Neuronal loss in familial frontotemporal dementia with ubiquitin-positive,tau-negative inclusions

The neuronal density in the frontal, temporal, and parietal lobes was determined in nine cases of familial frontotemporal dementia with ubiquitin-positive, tau-negative inclusions (FTDU). The mean age at onset was 56.9 +/- 2.2 years and the duration of disease was 6.7 +/- 0.5 years. The mean age at death was 63.6 +/- 2.2 years. There was substantial loss (34%) of brain weight (877 +/- 73 g) in the familial cases in comparison with 10 normal aged controls (1326 +/- 50 g, P < 0.001). All of the familial FTDU cases showed atrophy of the frontal, temporal, and parietal lobes; neuronal loss; vacuolation in superficial laminae; reactive astrocytosis; and ubiquitin-positive, tau-negative intracytoplasmic and intranuclear inclusions and dystrophic neurites in varying sites and numbers. Neuronal loss was estimated in nine cases of familial FTDU and in 10 aged controls using a stereological probe, the optical "disector," and a computerized stereology system (CAST-Grid, Olympus, Denmark). There was a significant reduction in neuronal density in the frontal lobe (22.3 +/- 3.8 x 10(3)/mm(3)) of familial FTDU in comparison to aged controls (33.1 +/- 1.7 x 10(3) per mm(3), P < 0.05). An estimate of the relative numbers of neurons was calculated by multiplying the numerical density by the cortical thickness, which showed a striking loss of neurons of 56% in the frontal lobe, 52% loss in the temporal lobe, and a 49% loss in the parietal lobe of familial FTDU when compared to controls. This study shows that familial FTDU has profound focal neuronal loss in multiple association areas that relate to the clinical symptoms characteristic of the disease.     

A case of Pick's disease with unusual neuronal inclusions

An autopsy case of unusual Pick's diesease in a 61-year-old male is described. Findings included severe atrophy of the frontal and temporal lobes, pyramidal tracts and basal ganglia accompanied by numerous intraneuronal argyrophilic hyaline inclusions. His neurological symptoms were constantly progressive during the 12-year course, characterized by akinesia and emotional incontinence. The inclusions were round, well-demarcated, slightly eosinophilic and intensely argyrophilic bodies in the perikarya, and distributed mainly in the subiculum and Sommer's sector of the hippocampus, amygdala and affected gyri. Immunocytochemically, they contain antigenic determinants of both phosphorylated and nonphosphorylated neurofilaments, but were negative for ubiquitin. Ultrastructurally, they were composed primarily of skeins of neurofilaments intermingled with cell organelles. Tubular profiles studded with granular substances, previously reported as a feature of the generalized variant of Pick's disease, and Hirano body-like lattice structures were occasionally observed in the inclusions. This case represents a slowly progressive neurodegenerative disorder characterized by fronto-temporal lobar atrophy and might by categorized as a variant of Pick's disease. However, some unusual properties of neuronal inclusions may suggest a different pathogenesis from that in classical Pick's disease.     

Sporadic and familial dementia with ubiquitin-positive tau-negative inclusions: clinical features of one histopathological abnormality underlying frontotemporal lobar degeneration

BACKGROUND: Frontotemporal lobar degeneration comprises a group of diseases with clinical presentations and underlying histopathologies that overlap. Familial disease occurs in up to 50% of frontotemporal lobar degeneration cases. One of several underlying histopathological abnormalities is of ubiquitin-positive tau-negative inclusions, similar to those in motor neuron disease. OBJECTIVE: To compare clinical features of familial and sporadic cases in this pathological subgroup. DESIGN AND PATIENTS: Case note review of dementia patients with ubiquitin-positive tau-negative inclusion pathological abnormalities proven by autopsy. SETTING: United Kingdom tertiary referral center. MAIN OUTCOME MEASURES: Analysis of clinical features. RESULTS: Eleven familial cases (autosomal dominant) and 18 sporadic cases were identified. Most familial case patients presented with behavioral disturbances similar to those seen in sporadic behavioral cases. Semantic dementia was only seen in sporadic cases. Atypical features occurred in a minority. Sporadic and familial behavioral cases showed no differences in age at onset or disease duration. Neuropsychological test results revealed frontal or temporal deficits in most, but unexpected early parietal deficits in 1. CONCLUSIONS: Behavioral features in familial and sporadic cases were similar, but semantic dementia only occurred in sporadic cases. Diagnostic confusion with Alzheimer disease and corticobasal degeneration occurred in some cases.     

HDDD2 is a familial frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions caused by a missense mutation in the signal peptide of progranulin

OBJECTIVE: Familial autosomal dominant frontotemporal dementia with ubiquitin-positive, tau-negative inclusions in the brain linked to 17q21-22 recently has been reported to carry null mutations in the progranulin gene (PGRN). Hereditary dysphasic disinhibition dementia (HDDD) is a frontotemporal dementia with prominent changes in behavior and language deficits. A previous study found significant linkage to chromosome 17 in a HDDD family (HDDD2), but no mutation in the MAPT gene. Longitudinal follow-up has enabled us to identify new cases and to further characterize the dementia in this family. The goals of this study were to develop research criteria to classify the different clinical expressions of dementia observed in this large kindred, to identify the causal mutation in affected individuals and correlate this with phenotypic characteristics in this pedigree, and to assess the neuropathological characteristics using immunohistochemical techniques. METHODS: In this study we describe a detailed clinical, pathological and mutation analysis of the HDDD2 kindred. RESULTS: Neuropathologically, HDDD2 represents a familial frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions (FTLD-U). We developed research classification criteria and identified three distinct diagnostic thresholds, which helped localize the disease locus. The chromosomal region with the strongest evidence of linkage lies within the minimum critical region for FTLD-U. Sequencing of each exon of the PGRN gene led to the identification of a novel missense mutation, Ala-9 Asp, within the signal peptide. INTERPRETATION: HDDD2 is an FTLD-U caused by a missense mutation in the PGRN gene that cosegregates with the disease and with the disease haplotype in at-risk individuals. This mutation is the first reported pathogenic missense mutation in the signal peptide of the PGRN gene causing FTLD-U. In light of the previous reports of null mutations and its position in the gene, two possible pathological mechanisms are proposed: (1) the protein may accumulate within the endoplasmic reticulum due to inefficient secretion; and (2) mutant RNA may have a lower expression because of degradation via nonsense-mediated decay.     

Frontotemporal lobar degeneration with ubiquitin-positive inclusions: a molecular genetic update

Frontotemporal lobar degeneration (FTLD) is a clinically, pathologically and genetically highly complex disorder. In the last few years enormous progress has been made in dissecting the genetic etiology of FTLD. Mutations have been identified in the progranulin gene (PGRN), the charged multivesicular body protein 2B gene (CHMP2B) and the valosin-containing protein gene (VCP). Mutations in these genes all lead to FTLD pathology characterized by ubiquitin-immunoreactive neuronal cytoplasmic and intranuclear lentiform inclusions (FTLD-U). The similar pathology suggests that these genes may be connected trough a common disease pathway leading to neurodegeneration and the formation of these pathognomic inclusions. This review focuses on the molecular genetic processes underlying FTLD-U pathology.     

A new case of Pick's disease

Summary The fine structure of a cortical frontal biopsy of Pick's disease is described. Pick bodies appear made of unbranched 120 Å neurofilaments, sometimes clustered in geometrical pattern. Post-mortem examination, performed 8 years later, reveals typical lesions. The characteristics of Pick bodies are discussed.Part of this study was presented at the VIIIth International Congress of Neuropathology (Washington, Sept. 1978)This work was supported by INSERM, grant no. 76.5-206-6     

Cortical ubiquitin-positive inclusions in frontotemporal dementia without motor neuron disease: a quantitative immunocytochemical study

Ubiquitin-positive tau-negative inclusions were initially described in the rare form of frontotemporal dementia (FTD) associated with motor neuron disease. However, recent studies have indicated that these inclusions are also present in typical FTD, which is usually characterized by nonspecific histological changes. To examine the contribution of these inclusions to neuronal loss and to explore their relationship with disease duration, we performed a quantitative immunocytochemical analysis of 38 typical FTD cases. Relationships between neuron and ubiquitin inclusion densities as well as between duration of illness and neuropathological parameters was studied using linear regression in both univariate and multivariate models. Ubiquitin-positive tau-negative intracytoplasmic inclusions were present in 65.8% of cases in the dentate gyrus, 57.9% in temporal cortex and 31.6% in frontal cortex. The highest densities of ubiquitin-positive inclusions were consistently observed in the dentate gyrus, followed by the temporal and frontal cortex. There was no statistically significant relationship between neuron and ubiquitin-positive inclusion densities in any of the areas studied. In contrast, ubiquitin-positive inclusion densities in the dentate gyrus were negatively related to the duration of illness. Our data suggest that the development of ubiquitin-related pathology is the rule and not the exception in typical FTD, yet is not causally related to neuronal loss. They also reveal that the development of ubiquitin-positive inclusion densities in the dentate gyrus may be associated with a more aggressive form of the disease.     

Frontotemporal lobar degeneration with ubiquitin-positive, but TDP-43-negative inclusions

Frontotemporal lobar degeneration (FTLD) can be pathologically subdivided into tau-positive and tau-negative types. The most common tau-negative variant is FTLD with ubiquitin-immunoreactive lesions (FTLD-U). Recently, the TAR DNA binding protein 43 (TDP-43) was identified in neuronal inclusions in FTLD-U. After applying TDP-43 immunohistochemistry to a series of 44 cases of FTLD-U with no secondary pathology, three cases (7%) were identified with ubiquitin- and p62-positive neuronal cytoplasmic inclusions (NCI) that were negative for TDP-43. All the three cases had marked brain atrophy with striking atrophy of the striatum. Cases 1 and 2 presented at ages 43 and 38, respectively, as behavioral variant frontotemporal dementia (1 with positive family history) and had ubiquitin- and p62-positive NCI in frontotemporal neocortex and dentate granule cells of the hippocampus. Case 3 presented with the corticobasal syndrome. Unlike the other two cases, ubiquitin- and p62-positive NCI were also visible on hematoxylin and eosin stain. There were no neuronal intranuclear inclusions. Electron microscopic examination of the NCI in cases 2 and 3 revealed granulofilamentous inclusions. These cases confirm the existence of TDP-43-negative FTLD-U and extend the clinical and pathological spectrum of this disorder. The findings raise the possibly of an as yet identified protein that may play a pathogenic role in tau-negative FTLD.     

Hippocampal sclerosis and ubiquitin-positive inclusions in dementia lacking distinctive histopathology

The aim of this study was to determine the frequency of ubiquitin-positive inclusions (UPI) in dementia lacking distinctive histology (DLDH), and their relationship to other pathologic features, such as hippocampal sclerosis (HpScl), as well as genetic factors. Routine and immunohistochemical studies were carried out in a consecutive series of 29 cases of DLDH. 83% of the cases had UPI, while HpScl was demonstrated in 76%. There was no significant correlation among pathologic features or between pathologic features and genetic factors. The high prevalence of UPI demonstrated in this study implies that DLDH is similar to motor neuron disease inclusion dementia. The high prevalence of HpScl may be the cause of some of the clinical features observed in patients with frontotemporal lobar degeneration.     

Pick's disease: a case clinically resembling amyotrophic lateral sclerosis

A 50-year-old woman with a progressive neurologic illness clinically resembling amyotrophic lateral sclerosis had Pick's disease verified at autopsy. This case represents another example of Pick's disease in which the early manifestations were not those of dementia. This patient also showed some unusual histopathologic features, including degeneration of the substantia nigra and occasional "compound Pick bodies."     

Classic and generalized variants of Pick's disease: a clinicopathological, ultrastructural, and immunocytochemical comparative study

Six sporadic cases of dementia with lobar atrophy and neuronal cytoplasmic inclusions (Pick's disease) could be separated into two groups on the basis of the involvement of subcortical structures, the distribution and the histochemical, immunochemical, and ultrastructural characteristics of the inclusions, and possibly the age at onset. The first group (classic) was characterized by predominantly cortical atrophy and the presence in the hippocampus and neocortex of argyrophilic cytoplasmic inclusion bodies that reacted with a monoclonal antibody against neurofilament proteins and antitubulin antisera. Ultrastructurally the bodies were composed of straight fibrils of variable diameter, averaging 15 nm, and long-period constricted fibrils. The second group (generalized) showed subcortical as well as antibodies against neurofilaments and microtubules. Ultrastructurally the straight fibrils composing the bodies were coated with granular material, presumed to be derived from ribosomes. The generalized cases occurred in younger patients than did the classic cases in this series.     

Pick-body-like inclusions in corticobasal degeneration differ from Pick bodies in Pick's disease

In corticobasal degeneration (CBD), tau-positive cytoplasmic inclusions resembling Pick bodies (PBs) appear in the cerebral cortex. Tau immunoreactivity in PBs is expressed mainly on filamentous elements, whereas that of PB-like inclusions in CBD is expressed on granules, which are densely packed mainly in the periphery of inclusions. PBs are clearly detectable by conventional Bodian silver impregnation but negative for the Gallyas-Braak (G-B) method and for PS262, which recognizes phosphorylation at Ser 262 of the entire tau sequence. Almost all PBs are negative for Ex10, which recognizes 4-repeat tau specifically. In contrast to PBs, PB-like inclusions in CBD could not be detected by the Bodian method, but were positive for the G-B method, PS262 and Ex10. In summary, PBs and PB-like inclusions exhibit distinct differences. These results are useful for the argument of an overlap between PiD and CBD as well as discussion of the phenotypic resemblance of PB-like inclusions bearing types of FTDP-17 to Pick's disease.     

Voxel-based morphometry in frontotemporal lobar degeneration with ubiquitin-positive inclusions with and without progranulin mutations

BACKGROUND: Mutations in the progranulin gene (PGRN) have recently been identified as a cause of frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) in some families. OBJECTIVE: To determine whether there is a difference in the patterns of atrophy in FTLD-U cases with and without PGRN mutations. DESIGN: Case-control study. SETTING: Brain bank of a tertiary care medical center. Patients Eight subjects who had screened positive for PGRN mutations (PGRN-positive) and who underwent volumetric magnetic resonance imaging were identified. Subjects were then matched by clinical diagnosis to a group of 8 subjects with a pathological diagnosis of FTLD-U who had screened negative for PGRN mutations (PGRN-negative). All subjects were then age-matched and sex-matched to a control subject. MAIN OUTCOME MEASURES: Voxel-based morphometry was used to assess the patterns of gray matter atrophy in the PGRN-positive group compared with the PGRN-negative group and compared with controls. RESULTS: The PGRN-positive group showed a widespread and severe pattern of gray matter loss predominantly affecting the frontal, temporal, and parietal lobes. The PGRN-negative group showed a less severe pattern of gray matter loss restricted mainly to the temporal and frontal lobes. On direct comparison, the PGRN-positive group showed greater gray matter loss in the frontal and parietal lobes compared with the PGRN-negative group. CONCLUSION: Findings from this study suggest that PGRN mutations may be associated with a specific and severe pattern of cerebral atrophy in subjects with FTLD-U.     

TDP-43 pathologic lesions and clinical phenotype in frontotemporal lobar degeneration with ubiquitin-positive inclusions

BACKGROUND: TDP-43 is a major ubiquitinated disease protein in the pathologic condition of frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). OBJECTIVE: To investigate the demographic, clinical, and neuropsychological features associated with subtypes of FTLD-U with TDP-43 inclusions (FTLD-U/TDP-43). DESIGN: Retrospective clinical-pathologic study. SETTING: Academic medical center. Patients Twenty-three patients with histopathologically proven FTLD-U. MAIN OUTCOME MEASURES: Demographic, symptom, neuropsychological, and autopsy characteristics. RESULTS: There are notably different clinical and neuropsychological patterns of impairment in FTLD-U subtypes. Patients with FTLD-U/TDP-43 characterized by numerous neuronal intracytoplasmic inclusions have shorter survival; patients with FTLD-U/TDP-43 featuring numerous neurites have difficulty with object naming; and patients with FTLD-U/TDP-43 in whom neuronal intranuclear inclusions are present have substantial executive deficits. There are also different anatomical distributions of ubiquitin pathologic features in FTLD-U subgroups, consistent with their cognitive deficits. CONCLUSION: Distinct TDP-43 profiles may affect clinical phenotypes differentially in patients with FTLD-U.     

Niemann-Pick disease, type A: a case report

Niemann-Pick disease (NPD) type A is a rapidly developing metabolic illness, with autosomal recessive mode of inheritance. A deficiency of the lysosomal enzyme--acid sphingomyelinase (ASM) produces the clinical phenotype with multiple organ involvement including the central nervous system. Type A NPD is characterized by failure to thrive, hepatosplenomegaly and rapidly progressive neurodegenerative course that leads to death by the age of 2-3 years. The authors report a 3-year-old boy with fatal course of the disease.     

Connatal type of Pelizaeus-Merzbacher disease: a case report

Pelizaeus-Merzbacher disease (PMD) is a hereditary disorder with myelin dysplasia in the central nervous system. The connatal type is a more severe form compared to the classical type and shows developmental arrest or deterioration, nystagmus, spasticity, and/or convulsions in the neonatal period. A 1 1/4-year-old Japanese boy diagnosed as connatal type PMD is reported here. Soon after his birth, he demonstrated horizontal and rotatory nystagmus and opisthotonic posture. At the age of 10 months, he had difficulty in feeding. At the age of 1 year, he presented more severe opisthotonic posture and frequent vomiting. He showed deterioration in gross motor development. His chromosome analysis showed a normal male karyotype. Electroencephalogram did not show a sleep spindle. Auditory evoked brainstem responses (ABR) showed only wave I on both sides. Visual evoked potentials (VEP) showed prolongation of latencies. These results were compatible with PMD. Nuclear magnetic resonance imaging (MRI) demonstrated in the white matter of cerebrum and brainstem no high intensities on T1-weighted images and diffuse high intensities on T2-weighted images. Such absence of myelination including the brainstem was characteristic to the connatal type PMD. The diffuse disturbance of myelination appeared to correlate with the severity of clinical symptoms.