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  • An anterograde pathway for sensory axon degeneration gated by a cytoplasmic action of the transcriptional regulator P53. Developmental cell Simon, D. J., Belsky, D. M., Bowen, M. E., Ohn, C. Y., O'Rourke, M. K., Shen, R., Kim, G., Pitts, J., Attardi, L. D., Tessier-Lavigne, M. 2021; 56 (7): 976

    Abstract

    Axon remodeling through sprouting and pruning contributes to the refinement of developing neural circuits. A prominent example is the pruning of developing sensory axons deprived of neurotrophic support, which is mediated by a caspase-dependent (apoptotic) degeneration process. Distal sensory axons possess a latent apoptotic pathway, but a cell body-derived signal that travels anterogradely down the axon is required for pathway activation. The signaling mechanisms that underlie this anterograde process are poorly understood. Here, we show that the tumor suppressor P53 is required for anterograde signaling. Interestingly loss of P53 blocks axonal but not somatic (i.e., cell body) caspase activation. Unexpectedly, P53 does not appear to have an acute transcriptional role in this process and instead appears to act in the cytoplasm to directly activate the mitochondrial apoptotic pathway in axons. Our data support the operation of a cytoplasmic role for P53 in the anterograde death of developing sensory axons.

    View details for DOI 10.1016/j.devcel.2021.03.011

    View details for PubMedID 33823136

  • Distribution of TDP-43 Pathology in Hippocampal Synaptic Relays Suggests Transsynaptic Propagation in Frontotemporal Lobar Degeneration JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY Jamshidi, P., Kim, G., Shahidehpour, R. K., Bolbolan, K., Gefen, T., Bigio, E. H., Mesulam, M., Geula, C. 2020; 79 (6): 585–91

    Abstract

    Hyperphosphorylation, nuclear depletion, and aggregation of TDP-43 in ubiquitinated inclusions is a hallmark of frontotemporal lobar degeneration (FTLD-TDP). Evidence of potential spread of TDP-43 along synaptic connections in the human is largely limited to qualitative and semiquantitative observations. We quantitatively investigated potential transsynaptic propagation of TDP-43 across the well-established chain of single synaptic connections of the hippocampus. Hippocampi from 5 participants with clinical diagnoses of primary progressive aphasia and 2 participants with behavioral variant frontotemporal dementia, all with postmortem diagnoses of FTLD-TDP, were examined. TDP-43-positive mature (darkly stained) and pre-inclusions (diffuse puncta or fibrillar staining) in the granule cell layer of dentate gyrus (DG) and pyramidal cell layers of Cornu Ammonis (CA)3, CA2, and CA1 were quantified using unbiased stereology. The density of mature TDP-43 inclusions was higher in the DG than in the CA fields (p < 0.05). There were no differences in inclusion densities across the CA fields. TDP-43 pre-inclusions densities were not different across the 4 subregions. There was significantly higher preinclusion density than mature inclusions in CA3, but not in other subregions. Analysis of normalized total counts in place of densities revealed virtually identical results. Our finding of greatest mature inclusion deposition in the DG, coupled with more preinclusions than mature inclusions at the next relay station (CA3), and reduced densities of both in CA2-CA1, provide evidence in support of a sequential transsynaptic propagation mechanism of TDP-43 aggregates.

    View details for DOI 10.1093/jnen/nlaa029

    View details for Web of Science ID 000538796100002

    View details for PubMedID 32388566

    View details for PubMedCentralID PMC7241939

  • ALS Genetics: Gains, Losses, and Implications for Future Therapies. Neuron Kim, G. n., Gautier, O. n., Tassoni-Tsuchida, E. n., Ma, X. R., Gitler, A. D. 2020

    Abstract

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder caused by the loss of motor neurons from the brain and spinal cord. The ALS community has made remarkable strides over three decades by identifying novel familial mutations, generating animal models, elucidating molecular mechanisms, and ultimately developing promising new therapeutic approaches. Some of these approaches reduce the expression of mutant genes and are in human clinical trials, highlighting the need to carefully consider the normal functions of these genes and potential contribution of gene loss-of-function to ALS. Here, we highlight known loss-of-function mechanisms underlying ALS, potential consequences of lowering levels of gene products, and the need to consider both gain and loss of function to develop safe and effective therapeutic strategies.

    View details for DOI 10.1016/j.neuron.2020.08.022

    View details for PubMedID 32931756

  • Neuropathologic basis of in vivo cortical atrophy in the aphasic variant of Alzheimer's disease BRAIN PATHOLOGY Ohm, D., Fought, A. J., Rademaker, A., Kim, G., Sridhar, J., Coventry, C., Gefen, T., Weintraub, S., Bigio, E., Mesulam, M., Rogalski, E., Geula, C. 2020; 30 (2): 332–44

    Abstract

    The neuropathologic basis of in vivo cortical atrophy in clinical dementia syndromes remains poorly understood. This includes primary progressive aphasia (PPA), a language-based dementia syndrome characterized by asymmetric cortical atrophy. The neurofibrillary tangles (NFTs) and amyloid-ß plaques (APs) of Alzheimer's disease (AD) can cause PPA, but a quantitative investigation of the relationships between NFTs, APs and in vivo cortical atrophy in PPA-AD is lacking. The present study measured cortical atrophy from corresponding bilateral regions in five PPA-AD participants with in vivo magnetic resonance imaging scans 7-30 months before death and acquired stereologic estimates of NFTs and dense-core APs visualized with the Thioflavin-S stain. Linear mixed models accounting for repeated measures and stratified by hemisphere and region (language vs. non-language) were used to determine the relationships between cortical atrophy and AD neuropathology and their regional selectivity. Consistent with the aphasic profile of PPA, left language regions displayed more cortical atrophy (P = 0.01) and NFT densities (P = 0.02) compared to right language homologues. Left language regions also showed more cortical atrophy (P < 0.01) and NFT densities (P = 0.02) than left non-language regions. A subset of data was analyzed to determine the predilection of AD neuropathology for neocortical regions compared to entorhinal cortex in the left hemisphere, which showed that the three most atrophied language regions had greater NFT (P = 0.04) and AP densities (P < 0.01) than the entorhinal cortex. These results provide quantitative evidence that NFT accumulation in PPA selectively targets the language network and may not follow the Braak staging of neurofibrillary degeneration characteristic of amnestic AD. Only NFT densities, not AP densities, were positively associated with cortical atrophy within left language regions (P < 0.01) and right language homologues (P < 0.01). Given previous findings from amnestic AD, the current study of PPA-AD provides converging evidence that NFTs are the principal determinants of atrophy and clinical phenotypes associated with AD.

    View details for DOI 10.1111/bpa.12783

    View details for Web of Science ID 000486196000001

    View details for PubMedID 31446630

    View details for PubMedCentralID PMC7039764

  • Activated Microglia in Cortical White Matter Across Cognitive Aging Trajectories FRONTIERS IN AGING NEUROSCIENCE Gefen, T., Kim, G., Bolbolan, K., Geoly, A., Ohm, D., Oboudiyat, C., Shahidehpour, R., Rademaker, A., Weintraub, S., Bigio, E. H., Mesulam, M., Rogalski, E., Geula, C. 2019; 11: 94

    Abstract

    Activation of microglia, the primary mediators of inflammation in the brain, is a major component of gliosis and neuronal loss in a number of age-related neurodegenerative disorders, such as Alzheimer's disease (AD). The role of activated microglia in white matter, and its relationship with cognitive decline during aging are unknown. The current study evaluated microglia densities in the white matter of postmortem specimens from cognitively normal young adults, cognitively normal older adults, and cognitive "SuperAgers," a unique group of individuals over age 80 whose memory test scores are at a level equal to or better than scores of 50-to-65-year-olds. Whole hemisphere sections from cognitively normal old, young, and "SuperAgers" were used to quantify densities of human leukocyte antigen-D related (HLA-DR)-positive activated microglia underlying five cortical regions. Statistical findings showed a significant main effect of group on differences in microglia density where cognitively normal old showed highest densities. No difference between SuperAgers and young specimens were detected. In two autopsied SuperAgers with MRI FLAIR scans available, prominent hyperintensities in periventricular regions were observed, and interestingly, examination of corresponding postmortem sections showed only sparse microglia densities. In conclusion, activated microglia appear to respond to age-related pathologic changes in cortical white matter, and this phenomenon is largely spared in SuperAgers. Findings offer insights into the relationship between white matter neuroinflammatory changes and cognitive integrity during aging.

    View details for DOI 10.3389/fnagi.2019.00094

    View details for Web of Science ID 000468152600001

    View details for PubMedID 31139072

    View details for PubMedCentralID PMC6527736

  • Cortical cholinergic denervation in primary progressive aphasia with Alzheimer pathology NEUROLOGY Mesulam, M., Lalehzari, N., Rahmani, F., Ohm, D., Shahidehpour, R., Kim, G., Gefen, T., Weintraub, S., Bigio, E., Geula, C. 2019; 92 (14): E1580–E1588

    Abstract

    To investigate the status of the basal forebrain cholinergic system in primary progressive aphasia (PPA) as justification for cholinergic therapy.A cohort of 36 brains from PPA participants with the neuropathology of Alzheimer disease (PPA-AD, n = 14) or frontotemporal lobar degeneration (PPA-tau, n = 12; PPA-TDP, n = 10) were used for semiquantitative rating of degeneration and gliosis of basal forebrain cholinergic neurons (BFCN). A subpopulation of 5 PPA-AD and 7 control brains underwent detailed analysis of BFCN pathology and cortical cholinergic axonal loss employing immunohistochemical and histochemical methods and stereologic analysis.Semiquantitatively, 11 (∼80%) PPA-AD participants were rated as having moderate/severe BFCN loss and gliosis, whereas none of the PPA-tau and only 1 (10%) PPA-TDP participant received such a rating. Detailed analysis in the subpopulation of PPA-AD participants revealed substantial tangle formation, loss of BFCN, and degeneration of cortical cholinergic axons. Compared to controls, loss of p75 low affinity neurotrophin receptor-positive BFCN was detected in the PPA-AD participants (p < 0.01). Acetylcholinesterase-positive cholinergic axons in all cortical areas studied displayed loss in PPA-AD (p < 0.005-0.0001). The loss was more severe in the language-dominant left hemisphere and, within the left hemisphere, in language-affiliated cortical areas.Our results demonstrate prominent depletion of BFCN and cortical cholinergic axons in PPA-AD when compared with normal control or other neuropathologic variants of PPA. The demonstration of cholinergic denervation with an anatomy that fits the clinical picture suggests that cholinergic treatment is justified in patients with PPA who have positive AD biomarkers.

    View details for DOI 10.1212/WNL.0000000000007247

    View details for Web of Science ID 000480758600005

    View details for PubMedID 30842294

    View details for PubMedCentralID PMC6448447

  • Morphology and Distribution of TDP-43 Pre-inclusions in Primary Progressive Aphasia JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY Kim, G., Bolbolan, K., Shahidehpour, R., Jamshidi, P., Gefen, T., Ayala, I. A., Weintraub, S., Bigio, E. H., Mesulam, M., Geula, C. 2019; 78 (3): 229–37

    Abstract

    Diffusely stained phosphorylated 43-kDa TAR DNA-binding protein (TDP-43)-positive "pre-inclusions" have been described. This experiment investigated morphological subtypes of pre-inclusions and their relationship with TDP-43 inclusions in primary progressive aphasia (PPA), a dementia characterized by gradual dissolution of language. Brain sections from 5 PPA participants with postmortem diagnoses of frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) were immunohistochemically stained using an antibody to phosphorylated TDP-43 and quantitatively examined for regional and hemispheric distribution using unbiased stereology. Cortical TDP-43 pre-inclusions included smooth, granular/dot-like, or fibrillar staining with localization to the nucleus, cytoplasm, or both. Mature and pre-inclusions were quantified in a region with high and a region with low mature inclusion density, and contralateral homologs. Regions with lower mature inclusions were characterized by higher densities of pre-inclusions, while increasing burden of inclusions corresponded to lower densities of pre-inclusions (p < 0.05). Mature inclusions showed significant asymmetry that favored the language-dominant hemisphere (p < 0.01), while pre-inclusions displayed the opposite pattern (p < 0.01). Granular-type pre-inclusions were more abundant (p < 0.05) and drove the hemispheric and regional differences (p < 0.02). These results suggest that pre-inclusions are present in greater abundance prior to the formation of mature TDP-43 inclusions, and appear to develop through progressive stages into mature intracytoplasmic, or intranuclear aggregates.

    View details for DOI 10.1093/jnen/nlz005

    View details for Web of Science ID 000460628300004

    View details for PubMedID 30753613

    View details for PubMedCentralID PMC6380320

  • Combined Pathologies in FTLD-TDP Types A and C JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY Gefen, T., Ahmadian, S. S., Mao, Q., Kim, G., Seckin, M., Bonakdarpour, B., Ramos, E., Coppola, G., Rademakers, R., Rogalski, E., Rademaker, A., Weintraub, S., Mesulam, M., Geula, C., Bigio, E. H. 2018; 77 (5): 405–12

    Abstract

    This study investigated the presence of combined pathologies in a large cohort of autopsies that show a primary pathologic diagnosis of phosphorylated 43-kDa TAR DNA-binding protein (FTLD-TDP), the majority of which portrayed clinical phenotypes consistent with primary progressive aphasia or behavioral variant frontotemporal dementia (bvFTD). Thirty-eight cases with FTLD-TDP (30 type-A and 8 type-C) were identified to determine characteristic differences between cases with and without combined pathologies. Findings indicated that combined pathologies co-occur with FTLD-TDP type-A at a high frequency (50%)-greater than when compared to FTLD-TDP type-C cases (12.5%). Those with FTLD-TDP type-A and combined pathologies showed significantly longer lifespans (p < 0.05), and longer disease durations (p < 0.05), than those with only FTLD-TDP type-A. Cases with FTLD-TDP type-A and known genetic mutations tended not to show combined pathology. Those with the GRN mutation and FTLD-TDP type-A showed a significantly younger age of onset (p < 0.05) and younger age at death (p < 0.01) compared to noncarriers. In 1 bvFTD case, we highlight the rare presence of "triple" FTLD-TDP type-A, FTLD-tau, and Alzheimer pathology. The ante- and post-mortem features associated with combined pathologies in FTLD-related disorders are of useful consideration in the stratification of patients to drug trials, and in the development of therapeutic targets for FTLD.

    View details for DOI 10.1093/jnen/nly018

    View details for Web of Science ID 000432259700007

    View details for PubMedID 29584904

    View details for PubMedCentralID PMC6019001

  • Variations in Acetylcholinesterase Activity within Human Cortical Pyramidal Neurons Across Age and Cognitive Trajectories CEREBRAL CORTEX Janeczek, M., Gefen, T., Samimi, M., Kim, G., Weintraub, S., Bigio, E., Rogalski, E., Mesulam, M., Geula, C. 2018; 28 (4): 1329–37

    Abstract

    We described an extensive network of cortical pyramidal neurons in the human brain with abundant acetylcholinesterase (AChE) activity. Emergence of these neurons during childhood/adolescence, attainment of highest density in early adulthood, and virtual absence in other species led us to hypothesize involvement of AChE within these neurons in higher cortical functions. The current study quantified the density and staining intensity of these neurons using histochemical procedures. Few faintly stained AChE-positive cortical pyramidal neurons were observed in children/adolescents. These neurons attained their highest density and staining intensity in young adulthood. Compared with the young adult group, brains of cognitively normal elderly displayed no significant change in numerical density but a significant decrease in staining intensity of AChE-positive cortical pyramidal neurons. Brains of elderly above age 80 with unusually preserved memory performance (SuperAgers) showed significantly lower staining intensity and density of these neurons when compared with same-age peers. Conceivably, low levels of AChE activity could enhance the impact of acetylcholine on pyramidal neurons to counterbalance other involutional factors that mediate the decline of memory capacity during average aging. We cannot yet tell if elderly with superior memory capacity have constitutively low neuronal AChE levels or if this feature reflects adaptive neuroplasticity.

    View details for DOI 10.1093/cercor/bhx047

    View details for Web of Science ID 000428877200019

    View details for PubMedID 28334147

  • Asymmetric TDP pathology in primary progressive aphasia with right hemisphere language dominance NEUROLOGY Kim, G., Vahedi, S., Gefen, T., Weintraub, S., Bigio, E. H., Mesulam, M., Geula, C. 2018; 90 (5): E396-+

    Abstract

    To quantitatively examine the regional densities and hemispheric distribution of the 43-kDa transactive response DNA-binding protein (TDP-43) inclusions, neurons, and activated microglia in a left-handed patient with right hemisphere language dominance and logopenic-variant primary progressive aphasia (PPA).Phosphorylated TDP-43 inclusions, neurons, and activated microglia were visualized with immunohistochemical and histologic methods. Markers were quantified bilaterally with unbiased stereology in language- and memory-related cortical regions.Clinical MRI indicated cortical atrophy in the right hemisphere, mostly in the temporal lobe. Significantly higher densities of TDP-43 inclusions were present in right language-related temporal regions compared to the left or to other right hemisphere regions. The memory-related entorhinal cortex (ERC) and language regions without significant atrophy showed no asymmetry. Activated microglia displayed extensive asymmetry (R > L). A substantial density of neurons remained in all areas and showed no hemispheric asymmetry. However, perikaryal size was significantly smaller in the right hemisphere across all regions except the ERC. To demonstrate the specificity of this finding, sizes of residual neurons were measured in a right-handed case with PPA and were found to be smaller in the language-dominant left hemisphere.The distribution of TDP-43 inclusions and microglial activation in right temporal language regions showed concordance with anatomic distribution of cortical atrophy and clinical presentation. The results revealed no direct relationship between density of TDP-43 inclusions and activated microglia. Reduced size of the remaining neurons is likely to contribute to cortical atrophy detected by MRI. These findings support the conclusion that there is no obligatory relationship between logopenic PPA and Alzheimer pathology.

    View details for DOI 10.1212/WNL.0000000000004891

    View details for Web of Science ID 000427799000006

    View details for PubMedID 29305438

    View details for PubMedCentralID PMC5791793

  • Atrophy and microglial distribution in primary progressive aphasia with transactive response DNA-binding protein-43 kDa. Annals of neurology Kim, G. n., Bolbolan, K. n., Gefen, T. n., Weintraub, S. n., Bigio, E. H., Rogalski, E. n., Mesulam, M. M., Geula, C. n. 2018

    Abstract

    To quantitatively determine the density and distribution of activated microglia across cortical regions and hemispheres in the brains of primary progressive aphasia (PPA) participants with pathological diagnoses of frontotemporal lobar degeneration with transactive response DNA-binding protein-43 (TDP-43) inclusions and to examine the relationships between microglial densities, patterns of focal atrophy, (TDP-43) inclusions, and clinical phenotype.Activated microglia and TDP-43 inclusions were visualized in whole-hemisphere brain sections using immunohistochemical methods from five participants with PPA-TDP. Unbiased stereology was used to bilaterally quantify human leuckocyte antigen/D related-positive activated microglia and TDP-43 inclusions across five language-related regions. Density and distribution of both markers were compared across cortical regions and hemispheres, and their relationships to patterns of focal atrophy and clinical phenotype were determined.Activated microglia displayed asymmetric distribution favoring the language-dominant hemisphere, consistent with greater postmortem and/or in vivo atrophy in that hemisphere, in PPA-TDP. In one participant with no asymmetric atrophy, quantitative distribution of microglia also lacked asymmetry. Patterns of microglial activation also showed variation that favored areas of high atrophy in regions affiliated with language function, demonstrating concordance between patterns of microglial activation, atrophy, and clinical phenotype. TDP-43 also showed higher inclusion densities in areas of high atrophy than in regions with low atrophy, but no clear relationship with microglia density at a regional level.The initial activation of microglia is most likely a response to cortical abnormalities in PPA-TDP, which contribute to atrophy. The patterns of microglial activation, TDP-43 inclusion deposition, atrophy, and clinical phenotype suggest that activated microglia may make unique contributions to cortical thinning and TDP-43 inclusion formation. Ann Neurol 2018.

    View details for DOI 10.1002/ana.25240

    View details for PubMedID 29665116

  • Differential Neurotoxicity Related to Tetracycline Transactivator and TDP-43 Expression in Conditional TDP-43 Mouse Model of Frontotemporal Lobar Degeneration. The Journal of neuroscience : the official journal of the Society for Neuroscience Kukreja, L. n., Shahidehpour, R. n., Kim, G. n., Keegan, J. n., Sadleir, K. R., Russell, T. n., Csernansky, J. n., Mesulam, M. n., Vassar, R. J., Wang, L. n., Dong, H. n., Geula, C. n. 2018; 38 (27): 6045–62

    Abstract

    Frontotemporal lobar degeneration (FTLD) is among the most prevalent dementias of early-onset. Pathologically, FTLD presents with tauopathy or TAR DNA-binding protein 43 (TDP-43) proteinopathy. A biallelic mouse model of FTLD was produced on a mix FVB/129SVE background overexpressing wild-type human TDP-43 (hTDP-43) using tetracycline transactivator (tTA), a system widely used in mouse models of neurological disorders. tTA activates hTDP-43, which is placed downstream of the tetracycline response element. The original study on this transgenic mouse found hippocampal degeneration following hTDP-43 expression, but did not account for independent effects of tTA protein. Here, we initially analyzed the neurotoxic effects of tTA in postweaning age mice of either sex using immunostaining and area measurements of select brain regions. We observed tTA-dependent toxicity selectively in the hippocampus affecting the dentate gyrus significantly more than CA fields, whereas hTDP-43-dependent toxicity in bigenic mice occurred in most other cortical regions. Atrophy was associated with inflammation, activation of caspase-3, and loss of neurons. The atrophy associated with tTA expression was rescuable by the tetracycline analog, doxycycline, in the diet. MRI studies corroborated the patterns of atrophy. tTA-induced degeneration was strain-dependent and was rescued by moving the transgene onto a congenic C57BL/6 background. Despite significant hippocampal atrophy, behavioral tests in bigenic mice revealed no hippocampally mediated memory impairment. Significant atrophy in most cortical areas due solely to TDP-43 expression indicates that this mouse model remains useful for providing critical insight into co-occurrence of TDP-43 pathology, neurodegeneration, and behavioral deficits in FTLD.SIGNIFICANCE STATEMENT The tTA expression system has been widely used in mice to model neurological disorders. The technique allows investigators to reversibly turn on or off disease causing genes. Here, we report on a mouse model that overexpresses human TDP-43 using tTA and attempt to recapitulate features of TDP-43 pathology present in human FTLD. The tTA expression system is problematic, resulting in dramatic degeneration of the hippocampus. Thus, our study adds a note of caution for the use of the tTA system. However, because FTLD is primarily characterized by cortical degeneration and our mouse model shows significant atrophy in most cortical areas due to human TDP-43 overexpression, our animal model remains useful for providing critical insight on this human disease.

    View details for DOI 10.1523/JNEUROSCI.1836-17.2018

    View details for PubMedID 29807909

    View details for PubMedCentralID PMC6031584

  • Prominent microglial activation in cortical white matter is selectively associated with cortical atrophy in primary progressive aphasia. Neuropathology and applied neurobiology Ohm, D. T., Kim, G. n., Gefen, T. n., Rademaker, A. n., Weintraub, S. n., Bigio, E. H., Mesulam, M. M., Rogalski, E. n., Geula, C. n. 2018

    Abstract

    Primary progressive aphasia (PPA) is a clinical syndrome characterized by selective language impairments associated with focal cortical atrophy favouring the language dominant hemisphere. PPA is associated with Alzheimer's disease (AD), frontotemporal lobar degeneration (FTLD) and significant accumulation of activated microglia. Activated microglia can initiate an inflammatory cascade that may contribute to neurodegeneration, but their quantitative distribution in cortical white matter and their relationship with cortical atrophy remain unknown. We investigated white matter activated microglia and their association with grey matter atrophy in 10 PPA cases with either AD or FTLD-TDP pathology.Activated microglia were quantified with optical density measures of HLA-DR immunoreactivity in two regions with peak cortical atrophy, and one nonatrophied region within the language dominant hemisphere of each PPA case. Nonatrophied contralateral homologues of the language dominant regions were examined for hemispheric asymmetry.Qualitatively, greater densities of activated microglia were observed in cortical white matter when compared to grey matter. Quantitative analyses revealed significantly greater densities of activated microglia in the white matter of atrophied regions compared to nonatrophied regions in the language dominant hemisphere (P < 0.05). Atrophied regions of the language dominant hemisphere also showed significantly more activated microglia compared to contralateral homologues (P < 0.05).White matter activated microglia accumulate more in atrophied regions in the language dominant hemisphere of PPA. While microglial activation may constitute a response to neurodegenerative processes in white matter, the resultant inflammatory processes may also exacerbate disease progression and contribute to cortical atrophy.

    View details for DOI 10.1111/nan.12494

    View details for PubMedID 29679378

  • Asymmetric pathology in primary progressive aphasia with progranulin mutations and TDP inclusions NEUROLOGY Kim, G., Ahmadian, S. S., Peterson, M., Parton, Z., Memon, R., Weintraub, S., Rademaker, A., Bigio, E., Mesulam, M., Geula, C. 2016; 86 (7): 627–36

    Abstract

    To investigate quantitative regional distribution and hemispheric asymmetry of TDP-43 (TAR DNA-binding protein 43) inclusions, neurons, and activated microglia in primary progressive aphasia (PPA) with progranulin (GRN) mutations, and to determine concordance between distribution of pathology, clinical phenotype, and known atrophy patterns.Antibodies to phospho-TDP-43, NeuN (neuronal nuclei), and HLA-DR were used to visualize inclusions, neurons, and activated microglia in paraffin-embedded tissue sections from 4 participants with PPA: 2 of the agrammatic and 2 of the logopenic subtype. Unbiased stereological counting techniques were used for quantitation of immunoreactive profiles in language- and memory-related cortical areas bilaterally. Patterns of pathology across cortical areas and hemispheres were compared and their relationships with known patterns of atrophy investigated.Numerical densities of TDP-43 inclusions, and less so of activated microglia, were greater in language-related areas compared with memory-related areas. In language areas, neuronal density displayed a pattern opposite to inclusions and activated microglia. Densities of inclusions and microglia were greater (p < 0.05), and densities of neurons were lower (p < 0.005), in the left hemisphere compared with the right. In agrammatic PPA, the highest densities of TDP-43 inclusions were observed in left inferior or middle frontal gyri, and in logopenic participants, the highest density of inclusions was seen in left inferior parietal lobule. This distribution is consistent with subtype-specific peak atrophy sites.Distribution of TDP-43 inclusions and neurons, and to a smaller extent of activated microglia, show a regional and hemispheric pattern consistent with disease phenotype and known patterns of atrophy in PPA with GRN mutations.

    View details for DOI 10.1212/WNL.0000000000002375

    View details for Web of Science ID 000370299600007

    View details for PubMedID 26791154

    View details for PubMedCentralID PMC4762414

  • ACCUMULATION AND AGE-RELATED ELEVATION OF AMYLOID-beta WITHIN BASAL FOREBRAIN CHOLINERGIC NEURONS IN THE RHESUS MONKEY NEUROSCIENCE Norvin, D., Kim, G., Baker-Nigh, A., Geula, C. 2015; 298: 102–11

    Abstract

    Basal forebrain cholinergic neurons (BFCN) are selectively vulnerable to damage and loss in a number of neurodegenerative disorders that afflict the elderly, particularly Alzheimer's disease. The reasons for this selective vulnerability remain poorly understood. Given that intraneuronal accumulation of the amyloid-β peptide (Aβ) has been shown to exert deleterious effects on neurons, we tested potential accumulation of Aβ within BFCN in rhesus monkeys, which like the human display age-related accumulation of this peptide in plaques. The non-isoform-specific Aβ antibodies 1282 and 6E10 and the specific antibodies to 1-40 amino acid isoform of Aβ (Aβ1-40) and 1-42 amino acid isoform of Aβ (Aβ1-42) species were used in immunohistochemical experiments of basal forebrain in young and aged rhesus monkeys. All four antibodies visualized cortical plaques in the same sections in which BFCN were examined, in aged but not in young animals. The basal forebrain region within which the BFCN are localized was virtually free of plaques. Appreciable Aβ immunoreactivity was present within the nucleus basalis of Meynert-cholinergic cell group 4 (nbM-Ch4), the major component of BFCN, with all antibodies used. Quantitation of optical density indicated significant age-related increases in immunoreactivity in nbM-Ch4 neurons with the Aβ1-40 (p<0.002) and 1282 (p<0.03) antibodies. Immunoreactivity for 6E10 displayed a small, non-significant age-related increase in nbM-Ch4 neurons (p>0.05). No age-related changes were detected in Aβ1-42 immunoreactivity in these neurons. Unlike the BFCN, cortical neurons within the same sections were virtually devoid of Aβ immunoreactivity, particularly with isoform-specific antibodies. Both smooth and granular intraneuronal Aβ immunoreactivity, reminiscent of endosomal/lysosomal packaged peptide, were observed within nbM-Ch4 neurons. In some nbM-Ch4 neurons, 1282 immunoreactivity had the appearance of large peptide aggregates. Significant accumulation and age-related increase of Aβ in BFCN is likely to interfere with the normal functioning of these neurons. It remains to be determined if similar accumulation of Aβ occurs in human BFCN.

    View details for DOI 10.1016/j.neuroscience.2015.04.011

    View details for Web of Science ID 000354783300010

    View details for PubMedID 25869619

  • HISTOPATHOLOGIC SUBSTRATES OF CINGULATE INTEGRITY IN SUPERAGING: A STEREOLOGICAL STUDY Gefen, T., Papastefan, S., Peterson, M., Kim, G., Rogalski, E., Weintraub, S., Bigio, E., Mesulam, M., Geula, C. ELSEVIER SCIENCE INC. 2014: 718