Biomedical Research Institute of New Jersey

Cedar Glen West, NJ, United States

Biomedical Research Institute of New Jersey

Cedar Glen West, NJ, United States

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Iacono D.,Biomedical Research Institute of New Jersey | Iacono D.,Atlantic Neuroscience Institute | Iacono D.,Mount Sinai School of Medicine | Geraci-Erck M.,Biomedical Research Institute of New Jersey | And 6 more authors.
Neurology | Year: 2015

Objective: To quantify the loss of pigmented neurons in the substantia nigra (SN) of autopsy-confirmed Parkinson disease (PD) and incidental Lewy body disease (ILBD) vs age-matched controls (C). Methods: Unbiased stereology methods were used to rigorously count number and measure volumes of nigral pigmented neurons in PD, ILBD, and C brains. The obtained stereologic results were correlated with Lewy body (LB), amyloid plaque (AP), neurofibrillary tangle (NFT), and vascular pathology loads assessed in nigral and extranigral regions of each PD, ILBD, and C brain. The stereologic measurements were also correlated to predeath motor and cognitive scores as available for each participant. Results: A marked nigral neuronal loss (NNL) in PD (-82%) and ILBD (-40%) compared to C (p < 0.0001) was found. While there was significant correlation between NNL and LB in some cortical areas of PD (i.e., olfactory bulb), there were no correlations between NNL and LB, AP, or NFT loads or cerebral infarct volumes in any other examined regions for PD and ILBD brains. Conclusions: Using unbiased stereology methods, we show that there is a significant loss and absence of hypertrophic changes in nigral pigmented neurons of ILBD in comparison to C brains. Intriguingly, no significant correlations were found between NNL and LB loads in the SN of both PD and ILBD brains. These autopsy-verified stereologically based findings are novel and support ILBD as a pathologic condition. These results suggest possible new and alternative pathophysiologic hypotheses on the actual relationship between NNL and LB pathology. © 2015 American Academy of Neurology.


Iacono D.,Johns Hopkins University | Iacono D.,Biomedical Research Institute of New Jersey | Iacono D.,Atlantic Neuroscience Institute | Zandi P.,Johns Hopkins University | And 5 more authors.
Oncotarget | Year: 2015

Asymptomatic Alzheimer's disease (ASYMAD) subjects are individuals characterized by preserved cognition before death despite substantial AD pathology at autopsy. ASYMAD subjects show comparable levels of AD pathology, i.e. β-amyloid neuritic plaques (Aβ-NP) and tau-neurofibrillary tangles (NFT), to those observed in mild cognitive impairment (MCI) and some definite AD cases. Previous clinicopathologic studies on ASYMAD subjects have shown specific phenomena of hypertrophy in the cell bodies, nuclei, and nucleoli of hippocampal pyramidal neurons and other cerebral areas. Since it is well established that the allele APOε4 is a major genetic risk factor for AD, we examined whether specific alleles of APOE could be associated with the different clinical outcomes between ASYMAD and MCI subjects despite equivalent AD pathology. A total of 523 brains from the Nun Study were screened for this investigation. The results showed higher APOε2 frequency (p < 0.001) in ASYMAD (19.2%) vs. MCI (0%) and vs. AD (4.7%). Furthermore, higher education in ASYMAD vs. MCI and AD (p < 0.05) was found. These novel autopsy-verified findings support the hypothesis of the beneficial effect of APOε2 and education, both which seem to act as contributing factors in delaying or forestalling the clinical manifestations of AD despite consistent levels of AD pathology.


PubMed | Mount Sinai School of Medicine, Atlantic Neuroscience Institute and Biomedical Research Institute of New Jersey
Type: | Journal: Tremor and other hyperkinetic movements (New York, N.Y.) | Year: 2015

Dystonias (Dys) represent the third most common movement disorder after essential tremor (ET) and Parkinsons disease (PD). While some pathogenetic mechanisms and genetic causes of Dys have been identified, little is known about their neuropathologic features. Previous neuropathologic studies have reported generically defined neuronal loss in various cerebral regions of Dys brains, mostly in the basal ganglia (BG), and specifically in the substantia nigra (SN). Enlarged pigmented neurons in the SN of Dys patients with and without specific genetic mutations (e.g., GAG deletions in DYT1 dystonia) have also been described. Whether or not Dys brains are associated with decreased numbers or other morphometric changes of specific neuronal types is unknown and has never been addressed with quantitative methodologies.Quantitative immunohistochemistry protocols were used to estimate neuronal counts and volumes of nigral pigmented neurons in 13 SN of Dys patients and 13 SN of age-matched control subjects (C).We observed a significant reduction (20%) of pigmented neurons in the SN of Dys compared to C (p<0.01). Neither significant volumetric changes nor evident neurodegenerative signs were observed in the remaining pool of nigral pigmented neurons in Dys brains. These novel quantitative findings were confirmed after exclusion of possible co-occurring SN pathologies including Lewy pathology, tau-neurofibrillary tangles, -amyloid deposits, ubiquitin (ubiq), and phosphorylated-TAR DNA-binding protein 43 (pTDP43)-positive inclusions.A reduced number of nigral pigmented neurons in the absence of evident neurodegenerative signs in Dys brains could indicate previously unconsidered pathogenetic mechanisms of Dys such as neurodevelopmental defects in the SN.


Iacono D.,Johns Hopkins University | Iacono D.,Biomedical Research Institute of New Jersey | Resnick S.M.,U.S. National Institute on Aging | O'Brien R.,Johns Hopkins University | And 6 more authors.
Journal of Neuropathology and Experimental Neurology | Year: 2014

Older adults with intact cognition before death and substantial Alzheimer disease (AD) lesions at autopsy have been termed "asymptomatic AD subjects" (ASYMAD). We previously reported hypertrophy of neuronal cell bodies, nuclei, and nucleoli in the CA1 of the hippocampus (CA1), anterior cingulate gyrus, posterior cingulate gyrus, and primary visual cortex of ASYMAD versus age-matched Control and mild cognitive impairment (MCI) subjects. However, it was unclear whether the neuronal hypertrophy could be attributed to differences in the severity of AD pathology. Here, we performed quantitative analyses of the severity of β-amyloid (Aβ) and phosphorylated tau (tau) loads in the brains of ASYMAD, Control, MCI, and AD subjects (n = 15 per group) from the Baltimore Longitudinal Study of Aging. Tissue sections from CA1, anterior cingulate gyrus, posterior cingulate gyrus, and primary visual cortex were immunostained for Aβ and tau; the respective loads were assessed using unbiased stereology by measuring the fractional areas of immunoreactivity for each protein in each region. The ASYMAD and MCI groups did not differ in Aβ and tau loads. These data confirm that ASYMAD and MCI subjects have comparable loads of insoluble Aβ and tau in regions vulnerable to AD pathology despite divergent cognitive outcomes. These findings imply that cognitive impairment in AD may be caused or modulated by factors other than insoluble forms of Aβ and tau. © 2014 by the American Association of Neuropathologists, Inc.


Pappolla M.,University of Texas Medical Branch | Sambamurti K.,Medical University of South Carolina | Vidal R.,Indiana University | Pacheco-Quinto J.,Biomedical Research Institute of New Jersey | And 2 more authors.
Neurobiology of Disease | Year: 2014

Evidence has shown that lymphatic drainage contributes to removal of debris from the brain but its role in the accumulation of amyloid β peptides (Aβ) has not been demonstrated. We examined the levels of various forms of Aβ in the brain, plasma and lymph nodes in a transgenic model of Alzheimer's disease (AD) at different ages. Herein, we report on the novel finding that Aβ is present in the cervical and axillary lymph nodes of AD transgenic mice and that Aβ levels in lymph nodes increase over time, mirroring the increase of Aβ levels observed in the brain. Aβ levels in lymph nodes were significantly higher than in plasma. At age 15.5. months, there was a significant increase of monomeric soluble Aβ40 (p= 0.003) and Aβ42 (p= 0.05) in the lymph nodes over the baseline values measured at 6. months of age. In contrast, plasma levels of Aβ40 showed no significant changes (p= 0.68) and plasma levels Aβ42 significantly dropped (p= 0.02) at the same age. Aβ concentration was low to undetectable in splenic lymphoid tissue and several other control tissues including heart, lung, liver, kidneys and intestine of the same animals, strongly suggesting that Aβ peptides in lymph nodes are derived from the brain. © 2014 Elsevier Inc.


PubMed | Indiana University, University of Texas Medical Branch, Hirosaki University, Medical University of South Carolina and 2 more.
Type: | Journal: Neurobiology of disease | Year: 2014

Evidence has shown that lymphatic drainage contributes to removal of debris from the brain but its role in the accumulation of amyloid peptides (A) has not been demonstrated. We examined the levels of various forms of A in the brain, plasma and lymph nodes in a transgenic model of Alzheimers disease (AD) at different ages. Herein, we report on the novel finding that A is present in the cervical and axillary lymph nodes of AD transgenic mice and that A levels in lymph nodes increase over time, mirroring the increase of A levels observed in the brain. A levels in lymph nodes were significantly higher than in plasma. At age 15.5months, there was a significant increase of monomeric soluble A40 (p=0.003) and A42 (p=0.05) in the lymph nodes over the baseline values measured at 6months of age. In contrast, plasma levels of A40 showed no significant changes (p=0.68) and plasma levels A42 significantly dropped (p=0.02) at the same age. A concentration was low to undetectable in splenic lymphoid tissue and several other control tissues including heart, lung, liver, kidneys and intestine of the same animals, strongly suggesting that A peptides in lymph nodes are derived from the brain.


Pacheco-Quinto J.,Biomedical Research Institute of New Jersey | Eckman E.A.,Biomedical Research Institute of New Jersey
Journal of Biological Chemistry | Year: 2013

Background: Endothelin-converting enzymes (ECEs) degrade α-amyloid (Aα) peptide. Results: ECE inhibition produces, in addition to extracellular Aα accumulation, intracellular Aα accumulation within endosomal/ lysosomal and autophagic vesicles. Conclusion: An intracellular pool of Aα is regulated by ECE activity at the sites of production. Significance: ECE dysfunction may cause intraneuronal Aα accumulation, which is associated with neurotoxicity early in AD progression. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.


Pacheco-Quinto J.,Biomedical Research Institute of New Jersey | Herdt A.,Biomedical Research Institute of New Jersey | Eckman C.B.,Biomedical Research Institute of New Jersey | Eckman E.A.,Biomedical Research Institute of New Jersey
Journal of Alzheimer's Disease | Year: 2013

The efficient clearance of amyloid-β (Aβ) is essential to modulate levels of the peptide in the brain and to prevent it from accumulating in senile plaques, a hallmark of Alzheimer's disease (AD) pathology. We and others have shown that failure in Aβ catabolism can produce elevations in Aβ concentration similar to those observed in familial forms of AD. Based on the available evidence, it remains plausible that in late-onset AD, disturbances in the activity of Aβ degrading enzymes could induce Aβ accumulation, and that this increase could result in AD pathology. The following review presents a historical perspective of the parallel discovery of three vasopeptidases (neprilysin and endothelin-converting enzymes-1 and -2) as important Aβ degrading enzymes. The recognition of the role of these vasopeptidases in Aβ degradation, beyond bringing to light a possible explanation of how cardiovascular risk factors may influence AD risk, highlights a possible risk of the use of inhibitors of these enzymes for other clinical indications such as hypertension. We will discuss in detail the experiments conducted to assess the impact of vasopeptidase deficiency (through pharmacological inhibition or genetic mutation) on Aβ accumulation, as well as the cooperative effect of multiple Aβ degrading enzymes to regulate the concentration of the peptide at multiple sites, both intracellular and extracellular, throughout the brain. © 2013 - IOS Press and the authors. All rights reserved.


Pacheco-Quinto J.,Atlantic Health System | Pacheco-Quinto J.,Biomedical Research Institute of New Jersey | Eckman C.B.,Atlantic Health System | Eckman C.B.,Biomedical Research Institute of New Jersey | And 2 more authors.
Neurobiology of Aging | Year: 2016

Impaired clearance of amyloid-β peptide (Aβ) has been postulated to significantly contribute to the amyloid accumulation typical of Alzheimer's disease. Among the enzymes known to degrade Aβ in vivo are endothelin-converting enzyme (ECE)-1, ECE-2, and neprilysin (NEP), and evidence suggests that they regulate independent pools of Aβ that may be functionally significant. To better understand the differential regulation of Aβ concentration by its physiological degrading enzymes, we characterized the cell and region-specific expression pattern of ECE-1, ECE-2, and NEP by in situ hybridization and immunohistochemistry in brain areas relevant to Alzheimer's disease. In contrast to the broader distribution of ECE-1, ECE-2 and NEP were found enriched in GABAergic neurons. ECE-2 was majorly expressed by somatostatin-expressing interneurons and was active in isolated synaptosomes. NEP messenger RNA was found mainly in parvalbumin-expressing interneurons, with NEP protein localized to perisomatic parvalbuminergic synapses. The identification of somatostatinergic and parvalbuminergic synapses as hubs for Aβ degradation is consistent with the possibility that Aβ may have a physiological function related to the regulation of inhibitory signaling. © 2016 Elsevier Inc.


Impaired clearance of amyloid- peptide (A) has been postulated to significantly contribute to the amyloid accumulation typical of Alzheimers disease. Among the enzymes known to degrade A invivo are endothelin-converting enzyme (ECE)-1, ECE-2, and neprilysin (NEP), and evidence suggests that they regulate independent pools of A that may be functionally significant. To better understand the differential regulation of A concentration by its physiological degrading enzymes, we characterized the cell and region-specific expression pattern of ECE-1, ECE-2, and NEP by in situ hybridization and immunohistochemistry in brain areas relevant to Alzheimers disease. In contrast to the broader distribution of ECE-1, ECE-2 and NEP were found enriched in GABAergic neurons. ECE-2 was majorly expressed by somatostatin-expressing interneurons and was active in isolated synaptosomes. NEP messenger RNA was found mainly in parvalbumin-expressing interneurons, with NEP protein localized to perisomatic parvalbuminergic synapses. The identification of somatostatinergic and parvalbuminergic synapses as hubs for A degradation is consistent with the possibility that A may have a physiological function related to the regulation of inhibitory signaling.

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