TDP-43 Pathology Exacerbates Cognitive Decline in Primary Age-Related Tauopathy

Abstract

Objective: Primary age-related tauopathy (PART) refers to tau neurofibrillary tangles restricted largely to the medial temporal lobe in the absence of significant beta-amyloid plaques. PART has been associated with cognitive impairment, but contributions from concomitant limbic age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) are underappreciated.

Methods: We compare prevalence of LATE-NC and vascular copathologies in age- and Braak-matched patients with PART (n = 45, Braak stage I-IV, Thal phase 0-2) or early stage Alzheimer disease neuropathologic change (ADNC; n = 51, Braak I-IV, Thal 3-5), and examine their influence on clinical and cognitive decline.

Results: Concomitant LATE-NC and vascular pathology were equally common, and cognition was equally impaired, in PART (Mini-Mental State Examination [MMSE] = 24.8 ± 6.9) and ADNC (MMSE = 24.2 ± 6.0). Patients with LATE-NC were more impaired than those without LATE-NC on the MMSE (by 5.8 points, 95% confidence interval [CI] = 3.0-8.6), Mattis Dementia Rating Scale (DRS; 17.5 points, 95% CI = 7.1-27.9), Clinical Dementia Rating, sum of boxes scale (CDR-sob; 5.2 points, 95% CI = 2.1-8.2), memory composite (0.8 standard deviations [SD], 95% CI = 0.1-1.6), and language composite (1.1 SD, 95% CI = 0.2-2.0), and more likely to receive a dementia diagnosis (odds ratio = 4.8, 95% CI = 1.5-18.0). Those with vascular pathology performed worse than those without on the DRS (by 10.2 points, 95% CI = 0.1-20.3) and executive composite (1.3 SD, 95% CI = 0.3-2.3). Cognition declined similarly in PART and ADNC over the 5 years preceding death; however, LATE-NC was associated with more rapid decline on the MMSE (β = 1.9, 95% CI = 0.9-3.0), DRS (β = 7.8, 95% CI = 3.4-12.7), CDR-sob (β = 1.9, 95% CI = 0.4-3.7), language composite (β = 0.5 SD, 95% CI = 0.1-0.8), and vascular pathology with more rapid decline on the DRS (β = 5.2, 95% CI = 0.6-10.2).

Interpretation: LATE-NC, and to a lesser extent vascular copathology, exacerbate cognitive impairment and decline in PART and early stage ADNC. ANN NEUROL 2022;92:425-438.

Figure 1:. Comparative distributions of pathologies.

The distribution of Braak stages (A) and stages of concomitant LATE-NC pathology (B) did not differ between participants with PART and ADNC in our sample. However, those with relatively higher Braak stages (i.e. III-IV vs I-II) were more likely to have concomitant LATE-NC pathology (C), even in models adjusted for age and sex. In contrast, the number of concomitant ischemic vascular pathologies (tallied across infarcts, microinfarcts, and hemorrhages/microbleeds) did not differ between PART and ADNC (D), Braak stages (E), or presence of LATE-NC co-pathology (F).

Figure 2:. Clinical diagnoses of participants at the evaluation closest to autopsy by pathology.

The distributions of clinical diagnoses at the clinical evaluation closest to death presented in the participants divided by each of the four pathologic factors (A-D) suggests while there was no significant difference between individuals with PART vs ADNC and between those with vs without vascular pathology, individuals with higher Braak stages or concomitant LATE-NC were more likely to be demented prior to death. Since concomitant LATE-NC pathology is more likely among those with higher Braak stages (Figure 1C), we examined the interaction of those pathologies with regards to the diagnosis (D) and observed that either higher Braak stages, concomitant LATE-NC, or both appear to increase the likelihood of a dementia diagnosis compared to those with neither pathology. If the number of significant pathologic factors (tallied across higher Braak, concomitant LATE-NC, and concomitant Vascular) are examined by the final clinical diagnosis (F), we can see that those with dementia were far more likely (>75%) to have at least one of these pathologies compared to those with either MCI or Normal cognition (<50%).

Figure 3:. Cognitive performance at the evaluation closest to autopsy by pathologic factor

Cognitive performance of the participants at the evaluation closest to death is presented as a function of higher Braak stage (A), concomitant LATE-NC pathology (B), or concomitant vascular pathology (C) divided by group (i.e. PART vs ADNC). There were no significant differences in performance between PART and ADNC on any measures, and no significant interactions of the group term with each of the three other pathologic factors, suggesting that they produce similar effects on cognition across the groups. However, those with higher Braak stages performed worse on each of the three global cognitive measures (MMSE, DRS, CDR-sob), as well as the Memory cognitive composite. Similarly, those with concomitant LATE-NC pathology performed worse on the three global measures and both the Memory and Language composites. Those with concomitant vascular pathology declined more rapidly on the DRS. For effect sizes and p value please see Table 4.

Figure 4:. Rates of longitudinal cognitive decline prior to autopsy by pathologic factor

Trajectories of cognitive decline in the 5 years prior to autopsy of the participants are presented as a function of higher Braak stage (A), concomitant LATE-NC pathology (B), or concomitant vascular pathology (C) divided by group (i.e. PART vs ADNC). There were no significant differences in performance between PART and ADNC on any measures, and no significant interactions of the group term with each of the three other pathologic factors, suggesting that they produce similar effects on cognitive delcine across the groups. However, those with higher Braak stages declined more rapidly on the MMSE, CDR-sob, and the Memory composite. Similarly, those with concomitant LATE-NC pathology performed worse on all three global measures and the Language composite. Those with concomitant vascular pathology performed worse on the DRS and the Executive composite.