Citations

Frontotemporal lobar degeneration (FTLD) and motor neuron disease (MND) are considered separate diseases; yet, they can overlap (FTLD‐MND), affecting predominantly lower motor neurons. We reviewed all cases of FTLD‐MND (N=25) to determine if lower MND is a consistent feature. We identified 2 cases (8%) with pure upper MND or primary lateral sclerosis (PLS). Detailed neuropathological examination was conducted. Case 1: a 63‐year‐old man with 7‐years of executive dysfunction, aphasia, and choking. Family history was negative. Neurological examination 1‐year prior to death revealed spasticity and extensor plantar responses, without extrapyramidal or lower MND signs. Case 2: a 69‐year‐old man with 6‐years of expressive aphasia and apraxia. Family history was negative. Neurological examination 4‐years prior to death reveled asymmetric ideomotor apraxia and parkinsonism, but no signs of upper or lower MND. Brain weights were 1140 and 930 grams, respectively. Histological examination revealed neuronal loss and gliosis of motor cortex, severe in case 1 and mild‐to‐moderate in case 2, as well as neuronal loss and gliosis in frontotemporal and parietal (case 2 only) neocortices. Activated microglial and myelin stains revealed corticospinal tract destruction to the level of the medullary pyramids. The hypoglossal nuclei were preserved. Neither ubiquitin nor TDP‐43 immunohistochemistry identified intraneuronal inclusions. Case 1 also had features of tangle dominant dementia. FTLD with pure upper MND or PLS is rare, but does exist. Unlike in typical FTLD‐MND were disease duration is 2‐3 years, those with FTLD‐PLS seem to have longer illness duration and, hence, better prognosis. Further genetic studies are needed to determine if FTLD‐PLS is a variant of FTLD‐MND or a separate disease entity.

Coronin‐1a is an evolutionarily conserved protein involved in rearrangements of the actin cytoskeleton. The expression of coronin‐1a is restricted to cells of the hematopoietic lineage. Microglia are resident immune cells of the central nervous system thought to have hematopoietic origins. The aim of this study was to determine if coronin‐1a could be used as a marker for detecting microglia in mammalian species. Using a polyclonal antibody and immunohistochemistry, we show that coronin‐1a is an effective marker for microglia in tissue culture and archival formalin fixed, paraffin embedded tissue, including a range of neurodegenerative and neuroinflammatory conditions and transgenic mice. In human, monkey, horse, rat and mouse tissue coronin‐1a immunoreactivity was present in cells with the morphology and distribution of microglia, even in sections that had been stored for long periods of time. The identity of coronin‐1a positive cells as microglia was confirmed with double immunolabeling for HLA‐DR and Iba‐1. Coronin‐1a immunoreactivity was also detected in T‐ and B‐lymphocytes in lymphoid tissue and neuroinflammatory conditions, but it was not expressed by astrocytes or oligodendrocytes. The results demonstrate that coronin‐1a is a novel marker for microglia in routinely processed tissue from normal and neurodegenerative conditions in both humans and animals.

AbstractAmong individuals with dementia with Lewy bodies, pathologic correlates of clinical course include the presence and extent of coexisting Alzheimer’s pathology and the presence of transitional or diffuse Lewy body disease. The objectives of this study are to determine (i) whether 18F-fluorodeoxyglucose PET signature patterns of dementia with Lewy bodies are associated with the extent of coexisting Alzheimer’s pathology and the presence of transitional or diffuse Lewy body disease and (ii) whether these 18F-fluorodeoxyglucose pattern(s) are associated with clinical course in dementia with Lewy bodies. Two groups of participants were included: a pathology-confirmed subset with Lewy body disease (n = 34) and a clinically diagnosed group of dementia with Lewy bodies (n = 87). A subset of the clinically diagnosed group was followed longitudinally (n = 51). We evaluated whether 18F-fluorodeoxyglucose PET features of dementia with Lewy bodies (higher cingulate island sign ratio and greater occipital hypometabolism) varied by Lewy body disease subtype (transitional versus diffuse) and Braak neurofibrillary tangle stage. We investigated whether the PET features were associated with the clinical trajectories by performing regression models predicting Clinical Dementia Rating Scale Sum of Boxes. Among autopsied participants, there was no difference in cingulate island sign or occipital hypometabolism by Lewy body disease type, but those with a lower Braak tangle stage had a higher cingulate island sign ratio compared to those with a higher Braak tangle stage. Among the clinically diagnosed dementia with Lewy bodies participants, a higher cingulate island ratio was associated with better cognitive scores at baseline and longitudinally. A higher 18F-fluorodeoxyglucose PET cingulate island sign ratio was associated with lower Braak tangle stage at autopsy, predicted a better clinical trajectory in dementia with Lewy body patients and may allow for improved prognostication of the clinical course in this disease.

AbstractBackground: Abnormal aggregates of α‐synuclein are pathologic hallmarks of multiple system atrophy (MSA) and Lewy body disease (LBD). LBD sometimes coexists with MSA, but the impact of co‐pathology, particularly diffuse LBD, on presentation of MSA has not been studied. We aimed to determine the frequency and clinicopathologic features of MSA with LBD (MSA+LBD). Methods: Using hematoxylin & eosin and α‐synuclein‐immunostained slides, we assessed the distribution and severity of LBD in 230 autopsy‐confirmed MSA patients collected from 1998 to 2018. Alzheimer‐type pathology was assessed to assign the likelihood of clinical presentations of dementia with Lewy body (DLB) using the consensus criteria for DLB. We reviewed medical records to characterize clinicopathologic features of MSA+LBD. Genetic risk factors for LBD, including APOE ε4 allele and mutations in GBA, SNCA, LRRK2, and VPS35, were analyzed. Results: LBD was observed in 11 MSA patients (5%); seven were brainstem type, three were transitional type, and one was diffuse type. The latter four had an intermediate or high likelihood of DLB. Three of the four had an antemortem diagnosis of Parkinson’s disease with dementia (PDD) or clinically probable DLB. Two patients had neuronal loss in the substantia nigra, but not in striatal or olivocerebellar systems with widespread glial cytoplasmic inclusions, consistent with minimal change MSA. In these cases, LBD was considered the primary pathology, and MSA was considered coincidental. APOE ε4 allele frequency was not different between MSA+LBD and MSA without LBD. Two of nine MSA+LBD patients had a risk variant of GBA (p.T408M and p.E365K). Conclusions: Although rare, MSA with transitional or diffuse LBD can develop clinical features of PDD or DLB. Minimal change MSA can be interpreted as a coincidental, but distinct, α‐synucleinopathy in a subset of patients with diffuse LBD.

Progranulin is a mediator of development, tumorigenesis and wound repair. Mutations in the gene for progranulin cause frontotemporal dementia. Little is known about the role of progranulin in the nervous system. The cleavage products of progranulin, granulins, were first isolated from granule‐enriched fractions of human and equine neutrophils and from rat bone marrow. Immunohistochemistry of granulin has been reported in macrophages or monocytes. Here we use a post‐embedding immunogold labeling method to ultrastructurally localize progranulin in mouse and human tissue. Bone marrow from mouse femoral bone was fixed in 4% paraformaldehyde. Human choroid plexus and a brain abscess were obtained from autopsy brains fixed in formalin. Tissues were dehydrated in ethanols, infiltrated and embedded in LR White resin. Thin sections were collected on Formvar‐coated nickel grids and incubated with antibodies to mouse or human progranulin, followed by gold‐conjugated secondary antibodies. In all tissues progranulin was localized to secretory granules and vesicles in neutrophils and macrophages. Labeled granules had morphological features of secretory granules. They were membrane‐bound vesicles with pale to optically dense contents and ranged from 200 to 500 microns in diameter. This is the first report of the ultrastructural localization of progranulin to mouse and human neutrophils and macrophages in normal and inflammatory conditions, including neuroinflammatory disorders.

Abstract Background Intronic variant rs564309 in tripartite motif containing 11 (TRIM11 ) is associated with clinical phenotypic differences in progressive supranuclear palsy (PSP), whereby the minor allele (A) is more common in atypical PSP than typical PSP (PSP‐Richardson's syndrome). However, rs564309 has not been investigated relative to neuropathological outcomes. Objective Evaluate the association of rs564309 with the neuropathologically assessed severity of tau pathology, as measured by semi‐quantitative scores for neurofibrillary tangles, tufted astrocytes, neuropil threads, and oligodendroglial coiled bodies. Methods 797 neuropathologically confirmed PSP cases were genotyped for TRIM11 rs564309 and assessed for tau pathology across 20 neuroanatomical regions. Tau pathology measures and age at death were examined for association with TRIM11 rs564309‐A using multivariable linear regression models. Results TRIM11 rs564309‐A was associated with increased neurofibrillary tangles pathology ( P = 0.050), but was not significantly associated with age at death, neuropil threads, coiled bodies, or tufted astrocytes tau pathology scores. Conclusions TRIM11 rs564309 may influence burden of neurofibrillary tangles tau pathology in PSP; further study is warranted. © 2020 International Parkinson and Movement Disorder Society

Abstract Human neurodegenerative diseases can be characterized as disorders of protein aggregation. As a key player in cellular autophagy and the ubiquitin proteasome system, p62 may represent an effective immunohistochemical target, as well as mechanistic operator, across neurodegenerative proteinopathies. In this study, 2 novel mouse-derived monoclonal antibodies 5G3 and 2A5 raised against residues 360–380 of human p62/sequestosome-1 were characterized via immunohistochemical application upon human tissues derived from cases of C9orf72-expansion spectrum diseases, Alzheimer disease, progressive supranuclear palsy, Lewy body disease, and multiple system atrophy. 5G3 and 2A5 reliably highlighted neuronal dipeptide repeat, tau, and α-synuclein inclusions in a distribution similar to a polyclonal antibody to p62, phospho-tau antibodies 7F2 and AT8, and phospho-α-synuclein antibody 81A. However, antibodies 5G3 and 2A5 consistently stained less neuropil structures, such as tau neuropil threads and Lewy neurites, while 2A5 marked fewer glial inclusions in progressive supranuclear palsy. Both 5G3 and 2A5 revealed incidental astrocytic tau immunoreactivity in cases of Alzheimer disease and Lewy body disease with resolution superior to 7F2. Through their unique ability to highlight specific types of pathological deposits in neurodegenerative brain tissue, these novel monoclonal p62 antibodies may provide utility in both research and diagnostic efforts.

Abstract Since researchers identified α-synuclein as the principal component of Lewy bodies and Lewy neurites, studies have suggested that it plays a causative role in the pathogenesis of dementia with Lewy bodies and other ‘synucleinopathies’. While α-synuclein dyshomeostasis likely contributes to the neurodegeneration associated with the synucleinopathies, few direct biochemical analyses of α-synuclein from diseased human brain tissue currently exist. In this study, we analysed sequential protein extracts from a substantial number of patients with neuropathological diagnoses of dementia with Lewy bodies and corresponding controls, detecting a shift of cytosolic and membrane-bound physiological α-synuclein to highly aggregated forms. We then fractionated aqueous extracts (cytosol) from cerebral cortex using non-denaturing methods to search for soluble, disease-associated high molecular weight species potentially associated with toxicity. We applied these fractions and corresponding insoluble fractions containing Lewy-type aggregates to several reporter assays to determine their bioactivity and cytotoxicity. Ultimately, high molecular weight cytosolic fractions enhances phospholipid membrane permeability, while insoluble, Lewy-associated fractions induced morphological changes in the neurites of human stem cell-derived neurons. While the concentrations of soluble, high molecular weight α-synuclein were only slightly elevated in brains of dementia with Lewy bodies patients compared to healthy, age-matched controls, these observations suggest that a small subset of soluble α-synuclein aggregates in the brain may drive early pathogenic effects, while Lewy body-associated α-synuclein can drive neurotoxicity.

APOE4 exacerbates α-synuclein pathology in a synucleinopathy mouse model, and APOE4 genotype associates with increased α-synuclein pathology in humans.

ABSTRACTBackgroundCorticobasal degeneration (CBD) can present with various clinical phenotypes including Richardson's syndrome (RS). Although neuropathological examination can differentiate CBD and progressive supranuclear palsy (PSP) pathologies, no clinical or imaging findings can differentiate CBD from other pathologies when a patient presents with a variant type of CBD. As these various phenotypes are associated with non‐CBD pathologies, clinical diagnostic accuracy can be low for such patients.ObjectivesTo present clinical features of two cases with symptom progression in line with PSP‐RS, who were diagnosed with CBD based on neuropathological examination.MethodsBaseline, follow up examinations, and detailed neuropathological examinations of two CBD cases presenting and progressing in line with probable PSP‐RS are demonstrated.ResultsThe two cases clinically diagnosed as probable PSP‐RS were shown to have CBD upon neuropathological examination, which is the gold standard for diagnosis of both PSP and CBD.ConclusionsThese cases emphasize the importance of neuropathology for the definite diagnosis, and stress the need for distinctive markers to increase the reliability of clinical diagnosis before death.