Limbic-predominant age-related TDP-43 encephalopathy in the oldest old: a population-based study.

Population-based cohort studies are essential for understanding the pathological basis of dementia in older populations. Previous studies have shown that limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) increases with age, but there have been only a few studies, which have investigated this entity in a population-based setting. Here we studied the frequency of LATE-NC and its associations with other brain pathologies and cognition in a population aged ≥ 85 years. The population-based Vantaa 85+ study cohort includes all 601 individuals aged ≥ 85 years who were living in Vantaa, Finland in 1991. A neuropathological examination was performed on 304 subjects (50.5%) and LATE-NC staging was possible in 295 of those. Dementia status and Mini-Mental State Examination (MMSE) scores were defined in the baseline study and 3 follow-ups (1994-99). The LATE-NC stages were determined based on TDP-43 immunohistochemistry, according to recently updated recommendations. Arteriolosclerosis was digitally assessed by calculating the average sclerotic index of five random small arterioles in amygdala and hippocampal regions, and frontal white matter. The association of LATE-NC with arteriolosclerosis and previously determined neuropathological variables including Alzheimer's disease neuropathological change (ADNC), Lewy-related pathology (LRP), hippocampal sclerosis (HS), and cerebral amyloid angiopathy (CAA), and cognitive variables were analysed by Fisher's exact test, linear and logistic regression (univariate and multivariate) models. LATE-NC was found in 189 of 295 subjects (64.1%). Stage 2 was the most common (28.5%) and stage 3 the second most common (12.9%), whereas stages 1a, 1b and 1c were less common (9.5%, 5.1% and 8.1%, respectively). Stages 1a (P < 0.01), 2 (P < 0.001) and 3 (P < 0.001) were significantly associated with dementia and lower MMSE scores. LATE-NC was associated with ADNC (P < 0.001), HS (P < 0.001), diffuse neocortical LRP (P < 0.002), and arteriolosclerosis in amygdala (P < 0.02). In most cases LATE-NC occurred in combination alongside other neuropathological changes. There were only six subjects with dementia who had LATE-NC without high levels of ADNC or LRP (2% of the cohort, 3% of the cases with dementia), and five of these had HS. In all multivariate models, LATE-NC was among the strongest independent predictors of dementia. When LATE-NC and ADNC were assessed in a multivariate model without other dementia-associated pathologies, the attributable risk was higher for LATE-NC than ADNC (24.2% vs. 18.6%). This population-based study provides evidence that LATE-NC is very common and one of the most significant determinants of dementia in the general late-life aged population.

Accumulation of Lewy-Related Pathology Starts in Middle Age: The Tampere Sudden Death Study.

When effective treatments against neurodegenerative diseases become a reality, it will be important to know the age these pathologies begin to develop. We investigated alpha-synuclein pathology in brain tissue of the Tampere Sudden Death Study-unselected forensic autopsies on individuals living outside hospital institutions in Finland. Of 562 (16-95 years) participants, 42 were positive for Lewy-related pathology (LRP). The youngest LRP case was aged 54 years, and the frequency of LRP in individuals aged ≥50 years was 9%. This forensic autopsy study indicates LRP starts already in middle age and is more common than expected in the ≥50 years-of-age non-hospitalized population. ANN NEUROL 2024;95:843-848.

A postmortem study suggests a revision of the dual-hit hypothesis of Parkinson's disease.

The dual-hit hypothesis of Parkinson's disease (PD) originally postulated that a neurotropic pathogen leads to formation of α-synuclein pathology in the olfactory bulb (OB) and dorsal motor nucleus of the vagus (DMV) and then invades the brain from these two entry points. Little work has been conducted to validate an important underlying premise for the dual-hit hypothesis, namely that the initial Lewy pathology does arise simultaneously in the OB and the enteric nervous system (ENS) plexuses and DMV at the earliest disease stage. We conducted a focused re-analysis of two postmortem datasets, which included large numbers of mild Lewy body disease (LBD) cases. We found that cases with α-synuclein pathology restricted to the peripheral autonomic nervous system and/or lower brainstem (early body-first LBD cases) very rarely had any OB pathology, suggesting that Lewy pathology commonly arises in the ENS without concomitant involvement of the OB. In contrast, cases with mild amygdala-predominant Lewy pathology (early brain-first LBD cases) nearly always showed OB pathology. This is compatible with the first pathology being triggered in the OB or amygdala followed by secondary spreading to connected structures, but without early involvement of the ENS or lower brainstem. These observations support that the pathologic process starts in either the olfactory bulb or the ENS, but rarely in the olfactory bulb and gut simultaneously. More studies on neuropathological datasets are warranted to reproduce these findings. The agreement between the revised single-hit hypothesis and the recently proposed brain-first vs. body-first model of LBD is discussed.

HSV presence in brains of individuals without dementia: the TASTY brain series.

Herpes simplex virus (HSV) type 1 affects a majority of the population and recent evidence suggests involvement in Alzheimer's disease aetiology. We investigated the prevalence of HSV type 1 and 2 in the Tampere Autopsy Study (TASTY) brain samples using PCR and sero-positivity in plasma, and associations with Alzheimer's disease neuropathology. HSV was shown to be present in human brain tissue in 11/584 (1.9%) of samples in the TASTY cohort, of which six had Alzheimer's disease neuropathological amyloid beta (Aß) aggregations. Additionally, serological data revealed 86% of serum samples tested were IgG-positive for HSV. In conclusion, we report epidemiological evidence of the presence of HSV in brain tissue free from encephalitis symptoms in a cohort most closely representing the general population (a minimum prevalence of 1.9%). Whereas 6/11 samples with HSV DNA in the brain tissue had Aß aggregations, most of those with Aß aggregations did not have HSV present in the brain tissue.

Beer Drinking Associates with Lower Burden of Amyloid Beta Aggregation in the Brain: Helsinki Sudden Death Series.

BACKGROUND: Controversy surrounds the effect of alcohol consumption on the development of dementia and cognitive impairment. We investigated the association between consumption of different alcoholic beverages and ß-amyloid (Aß) aggregation in the brain, 1 of the neuropathological lesions of Alzheimer's disease. METHODS: In total, 125 males of the Helsinki Sudden Death autopsy Series were included with an age range at death 35 to 70 years. The consumption of alcohol, Aß aggregation in the brain, and Apolipoprotein E (APOE) genotype were assessed. Relatives answered a questionnaire to gather alcohol consumption history, and Aß was visualized by implementing immunohistochemical staining of brain sections. Aß immunoreactivity (IR) was assessed in a dichotomized (yes/no) fashion and as a stained area fraction (%). APOE genotype was assessed in DNA extracted from paraffin-embedded cardiac muscle samples. RESULTS: Increased age (p = 0.001; odds ratio [OR] = 1.09, confidence interval [CI] = 1.04 to 1.15) was associated with higher prevalence of Aß-IR. Beer drinking decreased (p = 0.024; OR = 0.35, CI = 0.14 to 0.87) the prevalence of Aß-IR and was associated with a significantly lower extent of Aß-IR (p = 0.022). The amount of alcohol consumed was not linked with Aß aggregation and neither was spirit nor wine consumption. CONCLUSIONS: Beer consumption may protect against Aß aggregation in brain. Further studies are necessary to fully understand the effects of alcohol on Aß pathology seen in brain tissue.

CLU, CR1 and PICALM genes associate with Alzheimer's-related senile plaques.

INTRODUCTION: APOE is the strongest risk gene for sporadic Alzheimer's disease (AD) so far. Recent genome wide association studies found links for sporadic AD with CLU and CR1 involved in Aß clearance, and PICALM affecting intracellular trafficking. METHODS: We investigated the associations of senile plaques (SP) and neurofibrillary tangles (NFT) with the proposed risk genes and APOE, in the Tampere Autopsy Study (TASTY) series (603 cases), a sample of the general population (0 to 97 yrs), who died out-of-hospital. RESULTS: Age and the APOEε4 allele associated strongly with all phenotypes of SP, as expected. In age and APOEε4 adjusted analyses, compared to the most common homozygous genotype, burnt out SP were more common among carriers of the C-allele of CLU, whereas the T-allele of PICALM and C-allele of CR1 were linked with lower SP coverage. We found no significant associations between any of the genetic variants and NFT. CONCLUSIONS: Marginal effects from CLU, CR1 and PICALM suggest that these genes have minimal effects on the development of AD lesions.