All Publications

  • Sex-Specific Oligodendroglia Response in Alzheimer's Disease Bharani, K., Dharshini, A., Oberhauser, J., Cobos, I. ELSEVIER SCIENCE INC. 2023: S1459
  • Septal rage in a human. A case report Bharani, K., Parvizi, J., Cobos, I., Vogel, H. OXFORD UNIV PRESS INC. 2022: 479-480
  • Regional binding of tau and amyloid PET tracers in Down syndrome autopsy brain tissue MOLECULAR NEURODEGENERATION Lemoine, L., Ledreux, A., Mufson, E. J., Perez, S. E., Simic, G., Doran, E., Lott, I., Carroll, S., Bharani, K., Thomas, S., Gilmore, A., Hamlett, E. D., Nordberg, A., Granholm, A. C. 2020; 15 (1): 68


    Tau pathology is a major age-related event in Down syndrome with Alzheimer's disease (DS-AD). Although recently, several different Tau PET tracers have been developed as biomarkers for AD, these tracers showed different binding properties in Alzheimer disease and other non-AD tauopathies. They have not been yet investigated in tissue obtained postmortem for DS-AD cases. Here, we evaluated the binding characteristics of two Tau PET tracers (3H-MK6240 and 3H-THK5117) and one amyloid (3H-PIB) ligand in the medial frontal gyrus (MFG) and hippocampus (HIPP) in tissue from adults with DS-AD and DS cases with mild cognitive impairment (MCI) compared to sporadic AD.Tau and amyloid autoradiography were performed on paraffin-embedded sections. To confirm respective ligand targets, adjacent sections were immunoreacted for phospho-Tau (AT8) and stained for amyloid staining using Amylo-Glo.The two Tau tracers showed a significant correlation with each other and with AT8, suggesting that both tracers were binding to Tau deposits. 3H-MK6240 Tau binding correlated with AT8 immunostaining but to a lesser degree than the 3H-THK5117 tracer, suggesting differences in binding sites between the two Tau tracers. 3H-THK5117, 3H-MK6240 and 3H-PIB displayed dense laminar binding in the HIPP and MFG in adult DS brains. A regional difference in Tau binding between adult DS and AD was observed suggesting differential regional Tau deposition in adult DS compared to AD, with higher THK binding density in the MFG in adult with DS compared to AD. No significant correlation was found between 3H-PIB and Amylo-Glo staining in adult DS brains suggesting that the amyloid PIB tracer binds to additional sites.This study provides new insights into the regional binding distribution of a first-generation and a second-generation Tau tracer in limbic and neocortical regions in adults with DS, as well as regional differences in Tau binding in adult with DS vs. those with AD. These findings provide new information about the binding properties of two Tau radiotracers for the detection of Tau pathology in adults with DS in vivo and provide valuable data regarding Tau vs. amyloid binding in adult DS compared to AD.

    View details for DOI 10.1186/s13024-020-00414-3

    View details for Web of Science ID 000595618900001

    View details for PubMedID 33222700

    View details for PubMedCentralID PMC7682014

  • Receptors for pro-resolving mediators are increased in Alzheimer's disease brain. Brain pathology (Zurich, Switzerland) Emre, C., Hjorth, E., Bharani, K., Carroll, S., Granholm, A. C., Schultzberg, M. 2020; 30 (3): 614-640


    Neuroinflammation is a key element of AD pathology and conceivably a result of a disturbed resolution. Resolution of inflammation is an active process which is strictly orchestrated following the acute inflammatory response after removal of the inflammatory stimuli. Acute inflammation is actively terminated by specialized pro-resolving mediators (SPMs) thereby promoting healing and return to homeostasis. Failed resolution may contribute to persistent neuroinflammation and aggravate AD pathology. BLT1 (leukotriene B4 receptor) and ChemR23 (chemerin receptor 23) are receptors for the SPM resolvin (Rv) E1 and are important clinical targets for ending inflammation. In AD, the levels of SPMs are decreased, and pro-inflammatory mediators are increased. In the current study, the distribution of BLT1 and ChemR23 receptors in control brains and in AD as well as correlations with AD pathology was examined for the first time. BLT1 and ChemR23 were analyzed in different regions of post-mortem human brain from cases with AD, early-onset AD and mild cognitive impairment (MCI) and healthy controls, using western blotting and immunohistochemistry. BLT1 and ChemR23 were detected in neurons and glial cells in all examined regions of the human brain, with markedly higher levels in AD than in controls. The receptor levels correlated with the density of staining for the inflammation markers HLA-DR and YKL-40 for microglia and astrocytes, respectively, and elevated staining coincided with high Braak stages in AD. The relative staining densities of these receptors were higher in the basal forebrain, cingulate gyrus and hippocampal regions compared to the cerebellum and frontal cortex (BA46). In conclusion, alterations in the expression of the resolution receptor BLT1 in AD have not been reported previously and the changes in both BLT1 and ChemR23 suggest a disturbed resolution pathway in several regions of the AD brain that may play a role in disease pathology.

    View details for DOI 10.1111/bpa.12812

    View details for PubMedID 31912564

    View details for PubMedCentralID PMC8018009

  • Serum pro-BDNF levels correlate with phospho-tau staining in Alzheimer's disease. Neurobiology of aging Bharani, K. L., Ledreux, A., Gilmore, A., Carroll, S. L., Granholm, A. C. 2020; 87: 49-59


    Disruption of brain-derived neurotrophic factor (BDNF) biosynthesis and/or signaling has been implicated in the pathogenesis of Alzheimer's disease (AD). We used postmortem brain and fluid samples from 20 patients with variable severity of AD and 11 controls to investigate whether BDNF levels in serum and brain tissue correlated with hippocampal pathology. Total BDNF, precursor BDNF (pro-BDNF), and mature BDNF were measured in cerebrospinal fluid, serum, and 3 postmortem brain regions. Histological markers for AD pathology, the BDNF cognate receptor (TrkB), and glia were measured in the hippocampus (HIP). Lower pro-BDNF levels were observed in the entorhinal and frontal cortices in AD cases compared with controls. AD cases also exhibited significantly lower staining densities of the cognate BDNF receptor TrkB in the HIP compared with controls, and TrkB staining was inversely correlated with both Amylo-Glo and pTau staining in the same region, suggesting a relationship between the density of the cognate BDNF receptor and accumulation of AD pathology. In addition, higher serum pro-BDNF levels correlated with lower HIP pro-BDNF levels and higher pTau staining in the HIP. Total BDNF levels in cortical regions were also negatively correlated with Amylo-Glo staining in the HIP suggesting that reduced BDNF cortical levels might influence hippocampal amyloid accumulation. These results strongly suggest that altered BDNF and TrkB receptors are involved in AD pathology and therefore warrant investigations into therapies involving the BDNF pathway.

    View details for DOI 10.1016/j.neurobiolaging.2019.11.010

    View details for PubMedID 31882186

  • A noradrenergic lesion aggravates the effects of systemic inflammation on the hippocampus of aged rats. PloS one Bharani, K. L., Derex, R., Granholm, A. C., Ledreux, A. 2017; 12 (12): e0189821


    Neuroinflammation is potentiated by early degeneration of the locus coeruleus noradrenergic pathway (LC-NE) commonly seen in aging-related neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. In animal models, lipopolysaccharide (LPS) induces strong peripheral immune responses that can cause cognitive changes secondary to neuroinflammation. The influence of the peripheral immune response on cognition might be exacerbated by LC-NE degeneration, but this has not been well characterized previously. In this study, we investigated how systemic inflammation affects neuroinflammation and cognition in aged rats that have had either normal or damaged LC-NE transmitter systems. Rats were first exposed to the selective noradrenergic (NE) neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) to induce degeneration of central NE pathways. Two weeks later, the rats received a low dose of LPS. This resulted in 3 treatment groups (Control, LPS-, and DSP4+LPS-treated rats) studied at 4 hours (short-term subgroup) and 7 days (long-term subgroup) following the LPS injection. DSP4+LPS-treated rats exhibited increased serum levels of several pro-inflammatory cytokines, increased astroglial and microglial activation in the hippocampus, and poorer performance in the novel object recognition task (NORT) compared to controls and LPS-treated rats. Additionally, serum and brain tissue levels of brain-derived neurotrophic factor (BDNF) were modulated over time in the DSP4+LPS group compared to the other two groups. Specifically, DSP4+LPS-treated rats in the short-term subgroup had lower hippocampal BDNF levels (~25%) than controls and LPS-treated rats, which negatively correlated with hippocampal astrogliosis and positively correlated with hippocampal IL-1β levels. Serum and hippocampal BDNF levels in the DSP4+LPS-treated rats in the long-term subgroup returned to levels similar to the control group. These results show that systemic inflammation in LC-NE-lesioned aged rats promotes an exacerbated systemic and central inflammatory response compared to LC-NE-intact rats and alters BDNF levels, indicating the important role of this neurotransmitter system in response to neuroinflammation.

    View details for DOI 10.1371/journal.pone.0189821

    View details for PubMedID 29261743

    View details for PubMedCentralID PMC5736222

  • Compensatory processing during rule-based category learning in older adults AGING NEUROPSYCHOLOGY AND COGNITION Bharani, K. L., Paller, K. A., Reber, P. J., Weintraub, S., Yanar, J., Morrison, R. G. 2016; 23 (3): 304-326


    Healthy older adults typically perform worse than younger adults at rule-based category learning, but better than patients with Alzheimer's or Parkinson's disease. To further investigate aging's effect on rule-based category learning, we monitored event-related potentials (ERPs) while younger and neuropsychologically typical older adults performed a visual category-learning task with a rule-based category structure and trial-by-trial feedback. Using these procedures, we previously identified ERPs sensitive to categorization strategy and accuracy in young participants. In addition, previous studies have demonstrated the importance of neural processing in the prefrontal cortex and the medial temporal lobe for this task. In this study, older adults showed lower accuracy and longer response times than younger adults, but there were two distinct subgroups of older adults. One subgroup showed near-chance performance throughout the procedure, never categorizing accurately. The other subgroup reached asymptotic accuracy that was equivalent to that in younger adults, although they categorized more slowly. These two subgroups were further distinguished via ERPs. Consistent with the compensation theory of cognitive aging, older adults who successfully learned showed larger frontal ERPs when compared with younger adults. Recruitment of prefrontal resources may have improved performance while slowing response times. Additionally, correlations of feedback-locked P300 amplitudes with category-learning accuracy differentiated successful younger and older adults. Overall, the results suggest that the ability to adapt one's behavior in response to feedback during learning varies across older individuals, and that the failure of some to adapt their behavior may reflect inadequate engagement of prefrontal cortex.

    View details for DOI 10.1080/13825585.2015.1091438

    View details for Web of Science ID 000372020600003

    View details for PubMedID 26422522

    View details for PubMedCentralID PMC4828326

  • Amyloid-beta protein clearance and degradation (ABCD) pathways and their role in Alzheimer's disease. Current Alzheimer research Baranello, R. J., Bharani, K. L., Padmaraju, V., Chopra, N., Lahiri, D. K., Greig, N. H., Pappolla, M. A., Sambamurti, K. 2015; 12 (1): 32-46


    Amyloid-β proteins (Aβ) of 42 (Aβ42) and 40 aa (Aβ40) accumulate as senile plaques (SP) and cerebrovascular amyloid protein deposits that are defining diagnostic features of Alzheimer's disease (AD). A number of rare mutations linked to familial AD (FAD) on the Aβ precursor protein (APP), Presenilin-1 (PS1), Presenilin- 2 (PS2), Adamalysin10, and other genetic risk factors for sporadic AD such as the ε4 allele of Apolipoprotein E (ApoE-ε4) foster the accumulation of Aβ and also induce the entire spectrum of pathology associated with the disease. Aβ accumulation is therefore a key pathological event and a prime target for the prevention and treatment of AD. APP is sequentially processed by β-site APP cleaving enzyme (BACE1) and γ-secretase, a multisubunit PS1/PS2-containing integral membrane protease, to generate Aβ. Although Aβ accumulates in all forms of AD, the only pathways known to be affected in FAD increase Aβ production by APP gene duplication or via base substitutions on APP and γ-secretase subunits PS1 and PS2 that either specifically increase the yield of the longer Aβ42 or both Aβ40 and Aβ42. However, the vast majority of AD patients accumulate Aβ without these known mutations. This led to proposals that impairment of Aβ degradation or clearance may play a key role in AD pathogenesis. Several candidate enzymes, including Insulin-degrading enzyme (IDE), Neprilysin (NEP), Endothelin-converting enzyme (ECE), Angiotensin converting enzyme (ACE), Plasmin, and Matrix metalloproteinases (MMPs) have been identified and some have even been successfully evaluated in animal models. Several studies also have demonstrated the capacity of γ-secretase inhibitors to paradoxically increase the yield of Aβ and we have recently established that the mechanism is by skirting Aβ degradation. This review outlines major cellular pathways of Aβ degradation to provide a basis for future efforts to fully characterize the panel of pathways responsible for Aβ turnover.

    View details for DOI 10.2174/1567205012666141218140953

    View details for PubMedID 25523424

    View details for PubMedCentralID PMC4820400

  • Dissociation of category-learning systems via brain potentials. Frontiers in human neuroscience Morrison, R. G., Reber, P. J., Bharani, K. L., Paller, K. A. 2015; 9: 389


    Behavioral, neuropsychological, and neuroimaging evidence has suggested that categories can often be learned via either an explicit rule-based (RB) mechanism critically dependent on medial temporal and prefrontal brain regions, or via an implicit information-integration (II) mechanism relying on the basal ganglia. In this study, participants viewed sine-wave gratings (Gabor patches) that varied on two dimensions and learned to categorize them via trial-by-trial feedback. Two different stimulus distributions were used; one was intended to encourage an explicit RB process and the other an implicit II process. We monitored brain activity with scalp electroencephalography (EEG) while each participant: (1) passively observed stimuli represented of both distributions; (2) categorized stimuli from one distribution, and, 1 week later; (3) categorized stimuli from the other distribution. Categorization accuracy was similar for the two distributions. Subtractions of Event-Related Potentials (ERPs) for correct and incorrect trials were used to identify neural differences in RB and II categorization processes. We identified an occipital brain potential that was differentially modulated by categorization condition accuracy at an early latency (150-250 ms), likely reflecting the degree of holistic processing. A stimulus-locked Late Positive Complex (LPC) associated with explicit memory updating was modulated by accuracy in the RB, but not the II task. Likewise, a feedback-locked P300 ERP associated with expectancy was correlated with performance only in the RB, but not the II condition. These results provide additional evidence for distinct brain mechanisms supporting RB vs. implicit II category learning and use.

    View details for DOI 10.3389/fnhum.2015.00389

    View details for PubMedID 26217210

    View details for PubMedCentralID PMC4493768

  • INCREASED P2 EVENT-RELATED POTENTIAL RESPONSE IN OLDER INDIVIDUALS WITH EXCEPTIONAL MEMORY FUNCTION Shukhman, R., Bharani, K. L., D'Aunno, K., Whitney, K., Hurley, R. S., Weintraub, S., Rogalski, E., Mesulam, M., Morrison, R. G. MIT PRESS. 2013: 190
  • METAMEMORY INTO MEMORY: THE NEURAL CORRELATES OF ADAPTIVE ENCODING Mandel, N., Shukhman, R., Endris, L., Rymut, I., Bharani, K. L., Hurley, R., Morrison, R. G. MIT PRESS. 2013: 225