Cardoso T. Risk of dementia in bipolar disorder and the interplay of lithium: a systematic review and meta-analyses.Objectives: To assess whether bipolar disorder (BD) increases the rate of dementia and whether lithium is related to a lower risk of dementia in BD. Methods: A total of 10 studies (6859 BD; 487 966 controls) were included in the meta-analysis to test whether BD is a risk factor for dementia. In addition, five studies (6483 lithium; 43 496 non-lithium) were included in the meta-analysis about the potential protective effect of lithium in BD. Results: BD increases the risk of dementia (odds ratio (OR): 2.96 [95% CI: 2.09-4.18], P < 0.001), and treatment with lithium decreases the risk of dementia in BD (OR: 0.51 [95% CI: 0.36-0.72], P < 0.0001). In addition, secondary findings from our systematic review showed that the risk of progression to dementia is higher in BD than in major depressive disorder (MDD). Moreover, the number of mood episodes predicted the development of dementia in BD. Conclusion: Individuals with BD are at higher risk of dementia than both the general population or those with MDD. Lithium appears to reduce the risk of developing dementia in BD.• The diagnosis of bipolar disorder increases the risk to develop dementia almost three-fold.• Treatment with lithium decreased the risk for dementia by 49% in individuals with bipolar disorder compared to controls/non-lithium treated people with BD.• Dementia can be seen as an endpoint of bipolar disorder staging model. Limitations• There is a possibility that publication bias may have potentially inflated our results.• The majority of the evidence comes from registry-based studies that have several limitations such as data collection, reliability of diagnosis, selection bias, and confounders.• Additional studies are needed to understand the pathophysiology of BD that leads to cognitive deterioration, brain abnormalities, and to the development of dementia. 510

Background: Approximately a third of frontotemporal dementia (FTD) is genetic with mutations in three genes accounting for most of the inheritance: C9orf72, GRN and MAPT. Impaired synaptic health is a common mechanism in all three genetic variants and so developing fluid biomarkers of this process could be useful as a readout of cellular dysfunction within therapeutic trials.Methods: A total of 193 cerebrospinal fluid (CSF) samples from the GENetic FTD Initiative including 77 presymptomatic (31 C9orf72, 23 GRN, 23 MAPT) and 55 symptomatic (26 C9orf72, 17 GRN, 12 MAPT) mutation carriers as well as 61 mutation-negative controls were measured using a microflow LC PRM-MS set-up targeting 15 synaptic proteins: AP-2 complex subunit beta, complexin-2, beta-synuclein, gamma-synuclein, 14-3-3 proteins (eta, epsilon, zeta/delta), neurogranin, Rab GDP dissociation inhibitor alpha (Rab GDI alpha), syntaxin-1B, syntaxin-7, phosphatidylethanolamine-binding protein 1 (PEBP-1), neuronal pentraxin receptor (NPTXR), neuronal pentraxin 1 (NPTX1), and neuronal pentraxin 2 (NPTX2). Mutation carrier groups were compared to each other and to controls using a bootstrapped linear regression model, adjusting for age and sex. Results: CSF levels of eight proteins were increased only in symptomatic MAPT mutation carriers (compared with controls) and not in symptomatic C9orf72 or GRN mutation carriers: beta-synuclein, gamma-synuclein, 14-3-3-eta, neurogranin, Rab GDI alpha, syntaxin-1B, syntaxin-7, and PEBP-1, with three other proteins increased in MAPT mutation carriers compared with the other genetic groups (AP-2 complex subunit beta, complexin-2, and 14-3-3 proteins zeta/delta). In contrast, CSF NPTX1 and NPTX2 levels were affected in all three genetic groups (decreased compared with controls), with NPTXR concentrations being affected in C9orf72 and GRN mutation carriers only (decreased compared with controls). No changes were seen in the CSF levels of these proteins in presymptomatic mutation carriers. Concentrations of the neuronal pentraxins were correlated with brain volumes in the presymptomatic period for C9orf72 and GRN groups, suggesting that they become abnormal in proximity to symptom onset.Conclusions: Differential synaptic impairment is seen in the genetic forms of FTD, with abnormalities in multiple measures in those with MAPT mutations, but only changes in neuronal pentraxins within the GRN and C9orf72 mutation groups. Such markers may be useful in future trials as measures of synaptic dysfunction, but further work is needed to understand how these markers change throughout the course of the disease.

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