Machine learning-based decision tree classifier for the diagnosis of progressive supranuclear palsy and corticobasal degeneration.

AIMS: This study aimed to clarify the different topographical distribution of tau pathology between progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) and establish a machine learning-based decision tree classifier. METHODS: Paraffin-embedded sections of the temporal cortex, motor cortex, caudate nucleus, globus pallidus, subthalamic nucleus, substantia nigra, red nucleus, and midbrain tectum from 1020 PSP and 199 CBD cases were assessed by phospho-tau immunohistochemistry. The severity of tau lesions (i.e., neurofibrillary tangle, coiled body, tufted astrocyte or astrocytic plaque, and tau threads) was semi-quantitatively scored in each region. Hierarchical cluster analysis was performed using tau pathology scores. A decision tree classifier was made with tau pathology scores using 914 cases. Cross-validation was done using 305 cases. An additional ten cases were used for a validation study. RESULTS: Cluster analysis displayed two distinct clusters; the first cluster included only CBD, and the other cluster included all PSP and six CBD cases. We built a decision tree, which used only seven decision nodes. The scores of tau threads in the caudate nucleus were the most decisive factor for predicting CBD. In a cross-validation, 302 out of 305 cases were correctly diagnosed. In the pilot validation study, three investigators made a correct diagnosis in all cases using the decision tree. CONCLUSION: Regardless of the morphology of astrocytic tau lesions, semi-quantitative tau pathology scores in select brain regions are sufficient to distinguish PSP and CBD. The decision tree simplifies neuropathologic differential diagnosis of PSP and CBD.

Preferential tau aggregation in von Economo neurons and fork cells in frontotemporal lobar degeneration with specific MAPT variants.

Tau aggregation is a hallmark feature in a subset of patients with frontotemporal dementia (FTD). Early and selective loss of von Economo neurons (VENs) and fork cells within the frontoinsular (FI) and anterior cingulate cortices (ACC) is observed in patients with sporadic behavioral variant FTD (bvFTD) due to frontotemporal lobar degeneration (FTLD), including FTLD with tau inclusions (FTLD-tau). Recently, we further showed that these specialized neurons show preferential aggregation of TDP-43 in FTLD-TDP. Whether VENs and fork cells are prone to tau accumulation in FTLD-tau remains unclear, and no previous studies of these neurons have focused on patients with pathogenic variants in the gene encoding microtubule-associated protein tau (FTLD-tau/MAPT). Here, we examined regional profiles of tau aggregation and neurodegeneration in 40 brain regions in 8 patients with FTLD-tau/MAPT and 7 with Pick's disease (PiD), a sporadic form of FTLD-tau that often presents with bvFTD. We further qualitatively assessed the cellular patterns of frontoinsular tau aggregation in FTLD-tau/MAPT using antibodies specific for tau hyperphosphorylation, acetylation, or conformational change. ACC and mid-insula were among the regions most affected by neurodegeneration and tau aggregation in FTLD-tau/MAPT and PiD. In these two forms of FTLD-tau, severity of regional neurodegeneration and tau protein aggregation were highly correlated across regions. In FTLD-tau/MAPT, VENs and fork cells showed disproportionate tau protein aggregation in patients with V337 M, A152T, and IVS10 + 16 variants, but not in patients with the P301L variant. As seen in FTLD-TDP, our data suggest that VENs and fork cells represent preferentially vulnerable neuron types in most, but not all of the MAPT variants we studied.

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.

MRI in the assessment of muscular pathology: a comparison between limb-girdle muscular dystrophies, hyaline body myopathies and myotonic dystrophies.

PURPOSE: The continuous discovery of new subtypes of neuromuscular disorders demands more accurate imaging analyses. We set out to establish the specific patterns of muscular involution using magnetic resonance imaging (MRI). MATERIALS AND METHODS: A systematic clinical evaluation based on the Medical Research Council scale and MRI was completed in ten patients with calpainopathy [limb-girdle muscular dystrophy (LGMD)-2A], 16 with dysferlinopathy (LGMD-2B), ten with hyaline body myopathy (HBM), six with myotonic dystrophy (MD) types 1 and 5 with MD type 2. Severity of fibroadipose degeneration was specifically staged using T1-weighted sequences. Turbo inversion recovery magnitude (TIRM) sequences were used to assess oedema-like changes. RESULTS: T1 scans showed recurrent patterns of fibroadipose replacement, whereas TIRM images revealed differences in oedema-like changes between the various diseases. In LGMD, the posterior compartments are more vulnerable to degeneration. In HBM, fatty muscle degeneration and oedema are allocated to muscles of the posterior compartments of the leg. In MD, fatty muscle degeneration and oedematous changes are allocated to muscles of the anterior thigh and posterior lower leg. CONCLUSIONS: Imaging examination suggests a characteristic pattern of muscle involvement. MRI represents an important diagnostic technique useful in differential diagnosis, thanks to the distinctive patterns observed in the distribution of muscular changes between the different muscular diseases.

Neuronal intranuclear and neuropil inclusions for pathological assessment of Huntington's disease.

To evaluate the usefulness of neuronal intranuclear inclusions and neuropil inclusions for the pathological assessment of Huntington's disease (HD), their presence in neocortex was assessed by ubiquitin and N-terminal huntingtin immunohistochemistry in a consecutive series of 195 autopsy brains of individuals with a positive or tentative clinical diagnosis of, or at risk for, HD. The findings were correlated with striatal pathology (n = 190), CAG repeat length (n = 85) and original pathological diagnosis (n = 186). The antibodies detected both these inclusions in 181 patients with HD pathology > or = Vonsattel et al's grade I, five patients lacking striatal tissue for review, and two at-risk individuals with grade 0 and grade I HD pathology, respectively. One patient with HD-like pathology and two patients and four at-risk individuals without HD pathology lacked HD inclusions. In the genetically analyzed cases, the inclusions were exclusively and consistently observed in association with repeat expansion [(CAG)(n) > or = 39, n = 81]. Thirteen inclusion-positive cases, including the grade 0 at-risk individual, had a false negative original pathological diagnosis of HD and four had an unjustly questionable diagnosis. A false positive diagnosis was made in the inclusion-negative case with HD-like pathology. These results indicate that immunohistochemical analysis for HD inclusions facilitates the pathological evaluation of HD and enhances its accuracy.

Lymphoglandular bodies in lymphoid lesions and non-lymphoid round cell tumours: a quantitative assessment.

Lymphoglandular bodies (cytoplasmic fragments) were counted in 10 high power fields (HPF) of the smears in 35 cases of non-Hodgkin lymphoma (NHL), 26 Hodgkin's disease (HD), 36 reactive lymphadenitis, 24 non-lymphoid round cell tumors, and 20 cases of secondaries in lymph nodes. The number of lymphoglandular bodies in both May-Grünwald-Giemsa (MGG) and hematoxylin-eosin (H&E) stained smears in NHL, HD, and reactive lymphadenitis were significantly higher compared to non-lymphoid round cell tumors (P < 0.001). In H&E stained smear 92.5% of NHL, 86.2% of reactive lymph nodes, and 66.7% of HD cases had > 100 lymphoglandular bodies per 10 HPF. In MGG stained smears 100% NHL, 89.7% of reactive lymphadenitis, and 66.7% of HD cases contained > 100 lymphoglandular bodies per 10 HPF. On the other hand only 4.8% of non-lymphoid round cell tumors crossed this level in both H&E stained and MGG stained smears. Number of lymphoglandular bodies was also significantly higher in MGG stained smears compared to H&E stained smears (P < 0.05 to < 0.01) and in fine-needle aspiration (FNA) smears compared to imprint smears (P < 0.01 to < 0.001) in cases of NHL, HD, and reactive lymphadenitis.

Pathology of the liver in mucopolysaccharidosis: light and electron microscopic assessment before and after bone marrow transplantation.

Serial liver biopsies were obtained in 20 patients undergoing bone marrow transplantation (BMT) for mucopolysaccharidosis (MPS). The 13 patients with MPS I, one with MPS II, four with MPS III, and two with MPS VI underwent liver biopsy prior to and from 1 to 37 months after BMT. The amount of accumulated glycosaminoglycan (GAG) was assessed by semiquantitation of Kupffer cell staining with colloidal iron and by counting the number of hepatocellular GAG-containing lysosomes in electron micrographs. Eleven of 13 patients with MPS I achieved engraftment, and 10 of the 11 cleared the Kupffer cells and hepatocytes of GAG by 3 to 19 months post-BMT. Two patients with autologous recovery demonstrated persistent hepatocyte inclusions. The three patients with MPS II and MPS VI engrafted and showed clearance of hepatocyte and Kupffer cell GAG by 7 months after BMT. All four patients with MPS III engrafted. Although the Kupffer cells in these patients were cleared of GAG by 12 months after BMT, hepatocellular inclusions persisted in all four. For MPS I, II and VI, donor engraftment was associated with resolution of lysosomal storage material in donor-derived Kupffer cells and untransplanted hepatocytes, indicative of transcellular metabolic correction. Failure of hepatocyte clearance in one case of MPS I and all patients with MPS III suggested a diminished capacity of the graft-derived enzyme to enter the hepatocyte lysosomes in these patients.