Tumefactive Primary Central Nervous System Vasculitis: Imaging Findings of a Rare and Underrecognized Neuroinflammatory Disease.

Primary central nervous system vasculitis (PCNSV) is a poorly understood neuroinflammatory disease of the CNS affecting the intracranial vasculature. Although PCNSV classically manifests as a multifocal beaded narrowing of the intracranial vessels, some patients may not have angiographic abnormalities. A rare subset of patients with PCNSV present with masslike brain lesions mimicking a neoplasm. In this article, we retrospectively review 10 biopsy-confirmed cases of tumefactive PCNSV (t-PCNSV). All cases of t-PCNSV in our series that underwent CTA or MRA were found to have normal large and medium-sized vessels. T-PCNSV had a variable MR imaging appearance with most cases showing cortical/subcortical enhancing masslike lesion (70%), often with microhemorrhages (80%). Diffusion restriction was absent in all lesions. In summary, normal vascular imaging does not exclude the diagnosis of t-PCNSV. Advanced imaging techniques including MR perfusion and MR spectroscopy failed to demonstrate specific findings for t-PCNSV but assisted in excluding neoplasm in the differential diagnosis. Biopsy remains mandatory for definitive diagnosis.

Progressive supranuclear palsy in a family with TDP-43 pathology.

UNLABELLED: A member of a family with an autosomal dominant pattern of frontotemporal dementia (FTD) with a TDP-43 pathological substrate in other members and no mutations in FTD-associated genes developed behavioral variant FTD followed by Progressive Supranuclear Palsy. Autopsy revealed a pure tauopathy of PSP pattern. CONCLUSIONS: The findings raise the possibility of shared pathogenic pathways and a proximal genetic abnormality between PSP and FTLD-43.

Tubuloreticular inclusions in inclusion body myositis.

OBJECTIVE: To evaluate whether patients with inclusion body myositis (IBM) can have tubuloreticular inclusions present in muscle endothelial cells. MATERIAL AND METHODS: Light microscopy with histochemical staining and electron microscopy of a right quadriceps muscle biopsy were used to identify the pathological features in an 83-year-old patient with a clinical diagnosis of IBM. RESULTS: Light microscopy showed rimmed vacuoles. Immunostaining for HLA-1 revealed widespread membrane labeling and for TDP-43 multiple areas of subsarcolemmal and sarcoplasmic staining. Electron microscopy revealed tubuloreticular inclusions in the cytoplasm of endothelial cells. Electron microscopy also showed the presence of myeloid bodies and aggregates of tubolo filaments in the nucleus and cytoplasm of myocytes which confirmed the diagnosis of inclusion body myositis. CONCLUSION: Tubuloreticular inclusions may be found in the muscle endothelial cells of patients with a clinical and pathological diagnosis of IBM.

Spontaneous middle-ear encephalocele: report of two cases and brief review.

We report two cases of middle-ear spontaneous (idiopathic) encephalocele in patients aged 69 and 82 years. To our knowledge the latter represents the oldest individual reported to have such a lesion. Microscopic examination shows a disorganized neuropil with reactive inflammatory changes and in one case, several cysts lined by simple cylindrical ciliated epithelium. Encephalocele must be included in the differential diagnoses of otorrhea and masses in the middle ear.

Do alpha-synuclein aggregates in autonomic plexuses predate Lewy body disorders?: a cohort study.

OBJECTIVE: To determine the prevalence of alpha-synuclein (AS) aggregates in abdominopelvic autonomic plexuses in the general population and to evaluate the relationship between this finding and the subsequent development of neurologic dysfunction. METHODS: First, surgical specimens from 100 patients (ages 44 to 84) undergoing a wide resection of an abdominopelvic organ were examined by anti-AS immunostaining. Second, 16 patients (6 AS+ and 10 randomly selected AS-) participated in yearly double-blinded neurologic assessments. RESULTS: AS aggregates were found in autonomic plexuses in 9% of the whole sample (95% CI 3.4 to 14.6%) but were more common in vesicoprostatic (26%) than in digestive tract (4%) specimens. At 16 months after the biopsy, no prevalent cases of Parkinson disease, dementia, or autonomic failure were diagnosed among participants. One AS+ patient had previously been diagnosed with REM sleep behavior disorder. Seven of 10 control subjects but none of the 6 AS+ patients had a diagnosis of hypertension (p = 0.01). During phase IV of Valsalva maneuver, AS+ group exhibited a longer blood pressure recovery time (p = 0.03), with one patient showing absence of blood pressure overshoot. Cardiac [(123)I]metaiodobenzylguanidine uptake was reduced in the AS+ group (p = 0.03). Striatal [(123)I]ioflupane uptake was abnormally low in only one AS+ patient. At 30 months after the biopsy, lower cardiac and striatal uptake values tended to correlate with higher Unified Parkinson's Disease Rating Scale III scores (p = 0.07). CONCLUSION: The common presence of alpha-synuclein aggregates in peripheral autonomic neurons may represent an early presymptomatic phase in the development of Lewy body disorders.

Promyelocytic leukaemia-immunoreactive neuronal intranuclear rodlets in the human brain.

In a previous study, we demonstrated immunoreactivity of a subset of neuronal intranuclear rodlets (INRs) in the human substantia nigra for promyelocytic leukaemia (PML) protein, the signature protein of PML bodies. In the present study, we extend these observations and describe the ultrastructural features, immunohistochemical staining characteristics, and topographical pattern of distribution of PML-immunoreactive intranuclear rodlets (PML-INRs). Consistent with a purported role for PML bodies in nuclear proteolysis and/or transcriptional regulation, PML-INRs are immunoreactive for components of the ubiquitin-proteasome system, the transcriptional regulator CREB-binding protein, acetylated histone H4, and the eukaryotic translation initiation factor eIF4E. Immunoelectron microscopy reveals that they all possess a filamentous core and, in some, this is surrounded by a granular shell. We further demonstrate that a proportion of INRs in extranigral sites also show partial immunoreactivity for PML. These observations indicate an intimate association between two neuronal nuclear bodies, PML bodies and INRs. Because both of these structures have been implicated in neurodegenerative disease, PML-INRs may provide a tool with which to study changes in nuclear substructure in disease.

Rate of progression of cognitive decline in Alzheimer's disease: effect of butyrylcholinesterase K gene variation.

OBJECTIVE: To determine whether individuals with Alzheimer's disease (AD) and the K variant allele of butyrylcholinesterase have a slower rate of cognitive decline than those without the K variant allele of butyrylcholinesterase. METHOD: The cognitive status of 339 community based subjects with AD was assessed with the Mini Mental State Examination at baseline and yearly over a three year follow up period. The rates of cognitive decline of subjects with and without the K variant allele were compared. RESULT: Presence of the K allele was associated with a slower average rate of cognitive decline in subjects with severe AD. CONCLUSIONS: This finding is consistent with the suggestion that the K variant of butyrylcholinesterase has an important role in disease progression in AD, and this may have implications for treatment.

[Spanish version of the 7 Minute screening neurocognitive battery. Normative data of an elderly population sample over 70]. / Versión española del Test de los 7 Minutos. Datos normativos de una muestra poblacional de ancianos de más de 70 años.

INTRODUCTION: To standardize the Spanish version of the 7 Minute screening neurocognitive battery (7MS) in a population sample of elderly over 70 years. METHODS: We examined 416 persons, living at home, participating in elderly the longitudinal study "Aging in Leganes", aged 71 to 99 years old (mean age: 79 +- 9.2 years; 51.7 % women; 10.6 illiterate, 25 % without formal education). In order to do so, we used an extensive clinical survey, general and neurological exam and extensive neuropsychological battery with several cognitive scales, attention, language, memory, visuomotor skill and reasoning tests, Jorm's IQCODE questionnaire, CES-D depression questionnaire and the 7MS including the Benton Orientation Test, Clock Drawing Test, Free and Cued Learning Test and Categorial Verbal Fluency. Dementia was diagnosed according to DSM-IV criteria but independently of the 7MS scores. Several methods to obtain the total score of the 7MS were analyzed and the normative parameters of the test were obtained in the subgroup of non-demented subjects. RESULTS: The easiest and most efficient method to obtain the total score of the 7MS was the sum of the z-scores of the four subtests. We present the mean values, -1 and -1.5 standard deviations, range and percentiles of the partial and total scores of the 7MS stratified by age (71-75, 76-80, 81-85 and > or = 86 years) and education (less than primary education and primary education or greater) in the subgroup of non-demented subjects. CONCLUSIONS: The normative data of the 7MS obtained in a representative sample of the general elderly population support its rigorous use in the Spanish clinical setting.

Frontotemporal dementia with ubiquitinated cytoplasmic and intranuclear inclusions.

Dementia of motor neuron disease type (DMND) is a variety of frontotemporal dementia (FTD) which is pathologically defined by characteristic neuronal ubiquitinated, tau- and synuclein-negative intracytoplasmic inclusions. Many cases with this pathology, however, do not have motor neuron disease. In the present study, we document the presence of ubiquitinated neuronal intranuclear inclusions in a sub-population of cases of neuropathologically verified DMND. Immunohistochemical localization of ubiquitin was performed on sections of post-mortem brain from 12 patients with DMND as well as from cases with other neurodegenerative diseases including amyotrophic lateral sclerosis, Parkinson's disease, dementia with Lewy bodies, corticobasal degeneration, progressive supranuclear palsy, and multiple system atrophy. All of the cases of DMND showed ubiquitinated, tau-negative intracytoplasmic inclusions in dentate granule cells and cortical neurons. Of these 12 cases of DMND, 3 also showed neuronal ubiquitinated intranuclear inclusions. In 1 of these cases, CAG repeat expansions in the genes known to harbor these mutations were excluded. Cases with intranuclear inclusions displayed striatal atrophy and reduced brain weight relative to non-inclusion-bearing cases. In addition, patients with intranuclear inclusions tended to have a younger age of onset, a prolonged duration of disease, absence of motor neuron symptoms, and a family history of dementia. Intranuclear inclusions were not identified in the control cases with other neurodegenerative diseases. Ubiquitinated neuronal intranuclear inclusions have not been reported previously in DMND. The presence of ubiquitinated intranuclear inclusions along with striatal atrophy in a subset of cases of DMND may signify the existence of a neuropathologically distinct subset of this unique form of FTD.

Cognitive impairment in sporadic ALS: a pathologic continuum underlying a multisystem disorder.

BACKGROUND: Traditionally considered a motor neuron-selective disorder, the clinical manifestations of ALS can include a frontotemporal dementia. Although the pathologic substrate of cognitive impairment remains to be defined, the presence of ubiquitin-immunoreactive (Ub+) intraneuronal inclusions in cortical regions has been suggested to constitute a pathologic marker of this process. METHODS: The authors compared the neuropathological features of four cognitively impaired patients with ALS, four cognitively intact patients with ALS, and four neurologically normal patients. The extent and load of Ub+ neuronal inclusions, Ub+ dystrophic neurites, and superficial linear spongiosis (SLS) was determined among a number of cortical, hippocampal, and subcortical regions. RESULTS: Although Ub+, alpha-synuclein-negative, and tau-negative neuronal inclusions were observed in both cognitively impaired and cognitively intact patients with ALS, their density and extent was greater among the former, with the difference greatest in the cingulate gyrus. Ub+ neurites were observed in a similar distribution. Only the presence of SLS, affecting the first and second cortical layers, reliably distinguished between the cognitively impaired and cognitively intact ALS subpopulations. In three of four cognitively impaired patients with ALS, SLS was associated with transcortical microglial activation, in the absence of detectable differences in astrocytosis, density of calbindin or parvalbumin neurons, or optical density of synaptophysin and SNAP-25. CONCLUSIONS: Although intraneuronal Ub+ inclusions and dystrophic neurites are observed in both ALS subpopulations, the presence of cognitive impairment was associated with a greater distribution and load of both neuropathologic features, suggesting a disease continuum. Moreover, cognitive impairment was uniformly associated with superficial linear spongiosis, a pathologic feature common to several forms of frontotemporal dementia.

Corticobasal degeneration and progressive supranuclear palsy share a common tau haplotype.

OBJECTIVE: To analyze the association of polymorphisms in the tau gene with pathologically confirmed corticobasal degeneration (CBD). BACKGROUND: The authors previously described an extended tau haplotype (H1) that covers the human tau gene and is associated with the development of progressive supranuclear palsy (PSP). The authors now extend this analysis to CBD, a neurodegenerative condition with clinical and neuropathologic similarities to PSP. Like PSP, CBD is associated with accumulation of aggregates containing the 4-repeat isoforms of tau. Because of difficulty in diagnosis of CBD, the authors only analyzed cases with pathologically confirmed CBD. METHODS: The authors collected 57 unrelated, neuropathologically confirmed cases of CBD. Tau sequencing in these cases failed to show the presence of pathogenic mutations. Polymorphisms that spanned the tau gene were analyzed in all CBD cases and controls. RESULTS: Analyzing tau polymorphisms in CBD cases showed that the frequency of H1 and H1/H1 was significantly increased when analyzing all cases and when separating by country of origin. H1 frequency in all CBD cases was 0.921, compared with a control frequency of 0.766 (X(2) = 9.1, p = 0.00255 [1df], OR 3.56 [8.43 > CI 95% > 1.53]). The H1/H1 frequency was also significantly higher at 0.842 compared with 0.596 in age-matched controls (X(2) = 17.42, p = 0.00016, 2df), OR 3.61 [7.05 > CI 95% > 1.85]). CONCLUSIONS: The CBD tau association described here suggests that PSP and CBD share a similar cause, although the pathogenic mechanism behind the two diseases leads to a different clinical and pathologic phenotype.

Clinical and pathologic features of two groups of patients with dementia with Lewy bodies: effect of coexisting Alzheimer-type lesion load.

The objectives of this study were to examine the clinical and pathologic features of two subgroups of patients with dementia with Lewy bodies (DLB) differing in Alzheimer disease (AD)-type pathology load and to identify clinical variables useful in the differential diagnosis from AD. The records of 64 consecutive demented patients were reviewed. Pathologic diagnoses were independently established [35 AD cases, 11 cases of pure dementia with Lewy bodies (pDLB), and 18 cases of combined AD plus Lewy bodies (AD+LB)], and several neurodegenerative lesions were quantified. Clinical and pathologic data were compared between groups with univariate and multivariate analyses. Compared with the other groups, pDLB cases had more frequent acute-subacute onset of dementia [45% vs. AD (3%) and AD+LB (16%)], early parkinsonism [45% vs. AD (0%) and AD+LB (0%)], early [27% vs. AD (0%) and AD+LB (0%)] and late [73% vs. AD (11%) and AD+LB (16%)] hallucinations, fluctuating course [46% vs. AD (9%) and AD+LB (22%)], delusions [45% vs. AD (11%) and AD+LB (6%)], spontaneous parkinsonism [63% vs. AD (8%) and AD+LB (16%)], less frequent ideomotor apraxia and loss of insight, earlier urinary incontinence [3.2 +/- 1.4 years after onset vs. AD (6.3 years) and AD+LB (5.8 years)], shorter duration of dementia [7.7 +/- 2.4 years vs. AD (9.6 years) and AD+LB (11 years)], milder atrophy in computed tomography scans, greater brain weight, more transcortical spongiosis, wider cortex and subcortex, and less amyloid angiopathy. All pDLB cases but no AD cases had abnormal CA2 neurites. The clinical features of AD+LB patients were similar to those of AD patients other than more frequent acute-subacute onset and fluctuating evolution. Discriminant analyses selected four clinical variables differentiating pDLB from the other two groups as a whole: acute-subacute onset, early parkinsonism, early hallucinations, and early onset of urinary incontinence. Two or more of these features identified pDLB with a sensitivity of 81.8% and a specificity of 95.9%. Differentiation between the three groups (pDLB, AD+LB, and AD) or between both groups with LB (DLB) from AD could be only attained in 70% of cases. We conclude that early symptomatology is the main clue for the diagnosis of pDLB. We identified by discriminant analysis a set of clinical diagnostic criteria similar to those proposed by the Consortium on Dementia With Lewy Bodies. Accuracy was excellent for the diagnosis of pDLB but only mediocre for separating AD+LB as well as the entire DLB group from AD.

Selective neuronal necrosis associated with status epilepticus: MR findings.

We present the MR imaging findings in an autopsy-proven case of selective neuronal necrosis involving the entire left cerebral hemispheric cortex, left thalamus, and contralateral cerebellum following a period of status epilepticus. Imaging findings include diffusion abnormality on diffusion-weighted images and increased intensity on T2-weighted images in the above-mentioned regions of the brain.

The corticobasal degeneration syndrome overlaps progressive aphasia and frontotemporal dementia.

OBJECTIVE: To provide evidence for the hypothesis that the corticobasal degeneration syndrome (CBDs) overlaps significantly with primary progressive aphasia and frontotemporal dementia, and that CBDs is part of the Pick complex. BACKGROUND: Corticobasal degeneration has been mainly described as a movement disorder, but cognitive impairment is also increasingly noted. METHODS: Thirty-five cases of clinically diagnosed CBDs were followed-up with clinical, neuropsychological, and neuroimaging investigations. Twenty-nine patients were seen prospectively in movement disorder and cognitive neurology clinics; five of these came to autopsy. Six other autopsied cases that fulfilled the clinical criteria of CBDs were added with retrospective review of records. RESULTS: All 15 patients presenting with movement disorders developed behavioral, cognitive, or language deficits shortly after onset or after several years. Patients presenting with cognitive problems (n = 20), progressive aphasia (n = 13), or frontotemporal dementia (n = 7) developed the movement disorder subsequently. Eleven cases with autopsy had CBD or other forms of the Pick complex. CONCLUSIONS: There is a clinical overlap between CBD, frontotemporal dementia, and primary progressive aphasia. There is also a pathologic overlap between these clinical syndromes. The recognition of this overlap will facilitate the diagnosis and avoid consideration of CBD as "heterogenous."

Monoclonal antibodies against Epstein-Barr virus cross-react with alpha-synuclein in human brain.

Using antibodies generated against the latent membrane protein 1 of Epstein-Barr virus, intense immunoreactivity of Lewy bodies (in PD and dementia with Lewy bodies) and glial cytoplasmic inclusions (in multiple system atrophy) was demonstrated. ELISA and Western blotting techniques confirmed that this immunolabeling was due to cross-reactivity of the antiviral antibody with alpha-synuclein, a neuronal protein implicated in the pathogenesis of PD. This example of cross-reactivity between Epstein-Barr virus and alpha-synuclein may bear implications for further elucidating infectious or autoimmune mechanisms in PD.

Corticobasal degeneration shares a common genetic background with progressive supranuclear palsy.

Corticobasal degeneration is a sporadic form of tauopathy, involving the cerebral cortex and extrapyramidal motor system. A series of affected subjects was genotyped for a set of genetic markers along the tau protein gene. A specific haplotype is significantly overrepresented in patients versus controls. This haplotype is the same already reported in association with progressive supranuclear palsy. These data show that corticobasal degeneration and progressive supranuclear palsy, in addition to several clinical, pathological, and molecular features, may have the same genetic background.

[Neuropathology of frontotemporal dementia]. / Neuropatología de la demencia frontotemporal.

The syndrome of progressive fronto-temporal dementia represents the clinical expression of several pathological processes, mostly degenerative, preferentially involving the frontal and temporal lobes. These processes include dementia with Pick bodies, cortico-basal degeneration, dementia with ITSNU (Inclusions Tau and Synuclein Negative, Ubiquitinated), also known as dementia of motorneuron disease type, dementia with basophilic inclusion bodies, and dementia lacking specific histopathology, and in addition all variants linked to mutations in the tau gene, located in chromosome 17. The term "Pick complex" encompasses these processes and their clinical manifestations, which in addition to fronto-temporal dementia include primary progressive aphasia and apraxic-motor syndromes. The pathologic processes are better discriminated by histopathology than distribution of atrophy, but the latter is the main determinant of the clinical presentation.