Parkinson's disease (PD) is one of the most common neurodegenerative disorders. The cardinal neuropathological features of PD include selective and progressive loss of pigmented neurons in the ...substantia nigra, deficiencies in dopaminergic signaling in the striatum, and occurrence of phosphorylated α‐synuclein‐identified Lewy bodies in the nervous system. Parkinsonism, the clinical presentation of movement disorders seen in PD, is a feature shared commonly by other pathologically distinct neurodegenerative diseases, such as progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and multiple system atrophy (MSA). Consequently, it is sometimes difficult to distinguish PD from such parkinsonism‐related neurological disorders. In addition, parkinsonism is not always a feature of certain neurodegenerative diseases, and it can sometimes develop as a result of various forms of drug intoxication or cerebrovascular disease. Here, we describe the clinicopathological features of three patients (cases 1, 2, and 3) diagnosed as having PSP, MSA, and PD, respectively, in each of whom the postmortem histopathological diagnosis differed from the final clinical diagnosis. Neuropathologically, they had suffered from coexistent disorders: PD, MSA, and argyrophilic grain disease (case 1); PD (case 2); and vascular parkinsonism (case 3). The variety of patients showing features of parkinsonism underlines the importance of careful long‐term follow up followed by postmortem neuropathological evaluation.
Progressive supranuclear palsy (PSP) is characterized by supranuclear gaze palsy, dystonic rigidity of the neck and upper trunk, frequent falls and mild cognitive impairment. Cerebellar ataxia is one ...of the exclusion criteria given by the National Institute of Neurological Disorders and Stroke and the Society for Progressive Supranuclear Palsy. As a result, pathologically proven PSP patients exhibiting cerebellar ataxia have often been misdiagnosed with spinocerebellar degeneration, specifically multiple system atrophy with predominant cerebellar ataxia (MSA-C). However, more recently, it has been recognized that patients with PSP can present with truncal and limb ataxia as their initial symptom and/or main manifestation. These patients can be classified as having PSP with predominant cerebellar ataxia (PSP-C), a new subtype of PSP. Since the development of this classification, patients with PSP-C have been identified primarily in Asian countries, and it has been noted that this condition is very rare in Western communities. Furthermore, the clinical features of PSP-C have been identified, enabling it to be distinguished from other subtypes of PSP and MSA-C. In this review, we describe the clinical and neuropathological features of PSP-C. The hypothesized pathophysiology of cerebellar ataxia in PSP-C is also discussed.
A nuclear protein, 43-kDa TAR DNA-binding protein (TDP-43), was recently identified as a component of the ubiquitinated inclusions (UIs) in frontotemporal lobar degeneration (FTLD-U) and sporadic ...amyotrophic lateral sclerosis (SALS). In the present study using immunohistochemistry, we examined various regions of the nervous system in a series of 35 SALS cases using a polyclonal antibody against TDP-43. Seven of the 35 cases had disease durations of more than 10 years with artificial respiratory support (ARS; duration: 69–156 months). In all cases, TDP-43-immunoreactive (ir) neuronal and glial cytoplasmic inclusions (NCIs and GCIs) were found together in many regions, including the histologically affected lower motor neuron nuclei. Cluster analysis of the distribution pattern of TDP-43-ir NCIs for cases without ARS (
n
= 28) identified two types (type 1,
n
= 16; type 2,
n
= 12). Type 2 was distinguished from type 1 by the presence of TDP-43-ir NCIs in the frontotemporal cortex, hippocampal formation, neostriatum and substantia nigra, and was significantly associated with dementia. Eleven of the 28 cases showed UIs in the hippocampal dentate granule cells, all of which had type-2 distribution pattern. Cases with ARS (
n
= 7) were also classified into the same types (type 1,
n
= 5; type 2,
n
= 2). Cases having type-1 distribution pattern (
n
= 21) showed no evident neuronal loss in most of the non-motor neuron nuclei where TDP-43-ir NCIs were present, whereas cases having type-2 distribution pattern (
n
= 14) often showed evident neuronal loss in the frontotemporal cortices, amygdaloid nuclei and substantia nigra. These findings indicate that SALS is a multisystem degenerative disease widely affecting both neurons and glial cells with a heterogeneous pattern of TDP-43-ir NCI distribution (SALS showing type-2 distribution pattern being closely linked to FTLD-U), and that long-term survival supported by a respirator has no apparent influence on the TDP-43 neuronal distribution pattern.
Mycosis fungoides (MF) is the most common cutaneous T-cell lymphoma. Early-stage MF patches or plaques often resemble inflammatory skin disorders (ISDs), including psoriasis and atopic dermatitis. ...Cell adhesion molecule 1 gene (CADM1), which was initially identified as a tumor suppressor gene in human non–small cell lung cancer, has been reported as a diagnostic marker for adult T-cell leukemia/lymphoma.
We investigated CADM1 expression in MF neoplastic cells, especially during early stages, and evaluated its usefulness as a diagnostic marker for MF.
We conducted a retrospective study by using immunohistochemical staining and confirmed the expression of CADM1 in MF. In addition, we compared CADM1 messenger RNA expression in microdissected MF samples and ISD samples.
In the overall study period, 55 of 58 MF samples (94.8 %) stained positive for CADM1. None of the 50 ISD samples showed positive reactivity (P < .0001). We found CADM1 messenger RNA expression in the intradermal lymphocytes of patients with MF but not in those of patients with an ISD.
We did not conduct a validation study for MF cases in other institutions.
CADM1-positive cells can be identified in early stages with fewer infiltrating cells and may be useful as a diagnostic marker for early-stage MF.
Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is clinically characterized by early-onset dementia, stroke, spondylosis deformans, and alopecia. ...In CARASIL cases, brain magnetic resonance imaging reveals severe white matter hyperintensities (WMHs), lacunar infarctions, and microbleeds. CARASIL is caused by a homozygous mutation in
high-temperature requirement A serine peptidase 1
(
HTRA1
). Recently, it was reported that several heterozygous mutations in
HTRA1
also cause cerebral small vessel disease (CSVD). Although patients with heterozygous
HTRA1
-related CSVD (symptomatic carriers) are reported to have a milder form of CARASIL, little is known about the clinical and genetic differences between the two diseases. Given this gap in the literature, we collected clinical information on
HTRA1
-related CSVD from a review of the literature to help clarify the differences between symptomatic carriers and CARASIL and the features of both diseases. Forty-six symptomatic carriers and 28 patients with CARASIL were investigated. Twenty-eight mutations in symptomatic carriers and 22 mutations in CARASIL were identified. Missense mutations in symptomatic carriers are more frequently identified in the linker or loop 3 (L3)/loop D (LD) domains, which are critical sites in activating protease activity. The ages at onset of neurological symptoms/signs were significantly higher in symptomatic carriers than in CARASIL, and the frequency of characteristic extraneurological findings and confluent WMHs were significantly higher in CARASIL than in symptomatic carriers. As previously reported, heterozygous
HTRA1
-related CSVD has a milder clinical presentation of CARASIL. It seems that haploinsufficiency can cause CSVD among symptomatic carriers according to the several patients with heterozygous nonsense/frameshift mutations. However, the differing locations of mutations found in the two diseases indicate that distinct molecular mechanisms influence the development of CSVD in patients with
HTRA1
-related CSVD. These findings further support continued careful examination of the pathogenicity of mutations located outside the linker or LD/L3 domain in symptomatic carriers.
Objective Cataract and chronic kidney disease (CKD) occur with increasing frequency with age and share common risk factors including smoking, diabetes, and hypertension. We evaluated the risk of ...incident cataract surgery in patients with non-dialysis-dependent CKD and dialysis-dependent CKD compared to non-CKD patients, while taking into account the competing risk of death. Methods The participants included 1,839 patients from Sado General Hospital enrolled in the Project in Sado for Total Health (PROST) between June 2008 and December 2016 (54% men; mean age, 69 years). Among these patients, 50%, 44%, and 6% had non-CKD, non-dialysis-dependent CKD, and dialysis-dependent CKD, respectively. Results During a median follow-up of 5.6 years (interquartile range, 4.7-7.1), 193 participants underwent cataract surgery 18.7 (95% confidence interval (CI), 16.2-21.5)/1,000 person-years and 425 participants died without undergoing cataract surgery 41.0 (95% CI, 37.4-45.2)/1,000 person-years. The cumulative incidence of cataract surgery was the highest in the dialysis-dependent CKD group, followed by the non-dialysis-dependent CKD and non-CKD groups (log-rank p=0.002). After adjusting for potential confounding factors, the dialysis-dependent CKD group hazard ratio (HR) 2.48; 95% CI 1.43-4.31, but not the non-dialysis-dependent CKD group (HR, 1.01; 95% CI 0.74-1.38), had a higher risk of cataract surgery than the non-CKD group. However, this association was no longer significant according to a competing risk analysis (sub-hazard ratio, 1.67; 95% CI 0.93-3.03). Conclusion Dialysis-dependent CKD patients were found to have an increased risk of cataract surgery; however, the association was attenuated and no longer significant when death was considered a competing risk.
It is increasingly becoming apparent that cerebrovascular dysfunction contributes to the pathogenic processes involved in vascular dementia, Alzheimer's disease, and other neurodegenerative ...disorders. Under these pathologic conditions, degeneration of cerebral blood vessels is frequently accompanied by a loss of mural cells from the vascular walls. Vascular mural cells play pivotal roles in cerebrovascular functions, such as regulation of cerebral blood flow and maintenance of the blood-brain barrier. Therefore, cerebrovascular mural cell impairment is involved in the pathophysiology of vascular-related encephalopathies, and protecting these cells is essential for maintaining brain health. However, our understanding of the molecular mechanism underlying mural cell abnormalities is incomplete. Several reports have indicated that dysregulated transforming growth factor β signaling is involved in the development of cerebral arteriopathies. These studies have specifically suggested the involvement of TGFβ overproduction. Although cerebrovascular toxicity via vascular fibrosis by extracellular matrix accumulation or amyloid deposition is known to occur with enhanced TGFβ production, whether increased TGFβ results in the degeneration of vascular mural cells in vivo remains unknown. Here, we demonstrated that chronic TGFβ1 overproduction causes dropout of mural cells and reduces their coverage on cerebral vessels in both smooth muscle cells and pericytes. Mural cell degeneration was also accompanied by vascular luminal dilation. TGFβ1 overproduction in astrocytes significantly increased TGFβ1 content in the cerebrospinal fluid and increased TGFβ signaling-regulated gene expression in both pial arteries and brain capillaries. These results indicate that TGFβ is an important effector that mediates mural cell abnormalities under pathological conditions related to cerebral arteriopathies.
Disappearance of TAR-DNA-binding protein 43 kDa (TDP-43) from the nucleus contributes to the pathogenesis of amyotrophic lateral sclerosis (ALS), but the nuclear function of TDP-43 is not yet fully ...understood. TDP-43 associates with nuclear bodies including Gemini of coiled bodies (GEMs). GEMs contribute to the biogenesis of uridine-rich small nuclear RNA (U snRNA), a component of splicing machinery. The number of GEMs and a subset of U snRNAs decrease in spinal muscular atrophy, a lower motor neuron disease, suggesting that alteration of U snRNAs may also underlie the molecular pathogenesis of ALS. Here, we investigated the number of GEMs and U11/12-type small nuclear ribonucleoproteins (snRNP) by immunohistochemistry and the level of U snRNAs using real-time quantitative RT-PCR in ALS tissues. GEMs decreased in both TDP-43-depleted HeLa cells and spinal motor neurons in ALS patients. Levels of several U snRNAs decreased in TDP-43-depleted SH-SY5Y and U87-MG cells. The level of U12 snRNA was decreased in tissues affected by ALS (spinal cord, motor cortex and thalamus) but not in tissues unaffected by ALS (cerebellum, kidney and muscle). Immunohistochemical analysis revealed the decrease in U11/12-type snRNP in spinal motor neurons of ALS patients. These findings suggest that loss of TDP-43 function decreases the number of GEMs, which is followed by a disturbance of pre-mRNA splicing by the U11/U12 spliceosome in tissues affected by ALS.
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