Showing papers by "John Q. Trojanowski published in 2005"

Diagnosis and management of dementia with Lewy bodies: Third report of the DLB Consortium

Abstract: The dementia with Lewy bodies (DLB) Consortium has revised criteria for the clinical and pathologic diagnosis of DLB incorporating new information about the core clinical features and suggesting improved methods to assess them. REM sleep behavior disorder, severe neuroleptic sensitivity, and reduced striatal dopamine transporter activity on functional neuroimaging are given greater diagnostic weighting as features suggestive of a DLB diagnosis. The 1-year rule distinguishing between DLB and Parkinson disease with dementia may be difficult to apply in clinical settings and in such cases the term most appropriate to each individual patient should be used. Generic terms such as Lewy body (LB) disease are often helpful. The authors propose a new scheme for the pathologic assessment of LBs and Lewy neurites (LN) using alpha-synuclein immunohistochemistry and semiquantitative grading of lesion density, with the pattern of regional involvement being more important than total LB count. The new criteria take into account both Lewy-related and Alzheimer disease (AD)-type pathology to allocate a probability that these are associated with the clinical DLB syndrome. Finally, the authors suggest patient management guidelines including the need for accurate diagnosis, a target symptom approach, and use of appropriate outcome measures. There is limited evidence about specific interventions but available data suggest only a partial response of motor symptoms to levodopa: severe sensitivity to typical and atypical antipsychotics in ∼50%, and improvements in attention, visual hallucinations, and sleep disorders with cholinesterase inhibitors.

Ways toward an early diagnosis in Alzheimer’s disease: The Alzheimer’s Disease Neuroimaging Initiative (ADNI)

Abstract: With the increasing life expectancy in developed countries, the incidence of Alzheimer’s disease (AD) and thus its socioeconomic impact are growing. Increasing knowledge over the last years about the pathomechanisms involved in AD allow for the development of specific treatment strategies aimed at slowing down or even preventing neuronal death in AD. However, this requires also that (1) AD can be diagnosed with high accuracy, because non-AD dementias would not benefit from an AD-specific treatment; (2) AD can be diagnosed in very early stages when any intervention would be most effective; and (3) treatment efficacy can be reliably and meaningfully monitored. Although there currently is no ideal biomarker that would fulfill all these requirements, there is increasing evidence that a combination of currently existing neuroimaging and cerebrospinal fluid (CSF) and blood biomarkers can provide important complementary information and thus contribute to a more accurate and earlier diagnosis of AD. The Alzheimer’s Disease Neuroimaging Initiative (ADNI) is exploring which combinations of these biomarkers are the most powerful for diagnosis of AD and monitoring of treatment effects.

Microtubule-binding drugs offset tau sequestration by stabilizing microtubules and reversing fast axonal transport deficits in a tauopathy model

Abstract: We tested the hypothesis that microtubule (MT)-binding drugs could be therapeutically beneficial in tauopathies by functionally substituting for the MT-binding protein tau, which is sequestered into inclusions of human tauopathies and transgenic mouse models thereof. Transgenic mice were treated for 12 weeks with weekly i.p. injections of 10 or 25 mg/m2 paclitaxel (Paxceed). Both doses restored fast axonal transport in spinal axons, wherein MT numbers and stable (detyrosinated) tubulins were increased, compared with sham treatment, and only Paxceed ameliorated motor impairments in tau transgenic mice. Thus, MT-stabilizing drugs could have therapeutic potential for treating neurodegenerative tauopathies by offsetting losses of tau function that result from the sequestration of this MT-stabilizing protein into filamentous inclusions.

Axonal transport defects: a common theme in neurodegenerative diseases.

Abstract: A core pathology central to most neurodegenerative diseases is the misfolding, fibrillization and aggregation of disease proteins to form the hallmark lesions of specific disorders. The mechanisms underlying these brain-specific neurodegenerative amyloidoses are the focus of intense investigation and defective axonal transport has been hypothesized to play a mechanistic role in several neurodegenerative disorders; however, this hypothesis has not been extensively examined. Discoveries of mutations in human genes encoding motor proteins responsible for axonal transport do provide direct evidence for the involvement of axonal transport in neurodegenerative diseases, and this evidence is supported by studies of animal models of neurodegeneration. In this review, we summarize recent findings related to axonal transport and neurodegeneration. Focusing on specific neurodegenerative diseases from a neuropathologic perspective, we highlight discoveries of human motor protein mutations in some of these diseases, as well as illustrate new insights from animal models of neurodegenerative disorders. We also review the current understanding of the biology of axonal transport including major recent findings related to slow axonal transport.

Frontotemporal dementia progresses to death faster than Alzheimer disease

Abstract: Background: Frontotemporal lobar degeneration (FTLD) is a common cause of non-Alzheimer dementia, but its natural history and the factors related to mortality in affected patients are not well understood. Methods: This retrospective, longitudinal study compared survival in FTLD (n = 177) with Alzheimer disease (AD; n = 395). Hazards analysis investigated the contribution of various demographic, neuropsychiatric, and neuropsychological variables and associated neurologic and neuropathologic findings. Results: The frontotemporal dementia (FTD) subtype of FTLD progressed faster than AD (median survival from retrospectively determined symptom onset, 8.7 ± 1.2 vs 11.8 ± 0.6 years, p p Conclusions: Frontotemporal lobar degeneration progresses more rapidly than Alzheimer disease, and the fastest-progressing cases are those with the frontotemporal dementia clinical subtype, coexisting motor neuron disease, or tau-negative neuropathology.

Cerebrospinal fluid profile in frontotemporal dementia and Alzheimer's disease

Abstract: We assessed cerebrospinal fluid (CSF) levels of tau and other biomarkers of neurodegenerative disease. CSF tau levels vary widely in reports of frontotemporal dementia (FTD). CSF samples were assayed for tau, amyloid beta1-42 (A1-42), and the isoprostane 8,12-iso-iPF2a-VI (iP) prospectively in 64 patients with FTD, retrospectively in 26 autopsied cases with FTD or Alzheimer's disease (AD), and in 13 healthy seniors. To validate our observations in vivo, we correlated CSF tau levels with cortical atrophy in 17 FTD patients using voxel-based morphometry analyses of high-resolution magnetic resonance imaging. CSF levels of tau, Abeta1-42, and iP differed significantly in FTD compared with AD. Individual patient analyses showed that 34% of FD patients had significantly low levels of CSF tau, although this was never seen in AD. A discriminant analysis based on CSF levels of tau, Abeta1-42, and iP was able to classify 88.5% of these patients in a manner that corresponds to their clinical or autopsy diagnosis. Magnetic resonance imaging studies showed that CSF tau levels correlate significantly with right frontal and left temporal cortical atrophy, brain regions known to be atrophic in patients with autopsy-proved FTD. We conclude that CSF tau levels are significantly reduced in many patients with FTD.

Transgenic Mouse Model of Tau Pathology in Astrocytes Leading to Nervous System Degeneration

Abstract: Filamentous tau inclusions in neurons and glia are neuropathological hallmarks of sporadic and familial tauopathies. Because tau gene mutations are pathogenic for the autosomal dominant tauopathy “frontotemporal dementia and parkinsonism linked to chromosome 17,” tau abnormalities are implicated directly in the onset and/or progression of disease. Although filamentous tau aggregates are acknowledged to play roles in degenerative mechanisms resulting in neuron loss, the contributions of glial tau pathology to neurodegeneration remain essentially unexplored. To begin to elucidate the role of glial pathology in tauopathies, we generated a transgenic (Tg) mouse model of astrocytic tau pathology by expressing the human tau protein driven by the glial fibrillary acidic protein (GFAP) promoter. Whereas endogenous tau was not detected in astrocytes of control mice, in GFAP/tau Tg mice there was robust astrocytic tau expression that was associated with a redistribution of the GFAP network. Subsequently, there was an age-dependent accumulation of tau pathology in astrocytes that was Gallyas and variably thioflavine S positive as observed in many tauopathies. The tau pathology in these Tg mice was abnormally phosphorylated, ubiquitinated, and filamentous, and the emergence of this pathology coincided with accumulation of insoluble tau protein. Furthermore, in regions with robust astrocytic tau pathology, there was mild blood- brain barrier disruption, induction of low-molecular-weight heat shock proteins, and focal neuron degeneration. Thus, these Tg mice recapitulate key features of astrocytic pathology observed in human tauopathies and demonstrate functional consequences of this pathology including neuron degeneration in the absence of neuronal tau inclusions.

Altered Neuronal Mitochondrial Coenzyme A Synthesis in Neurodegeneration with Brain Iron Accumulation Caused by Abnormal Processing, Stability, and Catalytic Activity of Mutant Pantothenate Kinase 2

Abstract: Mutations in the pantothenate kinase 2 (PANK2) gene have been identified in patients with neurodegeneration with brain iron accumulation (NBIA; formerly Hallervorden-Spatz disease). However, the mechanisms by which these mutations cause neurodegeneration are unclear, especially given the existence of multiple pantothenate kinase genes in humans and multiple PanK2 transcripts with potentially different subcellular localizations. We demonstrate that PanK2 protein is localized to mitochondria of neurons in human brain, distinguishing it from other pantothenate kinases that do not possess mitochondrial-targeting sequences. PanK2 protein translated from the most 5' start site is sequentially cleaved at two sites by the mitochondrial processing peptidase, generating a long-lived 48 kDa mature protein identical to that found in human brain extracts. The mature protein catalyzes the initial step in coenzyme A (CoA) synthesis but displays feedback inhibition in response to species of acyl CoA rather than CoA itself. Some, but not all disease-associated point mutations result in significantly reduced catalytic activity. The most common mutation, G521R, results in marked instability of the intermediate PanK2 isoform and reduced production of the mature isoform. These results suggest that NBIA is caused by altered neuronal mitochondrial lipid metabolism caused by mutations disrupting PanK2 protein levels and catalytic activity.

BACE overexpression alters the subcellular processing of APP and inhibits Aβ deposition in vivo

Abstract: Introducing mutations within the amyloid precursor protein (APP) that affect β- and γ-secretase cleavages results in amyloid plaque formation in vivo. However, the relationship between β-amyloid deposition and the subcellular site of Aβ production is unknown. To determine the effect of increasing β-secretase (BACE) activity on Aβ deposition, we generated transgenic mice overexpressing human BACE. Although modest overexpression enhanced amyloid deposition, high BACE overexpression inhibited amyloid formation despite increased β-cleavage of APP. However, high BACE expression shifted the subcellular location of APP cleavage to the neuronal perikarya early in the secretory pathway. These results suggest that the production, clearance, and aggregation of Aβ peptides are highly dependent on the specific neuronal subcellular domain wherein Aβ is generated and highlight the importance of perikaryal versus axonal APP proteolysis in the development of Aβ amyloid pathology in Alzheimer's disease.

Enhanced Neurofibrillary Tangle Formation, Cerebral Atrophy, and Cognitive Deficits Induced by Repetitive Mild Brain Injury in a Transgenic Tauopathy Mouse Model

Abstract: Traumatic brain injury (TBI) is a risk factors for Alzheimer's disease (AD), and repetitive TBI (rTBI) may culminate in dementia pugilistica (DP), a syndrome characterized by progressive dementia, ...

Elevation of 12/15 lipoxygenase products in AD and mild cognitive impairment.

Abstract: The 12/15 lipoxygenase (12/15LOX) enzyme is increased in pathologically affected frontal and temporal regions of Alzheimer's disease (AD) brains compared with controls. Herein, we measured 12(S)-HETE and 15(S)-HETE levels, products of 12/15LOX, in cerebrospinal fluid (CSF) of normal individuals, subjects with mild cognitive impairment (MCI) and AD. Compared with controls, there was a significant increase of both metabolites in CSF from AD and MCI, which correlated with lipid peroxidation and tau protein levels. These results suggest that the activation of this enzyme occurs early in the course of AD, before the onset of overt dementia, thereby implicating 12/15LOX-mediated lipid peroxidation in the pathogenesis of AD.

Axonal Degeneration Induced by Targeted Expression of Mutant Human Tau in Oligodendrocytes of Transgenic Mice That Model Glial Tauopathies

Abstract: Abundant filamentous tau inclusions in oligodendrocytes (OLGs) are hallmarks of neurodegenerative tauopathies, including sporadic corticobasal degeneration and hereditary frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). However, mechanisms of neurodegeneration in these tauopathies are unclear in part because of the lack of animal models for experimental analysis. We address this by generating transgenic (Tg) mice expressing human tau exclusively in OLGs using the 2′,3′-cyclic nucleotide 3′-phosphodiesterase promoter. Filamentous OLG tau inclusions developed in these Tg mice as a result of human tau expression in OLGs, especially those expressing the FTDP-17 human P301L mutant tau. Notably, structural disruption of myelin and axons preceded the emergence of thioflavin-S positive tau inclusions in OLGs, but impairments in axonal transport occurred even earlier, whereas motor deficits developed subsequently, especially in Tg mice with the highest tau expression levels. These data suggest that the accumulation of tau in OLG cause neurodegeneration, and we infer they do so by disrupting axonal transport. We suggest that similar defects may also occur in sporadic and hereditary human tauopathies with OLG tau pathologies.

Chronic lithium treatment decreases tau lesions by promoting ubiquitination in a mouse model of tauopathies

Abstract: Lithium, a widely used drug for treating affective disorders, is known to inhibit glycogen synthase kinase-3 (GSK-3), which is one of the major tau kinases. Thus, lithium could have therapeutic benefit in neurodegenerative tauopathies by reducing tau hyperphosphorylation. We tested this hypothesis and showed that long-term administration of lithium at relatively low therapeutic concentrations to transgenic mice that recapitulate Alzheimer’s disease (AD)-like tau pathologies reduces tau lesions, primarily by promoting their ubiquitination rather than by inhibiting tau phosphorylation. These findings suggest novel mechanisms whereby lithium treatment could ameliorate tauopathies including AD. Because lithium also has been shown to reduce the burden of amyloid-β pathologies, it is plausible that lithium could reduce the formation of both amyloid plaques and tau tangles, the two pathological hallmarks of AD, and thereby ameliorate the behavioral deficits in AD.

Neuropathologic, biochemical, and molecular characterization of the frontotemporal dementias

Abstract: The frontotemporal dementias (FTDs) are a heterogeneous group of neurodegenerative disorders that are characterized clinically by dementia, personality changes, language impairment, and occasionally extrapyramidal movement disorders. Historically, the diagnosis and classification of FTDs has been fraught with difficulties, especially with regard to establishing a consensus on the neuropathologic diagnosis. Recently, an international group of scientists participated in a consensus conference to develop such neuropathologic criteria. They recommended a diagnostic classification scheme that incorporated a biochemical analysis of the insoluble tau isoform composition, as well as ubiquitin immunohistochemistry. The use and reliability of this classification system has yet to be examined. In this study, we evaluated 21 cases of FTD. Using traditional histochemical stains and tau protein and ubiquitin immunohistochemistry, we separated each case into one of the following categories: classic Pick disease (PiD; n = 7), corticobasal degeneration (CBD; n = 5), dementia lacking distinctive histopathologic features (DLDH; n = 4), progressive supranuclear palsy (PSP; n = 2), frontotemporal lobar degeneration with motor neuron disease or motor neuron disease-type inclusions (FTLD-MND/MNI; n = 2), and neurofibrillary tangle dementia (NFTD; n = 1). Additionally, we independently categorized each case by the insoluble tau isoform pattern, including 3R (n = 5), 4R (n = 7), 3R/4R (n = 3), and no insoluble tau (n = 6). As suggested by the proposed diagnostic scheme, we found that the insoluble tau isoform patterns correlated strongly with the independently derived histopathologic diagnoses (p < 0.001). The data show that cases containing predominantly 3R tau were classic PiD (100%). Cases with predominantly 4R tau were either CBD (71%) or PSP (29%). Cases with both 3R and 4R tau were either a combination of PiD and Alzheimer disease (67%) or NFTD (33%). Finally, cases with no insoluble tau were either DLDH (67%) or FTLD-MND/MNI (33%). To further characterize these cases, we also performed quantitative Western blots for soluble tau, APOE genotyping, and, in selected cases, tau gene sequencing. We show that soluble tau is reduced in DLDH and FTLD-MND/MNI and that APOE4 is overrepresented in PiD and DLDH. We also identified a new family with the R406W mutation and pathology consistent with NFTD. This study validates the recently proposed diagnostic criteria and forms a framework for further refinement of this classification scheme.

Pathological tau: a loss of normal function or a gain in toxicity?

Abstract: Neurofibrillary tangles, composed of tau protein, are a central feature of Alzheimer disease. A new paper challenges the idea that these tau inclusions alone cause disease by showing that they can be dissociated from memory impairment and neuronal loss.

D2-40, a novel monoclonal antibody against the M2A antigen as a marker to distinguish hemangioblastomas from renal cell carcinomas.

Abstract: Hemangioblastomas (HB) are characterized by the presence of vacuolated tumor cells resembling the tumor cells seen in clear cell renal cell carcinomas (CRCC). The distinction between HB and metastatic CRCC in the brain is critical as they have different therapeutic and prognostic ramifications. The issue is further complicated by the possibility of both HB and metastatic CRCC in brains of patients with Von Hippel Lindau (VHL) disease. We studied the expression of a novel monoclonal antibody D2-40, which recognizes an oncofetal antigen (M2A) in HB and CRCC, by immunohistochemistry. The vacuolated tumor cells in all HB were stained positively with D2-40. Nineteen of 23 (83%) HB showed strong, membranous staining in the vacuolated tumor cells, and 4 of 23 (17%) showed weaker staining. No expression was seen in CRCC, either primary in the kidney (0/20), or metastatic CRCC in the brain (0/8). Three of the patients with HB also had VHL disease, and no difference was seen in D2-40 staining of HB in patients with or without VHL disease. Two of these three VHL disease patients had both primary CRCC and HB resected at our institution. In these two patients, strong D2-40 expression was seen in the HB, but no expression was seen in the CRCC, underlying the utility of this marker in distinguishing HB from CRCC in patients with VHL disease in addition to sporadic cases. In summary, the monoclonal antibody D2-40 is a useful marker to distinguish HB from CRCC.

The North American Multiple System Atrophy Study Group.

Abstract: The North American Multiple System Atrophy Study Group involves investigators in 12 US medical centers funded by a grant from the National Institutes of Health. The objectives are to examine the environmental and genetic risk factors for MSA; elucidate pathogenic mechanisms underlying the disorder; and refine evaluations used for assessment. During its first year, the group enrolled 87 patients, implemented four cores, and initiated four scientific projects. Most patients among the 87 had parkinsonian features, which frequently began asymmetrically and remained asymmetrical; one-third responded to levodopa and many developed levodopa complications; almost two-thirds of the patients had cerebellar dysfunction, of these 90% had ataxia; urinary incontinence occurred commonly, and sleep disorders affected most. The investigators studied the effects of oxidative and nitrative stress upon the formation of alpha-synuclein inclusions; generated transgenic models of alpha-synuclein accumulation that recapitulate several behavioral and neuropathological features of MSA; and compared the severity of the autonomic features of MSA, Parkinson's disease and dementia with Lewy bodies.

Impaired Rapid Eye Movement Sleep in the Tg2576 APP Murine Model of Alzheimer’s Disease with Injury to Pedunculopontine Cholinergic Neurons

Abstract: Impaired rapid eye movement sleep (REMS) is commonly observed in Alzheimer's disease, suggesting injury to mesopontine cholinergic neurons. We sought to determine whether abnormal β-amyloid peptides impair REMS and injure mesopontine cholinergic neurons in transgenic (hAPP695.SWE) mice (Tg2576) that model brain amyloid pathologies. Tg2576 mice and wild-type littermates were studied at 2, 6, and 12 months by using sleep recordings, contextual fear conditioning, and immunohistochemistry. At 2 months of age, REMS was indistinguishable by genotype but was reduced in Tg2576 mice at 6 and 12 months. Choline acetyltransferase-positive neurons in the pedunculopontine tegmentum of Tg2576 mice at 2 months evidenced activated caspase-3 immunoreactivity, and at 6 and 12 months the numbers of pedunculopontine tegmentum choline acetyltransferase-positive neurons were reduced in the Tg2576 mice. Other cholinergic groups involved in REMS were unperturbed. At 12 months, Tg2576 mice demonstrated increased 3-nitrotyrosine immunoreactivity in cholinergic projection sites but not in cholinergic soma. We have identified a population of selectively compromised cholinergic neurons in young Tg2576 mice that manifest early onset REMS impairment. The differential vulnerability of these cholinergic neurons to Aβ injury provides an invaluable tool with which to understand mechanisms of sleep/wake perturbations in Alzheimer's disease.

Microtubule-stabilising drugs for therapy of Alzheimer's disease and other neurodegenerative disorders with axonal transport impairments.

Abstract: Increasing evidence implicates impairments of axonal transport in mechanisms underlying diverse neurodegenerative disease. This evidence includes discoveries of mutations in genes encoding human motor proteins or proteins involved in stabilising the microtubule (MT) network required for maintenance of axonal transport in familial neurodegenerative disorders, as well as data from in vivo and in vitro model systems. Moreover, in sporadic neurodegenerative disorders such as Alzheimer's disease (AD), pathological alterations of the MT-binding protein tau are linked to impaired axonal transport and brain degeneration. Because MT-stabilising compounds hold promise for counteracting the loss of tau function in AD and sustaining effective axonal transport, we conclude that MT-binding/stabilising drugs show potential therapeutic utility for the treatment of AD and other neurodegenerative disorders characterised by altered MTs and impaired axonal transport.

Delayed transplantation of human neurons following brain injury in rats: a long-term graft survival and behavior study.

Abstract: The NTera2 (NT2) cell line is a homogeneous population of cells, which, when treated in vitro with retinoic acid, terminally differentiate into postmitotic neuronal NT2N cells. Although NT2N neurons transplanted in the acute (24 h postinjury) period survive for up to 1 month following experimental traumatic brain injury (TBI), nothing is known of their ability to survive for longer periods or of their effects when engrafted during the chronic postinjury period. Adult male Sprague-Dawley rats (n = 348; 360-400 g) were initially anesthetized and subjected to severe lateral fluid-percussion (FP) brain injury or sham injury. At 1 month postinjury, only brain-injured animals showing severe neurobehavioral deficits received cryopreserved NT2N neurons stereotaxically transplanted into three sites in the peri-injured cortex (n = 18). Separate groups of similarly brain-injured rats received human fibroblast cells (n = 13) or cell suspension vehicle (n = 14). Sham-injured animals (no brain injury) served as controls and received NT2N transplants (n = 24). All animals received daily immunosuppression for three months. Behavioral testing was performed at 1, 4, 8, and 12 weeks post-transplantation, after which animals were sacrificed for histological analysis. Nissl staining and anti-human neuronal specific enolase (NSE) immunostaining revealed that NT2N neurons transplanted in the chronic post-injury period survived up to 12 weeks post-transplantation, extended processes into the host cortex and immunolabeled positively for synaptophysin. There were no statistical differences in cognitive or motor function among the transplanted brain-injured groups. Long-term graft survival suggests that NT2N neurons may be a viable source of neural cells for transplantation after TBI and also that these grafts can survive for a prolonged time and extend processes into the host cortex when transplanted in the chronic post-injury period following TBI.

Lowering the risk of Alzheimer's disease: Evidence-based practices emerge from new research

Abstract: Background: The increasing prevalence of Alzheimer's disease (AD) and other aging-related dementias as the population ages will have a dramatic impact on both provision of health care and the economy if nothing is done to prevent or delay the onset of AD or to slow its progression. Methods: A comprehensive review of the literature in several promising areas of inquiry, other than those representing Food and Drug Administration (FDA)-approved AD- or dementia-specific pharmacologic therapies, that may impact the risk or progression of AD and related dementias was undertaken. Results: Results highlight a number of factors associated with AD and dementia. These include education and occupation, cognitive and leisure activities, exercise, cholesterol and statins, and head trauma. Conclusions: Factors associated with AD and dementia may have potential as strategies useful in preventing or delaying AD and dementia or slowing its progression. Further research is needed to determine the validity and strength of the associations and to ascertain causality. © 2005 The Alzheimer's Association. All rights reserved.

Genetic variation in the brain derived neurotrophic factor gene in Alzheimer's disease.

Abstract: Genes known to contribute to the genetic predisposition to Alzheimer's disease (AD) are active in pathways of neurodegeneration but explain only a minority of the genetic contribution to AD. A protein of importance in cerebral neurodegeneration is the brain-derived neurotrophic factor (BDNF). Variations in two single-nucleotide polymorphisms (SNPs) within the BDNF gene have previously been associated with AD, and one of these SNPs has also been associated with memory loss and affective disorders. We performed a case control study of three BDNF SNPs in 250 neuropathologically confirmed cases of AD and 194 unrelated controls. We did not find a significant association between the three BDNF SNPs studied and AD when evaluated individually or with haplotype analysis. Nor did BDNF genotype appear to affect the APOE e4 association with AD. The three SNPs studied were closely linked (D′ = 0.99 across the region). We discuss possible reasons for our failure to confirm the previously reported associations. © 2004 Wiley-Liss, Inc.

Rous-Whipple Award Lecture. The Alzheimer's brain: finding out what's broken tells us how to fix it.

Abstract: The unusual form of dementia described ∼100 years ago by Alois Alzheimer, now known as Alzheimer’s disease (AD), has become a scourge in the 21st century due to the unprecedented increase in human life expectancy since 1900, when AD was an uncommon cause of dementia. Indeed, because the risk of developing AD increases exponentially beyond the seventh decade of life, the prevalence of this neurodegenerative disorder will continue to rise inexorably in the coming decades unless effective interventions can delay its onset or retard its progression. The widespread international recognition of the urgency of this problem has accelerated efforts to translate the remarkable discoveries throughout the past 20 years from research on AD into meaningful therapies for this disorder. For example, advances in understanding mechanisms underlying the conversion of normal soluble tau and Aβ into insoluble fibrils that form neurofibrillary tangles (NFTs) and senile plaques (SPs), respectively, are beginning to clarify how these hallmark lesions of AD contribute to the dysfunction and degeneration of selectively vulnerable neurons in the AD brain. These new insights have led to the identification of multiple novel targets for AD drug discovery to block or reverse Aβ amyloidosis and, more recently, to develop tau-focused therapeutic interventions for the treatment of AD and related tauopathies.

Axonal transport defects: a common theme in neurodegenerative

Abstract: A core pathology central to most neurode- generative diseases is the misfolding, fibrillization and aggregation of disease proteins to form the hallmark lesions of specific disorders. The mechanisms under- lying these brain-specific neurodegenerative amyloi- doses are the focus of intense investigation and defective axonal transport has been hypothesized to play a mechanistic role in several neurodegenerative disorders; however, this hypothesis has not been extensively examined. Discoveries of mutations in hu- man genes encoding motor proteins responsible for axonal transport do provide direct evidence for the involvement of axonal transport in neurodegenerative diseases, and this evidence is supported by studies of animal models of neurodegeneration. In this review, we summarize recent findings related to axonal transport and neurodegeneration. Focusing on specific neurodegenerative diseases from a neuropathologic perspective, we highlight discoveries of human motor protein mutations in some of these diseases, as well as illustrate new insights from animal models of neuro- degenerative disorders. We also review the current understanding of the biology of axonal transport including major recent findings related to slow axonal transport.