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

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 (ß = 1.9, 95% CI = 0.9-3.0), DRS (ß = 7.8, 95% CI = 3.4-12.7), CDR-sob (ß = 1.9, 95% CI = 0.4-3.7), language composite (ß = 0.5 SD, 95% CI = 0.1-0.8), and vascular pathology with more rapid decline on the DRS (ß = 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.

Neurodegenerative proteinopathies associated with neuroinfections.

Infectious agents, including viruses and bacteria, are proposed to be involved in the pathogenesis of Alzheimer's disease (AD). According to this hypothesis, these agents have capacity to evade the host immune system leading to chronic infection, inflammation, and subsequent deposition of Aß and phosphorylated-tau in the brain. Co-existing proteinopathies and age-related pathologies are common in AD and the brains of elderly individuals, but whether these are also related to neuroinfections remain to be established. This study determined the prevalence and distribution of neurodegenerative proteinopathies in patients with infection-induced acute or chronic inflammation associated with herpes simplex virus (HSV) encephalitis (n = 13) and neurosyphilis (n = 23). The mean age at death in HSV patients was 53 ± 12 years (range 24-65 years) and survival was 9 days-6 years following initial infection. The mean age at death and survival in neurosyphilis patients was 60 ± 15 years (range 36-86 years) and 1-5 years, respectively. Neuronal tau-immunoreactivity and neurites were observed in 8 HSV patients and 19 neurosyphilis patients, and in approximately half of these, this was found in regions associated with inflammation and expanding beyond regions expected from the Braak stage of neurofibrillary degeneration. Five neurosyphilis patients had cortical ageing-related tau astrogliopathy. Aß-plaques were found in 4 HSV patients and 11 neurosyphilis patients. Lewy bodies were observed in one HSV patient and two neurosyphilis patients. TDP-43 pathology was absent. These observations provide insights into deposition of neurodegenerative proteins in neuroinfections, which might have implications for COVID-19 patients with chronic and/or post-infectious neurological symptoms and encephalitis.