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.

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.

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.

Qualitative and quantitative differences in senile plaque dystrophic neurites of Alzheimer's disease and normal aged brain.

We have investigated the relationship of plaque dystrophic neurites expressing beta-amyloid precursor protein (beta APP) to those bearing markers of neurofibrillary degeneration (tau), or accumulating the synaptic protein chromogranin A (CgA). In cortical and hippocampal plaques in Alzheimer's disease (AD) beta APP colocalized with CgA in a neuritic population largely distinct from the subset of neurites labeled by tau. Putaminal plaques generally incorporated only CgA/beta APP, but not tau neurites, and with a rare exception cerebellar plaques were not associated with neurites. Neocortical and hippocampal plaques, the only common type in a group of elderly non-demented subjects (non-AD), incorporated CgA/beta APP, but not tau neurites. In addition to this qualitative difference between the two groups, neocortical plaques with CgA/beta APP neurites were one order of magnitude more common in AD than in non-AD. We propose a hierarchical model of plaque formation in which A beta deposits do not incorporate tau neurites unless neurites bearing synaptic proteins and beta APP are also present. Finally, the minimal association of tau neurites with putaminal plaques, in the presence of tau-immunoreactive neuropil threads and neurofibrillary tangles in the neighborhood, suggests that plaque-independent mechanisms of development of tau neurites operate in AD.

A non-toxic method for the demonstration of gliosis.

Neuropathology laboratories have traditionally relied upon the Holzer method for demonstration of gliosis. However, concerns about the toxicity of aniline oil have markedly reduced the application of this method in recent times. Immunostains for glial fibrillary acidic protein (GFAP) are excellent for showing gliosis in grey matter but cannot distinguish normal from abnormal astrocytes in the white matter. The traditional phosphotungstic acid hematoxylin (PTAH) method stains myelin as well as glial fibers and, thus, is not useful for recognizing areas of gliosis. Here we present a method for the routine demonstration of gliosis based on a modification of Mallory's PTAH method. The staining of myelin is eliminated by increasing the concentration of potassium permanganate to 5% (from 0.25-1% in traditional methods). The use of aminoalkylsilane adhesive ensures that the sections do not detach during the procedure. Areas of gliosis stand out against a pale background because only abnormal astrocytes and their processes are stained, both in grey and white matter. The method minimizes the use of toxic chemicals and can be completed within an eight hour work day in any routine neurohistology laboratory, using formalin fixed, paraffin-embedded tissue.

Prevalence and disease associations of argyrophilic grains of Braak.

Braak's argyrophilic grains (BAG) are spindle-shaped structures originally described in patients with dementia. We have determined that the prevalence of BAGs in an unselected series of 300 consecutive autopsies of subjects over the age of 30 is 5.6%, or 11.7% if only subjects older than 65 are considered. All the 17 subjects identified were older than 68; 6 received other neuropathological diagnoses of degenerative disease and 11 did not. Only 2 of the latter had shown clinical evidence of mental impairment. Braak's argyrophilic grains were associated with ballooned neurons, superficial linear spongiosis, and gliosis of entorhinal cortex and amygdala. Subcortical neurofibrillary tangles were consistently found in patients with dementia, but not in other subjects. In a separate series studying the prevalence of BAG in neurodegenerative diseases, we found a strong, but not universal association with progressive supranuclear palsy, and to a lesser degree with the lobar atrophies (Pick's disease and corticobasal ganglionic degeneration). Numerous BAG were present in occasional cases of diffuse Lewy body disease, multiple systems atrophy, and motor neuron disease. We conclude that rather than defining a single disease, BAG constitute lesions that accompany several degenerative diseases, but also occur in normal elderly subjects, and rarely in demented subjects without other major histological findings.

Hirano bodies accumulate C-terminal sequences of beta-amyloid precursor protein (beta-APP) epitopes.

Hirano bodies (HB) are cytoplasmic inclusions predominantly found in the CA1 sector of the hippocampus. In Alzheimer's disease they are dislocated to the stratum pyramidale from their normal position in the stratum lacunosum. Hirano bodies are known to contain epitopes related to microfilaments (actin), neurofilaments, and microtubules (tau). In cryostat sections of the hippocampus from both Alzheimer's disease and normal patients, HB were decorated by two antisera raised against different sequences of the cytoplasmic domain of beta-amyloid precursor protein (beta-APP), and two antisera against the beta/A4 sequence of beta-APP, but not by two antisera directed against ectodomain (N-terminal) sequences of beta-APP. Thus, in contrast to dystrophic neurites in plaques, which are decorated by antibodies to either terminus of beta-APP, HB appear to be a site of preferential accumulation of C-terminal fragments of beta-APP, extending to include at least part of beta/A4.

Accumulation of phosphorylated neurofilaments in anterior horn motoneurons of amyotrophic lateral sclerosis patients.

Perikaryal collections of intermediate filaments have been described in the anterior horn motoneurons of patients with amyotrophic lateral sclerosis (ALS), but these inclusions have generally been considered rare and mainly associated with the familial form of ALS. Using the monoclonal antibody NF2F11, which recognizes phosphorylated neurofilament epitopes, we showed that focal collections of neurofilaments in anterior horn motoneurons were a characteristic finding in sporadic as well as in familial ALS; they were present in seven of nine ALS patients, but in none of nine control spinal cords. These neurofilamentous collections are not cross-reactive with antibodies directed against paired helical filaments and the microtubule associated protein tau. In addition, diffuse staining for phosphorylated neurofilament epitopes in chromatolytic anterior horn perikarya was significantly more frequent in ALS patients than in controls.

Multiple microabscesses in the central nervous system: a clinicopathologic study.

We reviewed 2,107 consecutive autopsies with neuropathologic examination at the Medical Center Hospital of Vermont, and identified 92 cases with significant pathologic evidence for infection involving the central nervous system (CNS). Of these, 35 took the form of multiple microabscesses. There were 19 men and 16 women, mean age 56. All patients were chronically ill, usually with an associated impaired immunity. The lung was the most frequent site of primary infection, and sepsis was often present. The most commonly identified causative organisms were Staphylococcus aureus and Candida albicans. Patients with CNS microabscesses developed a progressive encephalopathy associated with waxing and waning signs and symptoms. Laboratory and neuroradiologic studies were not helpful in elucidating the problem. We conclude that multiple microabscesses are a frequent, usually unrecognized, manifestation of CNS infection, and should be considered in the differential diagnosis of encephalopathy in hospitalized patients with chronic disease, immunosuppression and sepsis.

Meningioangiomatosis is associated with neurofibromatosis 2 but not with somatic alterations of the NF2 gene.

Meningioangiomatosis occurs sporadically and in patients with neurofibromatosis. The literature, however, is unclear concerning the type of neurofibromatosis associated with meningioangiomatosis. Because determining which form of neurofibromatosis predisposes to meningioangiomatosis would clarify the genetic alterations of this lesion, we reviewed all reported cases of meningioangiomatosis associated with neurofibromatosis in light of current diagnostic criteria for neurofibromatosis 1 (NF1) and neurofibromatosis 2 (NF2). All well-documented cases of meningioangiomatosis occurred in the setting of NF2, implying that germline alterations of the NF2 gene predispose to meningioangiomatosis. To determine whether sporadic (non-NF) cases of meningioangiomatosis arise from somatic alterations of the same gene, we screened the NF2 gene for mutations in 12 sporadic cases of meningioangiomatosis and in constitutional DNA from 6 of these 12 patients. No mutations were found in either the lesional or constitutional DNA, which suggests that sporadic meningioangiomatosis is not a forme fruste of NF2 and that somatic alterations of the NF2 gene do not play a major role in sporadic meningioangiomatosis. For some tumor suppressor genes, germline mutations may predispose to specific tumors, while similar sporadic lesions only rarely suffer somatic mutations in these genes. The present findings suggest a similar dichotomy for the NF2 gene in meningioangiomatosis.

Role of microglia in senile plaque formation.

To assess the role of microglial cells in senile plaque (SP) formation, we examined the density and distribution of microglia in the temporal neocortex of three groups of nondemented individuals, chosen to represent sequential stages of SP formation (no SP, n = 14; diffuse plaques (DP) only, n = 12; both DP and neuritic plaques (NP), n = 14) and patients with Alzheimer's disease (AD, n = 11). The mean density of microglia was significantly greater in the AD group. In nondemented individuals, the presence of NP but not DP was associated with an increased number of microglial cells. Most NP (91%) were focally associated with microglial cells. DP less commonly contained microglia, however, individuals with some NP had microglia within a greater proportion of their DP (47%) than did those with only DP (19%). These findings suggest that: (a) microglia are not involved in the formation of DP; (b) the presence of NP is associated with both an overall increase in microglia and the focal aggregation of cells around NP; (c) microglia may be locally involved in the conversion of DP into NP. This final point represents the most significant aspect of this study, providing the first quantitative evidence to support a specific role for microglia in the formation of NP from DP.

Hippocampal sclerosis and human memory.

OBJECTIVE: To study the effects of hippocampal sclerosis on preoperative neuropsychological memory tests. DESIGN: Analyses of variance and chi 2 tests were used to compare patient groups (divided retrospectively) with a control group. SETTING: Hospital epilepsy unit. PATIENTS AND OTHER PARTICIPANTS: All patients who underwent a temporal lobectomy for intractable seizure relief during the preceding 18 months were included if the following criteria were met: (1) age was between 15 and 55 years; (2) IQ was 80 or greater; (3) the left hemisphere was dominant for speech; (4) there had been no previous brain surgery; (5) sufficient hippocampal tissue had been supplied for pathologic study; and (6) there was no hippocampal abnormality other than sclerosis. The 40 patients who met all of these criteria were divided into groups based on pathological classification (presence or absence of hippocampal sclerosis) and side of excision. Ten normal control subjects, matched to the patients based on age and education, were also asked to perform the memory tests. All subjects approached gave their informed consent to participate in the study. INTERVENTIONS: None. MAIN OUTCOME MEASURES: None. RESULTS: No group demonstrated impairments on measures of attention or recognition memory. A deficit in learning paired-word associates was found for the left hippocampal sclerosis, right hippocampal sclerosis, and left no-hippocampal sclerosis groups, but on tests requiring the delayed recall of information, only patients with hippocampal sclerosis were impaired. For verbal tasks, the delayed recall deficit was limited to patients with left-sided sclerosis. CONCLUSIONS: Hippocampal sclerosis impairs the ability to learn associations and to retain information over a delay interval. For the learning and retention of verbal material, the left hippocampus is more important than the right.

Educational attainment and socioeconomic status of patients with autopsy-confirmed Alzheimer disease.

OBJECTIVE: To determine whether patients with autopsy-confirmed Alzheimer disease (AD) have different educational attainment and socioeconomic status than subjects without neurodegenerative disease. DESIGN: Comparison of 2 groups of autopsied patients. Information on education and occupation was obtained by telephone interview of relatives conducted post mortem. PATIENTS: One hundred fifteen patients enrolled in the University of Western Ontario Dementia Study with dementia and fulfilling diagnostic criteria of AD at autopsy were compared with 142 patients 65 years or older without dementia who died in the hospital and in whom autopsy did not show neurodegenerative disease. MAIN OUTCOME MEASURES: Highest education level attained, years of education, occupation, and socioeconomic and income levels. All results were adjusted for sex, age at time of death, and year of birth. RESULTS: There were no statistically significant differences in education, occupation, or socioeconomic and income levels between the groups. CONCLUSIONS: There is no evidence that educational attainment is different in patients with AD than in subjects who die in the hospital from other diseases. These results indicate that education does not protect against advanced AD.

Pathologic correlates of increased signals of the centrum ovale on magnetic resonance imaging.

The pathologic correlates of increased signal in the white matter of the centrum ovale in postmortem magnetic resonance imaging were investigated in an unselected series of 15 autopsies. Two types of magnetic resonance imaging hyperintensities could be separated on the basis of size (10-mm cutoff): extensive and punctate. The pathologic basis of extensive hyperintensities was large areas of pallor with ill-defined margins, located in the central white matter and sparing the subcortical U fibers on both myelin and axonal stains. Microscopically, these areas showed diffuse vacuolation and significant reduction in the areal densities of glial cells. This change was never seen in areas that did not show extensive white matter hyperdensities on magnetic resonance imaging. The correlates of punctate magnetic resonance imaging hyperintensities were less well defined; dilated Virchow-Robin spaces probably represent a common cause of this phenomenon.

Diffuse vacuolization (spongiosis) and arteriolosclerosis in the frontal white matter occurs in vascular dementia.

OBJECTIVE: To examine quantitatively white-matter changes at different sites in patients with definite vascular dementia and Alzheimer's disease. DESIGN: Prospective clinical and neuropathological series. SETTING: University Hospital clinics (Helsinki, Finland and London, Ontario). SUBJECTS: Twenty-two patients with a clinical and neuropathological diagnosis of vascular dementia and 20 patients with Alzheimer's disease. MEASURES: The frequencies of focal white-matter lesions, arteriolosclerosis, and cerebral amyloid angiopathy were assessed. Validated ratings and cell counts were done in the subcortical U-fiber, centrum semiovale, and periventricular areas of the frontal white matter. Degrees of abnormality (none, mild, moderate, severe) were rated for spongiosis (vacuolization of white matter), état criblé (widening of perivascular spaces), myelin loss, oligodendrocyte density, axonal loss, and overall. Densities of oligodendrocytes and astrocytes (cells per square millimeter) were determined. RESULTS: Patients with vascular dementia showed focal white-matter lesions and arteriolosclerosis more often than patients with Alzheimer's disease. The patients with vascular dementia also had significantly greater spongiosis (P<.001), état criblé (P=.004), myelin loss (P<.005) and overall white-matter abnormality (P<.001). Arteriolosclerosis was found in association with spongiosis but not with état criblé. Cerebral amyloid angiopathy did not appear to be related to any of the white-matter changes in patients with either vascular dementia or Alzheimer's disease. The U-fiber area showed fewer changes, and the periventricular area tended to be most affected. CONCLUSION: In addition to focal infarcts, patients with vascular dementia showed widespread diffuse changes, including spongiosis and arteriolosclerosis, along with état criblé and myelin loss. White-matter changes in patients with Alzheimer's disease could not be related to infarction. Pathologic changes in small blood vessels are associated with diffuse white-matter changes and may have a distinct role in the genesis of vascular dementia.

Comparative evolution of Alzheimer disease, vascular dementia, and mixed dementia.

OBJECTIVE: To compare the evolution of Alzheimer disease (AD), vascular dementia (VaD), and mixed dementia by cognitive domain. SETTING: The University of Western Ontario Dementia Study, which is a registry of cases of dementia seen for secondary and tertiary assessment in a university memory disorders clinica with extensive follow-up data and histopathological confirmation of clinical diagnoses. PATIENTS: One hundred twenty-nine patients with definite or probable AD, 12 patients with definite or probable VaD, and 36 patients with definite or probable mixed dementia. METHODS: Patients were grouped as having an early, moderate, or advanced stage of disease according to the extended scale for dementia (ESD). The ESD was subdivided into cognitive domains, and the domain scores were compared for each stage of disease by diagnostic category with the use of a 2-way analysis of variance with repeated measures. RESULTS: As expected, the scores in all domains decreased significantly with increasing severity. There was a significant difference in the decline in memory among the diagnostic groups (P = .02) that was mostly attributable to the difference between AD and mixed dementia (P = .03), with the difference between AD and VaD only approaching significance (P = .06). There was a similar finding for praxis. The interaction between diagnosis (AD and VaD) and severity was significant only for memory (P = .02), showing a less severe memory deficit at onset but a proportionately more rapid progression in VaD and arithmetic ability (AD and mixed dementia [P = .03]). CONCLUSIONS: Alzheimer disease, VaD, and mixed dementia evolve similarly as assessed using cognitive domains obtained by subdivision of the ESD in a patient population derived from a memory clinic and by analyzing VaD as a single entity. Only memory impairment evolves differently between AD and VaD, with this depending on the severity. Memory is more severely impaired in the early stage of AD; however, with increasing severity of dementia, memory impairment in VaD accelerates and catches up with AD at the level of moderate impairment. The differences between AD and mixed dementia are greater than those between mixed dementia and VaD, suggesting an important role for the ischemic component of mixed dementia. Simple neuropsychological tools (eg, the ESD) may be incapable of distinguishing between AD and VaD, and more focused instruments may be required. Inherent bias in case selection may prevent extrapolation of these results to VaD in general, but the neuropsychological criteria for VaD may need to vary, depending on the severity.

Nonsteroidal anti-inflammatory drug use and Alzheimer-type pathology in aging.

Anti-inflammatory drugs have been suggested as a possible treatment for Alzheimer's disease (AD). The association of immune proteins and immune-competent microglial cells with senile plaques (SP) in both AD and normal aging suggests that these drugs may be able to modify the course of AD, either by interfering with SP formation or by suppressing the inflammation associated with SP. We compared postmortem brain tissue from elderly, nondemented, arthritic patients with a history of chronic nonsteroidal anti-inflammatory drug (NSAID) use (n = 32, aged 77 +/- 7 years) and nondemented control subjects with no history of arthritis or other condition that might promote the regular use of NSAIDs (n = 34, aged 77 +/- 6 years). In both the NSAID-treated group and control subjects, 59% of patients had some SP. There was no difference between the two groups in the mean number of plaques or in the number of specific SP subtypes (diffuse or neuritic). The degree of neurofibrillary pathology was also similar. Activated microglia were identified using CR3/43, an anti-MHC class II antibody. Both patient age and the presence of SP correlated positively with the number of CR3/43+ microglia (p < 0.02), whereas NSAID use was associated with less microglial activation (p < 0.01). Control patients with SP had almost three times the number of activated microglia as NSAID-treated patients with SP (11 versus 4 cells/mm2, p < 0.02). These results suggest that if NSAID use is effective in treating AD, the mechanism is more likely to be through the suppression of microglial activity than by inhibiting the formation of SP or neurofibrillary tangles.

Temporal pattern of cognitive decline and incontinence is different in Alzheimer's disease and diffuse Lewy body disease.

Incontinence is a hallmark of dementia, but little is known about its inception in different types of dementing disease. We recorded the dates of onset of dementia and of urinary incontinence in 73 demented patients followed for 5.6 +/- 2.5 years. The pathologic diagnosis was Alzheimer's disease (AD) in 29 cases, diffuse Lewy body disease (DLBD) in 11 cases, AD with Lewy bodies (AD+LB) in 13 cases, and AD with vascular lesions (AD+VL) in 20 cases. The onset of urinary incontinence was significantly earlier in DLBD cases (3.2 +/- 1.4 years after dementia onset) than in AD (5.9 +/- 2.5), AD+LB (5.8 +/- 2.4), and AD+VL (6.5 +/- 2.3) (p < 0.01). At the onset of bladder incontinence, the mean score in the Extended Dementia Scale was significantly higher (i.e., cognition was better) in DLBD cases (109.3 +/- 70.8) than in AD (21.3 +/- 40.4), AD+LB (45.6 +/- 45.1), and AD+VL (39.2 +/- 54.9) cases (p < 0.01). Urinary incontinence is associated with severe cognitive decline in pure AD but usually precedes severe mental failure in DLBD cases. This temporal pattern of cognitive decline and incontinence could be useful in differentiating these two dementing illnesses.

The pathology and nosology of primary progressive aphasia.

We present three cases of primary progressive aphasia (PPA) with Pick-variant pathology to support a hypothesis of an underlying nosologic relatedness. Neuropathologic examination demonstrated focal brain atrophy with corresponding neuronal loss and gliosis, accompanied by superficial spongiosis. Specific histologic findings were ballooned neurons (Pick cells) in the atrophic areas, and in two of the cases, Pick bodies. They were immunoreactive for tau. In contrast to classic Pick's disease, there were no Pick bodies in the hippocampus. The intense neurofilament immunoreactivity of the perikarya of the ballooned neurons greatly facilitated their recognition. Based on our cases and a critical review of the literature, we hypothesize that the common underlying pathology of PPA is a variant of Pick's disease. Furthermore, we propose the concept of "Pick complex" to include other neurodegenerative diseases characterized by focal cortical degeneration, such as PPA, frontal lobe dementia, ALS with PPA, and corticonigral and corticobasal ganglionic degenerations.