Amalia Perna

All Publications

• Paradigm Shift: Multiple Potential Pathways to Neurodegenerative Dementia. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics Perna, A., Montine, K. S., White, L. R., Montine, T. J., Cholerton, B. A. 2023

  Abstract

  Neurodegenerative dementia can result from multiple underlying abnormalities, including neurotransmitter imbalances, protein aggregation, and other neurotoxic events. A major complication in identifying effective treatment targets is the frequent co-occurrence of multiple neurodegenerative processes, occurring either in parallel or sequentially. The path towards developing effective treatments for Alzheimer's disease (AD) and other dementias has been relatively slow and until recently has focused on disease symptoms. Aducanumab and lecanemab, recently approved by the FDA, are meant to target disease structures but have only modest benefit on symptom progression and remain unproven in reversing or preventing dementia. A third, donanemab, appears more promising but awaits FDA approval. Ongoing trials include potential cognition enhancers, new combinations of known drugs for synergistic effects, prodrugs with less toxicity, and increasing interest in drugs targeting neuroinflammation or microbiome. Scientific and technological advances offer the opportunity to move in new therapy directions, such as modifying microglia to prevent or suppress underlying disease. A major challenge, however, is that underlying comorbidities likely influence the effectiveness of therapies. Indeed, the full range of comorbidity, today only definitively identified postmortem, likely contributes to failed clinical trials and overmedication of older adults, since it is difficult to exclude (during life) people unlikely to respond. Our current knowledge thus signals that a paradigm shift towards individualized and multimodal treatments is necessary to effectively advance the field of dementia therapeutics.

  View details for DOI 10.1007/s13311-023-01441-w

  View details for PubMedID 37733209

  View details for PubMedCentralID 3312024

• Quantitative estimate of cognitive resilience and its medical and genetic associations. Alzheimer's research & therapy Phongpreecha, T., Godrich, D., Berson, E., Espinosa, C., Kim, Y., Cholerton, B., Chang, A. L., Mataraso, S., Bukhari, S. A., Perna, A., Yakabi, K., Montine, K. S., Poston, K. L., Mormino, E., White, L., Beecham, G., Aghaeepour, N., Montine, T. J. 2023; 15 (1): 192

  Abstract

  We have proposed that cognitive resilience (CR) counteracts brain damage from Alzheimer's disease (AD) or AD-related dementias such that older individuals who harbor neurodegenerative disease burden sufficient to cause dementia remain cognitively normal. However, CR traditionally is considered a binary trait, capturing only the most extreme examples, and is often inconsistently defined.This study addressed existing discrepancies and shortcomings of the current CR definition by proposing a framework for defining CR as a continuous variable for each neuropsychological test. The linear equations clarified CR's relationship to closely related terms, including cognitive function, reserve, compensation, and damage. Primarily, resilience is defined as a function of cognitive performance and damage from neuropathologic damage. As such, the study utilized data from 844 individuals (age = 79 ± 12, 44% female) in the National Alzheimer's Coordinating Center cohort that met our inclusion criteria of comprehensive lesion rankings for 17 neuropathologic features and complete neuropsychological test results. Machine learning models and GWAS then were used to identify medical and genetic factors that are associated with CR.CR varied across five cognitive assessments and was greater in female participants, associated with longer survival, and weakly associated with educational attainment or APOE ε4 allele. In contrast, damage was strongly associated with APOE ε4 allele (P value < 0.0001). Major predictors of CR were cardiovascular health and social interactions, as well as the absence of behavioral symptoms.Our framework explicitly decoupled the effects of CR from neuropathologic damage. Characterizations and genetic association study of these two components suggest that the underlying CR mechanism has minimal overlap with the disease mechanism. Moreover, the identified medical features associated with CR suggest modifiable features to counteract clinical expression of damage and maintain cognitive function in older individuals.

  View details for DOI 10.1186/s13195-023-01329-z

  View details for PubMedID 37926851

  View details for PubMedCentralID 6410486

• Cross-species comparative analysis of single presynapses. Scientific reports Berson, E., Gajera, C. R., Phongpreecha, T., Perna, A., Bukhari, S. A., Becker, M., Chang, A. L., De Francesco, D., Espinosa, C., Ravindra, N. G., Postupna, N., Latimer, C. S., Shively, C. A., Register, T. C., Craft, S., Montine, K. S., Fox, E. J., Keene, C. D., Bendall, S. C., Aghaeepour, N., Montine, T. J. 2023; 13 (1): 13849

  Abstract

  Comparing brain structure across species and regions enables key functional insights. Leveraging publicly available data from a novel mass cytometry-based method, synaptometry by time of flight (SynTOF), we applied an unsupervised machine learning approach to conduct a comparative study of presynapse molecular abundance across three species and three brain regions. We used neural networks and their attractive properties to model complex relationships among high dimensional data to develop a unified, unsupervised framework for comparing the profile of more than 4.5 million single presynapses among normal human, macaque, and mouse samples. An extensive validation showed the feasibility of performing cross-species comparison using SynTOF profiling. Integrative analysis of the abundance of 20 presynaptic proteins revealed near-complete separation between primates and mice involving synaptic pruning, cellular energy, lipid metabolism, and neurotransmission. In addition, our analysis revealed a strong overlap between the presynaptic composition of human and macaque in the cerebral cortex and neostriatum. Our unique approach illuminates species- and region-specific variation in presynapse molecular composition.

  View details for DOI 10.1038/s41598-023-40683-8

  View details for PubMedID 37620363

  View details for PubMedCentralID 3365257

• Whole genome deconvolution unveils Alzheimer's resilient epigenetic signature. Nature communications Berson, E., Sreenivas, A., Phongpreecha, T., Perna, A., Grandi, F. C., Xue, L., Ravindra, N. G., Payrovnaziri, N., Mataraso, S., Kim, Y., Espinosa, C., Chang, A. L., Becker, M., Montine, K. S., Fox, E. J., Chang, H. Y., Corces, M. R., Aghaeepour, N., Montine, T. J. 2023; 14 (1): 4947

  Abstract

  Assay for Transposase Accessible Chromatin by sequencing (ATAC-seq) accurately depicts the chromatin regulatory state and altered mechanisms guiding gene expression in disease. However, bulk sequencing entangles information from different cell types and obscures cellular heterogeneity. To address this, we developed Cellformer, a deep learning method that deconvolutes bulk ATAC-seq into cell type-specific expression across the whole genome. Cellformer enables cost-effective cell type-specific open chromatin profiling in large cohorts. Applied to 191 bulk samples from 3 brain regions, Cellformer identifies cell type-specific gene regulatory mechanisms involved in resilience to Alzheimer's disease, an uncommon group of cognitively healthy individuals that harbor a high pathological load of Alzheimer's disease. Cell type-resolved chromatin profiling unveils cell type-specific pathways and nominates potential epigenetic mediators underlying resilience that may illuminate therapeutic opportunities to limit the cognitive impact of the disease. Cellformer is freely available to facilitate future investigations using high-throughput bulk ATAC-seq data.

  View details for DOI 10.1038/s41467-023-40611-4

  View details for PubMedID 37587197

  View details for PubMedCentralID 6071637

• Prediction of neuropathologic lesions from clinical data. Alzheimer's & dementia : the journal of the Alzheimer's Association Phongpreecha, T., Cholerton, B., Bhukari, S., Chang, A. L., De Francesco, D., Thuraiappah, M., Godrich, D., Perna, A., Becker, M. G., Ravindra, N. G., Espinosa, C., Kim, Y., Berson, E., Mataraso, S., Sha, S. J., Fox, E. J., Montine, K. S., Baker, L. D., Craft, S., White, L., Poston, K. L., Beecham, G., Aghaeepour, N., Montine, T. J. 2023

  Abstract

  Post-mortem analysis provides definitive diagnoses of neurodegenerative diseases; however, only a few can be diagnosed during life.This study employed statistical tools and machine learning to predict 17 neuropathologic lesions from a cohort of 6518 individuals using 381 clinical features (Table S1). The multisite data allowed validation of the model's robustness by splitting train/test sets by clinical sites. A similar study was performed for predicting Alzheimer's disease (AD) neuropathologic change without specific comorbidities.Prediction results show high performance for certain lesions that match or exceed that of research annotation. Neurodegenerative comorbidities in addition to AD neuropathologic change resulted in compounded, but disproportionate, effects across cognitive domains as the comorbidity number increased.Certain clinical features could be strongly associated with multiple neurodegenerative diseases, others were lesion-specific, and some were divergent between lesions. Our approach could benefit clinical research, and genetic and biomarker research by enriching cohorts for desired lesions.

  View details for DOI 10.1002/alz.12921

  View details for PubMedID 36681388

• Histone H3 Lysine 4 and 27 Trimethylation Landscape of Human Alzheimer's Disease. Cells Persico, G., Casciaro, F., Amatori, S., Rusin, M., Cantatore, F., Perna, A., Auber, L. A., Fanelli, M., Giorgio, M. 2022; 11 (4)

  Abstract

  BACKGROUND: Epigenetic remodeling is emerging as a critical process for both the onset and progression of Alzheimer's disease (AD), the most common form of neurodegenerative dementia. However, it is not clear to what extent the distribution of histone modifications is involved in AD.METHODS: To investigate histone H3 modifications in AD, we compared the genome-wide distributions of H3K4me3 and H3K27me3 in entorhinal cortices from severe sporadic AD patients and from age-matched healthy individuals of both sexes.RESULTS: AD samples were characterized by typical average levels and distributions of the H3K4me3 and H3K27me3 signals. However, AD patients showed a lower H3K4me3 and higher H3K27me3 signal, particularly in males. Interestingly, the genomic sites found differentially trimethylated at the H3K4 between healthy and AD samples involve promoter regions of genes belonging to AD-related pathways such as glutamate receptor signaling.CONCLUSIONS: The signatures of H3K4me3 and H3K27me3 identified in AD patients validate the role of epigenetic chromatin remodeling in neurodegenerative disease and shed light on the genomic adaptive mechanisms involved in AD.

  View details for DOI 10.3390/cells11040734

  View details for PubMedID 35203383

• Revealing NOTCH-dependencies in synaptic targets associated with Alzheimer's disease MOLECULAR AND CELLULAR NEUROSCIENCE Perna, A., Marathe, S., Dreos, R., Falquet, L., Egger, H., Auber, L. 2021; 115: 103657

  Abstract

  Recent studies have identified NOTCH signaling as a contributor of neurodegeneration including Alzheimer's disease' (AD) pathophysiology. As part of the efforts to understand molecular mechanisms and players involved in neurodegenerative dementia, we employed transgenic mouse models with Notch1 and Rbpjk loss of function (LOF) mutation in pyramidal neurons of the CA fields. Using RNA-seq, we have investigated the differential expression of NOTCH-dependent genes either upon environmental enrichment (EE) or upon kainic acid (KA) injury. We found a substantial genetic diversity in absence of both NOTCH1 receptor or RBPJK transcriptional activator. Among differentially expressed genes, we observed a significant upregulation of Gabra2a in both knockout models, suggesting a role for NOTCH signaling in the modulation of E/I balance. Upon excitotoxic stimulation, loss of RBPJK results in decreased expression of synaptic proteins with neuroprotective effects. We confirmed Nptx2, Npy, Pdch8, TncC as direct NOTCH1/RBPJK targets and Bdnf and Scg2 as indirect targets. Finally, we translate these findings into human entorhinal cortex containing the hippocampal region from AD patients performing targeted transcripts analysis. We observe an increased trend for RBPJK and the ligand DNER starting in the mild-moderate stage of the disease with no change of NOTCH1 expression. Alongside, expression of the Notch targets Hes5 and Hey1 tend to rise in the intermediate stage of the disease and drop in severe AD. Similarly the newly discovered NOTCH targets, NPTX2, NPY, BDNF show an up-warding tendency during the mild-moderate stage, and decline in the severe phase of the disease. This study identifies NOTCH as a central signaling cascade capable of modulating synaptic transmission in response to excitatory insult through the activation of neuroprotective genes that have been associated to AD.

  View details for DOI 10.1016/j.mcn.2021.103657

  View details for Web of Science ID 000696891700005

  View details for PubMedID 34314836

• Classifying dementia progression using microbial profiling of saliva ALZHEIMER'S & DEMENTIA: DIAGNOSIS, ASSESSMENT & DISEASE MONITORING Bathini, P., Foucras, S., Dupanloup, I., Imeri, H., Perna, A., Berruex, J., Doucey, M., Annoni, J., Alberi, L. 2020; 12 (1): e12000

  Abstract

  There is increasing evidence linking periodontal infections to Alzheimer's disease (AD). Saliva sampling can reveal information about the host and pathogen interactions that can inform about physiological and pathological brain states.A cross-sectional cohort of age-matched participants (78) was segmented according to their chemosensory (University of Pennsylvania Smell Identification Test; UPSIT) and cognitive scores (Mini-Mental State Exam; MMSE and clinical dementia rating; CDR). Mid-morning saliva was sampled from each participant and processed for microbiome composition and cytokine analysis. Linear discriminant analysis (LDA) was used to unravel specific changes in microbial and immunological signatures and logistic regression analysis (LRA) was employed to identify taxa that varied in abundance among patient groups.Using olfaction we distinguish in the cognitively normal population a segment with high chemosensory scores (CNh, 27) and another segment with chemosensory scores (CNr, 16) as low as mild cognitive impairment (MCI, 21) but higher than the AD group (17). We could identify stage-specific microbial signatures changes but no clearly distinct cytokine profiles. Periodontal pathogen species as Filifactor villosus decline with the increasing severity of AD, whereas opportunistic oral bacteria such as Leptotrichia wadei show a significant enrichment in MCI.The salivary microbiome indicates stage-dependent changes in oral bacteria favoring opportunistic species at the expense of periodontal bacteria, whereas the inflammatory profiles remain mainly unchanged in the sampled population.

  View details for DOI 10.1002/dad2.12000

  View details for Web of Science ID 000707203600001

  View details for PubMedID 32775594

  View details for PubMedCentralID PMC7406179

• TF-ChIP Method for Tissue-Specific Gene Targets FRONTIERS IN CELLULAR NEUROSCIENCE Perna, A., Alberi, L. 2019; 13: 95

  Abstract

  Chromatin immunoprecipitation (ChIP) is an assay developed in order to define the dynamic nature of transcription processes. This method has been widely employed to identify methylated and acetylated DNA sequences in a variety of organs both in animals and humans. Nevertheless, this technique is significantly less employed to study transcriptional targets of specific nuclear signaling factors (TFs) and the data published so far have mainly used cell culture material and have been hardly reproduced in ex-vivo tissue. As nuclear signaling underlies important adaptive and maladaptive responses in chronic conditions such as cancer and neurodegeneration, there is a need for streamlining the upfront workflow of TF-ChIP for subsequent target sequencing. Based on the typical low concentration of the signaling transcriptional complex and the complexity/length of the ChIP Seq protocol, the field of cellular signaling has been confronted with a major roadblock in identifying clinically relevant targets of pathological and physiological signaling pathways. The present protocol offers a standardized procedure for detecting signaling targets in any whole tissue or specific dissected regions. The advantages of the protocol compared to the existing published methods are: (1) the small amount of starting material; appropriate for tissue subregions; (2) the optimization of DNA fragmentation from whole tissue; (3) suitability for sparsely populated tissues (i.e., brain); (4) the specificity of the TF-targeting readout; and (5) high DNA quality for sequencing or hybridization. The present protocol is highly detailed and can be reproduced using both fresh and fresh-frozen tissue. This is particularly relevant in the clinical setting, where specimen integrity is often the limiting step and where transcriptional target profiling is therapeutically relevant. The method is centered on Notch signaling but can be applied to a variety of nuclear signaling pathways as long as specific antibodies are available for pull down. Taken the superior yield/readout of this procedure, ChIP may finally provide relevant information about dynamic downstream gene changes in vivo for use in both basic research and clinical applications.

  View details for DOI 10.3389/fncel.2019.00095

  View details for Web of Science ID 000461788300001

  View details for PubMedID 30941015

  View details for PubMedCentralID PMC6433963