Matthew D. Cykowski

Expanding the spectrum of neuronal pathology in multiple system atrophy

Multiple system atrophy is a sporadic alpha-synucleinopathy that typically affects patients in their sixth decade of life and beyond. The defining clinical features of the disease include progressive autonomic failure, parkinsonism, and cerebellar ataxia leading to significant disability. Pathologically, multiple system atrophy is characterized by glial cytoplasmic inclusions containing filamentous alpha-synuclein. Neuronal inclusions also have been reported but remain less well defined. This study aimed to further define the spectrum of neuronal pathology in 35 patients with multiple system atrophy (20 male, 15 female; mean age at death 64.7 years; median disease duration 6.5 years, range 2.2 to 15.6 years). The morphologic type, topography, and frequencies of neuronal inclusions, including globular cytoplasmic (Lewy body-like) neuronal inclusions, were determined across a wide spectrum of brain regions. A correlation matrix of pathologic severity also was calculated between distinct anatomic regions of involvement (striatum, substantia nigra, olivary and pontine nuclei, hippocampus, forebrain and thalamus, anterior cingulate and neocortex, and white matter of cerebrum, cerebellum, and corpus callosum). The major finding was the identification of widespread neuronal inclusions in the majority of patients, not only in typical disease-associated regions (striatum, substantia nigra), but also within anterior cingulate cortex, amygdala, entorhinal cortex, basal forebrain and hypothalamus. Neuronal inclusion pathology appeared to follow a hierarchy of region-specific susceptibility, independent of the clinical phenotype, and the severity of pathology was duration-dependent. Neuronal inclusions also were identified in regions not previously implicated in the disease, such as within cerebellar roof nuclei. Lewy body-like inclusions in multiple system atrophy followed the stepwise anatomic progression of Lewy body-spectrum disease inclusion pathology in 25.7% of patients with multiple system atrophy, including a patient with visual hallucinations. Further, the presence of Lewy body-like inclusions in neocortex, but not hippocampal alpha-synuclein pathology, was associated with cognitive impairment (P = 0.002). However, several cases had the presence of isolated Lewy body-like inclusions at atypical sites (e.g. thalamus, deep cerebellar nuclei) that are not typical for Lewy body-spectrum disease. Finally, interregional correlations (rho ≥ 0.6) in pathologic glial and neuronal lesion burden suggest shared mechanisms of disease progression between both discrete anatomic regions (e.g. basal forebrain and hippocampus) and cell types (neuronal and glial inclusions in frontal cortex and white matter, respectively). These findings suggest that in addition to glial inclusions, neuronal pathology plays an important role in the developmental and progression of multiple system atrophy.

New Old Pathologies: AD, PART, and Cerebral Age-Related TDP-43 With Sclerosis (CARTS).

The pathology-based classification of Alzheimer’s disease (AD) and other neurodegenerative diseases is a work in progress that is important for both clinicians and basic scientists. Analyses of large autopsy series, biomarker studies, and genomics analyses have provided important insights about AD and shed light on previously unrecognized conditions, enabling a deeper understanding of neurodegenerative diseases in general. After demonstrating the importance of correct disease classification for AD and primary age-related tauopathy, we emphasize the public health impact of an underappreciated AD “mimic,” which has been termed “hippocampal sclerosis of aging” or “hippocampal sclerosis dementia.” This pathology affects >20% of individuals older than 85 years and is strongly associated with cognitive impairment. In this review, we provide an overview of current hypotheses about how genetic risk factors (GRN, TMEM106B, ABCC9, and KCNMB2), and other pathogenetic influences contribute to TDP-43 pathology and hippocampal sclerosis. Because hippocampal sclerosis of aging affects the “oldest-old” with arteriolosclerosis and TDP-43 pathologies that extend well beyond the hippocampus, more appropriate terminology for this disease is required. We recommend “cerebral age-related TDP-43 and sclerosis” (CARTS). A detailed case report is presented, which includes neuroimaging and longitudinal neurocognitive data. Finally, we suggest a neuropathology-based diagnostic rubric for CARTS.

Hippocampal sclerosis but not normal aging or Alzheimer disease is associated with TDP-43 pathology in the basal forebrain of aged persons

Transactivating responsive sequence (TAR) DNA-binding protein 43-kDa (TDP-43) pathology has been described in various brain diseases, but the full anatomical distribution and clinical and biological implications of that pathology are incompletely characterized. Here, we describe TDP-43 neuropathology in the basal forebrain, hypothalamus, and adjacent nuclei in 98 individuals (mean age, 86 years; median final mini-mental state examination score, 27). On examination blinded to clinical and pathologic diagnoses, we identified TDP-43 pathology that most frequently involved the ventromedial basal forebrain in 19 individuals (19.4%). As expected, many of these brains had comorbid pathologies including those of Alzheimer disease (AD), Lewy body disease (LBD), and/or hippocampal sclerosis of aging (HS-Aging). The basal forebrain TDP-43 pathology was strongly associated with comorbid HS-Aging (odds ratio = 6.8, p = 0.001), whereas there was no significant association between basal forebrain TDP-43 pathology and either AD or LBD neuropathology. In this sample, there were some cases with apparent preclinical TDP-43 pathology in the basal forebrain that may indicate that this is an early affected area in HS-Aging. We conclude that TDP-43 pathology in the basal forebrain is strongly associated with HS-Aging. These results raise questions about a specific pathogenetic relationship between basal forebrain TDP-43 and non-HS-Aging comorbid diseases (AD and LBD).

Melanotic Xp11 translocation renal cancer: report of a case with a unique intratumoral sarcoid-like reaction

BackgroundMelanotic Xp11 translocation renal cancer is a rare tumor belonging to the family of microphthalmia-associated transcription factor (MiTF)/transcription factor E (TFE) neoplasms. This tumor family also includes alveolar soft part sarcoma, perivascular epithelioid cell neoplasms, Xp11 translocation renal cell carcinoma, and melanoma. To date, six confirmed melanotic Xp11 translocation cancers (five renal, one ovarian) have been reported in the literature.Case ReportHere, we report the clinical, histologic, immunohistochemical, and molecular features of a unique melanotic Xp11 translocation renal cancer arising in a 34-year-old African-American female. Histologically, the tumor was composed of epithelioid tumor cells arranged in a nested pattern. The cells had clear to eosinophilic granular cytoplasm, vesicular nuclear chromatin, and prominent nucleoli. Multifocal intracytoplasmic deposits of granular brown melanin pigment were identified and confirmed by Fontana-Masson stain. An unusual histologic feature, not previously reported in melanotic Xp11 translocation renal cancer, was a sarcoid-like granulomatous reaction consisting of tight epithelioid granulomas with lymphocytic cuffing, numerous giant cells, and calcifications. Nuclear transcription factor E3 expression was identified by immunohistochemistry and TFE3 rearrangement was confirmed by fluorescence in situ hybridization. Additional immunohistochemical findings included immunoreactivity for HMB45, cathepsin K, and progesterone receptor; negative staining was seen with actin, desmin, cytokeratins, epithelial membrane antigen, CD10, vimentin, and PAX-8. The patient is currently free of disease, two years following initial clinicoradiologic presentation and twenty-two months following partial nephrectomy without additional therapy.ConclusionThis report further expands the spectrum of morphologic and clinical findings previously described in melanotic Xp11 translocation renal cancer, a distinctive tumor showing overlapping features between Xp11 translocation renal cell carcinoma, melanoma, and perivascular epithelioid cell neoplasms.Virtual slidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/7225796341180634

Clinical Significance of TDP-43 Neuropathology in Amyotrophic Lateral Sclerosis

To determine the significance of TAR DNA binding protein 43 kDa (TDP-43) pathology in amyotrophic lateral sclerosis (ALS), we examined the whole brains and spinal cords of 57 patients (35 men; 22 women; mean age 63.3 years; 15 patients with c9orf72-associated ALS [c9ALS]). TDP-43 pathologic burden was determined relative to symptom onset site, disease duration, progression rate, cognitive status, and c9ALS status. There was a trend for greater TDP-43 pathologic burden in cognitively impaired patients (p = 0.07), though no association with disease duration or progression rate was seen. Shorter disease duration (p = 0.0016), more severe striatal pathology (p = 0.0029), and a trend toward greater whole brain TDP-43 pathology (p = 0.059) were found in c9ALS. Cluster analysis identified “TDP43-limited,” “TDP43-moderate,” and “TDP43-severe” subgroups. The TDP43-limited group contained more cognitively intact (p = 0.005) and lower extremity onset site (p = 0.019) patients, while other subgroups contained more cognitively impaired patients. We conclude that TDP-43 pathologic burden in ALS is associated with cognitive impairment and c9ALS, but not duration of disease or rate of progression. Further, we demonstrate a subgroup of patients with low TDP-43 burden, lower extremity onset, and intact cognition, which requires further investigation.

Spinal Anaplastic Oligodendroglioma With Oligodendrogliomatosis: Molecular Markers and Management: Case Report

BACKGROUND AND IMPORTANCE Spinal cord oligodendrogliomas are rare tumors, with a reported incidence varying between 0.8% and 4.7% of all spinal cord tumors and just over 50 cases reported in the literature. Of these, only 9 cases are histologically defined as anaplastic oligodendrogliomas, with few having complete molecular characterization. The diffuse tumor spread that can occur along the subarachnoid space with secondary invasion of the leptomeninges is called oligodendrogliomatosis and is associated with poor outcome. CLINICAL PRESENTATION A 68-year-old man with a history of lumbar stenosis status after lumbar decompression presented with new-onset right lower-extremity weakness. Magnetic resonance imaging demonstrated an intramedullary lesion from T9 to T12. During an attempted diagnostic biopsy, numerous intradural intramedullary lesions not present on magnetic resonance imaging were observed. Tissue biopsy demonstrated a 1p/19q-codeleted anaplastic oligodendroglioma with diffuse oligodendrogliomatosis. Postoperative treatment included 39.2-Gy radiation over 22 fractions from T1 to the bottom of the thecal sac with a boost to the T9-T12 area, the primary site of disease, to a total dose of 43.2 Gy in 24 fractions, followed by adjuvant temozolomide at a dose of 200 mg/m on days 1 to 5 in a 28-day cycle. At the 1-year follow-up, the patient demonstrated moderate neurological improvement. CONCLUSION Management, prognosis, and use of molecular data in the decision-making algorithm for these patients are discussed, together with a review of all cases of primary intradural intramedullary spinal anaplastic oligodendrogliomas reported to date. Our study indicates that the combination of sequential treatment with radiation and temozolomide might provide a favorable outcome in the case of 1p/19q-codeleted spinal anaplastic oligodendrogliomas and that molecular analysis can be beneficial in guiding treatment strategies, although the impact of IDH mutations on these tumors is still unclear.

Medullary neuronal loss is not associated with α‐synuclein burden in multiple system atrophy

Accumulation of α‐synuclein in multiple system atrophy (MSA) affects medullary autonomic and respiratory control areas, including the rostral ventrolateral medulla and raphe nuclei. Relative neuronal vulnerability and its relationship to α‐synuclein accumulation in these areas are unknown. The aim of this study was to determine the extent of loss of adrenergic neurons in the rostral ventrolateral medulla and serotonergic neurons in the ventrolateral medulla and raphe nuclei and its relationship with α‐synuclein accumulation.

Brain metastasis of crystal-deficient, CD68-positive alveolar soft part sarcoma: ultrastructural features and differential diagnosis

ABSTRACT We report a case of alveolar soft part sarcoma (ASPS) presenting as an isolated frontal lobe metastasis. The tumor demonstrated little or no immunoreactivity for a broad panel of antibodies yet strong, diffuse immunoreactivity with CD68. On electron microscopy, the characteristic rectangular to rhomboid crystalline inclusions of ASPS were not present. Electron-dense granules resembling peroxisomes were present, sometimes in association with elongated granular structures having a periodic, lattice-like arrangement. Metastatic ASPS was confirmed by demonstration of an ASPSCR1–TFE3 fusion and imaging studies that excluded metastatic Xp11.2 translocation renal cell carcinoma. The primary site was subsequently identified in the lower extremity.

Epithelial and organ-related marker expression in pituitary adenomas.

The histologic expression of epithelial and organ‐related immunohistochemical markers in primary sellar region tumors has received little attention to date. This lack of empirical data may lead to mistaken assumptions in the evaluation of sellar region neoplasms. To address this issue, the frequency and specificity of epithelial (cytokeratin 7(CK7), CK20) and organ‐related differentiation markers (gross cystic disease fluid protein‐15 (GCDFP‐15), thyroid transcription factor‐1 (TTF‐1), Napsin A, paired box 8 (PAX‐8), hepatocyte paraffin 1 (HepPar1) and estrogen receptor (ER)) were studied in 40 patients with adenomas comprising five hormonal sub‐types. Non‐parametric statistical procedures were used to examine associations between marker expression and tumor sub‐type. CK7 and CK20 immunoreactivity were seen in 48% and 8% of tumors, respectively, although never in a diffuse pattern. CK20 expression was nearly exclusive to corticotrophs, whereas CK7 frequently highlighted cells with dendritic‐type morphology. The specificity of organ‐related differentiation markers was 100% (monoclonal Napsin A, GCDFP‐15 and TTF‐1), 97% (HepPar1 and PAX‐8), 90% (polyclonal Napsin A) and 72% (ER); no tumors demonstrated significant co‐expression of these organ‐related markers with either CK7 or CK20. The first major conclusion of this study is that CK7 staining in adenoma is more frequent than has been previously than has been previously described. CK7 immunoreactive cells often displayed a dendritic‐type morphology, including within large macroadenomas, which raises the question as to whether these represent tumor cells with folliculo‐stellate cell‐type differentiation, as these also have dendritic cell‐type morphology and express CK7 in non‐neoplastic glands. The second major conclusion, which confirms earlier findings, is that CK20 staining is a very infrequent immunohistochemical finding in adenomas that is virtually limited to corticotrophs and thus is helpful in diagnostic confirmation of that sub‐type. The final conclusion is in regard to those features that separate adenomas from sellar region metastases: adenomas do not demonstrate significant expression of TTF‐1, monoclonal Napsin A, PAX‐8, HepPar1 or GCDFP‐15, nor do they exhibit diffuse expression of CK7 and CK20.

REST overexpression in mice causes deficits in spontaneous locomotion

Overexpression of REST has been implicated in brain tumors, ischemic insults, epilepsy, and movement disorders such as Huntington’s disease. However, owing to the lack of a conditional REST overexpression animal model, the mechanism of action of REST overexpression in these disorders has not been established in vivo. We created a REST overexpression mouse model using the human REST (hREST) gene. Our results using these mice confirm that hREST expression parallels endogenous REST expression in embryonic mouse brains. Further analyses indicate that REST represses the dopamine receptor 2 (Drd2) gene, which encodes a critical nigrostriatal receptor involved in regulating movement, in vivo. Overexpression of REST using Drd2-Cre in adult mice results in increased REST and decreased DRD2 expression in the striatum, a major site of DRD2 expression, and phenocopies the spontaneous locomotion deficits seen upon global DRD2 deletion or specific DRD2 deletion from indirect-pathway medium spiny neurons. Thus, our studies using this mouse model not only reveal a new function of REST in regulating spontaneous locomotion but also suggest that REST overexpression in DRD2-expressing cells results in spontaneous locomotion deficits.