Cerebral atherosclerosis is associated with cystic infarcts and microinfarcts but not Alzheimer pathologic changes.

BACKGROUND AND PURPOSE: Some studies have reported associations between intracranial atherosclerosis and Alzheimer disease pathology. We aimed to correlate severity of cerebral atherosclerosis, arteriolosclerosis, and cerebral amyloid angiopathy with neurofibrillary tangles, neuritic plaques, and cerebral infarcts. METHODS: This autopsy study (n=163) was drawn from a longitudinal study of subcortical ischemic vascular disease, Alzheimer disease, and normal aging. Multivariable logistic regression models were used to test associations among the 3 forms of cerebrovascular disease and the presence of ischemic and neurodegenerative brain lesions. Apolipoprotein E genotype was included as a covariate in these multivariable models. RESULTS: Cerebral atherosclerosis was positively associated with microinfarcts (odds ratio [OR], 2.3; 95% confidence interval [CI], 1.2-4.4) and cystic infarcts (OR, 2.0; 95% CI, 1.0-4.2) but not Alzheimer disease pathology. Arteriolosclerosis showed a positive correlation with lacunar infarcts (OR, 2.0; 95% CI, 1.0-4.2) but not Alzheimer disease pathology. Cerebral amyloid angiopathy was inversely associated with lacunar infarcts (OR, 0.6; 95% CI, 0.41-1.1), but positively associated with Braak and Braak stage (OR, 1.5; 95% CI, 1.1-2.1) and Consortium to Establish a Registry for Alzheimer Disease plaque score (OR, 1.5; 95% CI, 1.1-2.2). CONCLUSIONS: Microinfarcts, which have been correlated with severity of cognitive impairment, were most strongly associated with atherosclerosis. Possible pathogenetic mechanisms include artery-to-artery emboli, especially microemboli that may include atheroemboli or platelet-fibrin emboli. Arteriolosclerosis was positively, whereas cerebral amyloid angiopathy was negatively correlated with lacunar infarcts, which might prove helpful in clinical differentiation of arteriolosclerotic from cerebral amyloid angiopathy-related vascular brain injury.

Prevalence, laterality, and comorbidity of hippocampal sclerosis in an autopsy sample.

Hippocampal sclerosis (HS) is a common and often asymmetric neuropathological finding among elderly persons who experience progressive memory loss, but its cause is unknown and it is rarely diagnosed during life. In order to improve both understanding and diagnosis of late-life HS, bilateral hippocampi and cerebral hemispheres were reviewed in 130 consecutive autopsy cases drawn from a longitudinal study of subjects with subcortical ischemic vascular dementia (IVD), Alzheimer disease (AD) and normal aging. HS was found in 31 of 130 cases (24.5%). Of these, 45% were bilateral, 32% left-sided, and 23% right-sided. The majority of HS cases involved the entire rostral-caudal extent of the hippocampus. However, in 7 cases HS was focal in nature and was only found at or anterior to the lateral geniculate nucleus. In 77% of cases, HS was accompanied by other types of pathology ('mixed' HS), but in 23% of cases it was the sole neuropathologic finding ('pure' HS). TDP-43-positive cytoplasmic inclusions were found in dentate granule cells in 93% of all HS cases, 55% of AD cases with no HS, but 0% of IVD cases with no HS. MRI hippocampal volumes were significantly lower in bilateral HS compared to AD (p < 0.001) and in unilateral HS cases compared to cases with intact hippocampi (p < 0.001). Since HS may occur unilaterally in approximately a quarter of cases, its prevalence may be underestimated if only one cerebral hemisphere is examined. The presence of TDP-43 inclusions in HS cases, regardless of accompanying pathologies (e.g., AD, IVD, FTLD), is consistent with an underlying neurodegenerative pathogenetic mechanism. Further studies are warranted to determine whether greater severity of hippocampal atrophy on MRI may assist the clinical differentiation of HS from AD.

Preservation of neurons of the nucleus basalis in subcortical ischemic vascular disease.

OBJECTIVE: To investigate loss of neurons in the nucleus basalis (NB) of Meynert in patients with subcortical ischemic vascular disease (SIVD) compared with healthy controls, patients with Alzheimer disease (AD), and patients with mixed AD and SIVD. DESIGN: Autopsied cases drawn from a longitudinal observational study of patients with SIVD, patients with AD, and healthy controls. SETTING: Multi center, university-affiliated, program project neuropathology core. PATIENTS: Patients with pathologically defined SIVD (n = 16), AD (n = 20), and mixed AD and SIVD (n = 10) and healthy controls matched by age and educational level (n = 17) were studied. MAIN OUTCOME MEASURES: The NB neuronal cell counts in each group and their correlation with the extent of magnetic resonance imaging white matter lesions and Clinical Dementia Rating (CDR) scores closest to death. RESULTS: No significant loss of neurons was found in SIVD patients compared with age-matched controls in contrast to the AD and mixed groups, who had significant neuronal loss. A significant inverse correlation between NB neurons and CDR scores was found in the AD group but not in the SIVD and mixed groups. The NB cell counts were not correlated with either the extent of white matter lesions or cortical gray matter volume in the SIVD or AD groups. CONCLUSIONS: These findings inveigh against primary loss of cholinergic neurons in SIVD patients but do not rule out the possibility of secondary cholinergic deficits due to disruptions of cholinergic projections to cerebral cortex.

Clinical emergence of neurometastatic merkel cell carcinoma: a surgical case series and literature review.

Merkel cell carcinoma (MCC) is a rare cutaneous neuroendocrine neoplasm of possible viral origin and is known for its aggressive behavior. The incidence of MCC has increased in the last 15 years. Merkel cell carcinoma has the potential to metastasize, but rarely involves the central nervous system. Herein, we report three consecutive surgical cases of MCC presenting at a single institution within 1 year. We used intracavitary BCNU wafers (Gliadel(®)) in two cases. Pathological features, including CK20 positivity, consistent with MCC, were present in all cases. We found 33 published cases of MCC with CNS involvement. We suggest that the incidence of neurometastatic MCC may be increasing, parallel to the increasing incidence of primary MCC. We propose a role for intracavitary BCNU wafers in the treatment of intra-axial neurometastatic MCC.

Alzheimer abnormalities of the amygdala with Klüver-Bucy syndrome symptoms: an amygdaloid variant of Alzheimer disease.

BACKGROUND: Neurofibrillary tangles and beta-amyloid plaques have been observed in the amygdala in Alzheimer disease. A disproportionate abundance of this abnormality in the amygdala may cause behavioral symptoms similar to Klüver-Bucy syndrome. OBJECTIVES: To describe an atypical behavioral presentation of Alzheimer disease and to review the literature on the subject. DESIGN: Case study. SETTING: Outpatient specialty clinic. PATIENT: A 70-year-old man with progressive behavioral symptoms of hyperorality, hypersexuality, hypermetamorphosis, visual agnosia, hyperphagia, and apathy who died at age 77 of asphyxiation on a foreign object. MAIN OUTCOME MEASURES: Clinical symptomatology, brain imaging, and neuropathology. RESULTS: The pathologic diagnosis was Alzheimer disease with abundant tangles and plaques in the lateral amygdala. CONCLUSIONS: This case represents a variant of Alzheimer disease with prominent amygdala abnormalities and a Klüver-Bucy phenotype that was misdiagnosed as frontotemporal dementia. Clinical and imaging findings that may aid in accurate diagnosis are reviewed.

Neuropathological basis of magnetic resonance images in aging and dementia.

OBJECTIVE: Magnetic resonance (MR) imaging is used widely for assessment of patients with cognitive impairment, but the pathological correlates are unclear, especially when multiple pathologies are present. METHODS: This report includes 93 subjects from a longitudinally followed cohort recruited for the study of Alzheimer's disease (AD) and subcortical cerebrovascular disease (CVD). MR images were analyzed to quantify cortical gray matter volume, hippocampal volume, white matter hyperintensities, and lacunes. Neuropathological examination quantified CVD parenchymal pathology, AD pathology (defined as Consortium to Establish a Registry for Alzheimer's Disease scores and Braak and Braak stage), and hippocampal sclerosis. Subjects were pathologically classified as 12 healthy control subjects, 46 AD, 14 CVD, 9 mixed AD/CVD, and 12 cognitively impaired patients without significant AD/CVD pathology. Multivariate models tested associations between magnetic resonance and pathological findings across the entire sample. RESULTS: Pathological correlates of cortical gray matter volume were AD, subcortical vascular pathology, and arteriosclerosis. Hippocampal volume was related to AD pathology and hippocampal sclerosis, and the effects of hippocampal sclerosis were greater for subjects with low levels of AD pathology. White matter hyperintensities were related to age and to white matter pathology. Number of MRI lacunes was related to subcortical vascular pathology. INTERPRETATION: In this clinical setting, the presence of lacunes and white matter changes provide a good signal for vascular disease. The neuropathological basis of MR defined cerebral cortical and hippocampal atrophy in aging and dementia is complex, with several pathological processes converging on similar brain structures that mediate cognitive decline.

Cognitive impact of subcortical vascular and Alzheimer's disease pathology.

OBJECTIVE: To assess the interactions among three types of pathology (ie, cerebrovascular disease, hippocampal sclerosis [HS], and Alzheimer's disease [AD]), cognitive status, and apolipoprotein E genotype. METHODS: We report clinicopathological correlations from 79 autopsy cases derived from a prospective longitudinal study of subcortical ischemic vascular disease and AD. RESULTS: Thirty percent of the cases had significant cerebrovascular parenchymal pathology scores (CVDPS), 54% had significant AD pathology, and 18% had HS. In an ordinal logistic regression analysis that included interaction terms to assess the effects of each pathological variable when the other variables are interpolated to zero, each of the three pathology variables contributed independently to cognitive status: Braak and Braak stage odds ratio (OR) = 2.84 (95% confidence interval, 1.81-4.45), HS score OR = 2.43 (95% confidence interval, 1.01-5.85), and CVDPS OR = 1.02 (95% confidence interval, 1.00-1.04). Only Braak and Braak stage contributed to a global neuropsychological measure of cognitive impairment. Apolipoprotein E4 genotype was associated with Braak and Braak stage (OR, 1.31 [95% confidence interval, 1.03-1.68]), but not CVDPS or HS scores. INTERPRETATION: In this convenience sample enriched for subcortical ischemic vascular disease, HS was a common unsuspected neuropathological finding. Apolipoprotein E4 genotype was associated with cerebral amyloid angiopathy, but not HS or arteriosclerosis. When Braak and Braak stage was interpolated to zero, both CVDPS and HS contributed to cognitive impairment. However, advancing stages of AD pathology overwhelmed the effects of CVDPS and HS, to become the major determinant of dementia.

Correlates of hippocampal neuron number in Alzheimer's disease and ischemic vascular dementia.

The cornu ammonis 1 region of the hippocampus (CA1) sector of hippocampus is vulnerable to both Alzheimer's disease (AD)-type neurofibrillary degeneration and anoxia-ischemia. The objective of this article is to compare number and size of neurons in CA1 in AD versus ischemic vascular dementia. Unbiased stereological methods were used to estimate the number and volume of neurons in 28 autopsy-derived brain samples. For each case, the entire hippocampus from one cerebral hemisphere was sliced into 5mm slabs (5-7 slabs/case), cut into 50 microm sections, and stained with gallocyanine. Using the optical dissector, we systematically sampled the number and size of neurons throughout the extent of CA1 and CA2. The total number of neurons was significantly less in AD compared with ischemic vascular dementia (p < 0.02), but there was no significant difference in neuron size. The greatest loss of neurons was observed in two cases with combined AD and hippocampal sclerosis. Regardless of causative diagnosis, the number of CA1 neurons correlates with magnetic resonance imaging-derived hippocampal volume (r = 0.72; p < 0.001) and memory score (r = 0.62; p < 0.01). We conclude that although CA1 neuron loss is more consistently observed in AD than ischemic vascular dementia, severity of loss shows the expected correlation with structure and function across causative subtype. Reductions in magnetic resonance imaging-derived hippocampal volume reflect loss, rather than shrinkage, of CA1 neurons.

Simultaneous symptomatic Rathke's cleft cyst and GH secreting pituitary adenoma: a case report.

A case of symptomatic Rathke's cleft cyst and growth hormone (GH) secreting pituitary adenoma is described. A patient presented with a visual field deficit and a brain magnetic resonance imaging (MRI) study demonstrated compression of the optic chiasm by a large suprasellar cyst and a small lesion in the sellar consistent with a microadenoma. Preoperative clinical evaluation revealed mild acromegalic features, glucose intolerance, hypertension, hypercholesterolemia, and carpel tunnel syndrome, and blood testing confirmed an elevated insulin-like growth factor-1 (IGF-1). A modified transsphenoidal skull based approach was performed for selective transsphenoidal adenomectomy and decompression of the surprasellar cyst. The patient had an uneventful postoperative course with resolution of the visual field deficits and dysmenorrhea. Endocrine testing at two-month post procedure were normal. While there have been a small number of cases reported of concomitant pituitary adenomas and Rathke's cleft cysts, there is no report known to these authors of coexisting symptomatic lesions.

In situ hybridization for detection of nocardial 16S rRNA: reactivity within intracellular inclusions in experimentally infected cynomolgus monkeys--and in Lewy body-containing human brain specimens.

Our previous studies found that experimental infection of BALB/c mice with the Gram-positive bacterium Nocardia asteroides induced a parkinsonian-type syndrome with levodopa-responsive movement abnormalities, loss of nigrostriatal dopaminergic neurons, depletion of striatal dopamine, and intraneuronal inclusions in the substantia nigra (SN) with an appearance similar to Lewy bodies. In the present study, an in situ hybridization technique was developed to detect nocardial 16S ribosomal RNA (rRNA), using a Nocardia-specific probe (B77). Cerebral cortical specimens from cynomolgus monkeys were examined for the presence of nocardial RNA 48 h, 3.5 months, and 1 year after experimental infection with N. asteroides. Hybridization reactions were detected within Nocardia-like structures 48 h after infection and within intracellular inclusion bodies (immunoreactive for alpha-synuclein and ubiquitin) in one of two 3.5-month-infected monkeys. The in situ hybridization procedure was then applied in a blinded fashion to 24 human SN specimens with Lewy bodies and 11 human SN specimens without Lewy bodies (including five normal controls). Hybridization reactions were detected in nine Lewy body-containing specimens and none of the others. Reactivity was limited to inclusions with the appearance of Lewy bodies, with the exception of one specimen in which intracellular reactivity was also observed in Nocardia-like structures. These results suggest a possible association between Nocardia and neurodegenerative disorders in which Lewy bodies are present.

AIDS-related myopathy.

Infection with the human immunodeficiency virus (HIV) is often associated with the acquired immunodeficiency syndrome (AIDS), and wasting is one of the defining clinical features of AIDS. Muscular weakness due to myopathy may develop at any stage of HIV infection. We report two illustrative cases of HIV-associated myopathies. One was due to inflammatory myosits most likely directly related to the HIV infection, and the other was most likely the result of mitochondrial damage due to zidovudine, a nucleoside analogue commonly used in treating HIV infection. Biopsies from both patients showed alterations of myofiber structures, of varying severity, culminating in necrosis, lipid droplets, and lymphoplasmocytic inflammatory response. The zidovudine-treated patient also showed distinctive mitochondrial changes, predominantly enlargement, variation in shape and size, and disorganization of the cristae. These two types of HIV-associated inflammatory myopathies are reviewed, along with other HIV-associated myopathies, including HIV wasting syndrome, nemaline rod myopathy, pyomyositis, rhabdomyolysis, cardiomyopathy, and other miscellaneous myopathies associated with HIV infection.