Associations between cerebrospinal fluid markers and cognition in ageing and dementia: A systematic review.

A biomarker associated with cognition in neurodegenerative dementias would aid in the early detection of disease progression, complement clinical staging and act as a surrogate endpoint in clinical trials. The current systematic review evaluates the association between cerebrospinal fluid protein markers of synapse loss and neuronal injury and cognition. We performed a systematic search which revealed 67 studies reporting an association between cerebrospinal fluid markers of interest and neuropsychological performance. Despite the substantial heterogeneity between studies, we found some evidence for an association between neurofilament-light and worse cognition in Alzheimer's diseases, frontotemporal dementia and typical cognitive ageing. Moreover, there was an association between cerebrospinal fluid neurogranin and cognition in those with an Alzheimer's-like cerebrospinal fluid biomarker profile. Some evidence was found for cerebrospinal fluid neuronal pentraxin-2 as a correlate of cognition across dementia syndromes. Due to the substantial heterogeneity of the field, no firm conclusions can be drawn from this review. Future research should focus on improving standardization and reporting as well as establishing the importance of novel markers such as neuronal pentraxin-2 and whether such markers can predict longitudinal cognitive decline.

Predictive blood biomarkers and brain changes associated with age-related cognitive decline.

Growing evidence supports the use of plasma levels of tau phosphorylated at threonine 181, amyloid-ß, neurofilament light and glial fibrillary acidic protein as promising biomarkers for Alzheimer's disease. While these blood biomarkers are promising for distinguishing people with Alzheimer's disease from healthy controls, their predictive validity for age-related cognitive decline without dementia remains unclear. Further, while tau phosphorylated at threonine 181 is a promising biomarker, the distribution of this phospho-epitope of tau in the brain is unknown. Here, we tested whether plasma levels of tau phosphorylated at threonine 181, amyloid-ß, neurofilament light and fibrillary acidic protein predict cognitive decline between ages 72 and 82 in 195 participants in the Lothian birth cohorts 1936 study of cognitive ageing. We further examined post-mortem brain samples from temporal cortex to determine the distribution of tau phosphorylated at threonine 181 in the brain. Several forms of tau phosphorylated at threonine 181 have been shown to contribute to synapse degeneration in Alzheimer's disease, which correlates closely with cognitive decline in this form of dementia, but to date, there have not been investigations of whether tau phosphorylated at threonine 181 is found in synapses in Alzheimer's disease or healthy ageing brain. It was also previously unclear whether tau phosphorylated at threonine 181 accumulated in dystrophic neurites around plaques, which could contribute to tau leakage to the periphery due to impaired membrane integrity in dystrophies. Brain homogenate and biochemically enriched synaptic fractions were examined with western blot to examine tau phosphorylated at threonine 181 levels between groups (n = 10-12 per group), and synaptic and astrocytic localization of tau phosphorylated at threonine 181 were examined using array tomography (n = 6-15 per group), and localization of tau phosphorylated at threonine 181 in plaque-associated dystrophic neurites with associated gliosis were examined with standard immunofluorescence (n = 8-9 per group). Elevated baseline plasma tau phosphorylated at threonine 181, neurofilament light and fibrillary acidic protein predicted steeper general cognitive decline during ageing. Further, increasing tau phosphorylated at threonine 181 over time predicted general cognitive decline in females only. Change in plasma tau phosphorylated at threonine 181 remained a significant predictor of g factor decline when taking into account Alzheimer's disease polygenic risk score, indicating that the increase of blood tau phosphorylated at threonine 181 in this cohort was not only due to incipient Alzheimer's disease. Tau phosphorylated at threonine 181 was observed in synapses and astrocytes in both healthy ageing and Alzheimer's disease brain. We observed that a significantly higher proportion of synapses contain tau phosphorylated at threonine 181 in Alzheimer's disease relative to aged controls. Aged controls with pre-morbid lifetime cognitive resilience had significantly more tau phosphorylated at threonine 181 in fibrillary acidic protein-positive astrocytes than those with pre-morbid lifetime cognitive decline. Further, tau phosphorylated at threonine 181 was found in dystrophic neurites around plaques and in some neurofibrillary tangles. The presence of tau phosphorylated at threonine 181 in plaque-associated dystrophies may be a source of leakage of tau out of neurons that eventually enters the blood. Together, these data indicate that plasma tau phosphorylated at threonine 181, neurofilament light and fibrillary acidic protein may be useful biomarkers of age-related cognitive decline, and that efficient clearance of tau phosphorylated at threonine 181 by astrocytes may promote cognitive resilience.

Interactions between apolipoprotein E, sex, and amyloid-beta on cerebrospinal fluid p-tau levels in the European prevention of Alzheimer's dementia longitudinal cohort study (EPAD LCS).

BACKGROUND: Alzheimer's Disease, the leading cause of dementia, is over-represented in females. The apolipoprotein E (APOE)ε4 allele is the strongest genetic risk factor for late-onset AD and is associated with aberrant cerebrospinal fluid levels (CSF) of total tau (t-tau), phosphorylated tau (p-tau), and amyloid-ß (Aß). There is some evidence that sex may mediate the relationship between APOE status and CSF tau, however, evidence is mixed. METHODS: We aimed to examine the interaction between sex, APOE ε4 status, CSF Aß on t-tau and p-tau in 1599 mid-to-late life individuals without a diagnosis of dementia in the European Prevention of Alzheimer's Dementia (EPAD) longitudinal cohort study. FINDINGS: We found a significant interaction between APOE status, sex, and CSF Aß on CSF p-tau levels (ß = 0·18, p = 0·04). Specifically, there was a stronger association between APOE status and CSF Aß42 on CSF p-tau in males compared to females. Further, in females with high Aß levels (reflecting less cortical deposition), ε4 carriers had significantly elevated p-tau levels relative to non-carriers (W = 39663, p = 0·01). However, there were no significant differences in p-tau between male ε4 carriers and non-carriers with high Aß (W = 23523, p = 0·64). INTERPRETATION: An interaction between sex and cerebrospinal fluid Aß may mediate the relationship between APOE status and CSF p-tau. These data suggest tau accumulation may be independent of Aß in females, but not males. FUNDING: Innovative Medicines Initiative, Swedish Research Council, Alzheimer Drug Discovery Foundation, Swedish Alzheimer Foundation, the Swedish state under the agreement between the Swedish government and the County Councils: the ALF-agreement, and the Alzheimer's Association 2021 Zenith Award.

Pituitary volume in individuals at elevated risk for psychosis: A systematic review and meta-analysis.

BACKGROUND: Pituitary volume (PV) abnormalities, representing one of several markers of hypothalamic-pituitary-adrenal (HPA) axis dysregulation, have been observed in psychosis, with variable patterns across illness stages. Typically, enlargements characterise first-episode patients, with reductions observed in those with chronic illness relative to healthy controls. Findings in high-risk populations have been inconsistent, highlighting the need for an updated review of the evidence. METHODS: We searched PubMed, PsycINFO, and EMBASE for studies examining PV in high-risk [clinical high-risk (CHR), family history of psychosis (FHx), schizotypal personality disorder (SPD), and psychotic-experiences (PEs)] and healthy individuals. Random effects models were used to examine group differences in PV (Hedges g) with stratified analyses and meta-regression employed to investigate the effect of high-risk category, transition status, age, sex, and antipsychotic medication. RESULTS: Ten studies, yielding 11 effect sizes, were eligible for inclusion. Overall, high-risk individuals had significantly larger PV relative to healthy controls (g = 0.16 [95% CI: 0.01 to 0.32] p = 0.04), despite showing a reduction in whole brain volume (g = -0.17, [95% CI. -0.30 to -0.03] p = 0.020). Individual sub-group analyses for CHR and FHx groups showed no significant differences relative to controls; however, larger PV increases characterised those who later transitioned to psychosis (g = 0.55, [95% CI. 0.06 to 1.04] p = 0.028). Larger effect sizes were positively associated with the proportion of high-risk individuals receiving antipsychotic medication. CONCLUSIONS: PV enlargements characterise high-risk individuals and are more pronounced among those who later develop psychosis. We provide recommendations for future studies.