About

Brian Bacskai's laboratory uses sophisticated optical techniques to address fundamental questions in Alzheimer's disease research.

Research topics

• Medicine
• Biochemistry
• Biology
• Internal medicine
• Pathology
• Cell biology
• Gerontology
• Chemistry
• Library science
• Neuroscience

Selected publications

• Role of dysregulated calcium homeostasis in astrocytes in neurodegenerative disorders

  Nature reviews. Neuroscience · 2026-03-26

  articleSenior author
  PublisherDOI

• High-Speed Wide-Field Fluorescence Lifetime Imaging for Intraoperative Tumor Visualization and In Vivo Multiplexing

  Research Square · 2025-05-05 · 1 citations

  preprintOpen access
  PublisherOA PDFDOI

• High-speed wide-field fluorescence lifetime imaging for intraoperative tumor visualization and in vivo multiplexing

  Biomedical Optics Express · 2025-08-06 · 3 citations

  articleOpen accessCorresponding

  We present a technique for fast wide-field fluorescence lifetime (FLT) imaging using simultaneous steady-state and time- (or frequency-) domain measurements acquired in a single shot and exploiting the theoretical dependence of fluorescence intensity on FLT. Using theory, simulations, and in vitro experiments, we show that the single-shot FLT (S-FLT) method can provide absolute FLTs at a higher signal-to-noise ratio compared to other high-speed FLT imaging techniques, without the need for sample-dependent system calibration or model training. We demonstrate that S-FLT can provide accurate tumor delineation in real-time during surgical resections in preclinical tumor models in vivo and in clinical patient specimens ex vivo . We also extend S-FLT for real-time multiplexing and demonstrate this technique for quantifying dynamic FLT changes in vitro and for multiplexing of organ-targeted NIR fluorophores in vivo . Our results suggest that S-FLT can enable real-time quantitative high-throughput studies in preclinical applications and accurate tumor margin delineation in real-time during surgeries.

  PublisherDOI

• CAA-related enlarged perivascular spaces are associated with abnormal angioarchitecture in human brain tissue: A key role for white matter atrophy?

  Journal of Cerebral Blood Flow & Metabolism · 2025-09-08 · 1 citations

  articleOpen access

  Cerebral Amyloid Angiopathy, a common age-related small vessel disease leading to hemorrhagic stroke, shares many characteristics with Alzheimer's disease: toxic amyloid deposits, microvascular alterations and enlarged perivascular spaces (EPVS). Together, PVS enlargement, reduced amyloid-β clearance and further accumulation form a vicious cycle underlying disease progression. Yet, the neuropathological correlates of EPVS, including the associated angioarchitecture, are poorly understood. We provide quantitative 3D reconstructions of human brain microvascular networks and their topographical associations with EPVS in large volumes of cleared human tissue spanning over the gray/white matter interface. We reveal the existence of six vessel/PVS morphotypes, including sinusoid and helical vessels, enclosed in increasingly enlarged PVS, and increasingly disconnected from their surrounding network. Based on the buckling of elongated structures, we discuss how they likely result from generic processes of mechanical origin, driven by white matter atrophy, thus advancing our understanding of the pathophysiological overlap between amyloid-related and cerebrovascular disease.

  PublisherOA PDFDOI

• Age-associated T cell immunity decreases circulating endothelial progenitor cells

  Stem Cells · 2025-10-21 · 1 citations

  article

  A reduction in circulating endothelial progenitor cells (EPCs) comprise an important part of vascular aging. However, the underlying mechanisms that mediate this EPC decline remain unclear. Here, we demonstrate a novel molecular mechanism where aging increases inhibitory T cell subsets and impairs SDF1-mediated increase of circulating EPCs. SomaScan proteomics and western blot analysis revealed FABP4 as the top upregulated protein in plasma and was also increased in the bone marrow in aging. Importantly, treatment with FABP4 in bone marrow cells increased inhibitory T cells while decreased SDF-1 receptor, CXCR4 in EPCs, whereas blocking FABP4 signaling by BMS309403 or depleting these T cells restored surface expression of CXCR4 in EPCs. Notably, FABP4-mediated decrease of circulating EPC in aging were restored by therapeutic administration of mitochondria, wherein plasma FABP4 was decreased along with reducing inhibitory T cell induction in bone marrow and increasing circulating EPCs in older mice. Collectively, these findings provide new insight into the involvement of age-associated T cell immunity in EPC dysregulation, and FABP4 may be a therapeutic target to detain vascular aging.

  PublisherDOI

• Rapid Brain Hemorrhage in Mice Treated with Anti-Amyloid-Beta Immunotherapy in the Absence of Amyloid Plaque Clearance or Marked Astrocyte Dysfunction

  SSRN Electronic Journal · 2025-01-01

  preprintOpen accessSenior author
  PublisherDOI

• Somatostatin interneuron inhibition as a strategy to restore excitation‐inhibition balance in Alzheimer's disease

  Alzheimer s & Dementia · 2025-12-01

  articleOpen accessSenior author

  BACKGROUND: Alzheimer's disease (AD) is characterized by the accumulation of extracellular amyloid plaques, leading to aberrant neuronal activity and an imbalance between excitatory and inhibitory activity. This disruption contributes to network dysfunction and cognitive impairment in AD patients. Our previous work has demonstrated that excitatory neuron activity is reduced in APP/PS1 mice, while somatostatin (SOM) inhibitory interneuron activity is increased near amyloid plaques under isoflurane anesthesia. Given this imbalance, we hypothesized that inhibiting SOM interneurons could restore excitatory neuron activity and improve memory deficits in AD mouse models. To test this, we employed both acute and chronic chemogenetic approaches to manipulate SOM interneuron activity. METHODS: We used in vivo calcium imaging in APP and wild-type (WT) mice to evaluate excitatory neurons after acute chemogenetic inhibition of SOM interneurons. For chronic inhibition, we intravenously delivered AAVPHP.eB encoding chemogenetic receptors to achieve non-invasive, brain-wide inhibition of SOM interneurons in APP/PS1 and WT mice. We then administered C21 subcutaneously for 16 days, followed by behavioral assessments. Behavioral tests evaluated locomotion and memory consolidation. RESULTS: Calcium imaging confirmed that the excitation-inhibition (E/I) imbalance persists in awake APP mice, demonstrating increased SOM interneuron activity and decreased excitatory neuron activity, mirroring our findings under anesthesia. Acute chemogenetic inhibition of SOM interneurons successfully enhanced excitatory neuron activity, supporting the hypothesis that reducing SOM interneuron activity can restore E/I balance in APP/PS1 mice. However, chronic inhibition of SOM interneurons failed to restore behavioral deficits in APP/PS1 mice, as no significant differences were observed in locomotor activity, working memory, or fear memory acquisition and recall in APP/PS1 or WT mice. CONCLUSION: While acute inhibition of SOM interneurons can restore excitatory neuron activity, brain-wide chronic inhibition does not effectively improve memory function in APP/PS1 mice under the current experimental conditions.

  PublisherOA PDFDOI

• Vasomotion loss precedes impaired cerebrovascular reactivity and microbleeds in cerebral amyloid angiopathy

  Brain Communications · 2025-01-01 · 8 citations

  articleOpen access

  Abstract Cerebral amyloid angiopathy (CAA) is a cerebral small vessel disease in which amyloid-β accumulates in vessel walls. CAA is a leading cause of symptomatic lobar intracerebral haemorrhage and an important contributor to age-related cognitive decline. Recent work has suggested that vascular dysfunction may precede symptomatic stages of CAA, and that spontaneous slow oscillations in arteriolar diameter (termed vasomotion), important for amyloid-β clearance, may be impaired in CAA. To systematically study the progression of vascular dysfunction in CAA, we used the APP23 mouse model of amyloidosis, which is known to develop spontaneous cerebral microbleeds mimicking human CAA. Using in vivo 2-photon microscopy, we longitudinally imaged unanesthetized APP23 transgenic mice and wildtype (WT) littermates from 7 to 14 months of age, tracking amyloid-β accumulation and vasomotion in individual pial arterioles over time. MRI was used in separate groups of 12-, 18- and 24-month-old APP23 transgenic mice and WT littermates to detect microbleeds and to assess cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) with pseudo-continuous arterial spin labelling. We observed a significant decline in vasomotion with age in APP23 mice, while vasomotion remained unchanged in WT mice with age. This decline corresponded in timing to initial vascular amyloid-β deposition (∼8–10 months of age), although it was more strongly correlated with age than with vascular amyloid-β burden in individual arterioles. Declines in vasomotion preceded the development of MRI-visible microbleeds and the loss of smooth muscle actin in arterioles, both of which were observed in the majority of APP23 mice by 18 months of age. Additionally, CBF and evoked CVR were intact in APP23 mice at 12 months of age, but significantly lower in APP23 mice by 24 months of age. Our findings suggest that a decline in spontaneous vasomotion is an early, potentially pre-symptomatic, manifestation of CAA and vascular dysfunction, and a possible future treatment target.

  PublisherDOI

• Aducanumab binds high molecular weight soluble Aβ oligomers and restores intracellular calcium levels

  Alzheimer s Research & Therapy · 2025-08-04

  articleOpen access

  BACKGROUND: Alzheimer's disease (AD) is characterized by amyloid-beta (Aβ) accumulation, leading to the formation of neurotoxic soluble oligomers (AβOs) that impair calcium homeostasis in neurons and astrocytes. Aducanumab, a fully human monoclonal antibody targeting aggregated Aβ, has been approved for AD treatment due to its ability to reduce amyloid plaque burden. However, its specificity toward different AβO species and its functional impact on calcium homeostasis remain unclear. METHODS: We investigated aducanumab's ability to recognize and immunodeplete low-molecular-weight (LMW) and high-molecular-weight (HMW) AβOs using three Aβ preparations: (1) transgenic conditioned media (TgCM) from cultured Tg2576 neurons, (2) synthetic Aβ42-derived diffusible ligands (ADDLs), and (3) TBS-soluble fractions from aged Tg2576 mouse brain. Size exclusion chromatography and ELISA were used to characterize AβO species. Multiphoton calcium imaging of neuron-astrocyte co-cultures was performed to assess the impact of aducanumab on AβO-induced calcium overload. RESULTS: Aducanumab preferentially bound and immunodepleted HMW AβOs in ADDLs and the TBS-soluble fraction of Tg2576 mouse brain extracts but did not recognize LMW AβOs in TgCM. In calcium imaging experiments, all three AβO preparations induced calcium overload in neuron-astrocyte co-cultures. Immunodepletion with aducanumab prevented calcium overload in cultures exposed to ADDLs and Tg2576 brain extracts but not in those treated with immunodepleted TgCM, indicating that aducanumab selectively neutralizes HMW AβOs. CONCLUSIONS: Our findings demonstrate that aducanumab specifically targets HMW AβOs, mitigating their neurotoxic effects by restoring intracellular calcium homeostasis. These results provide mechanistic insight into aducanumab's therapeutic action and support its potential role in modifying AD pathology by selectively neutralizing Aβ species.

  PublisherOA PDFDOI

• Shallow-angle intracranial cannula for repeated infusion and in vivo imaging with multiphoton microscopy

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-01-23 · 1 citations

  preprintOpen accessSenior author

  Multiphoton microscopy serves as an essential tool for high-resolution imaging of the living mouse brain. To facilitate optical access to the brain during imaging, the cranial window surgery is commonly used. However, this procedure restricts physical access above the imaging area and hinders the direct delivery of imaging agents and drugs. To overcome this limitation, we have developed a cannula delivery system that enables the implantation of a low-profile cannula nearly parallel to the brain surface at angles as shallow as 8 degrees, while maintaining compatibility with multiphoton microscopy. To validate this approach, we perform direct infusion and imaging of various fluorescent cell markers in the brain. Additionally, we successfully demonstrate tracking of degenerating neurons over time in Alzheimer's disease mice using Fluoro-Jade C. Furthermore, we show longitudinal imaging of brain tissue partial pressure of oxygen using a phosphorescent oxygen sensor. Our developed technique should enable a wide range of new longitudinal imaging studies in the mouse brain.

  PublisherOA PDFDOI

Recent grants

• Astrocytes as governing pathological drivers of neurovascular dysfunction in AD

  NIH · $4.4M · 2017–2028

• Slow-wave activity as a modifier of the progression of neurodegeneration in Alzheimer's disease

  NIH · $3.7M · 2019–2024

• Molecular pathways leading to neurodegeneration in vivo

  NIH · $2.4M · 2015–2021

• NIH Grant R01AG020570

  NIH · $1.2M · 2009

• NIH Grant U41RR019703

  NIH · $34.5M · 2010

Frequent coauthors

• Bradley T. Hyman

  Massachusetts General Hospital

  281 shared

• Steven S. Hou

  221 shared

• Ksenia V. Kastanenka

  156 shared

• Matthew P. Frosch

  Massachusetts General Hospital

  152 shared

• Steven M. Greenberg

  Massachusetts General Hospital

  139 shared

• Susanne J. van Veluw

  Massachusetts General Hospital

  104 shared

• Mónica García‐Alloza

  Biomedical Research and Innovation Institute of Cadiz

  102 shared

• Tara L. Spires‐Jones

  University of Edinburgh

  91 shared

Labs

• Bacskai Lab at MINDPI