlation between cerebrospinal fluid total tau and synaptic biomarkers than neurodegeneration biomarkers in both groups. Synaptic biomarkers explain a greater proportion of variance in cerebrospinal fluid total tau levels compared to neurodegeneration biomarkers. Notably, cerebrospinal fluid total tau levels are elevated in individuals with abnormalities only in synaptic biomarkers, but not in individuals with abnormalities only in neurodegeneration biomarkers.
Soares C, Bellaver B, Ferreira PCL, Povala G, Aguzzoli C, Ferrari-Souza JP, Zalzale H, Lussier FZ, Rohden F, Abbas S, Bauer-Negrini G, Leffa DT, Benedet AL, Langhough R, Betthauser TJ, Christian BT, Wilson RE, Tudorascu DL, Rosa-Neto P, Karikari TK, Zetterberg H, Blennow K, Zimmer ER, Johnson SC, Pascoal TA.
Nature Communications 16, 8076 (2025). https://doi.org/10.1038/s41467-025-63545-5
Older and Wiser? The Neural Correlates of Worry Induction and Reappraisal in Older Adults
Pathological worry (excessive, distressing, and pervasive worry) frequently occurs in mood and anxiety disorders. In late-life, pathological worry has been associated with health issues including elevated risk of cardiovascular disease, reduced gray matter volume, accelerated brain aging, increased depositions of cortical beta amyloid, and greater risk of cognitive decline. A group of investigators conducted a study to identify neuro-endophenotypes separating severe, pathological worry from mild worry processes in individuals age 50 and older. Participants completed a naturalistic worry induction and reappraisal task during functional magnetic resonance imaging (fMRI), and rated worry severity after each condition.
Results of the study showed that worry induction was associated with a complex network (including frontal medial areas, cingulate, supplemental motor area, visual processing areas, and basal ganglia and thalamus), while worry reappraisal was associated with a large network extended into multiple prefrontal and parietal regions. Regions associated with the frontoparietal executive control network differentiate between reappraisal and worry induction. Activity during worry induction clustered into a largely hyperactive compared to a largely hypoactive group; the hypoactive group exhibited higher reflection, lower in-scanner worry, and greater cumulative illness compared to hyperactive group.
Karim HT, Gross JJ, Mennin D, Gerlach A, Tudorascu DL, Butters MA, Ladouceur C, Andreescu C.
Neuropsychopharmacology. 50, 1949–1958 (2025). https://doi.org/10.1038/s41386-025-02193-1