Major discoveries in the biology of nervous system tumors have raised the question of how non-histological data such as molecular information can be incorporated into the next World Health Organization (WHO) classification of central nervous system tumors. To address this question, a meeting of neuropathologists with expertise in molecular diagnosis was held in Haarlem, the Netherlands, under the sponsorship of the International Society of Neuropathology (ISN). Prior to the meeting, participants solicited input from clinical colleagues in diverse neuro-oncological specialties. The present "white paper" catalogs the recommendations of the meeting, at which a consensus was reached that incorporation of molecular information into the next WHO classification should follow a set of provided "ISN-Haarlem" guidelines. Salient recommendations include that (i) diagnostic entities should be defined as narrowly as possible to optimize interobserver reproducibility, clinicopathological predictions and therapeutic planning; (ii) diagnoses should be "layered" with histologic classification, WHO grade and molecular information listed below an "integrated diagnosis"; (iii) determinations should be made for each tumor entity as to whether molecular information is required, suggested or not needed for its definition; (iv) some pediatric entities should be separated from their adult counterparts; (v) input for guiding decisions regarding tumor classification should be solicited from experts in complementary disciplines of neuro-oncology; and (iv) entity-specific molecular testing and reporting formats should be followed in diagnostic reports. It is hoped that these guidelines will facilitate the forthcoming update of the fourth edition of the WHO classification of central nervous system tumors.
Repetitive brain trauma is associated with a progressive neurological deterioration, now termed as chronic traumatic encephalopathy ( CTE ). Most instances of CTE occur in association with the play of sports, but CTE has also been reported in association with blast injuries and other neurotrauma. Symptoms of CTE include behavioral and mood changes, memory loss, cognitive impairment and dementia. Like many other neurodegenerative diseases, CTE is diagnosed with certainty only by neuropathological examination of brain tissue. CTE is a tauopathy characterized by the deposition of hyperphosphorylated tau (p‐tau) protein as neurofibrillary tangles, astrocytic tangles and neurites in striking clusters around small blood vessels of the cortex, typically at the sulcal depths. Severely affected cases show p‐tau pathology throughout the brain. Abnormalities in phosphorylated 43 k D a TAR DNA ‐binding protein are found in most cases of CTE ; beta‐amyloid is identified in 43%, associated with age. Given the importance of sports participation and physical exercise to physical and psychological health as well as disease resilience, it is critical to identify the genetic risk factors for CTE as well as to understand how other variables, such as stress, age at exposure, gender, substance abuse and other exposures, contribute to the development of CTE .
While a history of a single traumatic brain injury (TBI) is associated with the later development of syndromes of cognitive impairment such as Alzheimer's disease, the long‐term pathology evolving after single TBI is poorly understood. However, a progressive tauopathy, chronic traumatic encephalopathy, is described in selected cohorts with a history of repetitive concussive/mild head injury. Here, post‐mortem brains from long‐term survivors of just a single TBI (1–47 years survival; n = 39) vs. uninjured, age‐matched controls (n = 47) were examined for neurofibrillary tangles (NFTs) and amyloid‐β (Aβ) plaques using immunohistochemistry and thioflavine‐S staining. Detailed maps of findings permitted classification of pathology using semiquantitative scoring systems. NFTs were exceptionally rare in young, uninjured controls, yet were abundant and widely distributed in approximately one‐third of TBI cases. In addition, Aβ‐plaques were found in a greater density following TBI vs. controls. Moreover, thioflavine‐S staining revealed that while all plaque‐positive control cases displayed predominantly diffuse plaques, 64% of plaque‐positive TBI cases displayed predominantly thioflavine‐S‐positive plaques or a mixed thioflavine‐S‐positive/diffuse pattern. These data demonstrate that widespread NFT and Aβ plaque pathologies are present in up to a third of patients following survival of a year or more from a single TBI. This suggests that a single TBI induces long‐term neuropathological changes akin to those found in neurodegenerative disease.
Somatic mutations of the H3F3A and HIST1H3B genes encoding the histone H3 variants, H3.3 and H3.1, were recently identified in high‐grade gliomas arising in the thalamus, pons and spinal cord of children and young adults. However, the complete range of patients and locations in which these tumors arise, as well as the morphologic spectrum and associated genetic alterations remain undefined. Here, we describe a series of 47 diffuse midline gliomas with histone H3‐K27M mutation. The 25 male and 22 female patients ranged in age from 2 to 65 years (median = 14). Tumors were centered not only in the pons, thalamus, and spinal cord, but also in the third ventricle, hypothalamus, pineal region and cerebellum. Patients with pontine tumors were younger (median = 7 years) than those with thalamic (median = 24 years) or spinal (median = 25 years) tumors. A wide morphologic spectrum was encountered including gliomas with giant cells, epithelioid and rhabdoid cells, primitive neuroectodermal tumor (PNET)‐like foci, neuropil‐like islands, pilomyxoid features, ependymal‐like areas, sarcomatous transformation, ganglionic differentiation and pleomorphic xanthoastrocytoma (PXA)‐like areas. In this series, histone H3‐K27M mutation was mutually exclusive with IDH1 mutation and EGFR amplification, rarely co‐occurred with BRAF‐V600E mutation, and was commonly associated with p53 overexpression, ATRX loss (except in pontine gliomas), and monosomy 10.
Heterozygous point mutations of isocitrate dehydrogenase (IDH)1 codon 132 are frequent in grade II and III gliomas. Recently, we reported an antibody specific for the IDH1R132H mutation. Here we investigate the capability of this antibody to differentiate wild type and mutated IDH1 protein in central nervous system (CNS) tumors by Western blot and immunohistochemistry. Results of protein analysis are correlated to sequencing data. In Western blot, anti-IDH1R132H mouse monoclonal antibody mIDH1R132H detected a specific band only in mutated tumors. Immunohistochemistry of 345 primary brain tumors demonstrated a strong cytoplasmic and weaker nuclear staining in 122 cases. Correlation with direct sequencing of 186 cases resulted in consensus of 177 cases. Genetic retesting of cases with conflicting findings resulted in a match of 186/186 cases, with all discrepancies resolving in favor of immunohistochemistry. Intriguing is the ability of mIDH1R132H to detect single infiltrating tumor cells. The very high frequency and the distribution of this mutation among specific brain tumor entities allow the highly sensitive and specific discrimination of various tumors by immunohistochemistry, such as anaplastic astrocytoma from primary glioblastoma or diffuse astrocytoma World Health Organization (WHO) grade II from pilocytic astrocytoma or ependymoma. Noteworthy is the discrimination of the infiltrating edge of tumors with IDH1 mutation from reactive gliosis.
Neurovascular dysfunction contributes to A lzheimer's disease ( AD ). Cerebrovascular abnormalities and blood–brain barrier ( BBB ) damage have been shown in AD . The BBB dysfunction can lead to leakage of potentially neurotoxic plasma components in brain that may contribute to neuronal injury. Pericytes are integral in maintaining the BBB integrity. Pericyte‐deficient mice develop a chronic BBB damage preceding neuronal injury. Moreover, loss of pericytes was associated with BBB breakdown in patients with amyotrophic lateral sclerosis. Here, we demonstrate a decrease in mural vascular cells in AD , and show that pericyte number and coverage in the cortex and hippocampus of AD subjects compared with neurologically intact controls are reduced by 59% and 60% ( P < 0.01), and 32% and 33% ( P < 0.01), respectively. An increase in extravascular immunoglobulin G ( IgG ) and fibrin deposition correlated with reductions in pericyte coverage in AD cases compared with controls; the Pearson's correlation coefficient r for the magnitude of BBB breakdown to IgG and fibrin vs. reduction in pericyte coverage was −0.96 ( P < 0.01) and −0.81 ( P < 0.01) in the cortex, respectively, and −0.86 ( P < 0.01) and −0.98 ( P < 0.01) in the hippocampus, respectively. Thus, deficiency in mural vascular cells may contribute to disrupted vascular barrier properties and resultant neuronal dysfunction during AD pathogenesis.
Neuromyelitis optica ( NMO ) is a disabling autoimmune astrocytopathy characterized by typically severe and recurrent attacks of optic neuritis and longitudinally extensive myelitis. Until recently, NMO was considered an acute aggressive variant of multiple sclerosis ( MS ), despite the fact that early studies postulated that NMO and MS may be two distinct diseases with a common clinical picture. With the discovery of a highly specific serum autoantibody ( NMO ‐ IgG ), Lennon and colleagues provided the first unequivocal evidence distinguishing NMO from MS and other central nervous system ( CNS ) inflammatory demyelinating disorders. The target antigen of NMO ‐ IgG was confirmed to be aquaporin‐4 ( AQP4 ), the most abundant water channel protein in the CNS , mainly expressed on astrocytic foot processes at the blood–brain barrier, subpial and subependymal regions. Pathological studies demonstrated that astrocytes were selectively targeted in NMO as evidenced by the extensive loss of immunoreactivities for the astrocytic proteins, AQP4 and glial fibrillary acidic protein ( GFAP ), as well as perivascular deposition of immunoglobulins and activation of complement even within lesions with a relative preservation of myelin. In support of these pathological findings, GFAP levels in the cerebrospinal fluid ( CSF ) during acute NMO exacerbations were found to be remarkably elevated in contrast to MS where CSF ‐ GFAP levels did not substantially differ from controls. Additionally, recent experimental studies showed that AQP4 antibody is pathogenic, resulting in selective astrocyte destruction and dysfunction in vitro , ex vivo and in vivo . These findings strongly suggest that NMO is an autoimmune astrocytopathy where damage to astrocytes exceeds both myelin and neuronal damage. This chapter will review recent neuropathological studies that have provided novel insights into the pathogenic mechanisms, cellular targets, as well as the spectrum of tissue damage in NMO .
Diffuse astrocytoma of World Health Organization (WHO) grade II has an inherent tendency to spontaneously progress to anaplastic astrocytoma WHO grade III or secondary glioblastoma WHO grade IV. We explored the role of microRNAs (miRNAs) in glioma progression by investigating the expression profiles of 157 miRNAs in four patients with primary WHO grade II gliomas that spontaneously progressed to WHO grade IV secondary glioblastomas. Thereby, we identified 12 miRNAs (miR-9, miR-15a, miR-16, miR-17, miR-19a, miR-20a, miR-21, miR-25, miR-28, miR-130b, miR-140 and miR-210) showing increased expression, and two miRNAs (miR-184 and miR-328) showing reduced expression upon progression. Validation experiments on independent series of primary low-grade and secondary high-grade astrocytomas confirmed miR-17 and miR-184 as promising candidates, which were selected for functional analyses. These studies revealed miRNA-specific influences on the viability, proliferation, apoptosis and invasive growth properties of A172 and T98G glioma cells in vitro. Using mRNA and protein expression profiling, we identified distinct sets of transcripts and proteins that were differentially expressed after inhibition of miR-17 or overexpression of miR-184 in glioma cells. Taken together, our results support an important role of altered miRNA expression in gliomas, and suggest miR-17 and miR-184 as interesting candidates contributing to glioma progression.
The 18 kDa translocator protein ( TSPO ), previously known as the peripheral benzodiazepine receptor, is expressed in the injured brain. It has become known as an imaging marker of “neuroinflammation” indicating active disease, and is best interpreted as a nondiagnostic biomarker and disease staging tool that refers to histopathology rather than disease etiology. The therapeutic potential of TSPO as a drug target is mostly based on the understanding that it is an outer mitochondrial membrane protein required for the translocation of cholesterol, which thus regulates the rate of steroid synthesis. This pivotal role together with the evolutionary conservation of TSPO has underpinned the belief that any loss or mutation of TSPO should be associated with significant physiological deficits or be outright incompatible with life. However, against prediction, full Tspo knockout mice are viable and across their lifespan do not show the phenotype expected if cholesterol transport and steroid synthesis were significantly impaired. Thus, the “translocation” function of TSPO remains to be better substantiated. Here, we discuss the literature before and after the introduction of the new nomenclature for TSPO and review some of the newer findings. In light of the controversy surrounding the function of TSPO , we emphasize the continued importance of identifying compounds with confirmed selectivity and suggest that TSPO expression is analyzed within specific disease contexts rather than merely equated with the reified concept of “neuroinflammation.”
There are over 120 types of brain tumor and approximately 45% of primary brain tumors are gliomas, of which glioblastoma multiforme ( GBM ) is the most common and aggressive with a median survival rate of 14 months. Despite progress in our knowledge, current therapies are unable to effectively combat primary brain tumors and patient survival remains poor. Tumor metabolism is important to consider in therapeutic approaches and is the focus of numerous research investigations. Lactate dehydrogenase A ( LDHA ) is a cytosolic enzyme, predominantly involved in anaerobic and aerobic glycolysis (the W arburg effect); however, it has multiple additional functions in non‐neoplastic and neoplastic tissues, which are not commonly known or discussed. This review summarizes what is currently known about the function of LDHA and identifies areas that would benefit from further exploration. The current knowledge of the role of LDHA in the brain and its potential as a therapeutic target for brain tumors will also be highlighted. The W arburg effect appears to be universal in tumors, including primary brain tumors, and LDHA (because of its involvement with this process) has been identified as a potential therapeutic target. Currently, there are, however, no suitable LDHA inhibitors available for tumor therapies in the clinic.
Antibodies to aquaporin‐4 (called NMO ‐ IgG or AQP4‐Ab ) constitute a sensitive and highly specific serum marker of neuromyelitis optica ( NMO ) that can facilitate the differential diagnosis of NMO and classic multiple sclerosis. NMO ‐ IgG / AQP4‐Ab seropositive status has also important prognostic and therapeutic implications in patients with isolated longitudinally extensive myelitis ( LETM ) or optic neuritis ( ON ). In this article, we comprehensively review and critically appraise the existing literature on NMO ‐ IgG / AQP4‐Ab testing. All available immunoassays—including tissue‐based ( IHC ), cell‐based ( ICC , FACS ) and protein‐based ( RIPA , FIPA , ELISA , W estern blotting) assays—and their differential advantages and disadvantages are discussed. Estimates for sensitivity, specificity, and positive and negative likelihood ratios are calculated for all published studies and accuracies of the various immunoassay techniques compared. Subgroup analyses are provided for NMO , LETM and ON , for relapsing vs. monophasic disease, and for various control groups (eg, MS vs. other controls). Numerous aspects of NMO ‐ IgG / AQP4‐Ab testing relevant for clinicians (eg, impact of antibody titers and longitudinal testing, indications for repeat testing, relevance of CSF testing and subclass analysis, NMO ‐ IgG / AQP4‐Ab in patients with rheumatic diseases) as well as technical aspects (eg, AQP4‐M1 vs. AQP4‐M23 ‐based assays, intact AQP4 vs. peptide substrates, effect of storage conditions and freeze/thaw cycles) and pitfalls are discussed. Finally, recommendations for the clinical application of NMO ‐ IgG / AQP4‐Ab serology are given.
Alzheimer's disease is the commonest dementia. One major characteristic of its pathology is accumulation of amyloid-beta (A beta) as insoluble deposits in brain parenchyma and in blood vessel walls [cerebral amyloid angiopathy (CAA)]. The distribution of A beta deposits in the basement membranes of cerebral capillaries and arteries corresponds to the perivascular drainage pathways by which interstitial fluid (ISF) and solutes are eliminated from the brain-effectively the lymphatic drainage of the brain. Theoretical models suggest that vessel pulsations supply the motive force for perivascular drainage of ISF and solutes. As arteries stiffen with age, the amplitude of pulsations is reduced and insoluble A beta is deposited in ISF drainage pathways as CAA, thus, further impeding the drainage of soluble A beta. Failure of perivascular drainage of A beta and deposition of A beta in the walls of arteries has two major consequences: (i) intracerebral hemorrhage associated with rupture of A beta-laden arteries in CAA; and (ii) Alzheimer's disease in which failure of elimination of ISF, A beta and other soluble metabolites from the brain alters homeostasis and the neuronal environment resulting in cognitive decline and dementia. Therapeutic strategies that improve elimination of A beta and other soluble metabolites from the brain may prevent cognitive decline in Alzheimer's disease.
Pediatric cortical glioneuronal benign tumors mainly include gangliogliomas ( GG ) [differential diagnoses pilocytic astrocytomas ( PA ) and pleomorphic xanthoastrocytomas ( PXA )] and dysembryoplastic neuroepithelial tumor ( DNT ). DNT include the specific form and the controversial non‐specific form that lack the specific glioneuronal element. Our aims were to search for BRAF V600E mutation and CD 34 expression in DNT , PXA , GG and PA to correlate BRAF V600E mutation with BRAF V600E expression and to evaluate their diagnostic and prognostic values. Ninety‐six children were included. BRAF V600E mutation was studied by sequencing and immunohistochemistry; CD 34 expression was analyzed by immunohistochemistry. BRAF V600E mutation was detected in PXA (60%), GG (38.7%), DNT (30%, including 3/11 specific and 3/9 non‐specific forms) and PA (12.5%). BRAF V600E expression was recorded in PXA (60%), GG (45.2%) and DNT (30%). CD34 expression was recorded in PXA (60%), GG (58.1%), DNT (25%) and PA (12.5%). Neither CD 34 expression nor BRAF V600E status was predictive of prognosis, except for PA tumors where CD 34 expression was associated with a shorter overall survival. In conclusion, DNT shared with PXA and GG , BRAF V600E mutation and/or CD 34 expression, which represent molecular markers for these tumors, and we recommend searching for CD 34 expression and BRAF V600E mutation in all DNT , especially the non‐specific forms.
H3F3A mutations are seen in ∼30% of pediatric glioblastoma ( GBMs ) and involve either the lysine residue at position 27 ( K27M ) or glycine at position 34 ( G34R/V ). Sixteen genes encode histone H 3, each variant differing in only a few amino acids. Therefore, how mutations in a single H 3 gene contribute to carcinogenesis is unknown. H3F3A K27M mutations are predicted to alter methylation of H3K27 . H3K27me3 is a repressive mark critical to stem cell maintenance and is mediated by EZH2 , a member of the polycomb‐group ( PcG ) family. We evaluated H3K27me3 and EZH2 expression using immunohistochemistry in 76 pediatric brain tumors. H3K27me3 was lowered/absent in tumor cells but preserved in endothelial cells and infiltrating lymphocytes in six out of 20 GBMs . H3K27me3 showed strong immunoreactivity in all other tumor subtypes. Sequencing of GBMs showed H3F3A K27M mutations in all six cases with lowered/absent H3K27me3 . EZH2 expression was high in GBMs , but absent/focal in other tumors. However, no significant differences in EZH2 expression were observed between H3F3A K27M mutant and wild type GBMs , suggesting that EZH2 mediated trimethylation of H3K27 is inhibited in GBM harboring K27M mutations. Our results indicate that H3F3A K27M mutant GBMs show decreased H3K27me3 that may be of both diagnostic and biological relevance.
Prognostic significance of histological anaplasia and BRAF V600E mutation were retrospectively evaluated in 74 patients with pleomorphic xanthoastrocytoma ( PXA ). Median age at diagnosis was 21.5 years (31 pediatric, 43 adult) and median follow‐up 7.6 years. Anaplasia ( PXA ‐ AF ), defined as mitotic index ≥ 5/ 10HPF and/or presence of necrosis, was present in 33 cases. BRAF V600E mutation was detected in 39 (of 60) cases by immunohistochemical and/or molecular analysis, all negative for IDH1 ( R132H ). Mitotic index ≥ 5/ 10HPF and necrosis were associated with decreased overall survival ( OS ; P = 0.0005 and P = 0.0002, respectively). In all cases except two, necrosis was associated with mitotic index ≥ 5/ 10HPF . Patients with BRAF V600E mutant tumors had significantly longer OS compared with those without BRAF V600E mutation ( P = 0.02). PXA ‐ AF patients, regardless of age, had significantly shorter OS compared with those without ( P = 0.0003). Recurrence‐free survival was significantly shorter for adult PXA ‐ AF patients ( P = 0.047) only. Patients who either recurred or died ≤3 years from diagnosis were more likely to have had either PXA ‐ AF at first diagnosis ( P = 0.008) or undergone a non‐gross total resection procedure ( P = 0.004) as compared with patients who did not. This study provides further evidence that PXA ‐ AF behaves more aggressively than PXA and may qualify for WHO grade III “anaplastic” designation.
Pediatric cortical glioneuronal benign tumors mainly include gangliogliomas (GG) [differential diagnoses pilocytic astrocytomas (PA) and pleomorphic xanthoastrocytomas (PXA)] and dysembryoplastic neuroepithelial tumor (DNT). DNT include the specific form and the controversial non-specific form that lack the specific glioneuronal element. Our aims were to search for BRAF(V600E) mutation and CD34 expression in DNT, PXA, GG and PA to correlate BRAF(V600E) mutation with BRAF(V600E) expression and to evaluate their diagnostic and prognostic values. Ninety-six children were included. BRAF(V600E) mutation was studied by sequencing and immunohistochemistry; CD34 expression was analyzed by immunohistochemistry. BRAF(V600E) mutation was detected in PXA (60%), GG (38.7%), DNT (30%, including 3/11 specific and 3/9 non-specific forms) and PA (12.5%). BRAF(V600E) expression was recorded in PXA (60%), GG (45.2%) and DNT (30%). CD34 expression was recorded in PXA (60%), GG (58.1%), DNT (25%) and PA (12.5%). Neither CD34 expression nor BRAF(V600E) status was predictive of prognosis, except for PA tumors where CD34 expression was associated with a shorter overall survival. In conclusion, DNT shared with PXA and GG, BRAF(V600E) mutation and/or CD34 expression, which represent molecular markers for these tumors, and we recommend searching for CD34 expression and BRAF(V600E) mutation in all DNT, especially the non-specific forms.
Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are among the human synucleinopathies, which show alpha-synuclein immunoreactive neuronal and/or glial aggregations and progressive neuronal loss in selected brain regions (eg, substantia nigra, ventral tegmental area, pedunculopontine nucleus). Despite several studies about brainstem pathologies in PD and DLB, there is currently no detailed information available regarding the presence of alpha-synuclein immunoreactive inclusions (i) in the cranial nerve, precerebellar, vestibular and oculomotor brainstem nuclei and (ii) in brainstem fiber tracts and oligodendroctyes. Therefore, we analyzed the inclusion pathologies in the brainstem nuclei (Lewy bodies, LB; Lewy neurites, LN; coiled bodies, CB) and fiber tracts (LN, CB) of PD and DLB patients. As reported in previous studies, LB and LN were most prevalent in the substantia nigra, ventral tegmental area, pedunculopontine and raphe nuclei, periaqueductal gray, locus coeruleus, parabrachial nuclei, reticular formation, prepositus hypoglossal, dorsal motor vagal and solitary nuclei. Additionally we were able to demonstrate LB and LN in all cranial nerve nuclei, premotor oculomotor, precerebellar and vestibular brainstem nuclei, as well as LN in all brainstem fiber tracts. CB were present in nearly all brainstem nuclei and brainstem fiber tracts containing LB and/or LN. These findings can contribute to a large variety of less well-explained PD and DLB symptoms (eg, gait and postural instability, impaired balance and postural reflexes, falls, ingestive and oculomotor dysfunctions) and point to the occurrence of disturbances of intra-axonal transport processes and transneuronal spread of the underlying pathological processes of PD and DLB along anatomical pathways.
Meningiomas are common central nervous system tumors. The World Health Organization ( WHO ) defines three grades, predictive of the risk of recurrence. These tumors can relapse frequently and sometimes undergo malignant transformation. Maintenance of telomere length is a key process in malignant progression, and mutations in TERT promoter have recently been identified in various types of cancer. We sequenced the TERT promoter in 85 meningiomas from 73 patients. We found a high incidence of TERT promoter mutations in patients with meningiomas undergoing malignant histological progression (28%, n = 5/18 patients). In this subset of patients with histological progression, TERT promoter mutations were found in both the lowest and the highest grade tumors, and in both NF 2 ‐mutated and nonmutated samples. In contrast, one mutation was identified in 35 meningiomas without recurrence or progression, belonging to various histological grades. This sample was an aggressive meningioma in a patient who died shortly after surgery. Interestingly, tumors showing relapse without histological progression were not mutated for TERT promoter (n = 20). Finally, TERT promoter mutations were associated with a marked increase in TERT expression. Thus, TERT promoter mutations are pivotal genetic alterations involved in malignant progression of meningiomas and could be used as a biomarker to identify meningiomas at risk of malignant transformation.
P arkinson's disease ( PD ) is the most prevalent movement disorder characterized by selective loss of midbrain dopaminergic ( DA ) neurons. MicroRNA ‐124 (mi R ‐124) is abundantly expressed in the DA neurons and its expression level decreases in the 1‐methyl‐4‐pheny‐1, 2, 3, 6‐tetrahydropyridine ( MPTP ) model of PD . However, whether the upregulation of miR‐124 could attenuate neurodegeneration remains unknown. Here, we employed miR‐124 agomir and miR‐124 mimics to upregulate mi R ‐124 expression in MPTP ‐treated mice and MPP + ‐intoxicated SH ‐ SY5Y cells, respectively. We found that loss of DA neurons and striatal dopamine in MPTP ‐treated mice was significantly reduced by upregulating mi R ‐124. In addition, we identified a target of mi R ‐124, B im that mediated the neuroprotection of mi R ‐124. Indeed, treatment of mi R ‐124 agomir in MPTP ‐treated mice inhibited B im expression, thus suppressing B ax translocation to mitochondria. Moreover, impaired autophagy process in MPTP ‐treated mice and MPP + ‐intoxicated SH ‐ SY5Y cells characterized as autophagosomes ( AP ) accumulation and lysosomal depletion were alleviated by the upregulation of miR‐124. Taken together, these results indicate that upregulation of mi R ‐124 could regulate apoptosis and impaired autophagy process in the MPTP model of PD , thus reducing the loss of DA neurons.
Dementia with Lewy bodies ( DLB ) and Parkinson's disease dementia ( PDD ) are characterized by the presence of α‐synuclein‐containing Lewy bodies and Lewy neurites. However, both dementias also show variable degrees of A lzheimer's disease ( AD ) pathology (senile plaques and neurofibrillary tangles), particularly in areas of the cortex associated with higher cognitive functions. This study investigates the contribution of the individual and combined pathologies in determining the rate of cognitive decline. Cortical α‐synuclein, phosphorylated tau (phosphotau) and Aβ plaque pathology in 34 PDD and 55 DLB patients was assessed semi‐quantitatively in four regions of the neocortex. The decline in cognition, assessed by Mini Mental State Examination, correlated positively with the cortical α‐synuclein load. Patients also had varying degrees of senile Aβ plaque and phosphotau pathology. Regression analyses pointed to a combined pathology (Aβ plaque plus phosphotau plus α‐synuclein‐positive features), particularly in the prefrontal cortex (BA9) and temporal lobe neocortex with the superior and middle temporal gyrus ( BA 21, 22), being a major determining factor in the development of dementia. Thus, cognitive decline in Lewy body dementias is not a consequence of α‐synuclein‐induced neurodegeneration alone but senile plaque and phosphorylated tau pathology also contribute to the overall deficits.