Alzheimer Disease: Greenberg SM

Zhang-Nunes SX, Maat-Schieman ML, van Duinen SG, Roos RA, Frosch MP, Greenberg SM. · Neurology Clinical Trials Unit and MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Boston 02114, USA. · Brain Pathol. · Pubmed #16612980 No free full text.

Abstract: We review the clinical, radiologic, and neuropathologic features of the hereditary and sporadic forms of cerebral amyloid angiopathy (CAA) associated with vascular deposition of the beta-amyloid peptide. Amino acid substitutions at 4 sites in the beta-amyloid precursor protein, all situated within the beta-amyloid peptide sequence itself, have been shown to cause heritable forms of CAA. The vascular diseases caused by these mutations are associated primarily with cerebral hemorrhages, white matter lesions, and cognitive impairment, and only variable extents of the plaque and neurofibrillary pathologies characteristic of Alzheimer disease. Sporadic CAA typically presents 20 or more years later than hereditary CAA, but is otherwise characterized by a comparable constellation of recurrent cerebral hemorrhages, white matter lesions, and cognitive impairment. The clinical, radiologic and pathologic similarities between hereditary and sporadic CAA suggest that important lessons for this common age-related process can be learned from the mechanisms by which mutation makes beta-amyloid tropic or toxic to vessels.

Lleó A, Greenberg SM, Growdon JH. · Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. · Annu Rev Med. · Pubmed #16409164 No free full text.

Abstract: Alzheimer's disease (AD) is an age-related neurodegenerative disease that affects approximately 4.5 million people in the United States. The mainstays of current pharmacotherapy for AD are compounds aimed at increasing the levels of acetylcholine in the brain, thereby facilitating cholinergic neurotransmission through inhibition of the cholinesterases. These drugs, known as acetylcholinesterase inhibitors (AChEIs), were first approved by the U.S. Food and Drug Administration (FDA) in 1995 based on clinical trials showing modest symptomatic benefit on cognitive, behavioral, and global measures. In 2004 the FDA approved memantine, an NMDA antagonist, for treating dementia symptoms in moderate to severe AD cases. In clinical practice, memantine may be co-administered with an AChEI, although neither drug individually or in combination affects the underlying pathophysiology of dementia. Dementia in AD results from progressive synaptic loss and neuronal death. As knowledge of the mechanisms responsible for neurodegeneration in AD increases, it is anticipated that neuroprotective drugs to slow or prevent neuronal dysfunction and death will be developed to complement current symptomatic treatments.

Greenberg SM, Gurol ME, Rosand J, Smith EE. · Neurology Clinical Trials Unit and Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Mass 02114, USA. · Stroke. · Pubmed #15459438 links to  free full text

Abstract: We review accumulating evidence that cerebrovascular amyloid deposition (cerebral amyloid angiopathy [CAA]) is an independent risk factor for cognitive dysfunction. The two population-based autopsy studies that have analyzed cognitive status during life as a function of CAA have each suggested deleterious effects of CAA on cognition even after controlling for age and Alzheimer disease pathology. We also review data from patients with CAA-related intracerebral hemorrhage (the one form of CAA that can be noninvasively recognized) suggesting associations of CAA with radiographic white matter abnormalities and cognitive impairment. These data highlight the importance of elucidating the effects of vascular amyloid on cerebrovascular function and of developing therapeutic strategies for this potentially widespread form of microvascular cognitive impairment.

Greenberg SM, Tennis MK, Brown LB, Gomez-Isla T, Hayden DL, Schoenfeld DA, Walsh KL, Corwin C, Daffner KR, Friedman P, Meadows ME, Sperling RA, Growdon JH. · Department of Neurology, Partners HealthCare Inc of Massachusetts General Hospital, Boston 02114, USA. · Arch Neurol. · Pubmed #10634454 links to  free full text

Abstract: OBJECTIVE: To determine the efficacy of donepezil hydrochloride for the treatment of Alzheimer disease in patients drawn from clinical practice. DESIGN: Two-center, randomized, placebo-controlled, double-masked crossover study. SETTING: Memory disorders units at Massachusetts General and Brigham and Women's hospitals, Boston. PATIENTS: Sixty individuals (30 men and 30 women; mean +/- SD age, 75.0+/-9.5 years) with probable Alzheimer disease and scores of 20 or less on the information-memory-concentration subscale of the Blessed Dementia Scale. INTERVENTIONS: Placebo wash-in, followed in randomized sequence by (1) donepezil hydrochloride therapy, 5 mg/d, for 6 weeks, followed by placebo washout for 6 weeks and (2) placebo treatment for 6 weeks. PRIMARY OUTCOME MEASURE: Change in Alzheimer's Disease Assessment Scale cognitive subscale scores from the beginning to the end of the two 6-week treatment periods. RESULTS: Among patients completing treatment and testing for both periods (n = 48), subscale scores improved (mean +/- SEM) 2.17+/-0.98 points (95% confidence interval, 0.20-4.10 points) during donepezil therapy relative to placebo therapy (P = .04). Scores returned toward baseline within 3 weeks of drug washout. There was no associated change in caregiver-rated global impression (donepezil vs placebo: proportion improved, 0.24 vs 0.22; proportion worsened, 0.27 vs 0.35; P = .34) or on specific tests of explicit memory or verbal fluency. Contrary to studies with tacrine, the presence of the apolipoprotein E epsilon4 allele did not predict donepezil treatment failure. Most common adverse events related to donepezil therapy were nausea (5 patients), diarrhea (3 patients), and agitation (3 patients). Serious events possibly related to drug use were seizure, pancreatitis, and syncope (1 patient each). CONCLUSION: This independent confirmation of data from phase 3 trials suggests that donepezil therapy modestly improves cognition in patients with Alzheimer disease who are encountered in clinical practice.

Garcia-Alloza M, Prada C, Lattarulo C, Fine S, Borrelli LA, Betensky R, Greenberg SM, Frosch MP, Bacskai BJ. · Alzheimer Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA. · J Neurochem. · Pubmed #19457117 No free full text.

Abstract: Cerebral amyloid angiopathy (CAA), characterized by extracellular beta-amyloid peptide (Abeta) deposits in vessel walls, is present in the majority of cases of Alzheimer's disease and is a major cause of hemorrhagic stroke. Although the molecular pathways activated by vascular Abeta are poorly understood, extracellular matrix metalloproteinases (MMP) and Abeta-induced oxidative stress appear to play important roles. We adapted fluorogenic assays for MMP activity and reactive oxygen species generation for use in vivo. Using multiphoton microscopy in APPswe/PS1dE9 and Tg-2576 transgenic mice, we observed strong associations between MMP activation, oxidative stress, and CAA deposition in leptomeningeal vessels. Antioxidant treatment with alpha-phenyl-N-tert-butyl-nitrone reduced oxidative stress associated with CAA (approximately 50% reduction) without affecting MMP activation. Conversely, a selection of agents that inhibit MMP by different mechanisms of action, including minocycline, simvastatin, and GM6001, reduced not only CAA-associated MMP activation (approximately 30-40% reduction) but also oxidative stress (approximately 40% reduction). The inhibitors of MMP did not have direct antioxidant effects. Treatment of animals with alpha-phenyl-N-tert-butyl-nitrone or minocycline did not have a significant effect on CAA progression rates. These data suggest a close association between Abeta-related MMP activation and oxidative stress in vivo and raise the possibility that treatment with MMP inhibitors may have beneficial effects by indirectly reducing the oxidative stress associated with CAA.

Smith EE, Greenberg SM. · Division of Neurology, Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada. · Stroke. · Pubmed #19443808 No free full text.

Abstract: Cerebrovascular disease and Alzheimer disease are common diseases of aging and frequently coexist in the same brain. Accumulating evidence suggests that the presence of brain infarction, including silent infarction, influences the course of Alzheimer disease. Conversely, there is evidence that beta-amyloid can impair blood vessel function. Vascular beta-amyloid deposition, also known as cerebral amyloid angiopathy, is associated with vascular dysfunction in animal and human studies. Alzheimer disease is associated with morphological changes in capillary networks, and soluble beta-amyloid produces abnormal vascular responses to physiological and pharmacological stimuli. In this review, we discuss current evidence linking beta-amyloid metabolism with vascular function and morphological changes in animals and humans.

Kimberly WT, Gilson A, Rost NS, Rosand J, Viswanathan A, Smith EE, Greenberg SM. · Hemorrhagic Stroke Research Program, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. · Neurology. · Pubmed #19349602 No free full text.

Abstract: BACKGROUND: Neuropathologic studies suggest an association between cerebral amyloid angiopathy (CAA) and small ischemic infarctions as well as hemorrhages. We examined the prevalence and associated risk factors for infarcts detected by diffusion-weighted imaging (DWI). METHODS: We performed retrospective analysis of MR images from 78 subjects with a diagnosis of probable CAA and a similar aged group of 55 subjects with Alzheimer disease or mild cognitive impairment (AD/MCI) for comparison. DWI and apparent diffusion coefficient (ADC) maps were inspected for acute or subacute infarcts. We also examined the association between DWI lesions and demographic variables, conventional vascular risk factors, and radiographic markers of CAA severity such as number of hemorrhages on gradient-echo MRI and volume of T2-hyperintense white matter lesions. RESULTS: Twelve of 78 subjects with CAA (15%) had a total of 17 DWI-hyperintense lesions consistent with subacute cerebral infarctions vs 0 of 55 subjects with AD/MCI (p = 0.001). The DWI lesions were located primarily in cortex and subcortical white matter. CAA subjects with DWI lesions had a higher median number of total hemorrhages (22 vs 4, p = 0.025) and no difference in white matter hyperintensity volume or conventional vascular risk factors compared to subjects with CAA without lesions. CONCLUSIONS: MRI evidence of small subacute infarcts is present in a substantial proportion of living patients with advanced cerebral amyloid angiopathy (CAA). The presence of these lesions is associated with a higher burden of hemorrhages, but not with conventional vascular risk factors. This suggests that advanced CAA predisposes to ischemic infarction as well as intracerebral hemorrhage.

Viswanathan A, Raj S, Greenberg SM, Stampfer M, Campbell S, Hyman BT, Irizarry MC. · Hemorrhagic Stroke Research Program, Massachusetts General Hospital Stroke Research Center, 175 Cambridge Street, Suite 300, Boston, MA 02114, USA. · Neurology. · Pubmed #19153374 No free full text.

Abstract: BACKGROUND: Amyloid-beta protein (Abeta) plays a key role in Alzheimer disease (AD) and is also implicated in cerebral small vessel disease. Serum total homocysteine (tHcy) is a risk factor for small vessel disease and cognitive impairment and correlates with plasma Abeta levels. To determine whether this association results from a common pathophysiologic mechanism, we investigated whether vitamin supplementation-induced reduction of tHcy influences plasma Abeta levels in the Vitamin Intervention in Stroke Prevention (VISP) study. METHODS: Two groups of 150 patients treated with either the high-dose or low-dose formulation of pyridoxine, cobalamin, and folic acid in a randomized, double-blind fashion were selected among the participants in the VISP study without recurrent stroke during follow-up and in the highest 10% of the distribution for baseline tHcy levels. Concentrations of plasma Abeta with 40 (Abeta40) and 42 (Abeta42) amino acids were measured at baseline and at the 2-year visit. RESULTS: tHcy levels significantly decreased with vitamin supplementation in both groups. tHcy were strongly correlated with Abeta40 but not Abeta42 concentrations. There was no difference in the change in Abeta40, Abeta42 (p = 0.40, p = 0.35), or the Abeta42/Abeta40 ratio over time (p = 0.86) between treatment groups. Abeta measures were not associated with cognitive change. CONCLUSIONS: This double-blind randomized controlled trial of vitamin therapy demonstrates a strong correlation between serum tHcy and plasma Abeta40 concentrations in subjects with ischemic stroke. Treatment with high dose vitamins does not, however, influence plasma levels of Abeta, despite their effect on lowering tHcy. Our results suggest that although tHcy is associated with plasma Abeta40, they may be regulated by independent mechanisms.

Holland CM, Smith EE, Csapo I, Gurol ME, Brylka DA, Killiany RJ, Blacker D, Albert MS, Guttmann CR, Greenberg SM. · Center for Neurological Imaging, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. · Stroke. · Pubmed #18292383 links to  free full text

Abstract: BACKGROUND AND PURPOSE: White-matter hyperintensities (WMHs) detected by magnetic resonance imaging are thought to represent the effects of cerebral small-vessel disease and neurodegenerative changes. We sought to determine whether the spatial distribution of WMHs discriminates between different disease groups and healthy aging individuals and whether these distributions are related to local cerebral perfusion patterns. METHODS: We examined the pattern of WMHs by T2/fluid-attenuated inversion recovery-weighted magnetic resonance imaging in 3 groups of subjects: cerebral amyloid angiopathy (n=32), Alzheimer disease or mild cognitive impairment (n=41), and healthy aging (n=29). WMH frequency maps were calculated for each group, and spatial distributions were compared by voxel-wise logistic regression. WMHs were also analyzed as a function of normal cerebral perfusion patterns by overlaying a single photon emission computed tomography atlas. RESULTS: Although WMH volume was greater in cerebral amyloid angiopathy and Alzheimer disease/mild cognitive impairment than in healthy aging, there was no consistent difference in the spatial distributions when controlling for total WMH volume. Hyperintensities were most frequent in the deep periventricular WM in all 3 groups. A strong inverse correlation between hyperintensity frequency and normal perfusion was demonstrated in all groups, demonstrating that WMHs were most common in regions of relatively lower normal cerebral perfusion. CONCLUSIONS: WMHs show a common distribution pattern and predilection for cerebral WM regions with lower atlas-derived perfusion, regardless of the underlying diagnosis. These data suggest that across diverse disease processes, WM injury may occur in a pattern that reflects underlying tissue properties, such as relative perfusion.

Smith EE, Egorova S, Blacker D, Killiany RJ, Muzikansky A, Dickerson BC, Tanzi RE, Albert MS, Greenberg SM, Guttmann CR. · Neurology Clinical Trials Unit, Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. · Arch Neurol. · Pubmed #18195145 links to  free full text

Abstract: OBJECTIVE: To determine whether magnetic resonance imaging (MRI) white matter hyperintensities (WMH), whole-brain atrophy, and cardiovascular risk factors predict the development of cognitive decline and dementia. DESIGN: Subjects were recruited into this prospective cohort study and followed for incident cognitive decline for mean (SD) 6.0 (4.1) years. Magnetic resonance imaging dual-echo sequences, obtained at baseline, were used to determine the volume of WMH and the brain parenchymal fraction (BPF), the proportion of the intracranial cavity occupied by brain. White matter hyperintensity volume was analyzed as the percentage of intracranial volume (WMHr); "high WMH" was defined as a WMHr more than 1 SD above the mean. SETTING: General community. PATIENTS: Volunteer sample consisting of 67 subjects with normal cognition and 156 subjects with mild cognitive impairment (MCI). MAIN OUTCOME MEASURES: Time to diagnosis of MCI (among those with normal cognition at baseline) or time to diagnosis of dementia, either all-cause or probable Alzheimer disease (AD) (among those with MCI at baseline). Cox proportional hazards models were used for multivariable analysis. RESULTS: High WMH was a predictor of progression from normal to MCI (adjusted hazard ratio [HR], 3.30; 95% confidence interval [CI], 1.33-8.17; P= .01) but not conversion from MCI to all-cause dementia. Conversely, BPF did not predict progression from normal to MCI but did predict conversion to dementia (adjusted HR, 1.10 for each 1% decrease in BPF; 95% CI, 1.02-1.19; P= .02). When conversion to AD dementia was considered as the outcome, BPF was likewise a predictor (adjusted HR, 1.16 for each 1% decrease in BPF; 95% CI, 1.08-1.24; P< .001), but high WMH was not. Past tobacco smoking was associated with both progression from normal to MCI (adjusted HR, 2.71; 95% CI, 1.12-6.55; P= .03) and conversion to all-cause dementia (adjusted HR, 2.08; 95% CI, 1.13-3.82; P= .02), but not AD dementia. CONCLUSIONS: These findings suggest that WMH are associated with the risk of progressing from normal to MCI. In persons whose cognitive abilities are already impaired, BPF predicts the conversion to dementia.

Johnson KA, Gregas M, Becker JA, Kinnecom C, Salat DH, Moran EK, Smith EE, Rosand J, Rentz DM, Klunk WE, Mathis CA, Price JC, Dekosky ST, Fischman AJ, Greenberg SM. · Department of Radiology, Massachusetts General Hospital, Boston, MA 02114, USA. · Ann Neurol. · Pubmed #17683091 No free full text.

Abstract: OBJECTIVE: Cerebrovascular deposition of beta-amyloid (cerebral amyloid angiopathy [CAA]) is a major cause of hemorrhagic stroke and a likely contributor to vascular cognitive impairment. We evaluated positron emission tomographic imaging with the beta-amyloid-binding compound Pittsburgh Compound B (PiB) as a potential noninvasive method for detection of CAA. We hypothesized that amyloid deposition would be observed with PiB in CAA, and based on the occipital predilection of CAA pathology and associated hemorrhages, that specific PiB retention would be disproportionately greater in occipital lobes. METHODS: We compared specific cortical PiB retention in 6 nondemented subjects diagnosed with probable CAA with 15 healthy control subjects and 9 patients with probable Alzheimer's disease (AD). RESULTS: All CAA and AD subjects were PiB-positive, both by distribution volume ratio measurements and by visual inspection of positron emission tomographic images. Global cortical PiB retention was significantly increased in CAA (distribution volume ratio 1.18 +/- 0.06) relative to healthy control subjects (1.04 +/- 0.10; p = 0.0009), but was lower in CAA than in AD subjects (1.41 +/- 0.17; p = 0.002). The occipital-to-global PiB ratio, however, was significantly greater in CAA than in AD subjects (0.99 +/- 0.07 vs 0.86 +/- 0.05; p = 0.003). INTERPRETATION: We conclude that PiB-positron emission tomography can detect cerebrovascular beta-amyloid and may serve as a method for identifying the extent of CAA in living subjects.

Kinnecom C, Lev MH, Wendell L, Smith EE, Rosand J, Frosch MP, Greenberg SM. · Hemorrhagic Stroke Research Program, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA. · Neurology. · Pubmed #17452586 No free full text.

Abstract: BACKGROUND: A subset of patients with cerebral amyloid angiopathy (CAA) present with cognitive symptoms, seizures, headaches, T2-hyperintense MRI lesions, and neuropathologic evidence of CAA-associated vascular inflammation. OBJECTIVE: To analyze the risk factors, diagnostic characteristics, and long-term course of this disorder. METHODS: We assessed 14 consecutive patients with pathologically diagnosed CAA-related inflammation, 12 with available neuroimaging and follow-up data. Patients were evaluated for MRI appearance, APOE genotype, and clinical course over a 46.8 +/- 29.1-month follow-up. RESULTS: Baseline MRI scans were characterized by asymmetric T2-hyperintense lesions extending to the subcortical white matter and occasionally the overlying gray matter, with signal properties suggesting vasogenic edema. Subjects could be divided into three groups based on response to immunosuppressive treatment: monophasic improvement (7/12), initial improvement followed by symptomatic relapse (3/12), and no evident response to treatment (2/12). The volume of MRI hyperintensities correlated with the severity of clinical symptoms. One patient experienced symptomatic intracerebral hemorrhage within a region of recurrent MRI hyperintensity. The APOE epsilon4/epsilon4 genotype was strongly associated with CAA-related inflammation, present in 76.9% (10/13) of subjects vs 5.1% (2/39) with symptomatic but noninflammatory CAA (p < 0.0001). CONCLUSION: Cerebral amyloid angiopathy-related inflammation represents a clinically, pathologically, radiographically, and genetically distinct disease subtype with implications for clinical practice and ongoing immunotherapeutic approaches to Alzheimer disease.

Prada CM, Garcia-Alloza M, Betensky RA, Zhang-Nunes SX, Greenberg SM, Bacskai BJ, Frosch MP. · Department of Neurology/Alzheimer Research Unit, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA. · J Neurosci. · Pubmed #17314293 links to  free full text

Abstract: Cerebral amyloid angiopathy (CAA) is the accumulation of amyloid-beta peptide (Abeta) in the vessel wall of arteries in the brain. Because CAA is commonly associated with Alzheimer's disease (AD), characterized by parenchymal deposition of the same peptide in the form of senile plaques, there is considerable interest in the relationship of the two deposits in generating human disease. The study of CAA is of particular importance for immunotherapeutic approaches to AD, because reports of anti-Abeta immunotherapy in mice and humans have suggested that, whereas CAA appeared resistant to clearance, its response to this treatment promoted potential adverse effects, including meningoencephalitis. We used multiphoton microscopy and longitudinal imaging to monitor CAA in a mouse model of amyloid deposition to evaluate the effects of anti-Abeta passive immunotherapy. We found detectable clearance of CAA deposits within 1 week after a single administration of antibody directly to the brain, an effect that was short-lived. Chronic administration of antibody over 2 weeks led to more robust clearance without evidence of hemorrhage or other destructive changes. We found that the progressive clearance of Abeta from vessels follows distinct kinetics from what has been previously reported for clearance of plaques (parenchymal deposits of Abeta). This quantitative in vivo imaging approach directly demonstrates that CAA in a transgenic mouse model can be cleared with an optimized immunotherapy.

Garcia-Alloza M, Robbins EM, Zhang-Nunes SX, Purcell SM, Betensky RA, Raju S, Prada C, Greenberg SM, Bacskai BJ, Frosch MP. · Alzheimer Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, 114 16th Street, Charlestown, MA 02129, USA. · Neurobiol Dis. · Pubmed #17029828 No free full text.

Abstract: Transgenic mice carrying disease-linked forms of genes associated with Alzheimer disease often demonstrate deposition of the beta-amyloid as senile plaques and cerebral amyloid angiopathy. We have characterized the natural history of beta-amyloid deposition in APPswe/PS1dE9 mice, a particularly aggressive transgenic mouse model generated with mutant transgenes for APP (APPswe: KM594/5NL) and PS1 (dE9: deletion of exon 9). Ex vivo histochemistry showed Abeta deposition by 4 months with a progressive increase in plaque number up to 12 months and a similar increase of Abeta levels. In vivo multiphoton microscopy at weekly intervals showed increasing beta-amyloid deposition as CAA and plaques. Although first appearing at an early age, CAA progressed at a significantly slower rate than in the Tg2576 mice. The consistent and early onset of beta-amyloid accumulation in the APPswe/PS1dE9 model confirms its utility for studies of biochemical and pathological mechanisms underlying beta-amyloid deposition, as well as exploring new therapeutic treatments.

Guo S, Wang S, Kim WJ, Lee SR, Frosch MP, Bacskai BJ, Greenberg SM, Lo EH. · Department of Neurology, Mass General Hospital, Charlestown, MA, USA. · Brain Res. · Pubmed #16919608 No free full text.

Abstract: Matrix metalloproteinase-9 (MMP-9) may play a role in the inflammatory glial response during Alzheimer's disease (AD). Astrocytes can degrade beta-amyloid (Abeta) and extracellular proteolysis via MMP-9 may be involved. Because Apolipoprotein E (APOE) genotype is an important factor for AD, we ask whether various apoE isoforms can influence Abeta-induced MMP-9 responses in primary rat astrocytes. Our data show that apoE4 significantly dampens Abeta-induced MMP-9 levels, possibly by downregulating the Rho-Rho kinase (ROCK) pathway. Reduction of astrocytic MMP-9 by apoE4 may affect Abeta clearance and promote Abeta deposition in AD.

Robbins EM, Betensky RA, Domnitz SB, Purcell SM, Garcia-Alloza M, Greenberg C, Rebeck GW, Hyman BT, Greenberg SM, Frosch MP, Bacskai BJ. · MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA. · J Neurosci. · Pubmed #16407531 links to  free full text

Abstract: Cerebral amyloid angiopathy (CAA), the deposition of cerebrovascular beta-amyloid (Abeta) in the walls of arterial vessels, has been implicated in hemorrhagic stroke and is present in most cases of Alzheimer disease. Previous studies of the progression of CAA in humans and animal models have been limited to the comparison of pathological tissue from different brains at single time points. Our objective was to visualize in real time the initiation and progression of CAA in Tg2576 mice by multiphoton microscopy through cranial windows. Affected vessels were labeled by methoxy-X04, a fluorescent dye that selectively binds cerebrovascular beta-amyloid and plaques. With serial imaging sessions spaced at weekly intervals, we were able to observe the earliest appearance of CAA in leptomeningeal arteries as multifocal deposits of band-like Abeta. Over subsequent imaging sessions, we were able to identify growth of these deposits (propagation), as well as appearance of new bands (additional initiation events). Statistical modeling of the data suggested that as the extent of CAA progressed in this vascular bed, there was increased prevalence of propagation over initiation. During the early phases of CAA development, the overall pathology burden progressed at a rate of 0.35% of total available vessel area per day (95% confidence interval, 0.3-0.4%). The consistent rate of disease progression implies that this model is amenable to investigations of therapeutic interventions.

Gurol ME, Irizarry MC, Smith EE, Raju S, Diaz-Arrastia R, Bottiglieri T, Rosand J, Growdon JH, Greenberg SM. · Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA. · Neurology. · Pubmed #16401840 No free full text.

Abstract: BACKGROUND: Microvascular brain injury, typically measured by extent of white matter hyperintensity (WMH) on MRI, is an important contributor to cognitive impairment in the elderly. Recent studies suggest a role for circulating beta-amyloid peptide in microvascular dysfunction and white matter disease. METHODS: The authors performed a cross-sectional study of clinical, biochemical, and genetic factors associated with WMH in 54 subjects with Alzheimer disease (AD) or mild cognitive impairment (AD/MCI) and an independent group of 42 subjects with cerebral amyloid angiopathy (CAA). Extent of WMH was determined by computer-assisted volumetric measurement normalized to intracranial size (nWMH). Biochemical measurements included plasma concentrations of the 40- and 42-amino acid species of beta-amyloid (Abeta40 and Abeta42) detected by specific enzyme-linked immunosorbent assays. RESULTS: Plasma Abeta40 concentrations were associated with nWMH in both groups (correlation coefficient = 0.48 in AD/MCI, 0.42 in CAA, p < or = 0.005). Plasma Abeta40 remained independently associated with nWMH after adjustment for potential confounders among age, hypertension, diabetes, homocysteine, creatinine, folate, vitamin B12, and APOE genotype. The presence of lacunar infarctions was also associated with increased Abeta40 in both groups. nWMH was greater in CAA (19.8 cm3) than AD (11.1 cm3) or MCI (10.0 cm3; p < 0.05 for both comparisons). CONCLUSIONS: Plasma beta-amyloid 40 concentration is independently associated with extent of white matter hyperintensity in subjects with Alzheimer disease, mild cognitive impairment, or cerebral amyloid angiopathy. If confirmed in longitudinal studies, these data would suggest circulating beta-amyloid peptide as a novel biomarker or risk factor for microvascular damage in these common diseases of the elderly.

Irizarry MC, Gurol ME, Raju S, Diaz-Arrastia R, Locascio JJ, Tennis M, Hyman BT, Growdon JH, Greenberg SM, Bottiglieri T. · The Massachusetts Alzheimer Disease Research Center, Massachusetts General Hospital, Boston, MA, USA. · Neurology. · Pubmed #16275827 No free full text.

Abstract: BACKGROUND: Elevated plasma total homocysteine (tHcy) is a risk factor for cardiovascular disease and is reported to be an independent risk factor for Alzheimer disease (AD) and cognitive decline. tHcy may potentiate neurotoxic and vasculopathic processes, including amyloid beta protein (Abeta) metabolism, implicated in neurodegenerative diseases. OBJECTIVE: To examine the relationship of plasma total tHcy levels with clinical, demographic, biochemical, and genetic factors in aging, mild cognitive impairment (MCI), AD, cerebral amyloid angiopathy (CAA), and Parkinson disease (PD). METHODS: Plasma tHcy, folate, vitamin B(12), creatinine, and Abeta levels were assessed in individuals evaluated in the Memory, Stroke, and Movement Disorders Units of Massachusetts General Hospital with diagnoses of AD (n = 145), MCI (n = 47), PD (n = 93), CAA (67), hypertensive intracerebral hemorrhage (hICH) (n = 25), and no dementia (n = 88). RESULTS: The tHcy levels did not differ across AD, MCI, CAA, hICH, and nondemented control subjects but were increased in the PD group (p < 0.01). The elevated levels within the PD group were due to high tHcy in individuals taking levodopa (p < 0.0001). Increasing tHcy was associated with worse cognition in the PD cases, but not the other diagnostic groups. tHcy levels positively correlated with plasma Abeta levels even after adjustments for age and creatinine (p < 0.0001). CONCLUSIONS: Mean tHcy levels increased with age but did not discriminate diagnostic groups aside from significant elevation in patients with PD taking levodopa. The positive association between tHcy and plasma Abeta levels raises the possibility that these circulating factors could interact to affect AD risk and cognition in PD.

Domnitz SB, Robbins EM, Hoang AW, Garcia-Alloza M, Hyman BT, Rebeck GW, Greenberg SM, Bacskai BJ, Frosch MP. · Alzheimer Research Unit, Massachusetts General Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA. · J Neuropathol Exp Neurol. · Pubmed #16042310 No free full text.

Abstract: Cerebral amyloid angiopathy (CAA), the deposition of beta-amyloid (Abeta3) in cerebral vessels, has been implicated as a common cause of hemorrhagic stroke and other forms of vascular disease. CAA is also a frequent concomitant of Alzheimer disease (AD). While the longterm consequences of CAA are well recognized from clinical and pathologic studies, numerous questions remain unanswered regarding the progression of the disease. Examination of CAA in traditional histologic sections does not easily allow for characterization of CAA, particularly in leptomeningeal vessels. In order to approach this topic, we used low magnification imaging of intact, postmortem brains from transgenic mouse models of AD-like pathology to define the spatial and temporal characteristics of CAA in leptomeningeal vessels. Imaging of brains from 10- to 26-month-old animals demonstrated a stereotypical pattern to the development of CAA, with vessels over the dorsal surface of the brain showing an anterior-to-posterior and large-to-small vessel gradient of involvement. High magnification imaging revealed that CAA deposition began with a banding pattern determined by the organization of the vascular smooth muscle cells. Further analysis of the pattern of amyloid deposits showed shrinkage and disappearance of the gaps between clusters of amyloid bands, gradually reaching a confluent pattern. These data led to a classification system to describe the severity of CAA deposition and demonstrate the potential of using intact brains to generate maps defining the progression and kinetics of CAA. This approach should lead to more informed analysis of the consequences of evolving therapeutic options for AD on this related form of vascular pathology.

Rebeck GW, Cho HS, Grabowski TJ, Greenberg SM. · Alzheimer Research Unit, Massachusetts General Hospital, Charlestown 02129, USA. · Amyloid. · Pubmed #11676289 No free full text.

Abstract: Analysis of causative mutations and genetic risk factors aid in the understanding of important processes of cerebral amyloid angiopathy (CAA) in humans. We identified a mutation at a novel site of the beta-amyloid precursor protein (AbetaPP) gene associated with familial CAA; this mutation causes an aspartate to asparagine substitution at position 23 of the Abeta peptide. Neuropathological analysis of a 68-year-old man with this mutation showed dramatic Abeta deposition in blood vessels, diffiuse parenchymal Abeta deposits, dystrophic neurites and neurofibrillary tangles. The Abeta deposition showed complete co-localization of Abeta40 and Abeta42, compared to the predominant Abeta42 deposition seen in AD. We hypothesize that the loss of an acidic residue at position 23 of Abeta might be important in the process of Abeta aggregation on smooth muscle cells on the cerebrovasculature. We also analyzed how the apolipoprotein E (APOE) gene might influence aggregation of Abeta by examining the physical association of apoE domains with Abeta via immunohistochemistry. We found that the lipid-binding domain of apoE was more strongly associated with Abeta than the receptor-binding domain, and that 40% of all Abeta deposits had no apoE bound to them. We suggest that the initial deposition of Abeta occurs in the absence of apoE, and that the process of Abeta deposit growth or stabilization is apoE-dependent.

Cho HS, Hyman BT, Greenberg SM, Rebeck GW. · Alzheimer Research Unit, Massachusetts General Hospital, Boston 02129, USA. · J Neuropathol Exp Neurol. · Pubmed #11305869 No free full text.

Abstract: Apolipoprotein E (apoE) and apoE-derived proteolytic fragments are present in amyloid deposits in Alzheimer disease (AD) and cerebral amyloid angiopathy (CAA). In this study, we examined which apoE fragments are most strongly associated with amyloid deposits and whether apoE receptor binding domains were present. We found that both apoE2- and apoE4-specific residues were present on plaques and blood vessels in AD and CAA. We quantified Abeta plaque burden and apoE plaque burdens in 5 AD brains. ApoE N-terminal-specific and C-terminal-specific antibodies covered 50% and 74% of Abeta plaque burden, respectively (p < 0.003). Double-labeling demonstrated that the plaque cores contained the entire apoE protein, but that outer regions contained only a C-terminal fragment, suggesting a cleavage in the random coil region of apoE. Presence of N- and C-terminal apoE cleavage fragments in brain extracts was confirmed by immunoblotting. The numbers of plaques identified by the apoE N-terminal-specific antibodies and the apoE C-terminal-specific antibody were equal, but were only approximately 60% of the total Abeta plaque number (p < 0.0001). Analysis of the size distribution of Abeta and apoE deposits demonstrated that most of the Abeta-positive, apoE-negative deposits were the smallest deposits (less than 150 microm2). These data suggest that C-terminal residues of apoE bind to Abeta and that apoE may help aid in the progression of small Abeta deposits to larger deposits. Furthermore, the presence of the apoE receptor binding domain in the center of amyloid deposits could affect surrounding cells via chronic interactions with cell surface apoE receptors.

Rebeck GW, Cheung BS, Growdon WB, Deng A, Akuthota P, Locascio J, Greenberg SM, Hyman BT. · Alzheimer Research Unit, Massachusetts General Hospital, Charlestown 02129, USA. · Neurosci Lett. · Pubmed #10505604 No free full text.

Abstract: Several studies have demonstrated genetic associations between Alzheimer's disease (AD) and polymorphisms in the promoter/enhancer regions of the apolipoprotein E (APOE) gene. These studies raise the possibility that APOE transcription control may be involved in altered risks for AD. We evaluated polymorphic sites in the intron-1 enhancer element (IE-1G/C) and in the APOE promoter (-219G/T). For the IE-1 polymorphism, we analyzed 433 individuals (183 AD and 250 controls), and found a strong linkage between the IE-1G allele and APOE-epsilon4. When we controlled for this linkage using log-linear model analysis, we found no independent association between the IE-1 polymorphism and AD. For the -219 polymorphism, we analyzed 475 individuals (168 AD cases, 234 controls, and 73 cases of cerebral amyloid angiopathy (CAA)). We found strong linkages between the -219G allele and APOE-epsilon2 and between the -219 T allele and APOE-epsilon4. Controlling for these linkages, we found no independent association between the -219 polymorphism and AD or CAA. Thus, our studies do not support independent associations between AD and either the IE-1 or the -219 polymorphisms.

Greenberg SM, Bacskai BJ, Hyman BT. · No affiliation provided · Nat Med. · Pubmed #12640449 No free full text.

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