Herpes simplex virus and rates of cognitive decline or whole brain atrophy in the Dominantly Inherited Alzheimer Network.

OBJECTIVE: To investigate whether herpes simplex virus type 1 (HSV-1) infection was associated with rates of cognitive decline or whole brain atrophy among individuals from the Dominantly Inherited Alzheimer Network (DIAN). METHODS: Among two subsets of the DIAN cohort (age range 19.6-66.6 years; median follow-up 3.0 years) we examined (i) rate of cognitive decline (N = 164) using change in mini-mental state examination (MMSE) score, (ii) rate of whole brain atrophy (N = 149), derived from serial MR imaging, calculated using the boundary shift integral (BSI) method. HSV-1 antibodies were assayed in baseline sera collected from 2009-2015. Linear mixed-effects models were used to compare outcomes by HSV-1 seropositivity and high HSV-1 IgG titres/IgM status. RESULTS: There was no association between baseline HSV-1 seropositivity and rates of cognitive decline or whole brain atrophy. Having high HSV-1 IgG titres/IgM was associated with a slightly greater decline in MMSE points per year (difference in slope - 0.365, 95% CI: -0.958 to -0.072), but not with rate of whole brain atrophy. Symptomatic mutation carriers declined fastest on both MMSE and BSI measures, however, this was not influenced by HSV-1. Among asymptomatic mutation carriers, rates of decline on MMSE and BSI were slightly greater among those who were HSV-1 seronegative. Among mutation-negative individuals, no differences were seen by HSV-1. Stratifying by APOE4 status yielded inconsistent results. INTERPRETATION: We found no evidence for a major role of HSV-1, measured by serum antibodies, in cognitive decline or whole brain atrophy among individuals at high risk of early-onset AD.

No evidence that herpes zoster is associated with increased risk of dementia diagnosis.

OBJECTIVE: To investigate whether herpes zoster (HZ) was associated with subsequent increased risk of dementia diagnosis. METHODS: We conducted a historical cohort study using primary care electronic health records from the Clinical Practice Research Datalink in the United Kingdom. Individuals with incident HZ aged ≥40 years from 2000 to 2017 were matched with up to four individuals without HZ by age, sex, primary care practise and calendar time. The primary outcome was a new diagnosis of all-cause dementia. We used the Cox proportional hazards regression adjusting for demographic, lifestyle and clinical confounders to assess any association between HZ and dementia. We investigated interactions with sex, frailty index and antiviral treatment and conducted various sensitivity analyses. RESULTS: The cohort comprised 177,144 individuals with HZ and 706,901 matched unexposed individuals (median age 65 years (IQR 55.1-75.0), 40% male) followed for a median duration of 4.6 years (IQR 2.0-8.1). In total, 26,585 (3%) patients had an incident dementia diagnosis recorded and 113,056 patients died (12.8%). HZ was associated with a small reduction in dementia diagnosis (adjusted HR 0.92 (95% CI 0.89-0.95)), occurring predominantly in frail individuals and females. For patients who were fit (578,115, 65%), no association was seen (adjusted HR 0.97, 95% CI 0.92-1.02). There was no association between HZ and a composite outcome of dementia or death (adjusted HR 1.00, 95% CI 0.99-1.02). Dementia risk did not vary by prescription of antiviral agents. Sensitivity analyses showed consistent results. INTERPRETATION: HZ was not associated with increased dementia diagnosis in a UK primary care-based cohort.

Viral population analysis and minority-variant detection using short read next-generation sequencing.

RNA viruses within infected individuals exist as a population of evolutionary-related variants. Owing to evolutionary change affecting the constitution of this population, the frequency and/or occurrence of individual viral variants can show marked or subtle fluctuations. Since the development of massively parallel sequencing platforms, such viral populations can now be investigated to unprecedented resolution. A critical problem with such analyses is the presence of sequencing-related errors that obscure the identification of true biological variants present at low frequency. Here, we report the development and assessment of the Quality Assessment of Short Read (QUASR) Pipeline (http://sourceforge.net/projects/quasr) specific for virus genome short read analysis that minimizes sequencing errors from multiple deep-sequencing platforms, and enables post-mapping analysis of the minority variants within the viral population. QUASR significantly reduces the error-related noise in deep-sequencing datasets, resulting in increased mapping accuracy and reduction of erroneous mutations. Using QUASR, we have determined influenza virus genome dynamics in sequential samples from an in vitro evolution of 2009 pandemic H1N1 (A/H1N1/09) influenza from samples sequenced on both the Roche 454 GSFLX and Illumina GAIIx platforms. Importantly, concordance between the 454 and Illumina sequencing allowed unambiguous minority-variant detection and accurate determination of virus population turnover in vitro.