Alberto Rábano

The amygdaloid complex is one of the most structurally and functionally heterogeneous regions of the mammalian brain, acting as an integrative node between sensory, mnemonic and visceral systems. It comprises a set of subnuclei whose cytoarchitectural differentiation, neurochemical profiles and anatomical boundaries have been debated since the earliest descriptions. This heterogeneity is established during ontogenetic development, assembling progenitors from pallial and subpallial domains, and preoptic and hypothalamic territories, resulting in a highly connected network. Maturation is not complete at birth, the amygdala changes through childhood and adolescence, leaving a protracted window of environmental sensitivity. Single-nucleus RNA sequencing and spatial transcriptomics have added a molecular layer to this framework, resolving populations that no single marker separates, and set explicit limits on the resolution at which rodent-derived subdivisions can be transferred to the human amygdala. Together these levels of description provide a structural framework for understanding its functions, which include emotional regulation and conditioned fear, social and sexual behaviours, decision-making, reward and punishment processing, empathy and memory modulation. Cross-species comparison reveals further variation, particularly the expansion of the basolateral complex in primates and the redistribution of neurons towards the lateral nucleus in humans. In summary, the amygdala acts as a densely connected hub with a broad role not only in physiological and psychological health but also in disease states; indeed, the amygdala is affected early in several neurodegenerative disorders, and in some (notably limbic-predominant age-related TDP-43 encephalopathy and argyrophilic grain disease) it is among the first regions in which pathology is detected.

Blood-based biomarkers are emerging as scalable tools for the diagnosis and monitoring of neurodegenerative diseases, but markers enabling differential diagnosis across major dementias remain limited. Here we show that large-scale plasma proteomics identifies disease-associated signatures across Alzheimer’s disease, dementia with Lewy bodies and frontotemporal dementia. We analyzed 1,318 plasma samples from well-characterized international cohorts and identified more than 200 dysregulated proteins across disease groups. Glial fibrillary acidic protein showed the strongest increase along the Alzheimer’s disease continuum, whereas integrin alpha-V and integrin alpha-M were consistently reduced in Lewy body disorders, including autopsy-confirmed cases. Elevated neurofilament light chain and lower glial fibrillary acidic protein were associated with frontotemporal dementia. We translated these findings into a 21-protein quantitative multiplex panel and validated it in an independent multicenter cohort ( n = 805). These findings support plasma proteomics as an approach for biomarker-based differential diagnosis and disease staging across major neurodegenerative dementias.

Huntington’s disease has traditionally been considered a motor disorder, but it is currently classified as a multisystem neurodegenerative disease that involves brain regions, such as the amygdala, and causes depression. The aim of the present study was to analyse the distribution of huntingtin in the human amygdaloid basolateral complex, considering its nuclei, sex, triplet repeats and Vonsattel score, as well as to characterize the cellular relationships between huntingtin and associated copathologies. The present study included 23 human brain samples from patients (males and females) with and without Huntington’s disease, Parkinson’s disease and Alzheimer’s disease. An unbiased stereology approach was used to quantify huntingtin deposits. Multiple immunofluorescence experiments were conducted to analyse the relationship between huntingtin and glial populations. Immunohistochemistry against pathological markers of other neurodegenerative diseases was also carried out. Quantification data did not reveal differences among different nuclei (basomedial, basolateral or lateral) in the basolateral complex or according to sex. Huntingtin deposits did not correlate with cytosine–adenine–guanine (CAG) repeats. However, these deposits were positively correlated with pathological Vonsattel grades. Additional aggregates of other pathological proteinopathies were also observed. This correlation between the human basolateral amygdaloid complex and the Vonsattel stage provides a new perspective for neuropathological diagnosis and helps in understanding nonmotor symptoms such as depression.

Progressive supranuclear palsy (PSP) is a rare 4-repeat tauopathy that causes behavioural, movement and cognitive abnormalities. We genotyped all available clinical and histopathological PSP cases in Spain and Portugal (N = 522), and conducted the largest PSP GWAS of the Iberian population to date. Genetic burden analysis revealed reduced diagnostic specificity in clinically diagnosed atypical PSP cases—when applying the 2017 MDS criteria—compared to Richardson’s syndrome cases. We independently replicated eight PSP risk variants in seven known loci (MAPT, MOBP, EIF2AK3, STX6, SLCO1A2, DUSP10 and APOE), and identified a novel locus in NFASC/CNTN2 (rs12744678 C: OR[95%CI] = 0.83[0.78–0.89]; p = 4.15·10⁻⁰⁸) after meta-analysis with a newly available Dutch cohort and publicly available summary statistics (3,099 PSP; 11,482 controls). Enrichment analysis and protein expression profiling highlighted oligodendrocyte function and myelination as likely contributors to PSP pathogenesis. Our findings broaden the genetic landscape of PSP and suggest potential therapeutic avenues focused on modulating neuron–oligodendrocyte interactions.

Plasma biomarkers are emerging as noninvasive tools to detect neurodegenerative diseases and monitor treatments in clinical trials. The bPRIDE study investigates blood-based biomarkers to improve the differential diagnosis and molecular staging of Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD). Using proximity extension assay proteomics, we analyzed n=1319 plasma samples from 6 well-characterized cohorts. More than 200 proteins were found dysregulated across the different groups. Levels of GFAP showed the most substantial increase along AD clinical continuum. Levels of Integrin proteins ITGAV and ITGAM were the strongest downregulated proteins in Lewy body disorders and correlated with α-synuclein pathology in an independent autopsy-confirmed cohort (n=129). High NEFL and low GFAP levels were the strongest markers specifically associated to FTD. Findings were translated into a selection of 21 proteins to enable classification and staging models across different causes of dementia with high diagnostic performances within one single assay.

DOPA Decarboxylase (DDC) has been proposed as a cerebrospinal fluid (CSF) biomarker with increased concentrations in Lewy body disorders (LBDs) and highest levels in patients receiving dopaminergic treatment. Here we evaluate plasma DDC, measured by proximity extension assay, and the effect of dopaminergic treatment in three independent LBD (with a focus on dementia with Lewy bodies (DLB) and Parkinson’s disease (PD)) cohorts: an autopsy-confirmed cohort (n = 71), a large multicenter, cross-dementia cohort (n = 1498) and a longitudinal cohort with detailed treatment information (n = 66, median follow-up time[IQR] = 4[4, 4] years). Plasma DDC was not altered between different LBDs and other disease groups or controls in absence of treatment. DDC levels increased over time in PD, being significantly associated to higher dosages of dopaminergic treatment. This emphasizes the need to consider treatment effect when analyzing plasma DDC, and suggests that plasma DDC, in contrast to CSF DDC, is of limited use as a diagnostic biomarker for LBD, but could be valuable for treatment monitoring.

Background/Objectives: Clinicopathological research in late-life dementia has focused recently on combined neurodegenerative and vascular conditions underlying the high phenotypic heterogeneity of patients. The Vallecas Alzheimer’s Reina Sofía (VARS) cohort (n > 550), and particularly the series of associated brain donations (VARSpath cohort) are presented here. The aim of this study is to contribute to research in dementia with a well-characterized cohort from a single center. Methods: A total of 167 patients with complete neuropathological work-ups were analyzed here. The cohort is characterized by a high female predominance (79%), advanced age at death (88 yrs.), and a high frequency of ApoE-e4 haplotype (43%). Results: The main neuropathological diagnosis was Alzheimer’s disease (79.6%), followed by vascular dementia (10.2%) and Lewy body dementia (6%). Overall, intermediate-to-high cerebrovascular disease was observed in 38.9%, Lewy body pathology in 57.5%, LATE (TDP-43 pathology) in 70.7%, ARTAG in 53%, and argyrophilic grain disease in 12% of the patients. More than one pathology with a clinically relevant burden of disease was present in 71.1% of the brains, and a selection of premortem neuropsychological and functional scores showed significant correlation with the number of co-pathologies identified in postmortem brains. Conclusions: The VARS cohort, with thorough clinical follow-up, regular blood sampling, 3-Tesla MR, and a high rate of postmortem brain donation, can provide essential multidisciplinary data in the rising age of modifying therapies and biomarkers for Alzheimer’s disease and related dementias.

Glial fibrillary acidic protein (GFAP), a proxy of astrocyte reactivity, has been proposed as biomarker of Alzheimer’s disease. However, there is limited information about the correlation between blood biomarkers and post-mortem neuropathology. In a single-centre prospective clinicopathological cohort of 139 dementia patients, for which the time-frame between GFAP level determination and neuropathological assessment was exceptionally short (on average 139 days), we analysed this biomarker, measured at three time points, in relation to proxies of disease progression such as cognitive decline and brain weight. Most importantly, we investigated the use of blood GFAP to detect the neuropathological hallmarks of Alzheimer’s disease, while accounting for potential influences of the most frequent brain co-pathologies. The main findings demonstrated an association between serum GFAP level and post-mortem tau pathology (β = 12.85; P < 0.001) that was independent of amyloid deposits (β = 13.23; P = 0.02). A mediation analysis provided additional support for the role of astrocytic activation as a link between amyloid and tau pathology in Alzheimer’s disease. Furthermore, a negative correlation was observed between pre-mortem serum GFAP and brain weight at post-mortem (r = −0.35; P < 0.001). This finding, together with evidence of a negative correlation with cognitive assessments (r = −0.27; P = 0.005), supports the role of GFAP as a biomarker for disease monitoring, even in the late phases of Alzheimer’s disease. Moreover, the diagnostic performance of GFAP in advanced dementia patients was explored, and its discriminative power (area under the receiver operator characteristic curve at baseline = 0.91) in differentiating neuropathologically-confirmed Alzheimer’s disease dementias from non-Alzheimer’s disease dementias was determined, despite the challenging scenario of advanced age and frequent co-pathologies in these patients. Independently of Alzheimer’s disease, serum GFAP levels were shown to be associated with two other pathologies targeting the temporal lobes—hippocampal sclerosis (β = 3.64; P = 0.03) and argyrophilic grain disease (β = −6.11; P = 0.02). Finally, serum GFAP levels were revealed to be correlated with astrocyte reactivity, using the brain GFAP-immunostained area as a proxy (ρ = 0.21; P = 0.02). Our results contribute to increasing evidence suggesting a role for blood GFAP as an Alzheimer’s disease biomarker, and the findings offer mechanistic insights into the relationship between blood GFAP and Alzheimer’s disease neuropathology, highlighting its ties with tau burden. Moreover, the data highlighting an independent association between serum GFAP levels and other neuropathological lesions provide information for clinicians to consider when interpreting test results. The longitudinal design and correlation with post-mortem data reinforce the robustness of our findings. However, studies correlating blood biomarkers and neuropathological assessments are still scant, and further research is needed to replicate and validate these results in diverse populations.