Tau maturation in the clinicopathological spectrum of Lewy body and Alzheimer's disease.

OBJECTIVE: Alzheimer's disease neuropathologic change and alpha-synucleinopathy commonly co-exist and contribute to the clinical heterogeneity of dementia. Here, we examined tau epitopes marking various stages of tangle maturation to test the hypotheses that tau maturation is more strongly associated with beta-amyloid compared to alpha-synuclein, and within the context of mixed pathology, mature tau is linked to Alzheimer's disease clinical phenotype and negatively associated with Lewy body dementia. METHODS: We used digital histology to measure percent area-occupied by pathology in cortical regions among individuals with pure Alzheimer's disease neuropathologic change, pure alpha-synucleinopathy, and a co-pathology group with both Alzheimer's and alpha-synuclein pathologic diagnoses. Multiple tau monoclonal antibodies were used to detect early (AT8, MC1) and mature (TauC3) epitopes of tangle progression. We used linear/logistic regression to compare groups and test the association between pathologies and clinical features. RESULTS: There were lower levels of tau pathology (ß = 1.86-2.96, p < 0.001) across all tau antibodies in the co-pathology group compared to the pure Alzheimer's pathology group. Among individuals with alpha-synucleinopathy, higher alpha-synuclein was associated with greater early tau (AT8 ß = 1.37, p < 0.001; MC1 ß = 1.2, p < 0.001) but not mature tau (TauC3 p = 0.18), whereas mature tau was associated with beta-amyloid (ß = 0.21, p = 0.01). Finally, lower tau, particularly TauC3 pathology, was associated with lower frequency of both core clinical features and categorical clinical diagnosis of dementia with Lewy bodies. INTERPRETATION: Mature tau may be more closely related to beta-amyloidosis than alpha-synucleinopathy, and pathophysiological processes of tangle maturation may influence the clinical features of dementia in mixed Lewy-Alzheimer's pathology.

Neuroanatomical and cellular degeneration associated with a social disorder characterized by new ritualistic belief systems in a TDP-C patient vs. a Pick patient.

Frontotemporal dementia (FTD) is a spectrum of clinically and pathologically heterogenous neurodegenerative dementias. Clinical and anatomical variants of FTD have been described and associated with underlying frontotemporal lobar degeneration (FTLD) pathology, including tauopathies (FTLD-tau) or TDP-43 proteinopathies (FTLD-TDP). FTD patients with predominant degeneration of anterior temporal cortices often develop a language disorder of semantic knowledge loss and/or a social disorder often characterized by compulsive rituals and belief systems corresponding to predominant left or right hemisphere involvement, respectively. The neural substrates of these complex social disorders remain unclear. Here, we present a comparative imaging and postmortem study of two patients, one with FTLD-TDP (subtype C) and one with FTLD-tau (subtype Pick disease), who both developed new rigid belief systems. The FTLD-TDP patient developed a complex set of values centered on positivity and associated with specific physical and behavioral features of pigs, while the FTLD-tau patient developed compulsive, goal-directed behaviors related to general themes of positivity and spirituality. Neuroimaging showed left-predominant temporal atrophy in the FTLD-TDP patient and right-predominant frontotemporal atrophy in the FTLD-tau patient. Consistent with antemortem cortical atrophy, histopathologic examinations revealed severe loss of neurons and myelin predominantly in the anterior temporal lobes of both patients, but the FTLD-tau patient showed more bilateral, dorsolateral involvement featuring greater pathology and loss of projection neurons and deep white matter. These findings highlight that the regions within and connected to anterior temporal lobes may have differential vulnerability to distinct FTLD proteinopathies and serve important roles in human belief systems.

Thinking of Me or Thinking of You? Behavioral Correlates of Self vs. Other Centered Worry and Reappraisal in Late-Life.

Psychotherapeutic approaches in late-life anxiety have limited effect on reducing worry severity. The self-referential processing of worry contents (self- vs. other-focused worry) and reappraisal styles (internal vs. external locus of control) are important elements in psychotherapy, but little is known about these processes in late-life. We aimed to characterize severe worry from a self-referential processing perspective. We recruited 104 older adults with various levels of worry and used a personalized task to induce and reappraise worry. We analyzed the association between (1) worry severity/frequency for worry content (self- or other-focused) and (2) for reappraisal style (internal vs. external locus of control) with clinical inventories measuring anxiety, worry, depression, rumination, neuroticism, emotion regulation strategies, perceived stress, and physical illness burden. Higher self-worry severity was associated with higher scores of clinical inventories of worry, depression, perceived stress, and neuroticism, whereas other-worry severity did not show any association. Greater self-worry frequency was associated with higher medical burden. External locus of control in reappraisal statements was associated with lower worry severity in men. Overall, more severe and frequent self-focused worry was associated with a greater psychological and physiological burden. These results are useful in tailoring psychotherapy for older adults with severe worry.