Alzheimer Lesions in the Autopsied Brains of People 30 to 50 Years of Age.

OBJECTIVE: To test the hypothesis that asymptomatic Alzheimer disease lesions may appear before 50 years of age. BACKGROUND: Alzheimer disease has an asymptomatic stage during which people are cognitively intact despite having substantial pathologic changes in the brain. While this asymptomatic stage is common in older people, how early in life it may develop has been unknown. METHODS: We microscopically examined the postmortem brains of 154 people aged 30 to 39 years (n=59) and 40 to 50 years (n=95) for specific Alzheimer lesions: beta-amyloid plaques, neurofibrillary tangles, and tau-positive neurites. We genotyped DNA samples for the apolipoprotein E gene (APOE). RESULTS: We found beta-amyloid lesions in 13 brains, all of them from people aged 40 to 49 with no history of dementia. These plaques were of the diffuse type only and appeared throughout the neocortex. Among these 13 brains, five had very subtle tau lesions in the entorhinal cortex and/or hippocampus. All individuals with beta-amyloid deposits carried one or two APOE4 alleles. Among the individuals aged 40 to 50 with genotype APOE3/4, 10 (36%) had beta-amyloid deposits but 18 (64%) had none. CONCLUSIONS: Our study demonstrates that beta-amyloid deposits in the cerebral cortex appear as early as 40 years of age in APOE4 carriers, suggesting that these lesions may constitute a very early stage of Alzheimer disease. Future preventive and therapeutic measures for this disease may have to be stratified by risk factors like APOE genotype and may need to target people in their 40s or even earlier.

Coexisting adult polyglucosan body disease with frontotemporal lobar degeneration with transactivation response DNA-binding protein-43 (TDP-43)-positive neuronal inclusions.

Frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) is one of the most common pathological findings associated with the clinical FTLD syndromes. However, molecular characterization with genetic sequencing and protein expression techniques are recognizing many new subtypes for FTLDs. FTLDs are diverse and new nomenclature schemes have been proposed based on the molecular defects that are being discovered ( Mackenzie et al., 2010 , Acta Neuropathologica, 119, 1). Adult polyglucosan body disease (APBD) is a very rare disorder associated with systemic neurological signs and symptoms including progressive dementia with executive dysfunction and motor neuron disease. We report the clinical course of an individual with a clinical FTLD and the as yet unreported findings of coexistent APBD with FTLD-U and transactivation response DNA-binding protein-43 (TDP-43)-positive inclusions at autopsy (or more accurately, FTLD-TDP). It is unclear if these distinct findings are coincidental in this individual, or if pathogenic pathways may intersect to promote these coexisting pathologies.

Dorsolumbosacral agenesis, nonterminal myelocystocele and secondary tonsillar herniation: prenatal and postnatal MRI evaluation and pathological correlation.

We present a complex case of dorsolumbosacral agenesis associated with a nonterminal myelocystocele and secondary tonsillar herniation. The secondary tonsillar herniation, mimicking a Chiari I malformation, was evident at postnatal life with concomitant enlargement of the myelocystocele. Prenatal and postnatal MRI proved invaluable in recognizing temporal change in the position of the cerebellar tonsils. Postmortem examination confirmed the presence of a nonterminal myelocystocele and dorsolumbosacral agenesis.

Striatal neuronal loss correlates with clinical motor impairment in Huntington's disease.

Huntington's disease (HD) is characterized clinically by chorea, motor impairment, psychiatric manifestations, and dementia. Atrophy of the striatum is the neuropathological hallmark of HD, and previous studies have suggested that striatal atrophy correlates more closely with motor impairment than with chorea. Motor impairment, as measured by motor impairment score, correlates with functional disability in HD patients, but chorea does not. In this study, we investigated the relation between neuronal loss and these motor features. We conducted neuropathological and stereologic assessments of neurons in putamen and subthalamic nuclei in HD patients and age-matched controls. In putamen, we estimated the total number and volume of medium spiny neurons labeled with dopamine- and cAMP-regulated phosphoprotein 32 kDa (DARPP-32). In subthalamic nuclei, we estimated the total number of neurons on hematoxylin & eosin/luxol fast blue stains. In putamen of HD, immunohistochemistry showed DARPP-32 neuronal atrophy with extensive disruption of neurites and neuropil; stereologic studies found significant decreases in both the number and size of DARPP-32 neurons; we also detected a significant reduction of overall putamen volume in HD patients, compared to controls. In subthalamic nuclei, there was a mild, but significant, neuronal loss in the HD group. The loss of neurons in putamen and subthalamic nuclei as well as putaminal atrophy were significantly correlated with severity of motor impairment, but not with chorea. Our findings suggest that neuronal loss and atrophy in striatum and neuronal loss in subthalamic nuclei contribute specifically to the motor impairment of HD, but not to chorea.

Plasma glial fibrillary acidic protein levels in children with sickle cell disease.

To determine if glial fibrillary acidic protein (GFAP) is associated with brain injury in children with sickle cell disease (SCD), we measured plasma GFAP among cross-sectional groups of unselected children with SCD, subsets of children with SCD and normal brain MRI or MRI evidence of cerebral infarct, healthy pediatric controls, and adults with brain injury. Children with SCD had higher plasma GFAP than healthy pediatric controls (mean concentrations 0.14 ± 0.37 vs. 0.07 ± 0.08 ng/mL; P 5 0.003); also, 16.0% (16/100) of children with SCD and cerebral infarct had GFAP elevations above the 95th percentile of healthy pediatric controls (P 5 0.04). Although not statistically significant, children with SCD and cerebral infarct had more elevated GFAP levels than with SCD and no infarct (16/100, 16.0% vs. 14/168, 8.3%; P 5 0.07). Children with SCD and acute brain ischemia had a higher proportion of elevated GFAP than SCD children with normal MRI (3/6, 50% vs.8.3%; P 5 0.01). GFAP was associated with elevated systolic blood pressure in the preceding year and correlated positively with white blood cell count and negatively with age and performance IQ. Plasma GFAP is elevated among children with SCD and may be associated with subclinical brain injury.

Age, Alzheimer's disease and dementia in the Baltimore Longitudinal Study of Ageing.

Recent studies suggest that dementia in the most elderly (90 years of age and above) is only modestly related to Alzheimer's disease pathology. This raises the possibility that other, as yet unknown, disease processes may underlie dementia in this rapidly growing demographic group, and that efforts designed to combat Alzheimer's disease may not be appropriate for treating dementia in very elderly subjects. To study this question more closely, we examined the relationship between neocortical Alzheimer-type brain pathology and dementia in consecutive autopsies from 209 participants in the Baltimore Longitudinal Study of Ageing, a prospective longitudinal cohort study of the effect of ageing on cognition. Almost half of the cohort was older than 90 years of age at death. We found that several measures of neocortical Alzheimer's pathology, including the Consortium to Establish a Registry of Alzheimer's Disease neuritic plaque score and the Braak neurofibrillary tangle score, remained significant predictors of dementia, independent of age. In participants older than 90 years of age, intracranial atherosclerosis emerged as an important predictor of dementia in subjects with low Alzheimer's pathology scores, but did not mitigate the importance or population attributable risk of high Alzheimer's pathology scores on the odds of dementia. There was evidence that the threshold score for neurofibrillary pathology to cause dementia increased in the oldest subjects, but this was offset by an overall increase in neurofibrillary pathology in this age group. We conclude that neocortical Alzheimer's disease pathology remains significantly correlated with dementia, independent of age. In the most elderly, atherosclerosis also emerged as a cause of dementia in subjects with low Alzheimer's pathology scores. We found no evidence for a significant number of elderly subjects having dementia without an apparent cause.

Moderate reduction of gamma-secretase attenuates amyloid burden and limits mechanism-based liabilities.

Although gamma-secretase is recognized as a therapeutic target for Alzheimer's disease, side effects associated with strong inhibition of this aspartyl protease raised serious concerns regarding this therapeutic strategy. However, it is not known whether moderate inhibition of this enzyme will allow dissociation of beneficial effects in the CNS from mechanism-based toxicities in the periphery. We tested this possibility by using a series of mice with genetic reduction of gamma-secretase (levels ranging from 25 to 64% of control mice). Here, we document that even 30% reduction of gamma-secretase can effectively ameliorate amyloid burden in the CNS. However, global reduction of this enzyme below a threshold level increased the risk of developing squamous cell carcinoma as well as abnormal proliferation of granulocytes in a gamma-secretase dosage-dependent manner. Importantly, we demonstrate that there exists a critical gamma-secretase level that reduces the risk of amyloidosis in the CNS and limits tumorigenesis in epithelia. Our findings suggest that moderate inhibition of gamma-secretase represents an attractive anti-amyloid therapy for Alzheimer's disease.

Elevated microsomal prostaglandin-E synthase-1 in Alzheimer's disease.

BACKGROUND: The proinflammatory prostaglandin E(2) (PGE(2)) fluctuates over time in the cerebrospinal fluid of patients with Alzheimer's disease (AD), but the cerebral distribution and expression patterns of microsomal prostaglandin-E synthase (mPGES)-1 have not been compared with those of normal human brains. METHODS: Middle frontal gyrus tissue from AD and age-matched control brains was analyzed by Western blot, immunofluorescence, and immunohistochemistry with mPGES-1-specific antibodies. RESULTS: Western blotting revealed that mPGES-1 expression was significantly elevated in AD tissue. Furthermore, immunofluorescence of mPGES-1 was observed in neurons, microglia, and endothelial cells of control and AD tissue. Although mPGES-1 was consistently present in astrocytes of control tissue, it was present in only some astrocytes of AD tissue. Immunohistochemical staining suggested that mPGES-1 was elevated in pyramidal neurons of AD tissue when compared with controls. CONCLUSIONS: The results suggest that mPGES-1 is normally expressed constitutively in human neurons, microglia, astrocytes, and endothelial cells but is up-regulated in AD.

The spectrum of preclinical Alzheimer's disease pathology and its modulation by ApoE genotype.

Sporadic Alzheimer's disease (AD) usually presents clinically after 65 years of age, but its pathological changes begin decades earlier. We examined for AD pathology in the postmortem brains of 431 of subjects aged 30-65 years not clinically characterized. Among 40-49 year olds, 15% showed diffuse amyloid ß (Aß) plaques, with a prevalence of 80% in ApoE4/E4, 42% in E4/E3, and <1% in E3/E3 subjects. Aß deposits appeared after age 49 years in subjects with E3/E3 genotypes. Neuritic plaques first appeared after age 50 years and increased steadily with age in all genotypes. Insoluble Aß42 levels were highest in parietal, temporal, and frontal lobes, but barely detectable in precuneus. Tau lesions were present in the hippocampus and entorhinal cortex in 7% of subjects aged <40 years and increased steadily with age reaching near 70% in the 60- to 65-year age group. In the locus coeruleus, tau lesions were present in 72% of subjects aged 31-40 years and 94% in the 41- to 50-year age group. Both Aß and tau lesions are present in the brains of young individuals decades before the age of clinical onset of AD. Aß lesions closely correlate with the ApoE4 allele and appear as the earliest event in the development of senile plaques.

Plasma arginine-vasopressin following experimental stroke: effect of osmotherapy.

Neurohumoral responses have been implicated in the pathogenesis of ischemia-evoked cerebral edema. In a well-characterized animal model of ischemic stroke, the present study was undertaken to 1) study the profile of plasma arginine-vasopressin (AVP), and 2) determine whether osmotherapy with mannitol and various concentrations of hypertonic saline (HS) solutions influence plasma AVP levels. Halothane-anesthetized adult male Wistar rats were subjected to 2 h of middle cerebral artery occlusion with the intraluminal filament technique. Plasma AVP levels (means +/- SD) were significantly elevated at 24 h (42 +/- 21 pg/ml), 48 h (50 +/- 28 pg/ml), and 72 h (110 +/- 47 pg/ml), and returned to baseline at 96 h (22 +/- 15 pg/ml) following middle cerebral artery occlusion compared with sham-operated controls (14 +/- 7 pg/ml). Plasma AVP levels at 72 h were significantly attenuated with 7.5% HS (37 +/- 8 pg/ml; 360 +/- 11 osmol/l) compared with 0.9% saline (73 +/- 6; 292 +/- 6 osmol/l), 3% HS (66 +/- 8 pg/ml; 303 +/- 12 osmol/l), or mannitol (74 +/- 9 pg/ml; 313 +/- 14 osmol/l) treatment. HS (7.5%) significantly attenuated water content in the ipsilateral and contralateral hemispheres compared with surgical shams, 0.9% saline, 3% HS, and mannitol treatments. Peak plasma AVP levels were not associated with direct histopathological injury to the anterior hypothalamus. Attenuation of brain water content with 7.5% HS treatment coincides with attenuated serum AVP levels, and we speculate that this may represent one additional mechanism by which osmotherapy attenuates edema associated with ischemic stroke.

Accreditation council for graduate medical education (ACGME) competencies in neuropathology training.

The Accreditation Council for Graduate Medical Education (ACGME) has defined 6 core competencies for all physicians: patient care; medical knowledge; practice-based learning and improvement; interpersonal and communication skills; professionalism; and systems-based practice. However, the specific wording of the descriptions often assumes that the physician is a clinician rather than a pathologist. Therefore, the American Association of Neuropathologists, Inc. asked its Professional Affairs Committee to examine the core competencies and determine how they relate to training in neuropathology. The Committee's report is presented here in 6 sections, corresponding to the 6 competencies. In each section, the ACGME definition of that particular competency is either quoted directly or, more often, modified slightly to clarify how the competency applies to neuropathology. Each of the defined competencies is then followed by possible assessment tools, selected from those recommended in the ACGME's "toolbox." Specific suggestions are given for designing tools that apply to neuropathology. Many of the suggested activities and documentation methods can be combined into efficient, carefully formulated training/evaluation exercises. Different tools may be more applicable in some training programs.

Transplanted human bone marrow cells generate new brain cells.

Multiple studies have reported that adult cells of bone marrow origin can differentiate into muscle, skin, liver, lung, epithelial cells, and neurons. To determine whether such cells might produce neurons and other cells in the human brain, we examined paraffin sections from female patients who had received bone marrow transplants from male donors. Y-chromosomes were labeled using autoradiography and fluorescent in situ hybridization. Neurons and astrocytes were identified histologically and immunohistochemically in neocortex, hippocampus, striatum, and cerebellum. However, most labeled cells in both gray and white matter appeared to be glia. Others have suggested that such Y-labeling represents fusion between host and donor cells, rather than true transdifferentiation. The possibilities of fusion and microchimerism were therefore examined using buccal epithelial cells as a model system. The female patients in this study had received either bone marrow or stem cell (CD34+ enriched) transplants from their brothers. Double labeling for X- and Y-chromosomes showed that Y-labeled buccal cells could not be explained by fusion. Genotyping studies of one patient, her brother, and her son ruled out the possibility of microchimerism. Whether, and under what circumstances, some form of bone marrow transplantation might provide adequate number of cells capable of replacing lost brain cells or enhancing their function will require additional studies.

Cardiovascular pathologies in mucopolysaccharidosis type VII (Sly Syndrome).

We present the cardiac findings from the autopsy of a 28-year-old male with mucopolysaccharidosis VII (MPS VII), also known as Sly Syndrome, whose diagnosis was confirmed by biochemical testing. The patient died a sudden cardiac death. Autopsy showed thickened and stenotic aortic valve leaflets as well as marked concentric intimal thickening of the aorta and muscular arteries. There was left ventricular hypertrophy as well as mild papillary muscle thickening and fusion. Increased colloid iron staining was seen in the small- and medium-sized arteries of the heart and at the intercalated discs. We discuss the patient's premortem echocardiographic and electrocardiographic studies. In addition, we discuss the pathogenesis of MPS VII and review previous literature on its anatomic and pathologic features.

Poly(ADP-ribose) polymerase impairs early and long-term experimental stroke recovery.

BACKGROUND AND PURPOSE: Poly(ADP-ribose) polymerase (PARP-1; Enzyme Commission 2.4.30) is a nuclear DNA repair enzyme that mediates early neuronal ischemic injury. Using novel 3-dimensional, fast spin-echo-based diffusion-weighted imaging, we compared acute (21 hours) and long-term (3 days) ischemic volume after middle cerebral artery (MCA) occlusion in PARP-1-null mutants (PARP-/-) versus genetically matched wild-type mice (WT mice). PARP-/- mice were also treated with viral transfection of wild-type PARP-1 to determine whether protection from MCA occlusion is lost with restoration of the gene product. METHODS: Halothane-anesthetized mice were treated with reversible MCA occlusion via intraluminal suture technique. Ischemic volumes were delineated by diffusion-weighted imaging with high spatial and temporal resolution during MCA occlusion and reperfusion. Recombinant Sindbis virus carrying beta-galactosidase (lacZ) or PARP-1 was injected into ipsilateral striatum, then animals underwent MCA occlusion 3 days later. Infarction volume was measured at 22 hours of reperfusion (2,3,5-triphenyltetrazolium chloride histology). RESULTS: Reduction in regional water apparent diffusion coefficient (ADC) during occlusion or secondary ADC decline during reperfusion was not different between groups. Ischemic volume was smaller early in occlusion in PARP-/- versus WT mice and remained less at 21 hours of reperfusion. Ischemic volume then increased from 1 to 2 days in all mice, then stabilized without further change. Ischemic damage was smaller in PARP-/- than in WT mice at 3 days. Transfection of PARP-1 into PARP-/- mice increased stroke damage relative to lacZ-injected PARP-/- and increased damage to that of the WT mice. Intraischemic laser-Doppler flowmetry and physiological variables were not different among groups. CONCLUSIONS: PARP-1 deficiency provides both early and prolonged protection from experimental focal stroke. The mechanism is not linked to preservation of ADC and mitigation of secondary energy depletion during early reperfusion.

Initial diagnoses of patients ultimately diagnosed with prion disease.

BACKGROUND: Prion diseases are rapidly progressive neurodegenerative diseases that frequently mimic other forms of dementia making them difficult to diagnose. OBJECTIVE: To explore factors associated with the initial diagnoses of cases later determined to be caused by prion disease in an attempt to recognize key clinical variables that impact the timely diagnosis of prion disease. METHODS: A retrospective chart review performed at Johns Hopkins Medicine and the Department of Veterans Affairs Health Care System (1995-2008) was conducted. Ninety-two subjects with definite or probable prion disease were included in the analyses. Demographic, clinical, diagnostic test results, neuropathologic, molecular, and genetic data were collected using a standardized instrument and compared between initial diagnosis groups. RESULTS: Cases were separated into five broad categories pertaining to their initial diagnoses: prion disease, non-prion-related dementia, psychiatric disorder, stroke, and other. The majority of cases did not receive an initial diagnosis of prion disease (n = 76, 83%). The plurality of subjects received an initial diagnosis of a non-prion disease related dementia (n = 33, 36%). Mean survival times varied between initial diagnosis groups (p = 0.042). Times to cerebrospinal fluid 14-3-3 analysis and electroencephalogram also differed between initial diagnosis groups. CONCLUSIONS: Most patients with prion disease are initially diagnosed with a non-prion disease related dementia. Several clinical features were associated with initial diagnoses including survival time, onset of specific symptoms, and times to 14-3-3 analyses and electroencephalogram. Expanding our knowledge of the various clinical presentations of prion disease, especially dementia, may aid in the earlier diagnoses of these rapidly progressive diseases.

Hippocampal sclerosis dementia with the C9ORF72 hexanucleotide repeat expansion.

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are the main syndromes of the chromosome 9 ORF72 (C9ORF72) hexanucleotide repeat expansion, but studies have shown a substantial phenotypic diversity that includes psychiatric presentations. This study describes hippocampal sclerosis dementia (HSD) in carriers of the C9ORF72 mutation. We compared clinical and neuropathological features of HSD in carriers and noncarriers autopsied at Johns Hopkins. Carriers presented with amnesia, agitation, dissocial behavior, and impaired self-care, whereas noncarriers showed little agitation. The groups were not dissimilar in cognitive or motor dysfunction. Neuropathological examination of carriers showed cerebellar neuronal inclusions positive for ubiquitin, p62, and ubiquilin-2, and negative for TAR DNA-binding protein 43. Noncarriers did not have cerebellar inclusions. C9ORF72 repeat-associated non-ATG translation was confirmed by immunohistochemistry. These observations broaden the C9ORF72 phenotype and place HSD in the FTD spectrum. The amnesic phenotype of HSD, which is consistent with the focal hippocampal atrophy, should be included in clinical categorizations of FTD.

Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature.

Clinicopathologic correlation studies are critically important for the field of Alzheimer disease (AD) research. Studies on human subjects with autopsy confirmation entail numerous potential biases that affect both their general applicability and the validity of the correlations. Many sources of data variability can weaken the apparent correlation between cognitive status and AD neuropathologic changes. Indeed, most persons in advanced old age have significant non-AD brain lesions that may alter cognition independently of AD. Worldwide research efforts have evaluated thousands of human subjects to assess the causes of cognitive impairment in the elderly, and these studies have been interpreted in different ways. We review the literature focusing on the correlation of AD neuropathologic changes (i.e. ß-amyloid plaques and neurofibrillary tangles) with cognitive impairment. We discuss the various patterns of brain changes that have been observed in elderly individuals to provide a perspective for understanding AD clinicopathologic correlation and conclude that evidence from many independent research centers strongly supports the existence of a specific disease, as defined by the presence of Aß plaques and neurofibrillary tangles. Although Aß plaques may play a key role in AD pathogenesis, the severity of cognitive impairment correlates best with the burden of neocortical neurofibrillary tangles.

αB-crystallin negative astrocytic inclusions.

We report on an unusual pathological finding of astrocytes, observed in the brain of a 16-year-old African-American male with severe intellectual disability and spastic quadriplegia. The brain showed bilateral pericentral, perisylvian polymicrogyria and pachygyria, in conjunction with a large number of hypertrophic astrocytes with eosinophilic granular cytoplasmic inclusions. The astrocytic abnormality was more severe in the dysgenetic area but present throughout the cerebral cortex. Astrocytic inclusions stained with acid fuchsin, azocarmine and Holzer's stain, and were immunoreactive for GFAP, S-100, and ubiquitin, but not for αB-crystallin, filamin, vimentin, nestin, tau or α-synuclein. Based on the case and a review of the literature, the authors postulate that these astrocytic inclusions in the cerebral cortex reflect abnormalities in radial glial developmental processes, such as migration, differentiation, or glial-neuronal interaction function during neuronal migration.

A mouse model of blast injury to brain: initial pathological, neuropathological, and behavioral characterization.

The increased use of explosives in recent wars has increased the number of veterans with blast injuries. Of particular interest is blast injury to the brain, and a key question is whether the primary overpressure wave of the blast is injurious or whether brain injury from blast is mostly due to secondary and tertiary effects. Using a shock tube generating shock waves comparable to open-field blast waves, we explored the effects of blast on parenchymatous organs of mice with emphasis on the brain. The main injuries in nonbrain organs were hemorrhages in the lung interstitium and alveolar spaces and hemorrhagic infarcts in liver, spleen, and kidney. Neuropathological and behavioral outcomes of blast were studied at mild blast intensity, that is, 68 ± 8 kPag (9.9 ± 1.2 psig) static pressure, 103 kPag (14.9 psig) total pressure and 183 ± 14 kPag (26.5 ± 2.1 psig) membrane rupture pressure. Under these conditions, we observed multifocal axonal injury, primarily in the cerebellum/brainstem, the corticospinal system, and the optic tract. We also found prolonged behavioral and motor abnormalities, including deficits in social recognition and spatial memory and in motor coordination. Shielding of the torso ameliorated axonal injury and behavioral deficits. These findings indicate that long CNS axon tracts are particularly vulnerable to the effects of blast, even at mild intensities that match the exposure of most veterans in recent wars. Prevention of some of these neurological effects by torso shielding may generate new ideas as to how to protect military and civilian populations in blast scenarios.