Cognitive impairment, including dementia, is commonly seen in those afflicted with Parkinson disease (PD), particularly at advanced disease stages. Pathologically, PD with dementia (PD-D) is most often associated with the presence of cortical Lewy bodies, as is the closely related dementia with Lewy bodies (DLB). Both PD-D and DLB are also frequently complicated by the presence of neurofibrillary tangles and amyloid plaques, features most often attributed to Alzheimer disease. Biomarkers are urgently needed to differentiate among these disease processes and predict dementia in PD as well as monitor responses of patients to new therapies. A few clinical assessments, along with structural and functional neuroimaging, have been utilized in the last few years with some success in this area. Additionally, a number of other strategies have been employed to identify biochemical/molecular biomarkers associated with cognitive impairment and dementia in PD, e.g. targeted analysis of candidate proteins known to be important to PD pathogenesis and progression in cerebrospinal fluid or blood. Finally, interesting results are emerging from preliminary studies with unbiased and high throughput genomic, proteomic and metabolomic techniques. The current findings and perspectives of applying these strategies and techniques are reviewed in this article, together with potential areas of advancement.

This review summarizes the scientific talks presented at the conference "Therapeutics for Cognitive Aging," hosted by the New York Academy of Sciences and the Alzheimer's Drug Discovery Foundation on May 15, 2009. Attended by scientists from industry and academia, as well as by a number of lay people-approximately 200 in all-the conference specifically tackled the many aspects of developing therapeutic interventions for cognitive impairment. Discussion also focused on how to define cognitive aging and whether it should be considered a treatable, tractable disease.

OBJECTIVE: The aim was to examine early event-related potential (ERP) changes during mental arithmetic calculation task in mild cognitive impairment patients compared to healthy elderly. METHODS: 16 mild cognitive impairment (MCI) subjects and 16 healthy Chinese older adults were studied. Event-related potentials were elicited using a simple mental calculation task. Performance on arithmetic calculation task, and the latency and amplitude of early event-related potential components (N1, P1, N170, and P2) were compared between the two groups. RESULTS: The reaction time of MCI group was significantly longer than that of control group (1691.03+/- 94.59 vs. 1539.55+/-27.76, P<0.01). The correct rate of MCI group (0.9463+/- 0.04) was significantly lower than that of control group (0.9776+/- 0.02,P<0.01). The latency of temporal- occipital N170 and central- prefrontal P2 of MCI group were significantly prolonged compared to controls. MCI subjects presented significantly higher P2 amplitude. Compared with healthy controls, N170 was significantly lower at left temporal-occipital region and higher at right temporal-occipital region in mild cognitive impairment. CONCLUSION: Mild Cognitive Impairment patients had deficit on simple calculation. The early arithmetic calculation processing mechanism of mild cognitive impairment patients may be different from normal people.

In Alzheimer disease (AD), which is the most common cause of dementia, the underlying disease pathology most probably precedes the onset of cognitive symptoms by many years. Thus, efforts are underway to find early diagnostic markers as well as disease-modifying treatments for this disorder. PET enables various brain systems to be monitored in living individuals. In patients with AD, PET can be used to investigate changes in cerebral glucose metabolism, various neurotransmitter systems, neuroinflammation, and the protein aggregates that are characteristic of the disease, notably the amyloid deposits. These investigations are helping to further our understanding of the complex pathophysiological mechanisms that underlie AD, as well as aiding the early and differential diagnosis of the disease in the clinic. In the future, PET studies will also be useful for identifying new therapeutic targets and monitoring treatment outcomes. Amyloid imaging could be useful as early diagnostic marker of AD and for selecting patients for anti-amyloid-beta therapy, while cerebral glucose metabolism could be a suitable PET marker for monitoring disease progression. For the near future, multitracer PET studies are unlikely to be used routinely in the clinic for AD, being both burdensome and expensive; however, such studies are very informative in a research context.

One of the hallmark pathologies of Alzheimer's disease (AD) is amyloid plaque deposition in the brain. Although the advent of new therapeutic strategies aimed at reducing b-amyloid burden in the brain is to potentially delay cognitive loss, improved methods for amyloid visualization have become more imperative. Studies so far have shown that positron emission tomography (PET) has produced the greatest strides toward accomplishing this ambitious goal. Several PET amyloid imaging ligands have recently been developed and tested in AD patients. High amyloid content can be detected in vivo by PET in prodromal AD preceding the impairment of functional activity. Hopefully, amyloid imaging may help in the early detection of the disease and can be used for evaluating new drug therapies in AD. This study provides an overview of recent advances in the development of amyloid imaging agents and includes a summary of the clinical significance of amyloid imaging.

In the last few years, many studies in the cognitive and system neuroscience found that a consistent network of brain regions, referred to as the default network, showed high levels of activity when no explicit task was performed. Some scientists believed that the resting state activity might reflect some neural functions that consolidate the past, stabilize brain ensembles and prepare us for the future. Here, we modeled default network as undirected weighted graph and then used graph theory to investigate the topological properties of the default network of the two groups of people with different intelligence levels. We found that, in both groups, the posterior cingulate cortex showed the greatest degree in comparison to the other brain regions in the default network, and that the medial temporal lobes and cerebellar tonsils were topologically separations from the other brain regions in the default network. More importantly, we found that the strength of some functional connectivities and the global efficiency of default network were significantly different between the superior intelligence group and the average intelligence group, which indicates that the functional integration of the default network might be related to the individual intelligent performance.

A central issue in cognitive neuroscience of aging research is pinpointing precise neural mechanisms that determine cognitive outcome in late adulthood as well as identifying early markers of less successful cognitive aging. One promising biomarker is beta amyloid (Abeta) deposition. Several new radiotracers have been developed that bind to fibrillar Abeta providing sensitive estimates of amyloid deposition in various brain regions. Abeta imaging has been primarily used to study patients with Alzheimer's Disease (AD) and individuals with Mild Cognitive Impairment (MCI); however, there is now building data on Abeta deposition in healthy controls that suggest at least 20% and perhaps as much as a third of healthy older adults show significant deposition. Considerable evidence suggests amyloid deposition precedes declines in cognition and may be the initiator in a cascade of events that indirectly leads to age-related cognitive decline. We review studies of Abeta deposition imaging in AD, MCI, and normal adults, its cognitive consequences, and the role of genetic risk and cognitive reserve.

Decrease in mitochondrial energy-transducing capacity is a feature of the aging process that accompanies redox alterations, such as increased generation of mitochondrial oxidants, altered GSH status, and increased protein oxidation. The decrease in mitochondrial energy-transducing capacity and altered redox status should be viewed as a concerted process that embodies the mitochondrial energy - redox axis and is linked through various mechanisms including:(a) an inter-convertible reducing equivalents pool (i.e., NAD(P)(+)/NAD(P)H) and (b) redox-mediated protein post-translational modifications involved in energy metabolism. The energy-redox axis provides the rationale for therapeutic approaches targeted to each or both component(s) of the axis that effectively preserves or improve mitochondrial function and that have implications for aging and age-related neurodegenerative disorders.

Focusing primarily on functional magnetic resonance imaging (fMRI), this article reviews evidence regarding the roles of subregions of the medial temporal lobes, prefrontal cortex, posterior representational areas, and parietal cortex in source memory. In addition to evidence from standard episodic memory tasks assessing accuracy for neutral information, the article considers studies assessing the qualitative characteristics of memories, the encoding and remembering of emotional information, and false memories, as well as evidence from populations that show disrupted source memory (older adults, individuals with depression, posttraumatic stress disorder, or schizophrenia). Although there is still substantial work to be done, fMRI is advancing understanding of source memory and highlighting unresolved issues. A continued 2-way interaction between cognitive theory, as illustrated by the source monitoring framework (M. K. Johnson, S. Hashtroudi,& D. S. Lindsay, 1993), and evidence from cognitive neuroimaging studies should clarify conceptualization of cognitive processes (e.g., feature binding, retrieval, monitoring), prior knowledge (e.g., semantics, schemas), and specific features (e.g., perceptual and emotional information) and of how they combine to create true and false memories.(PsycINFO Database Record (c) 2009 APA, all rights reserved).

Cognitively intact older individuals at risk for developing Alzheimer's disease frequently show increased functional magnetic resonance imaging (fMRI) brain activation presumably associated with compensatory recruitment, whereas mild cognitive impairment (MCI) patients tend not to show increased activation presumably due to reduced neural reserve. Previous studies, however, have typically used episodic memory activation tasks, placing MCI participants at a performance disadvantage relative to healthy elders. In this event-related fMRI study, we employed a low effort, high accuracy semantic memory task to determine if increased activation of memory circuits is preserved in amnestic MCI when task performance is controlled. Fifty-seven participants, aged 65-85 years, comprised three groups (n = 19 each): amnestic MCI patients; cognitively intact older participants at risk for developing Alzheimer's disease based on having at least one ApoE epsilon4 allele and a positive family history of Alzheimer's disease (At Risk); and cognitively intact participants without Alzheimer's disease risk factors (Control). fMRI was conducted on a 3T MR scanner while participants performed a famous name discrimination task. Participants also underwent neuropsychological testing outside the scanner; whole brain and hippocampal atrophy were assessed from anatomical MRI scans. The three groups did not differ on demographic variables or on fame discrimination performance (>87% correct for all groups). As expected, the amnestic MCI participants demonstrated reduced episodic memory performance. Spatial extent of activation (Fame-Unfamiliar subtraction) differentiated the three groups (Control = 0 ml, At Risk = 9.7 ml, MCI = 34.7 ml). The MCI and At Risk groups showed significantly greater per cent signal change than Control participants in 8 of 14 functionally defined regions, including the medial temporal lobe, temporoparietal junction, and posterior cingulate/precuneus. MCI participants also showed greater activation than Controls in two frontal regions. At Risk, but not MCI, participants showed increased activity in the left hippocampal complex; MCI participants, however, evidenced increased activity in this region when hippocampal atrophy was controlled. When performance is equated, MCI patients demonstrate functional compensation in brain regions subserving semantic memory systems that generally equals or exceeds that observed in cognitively intact individuals at risk for Alzheimer's disease. This hyperactivation profile in MCI is even observed in the left hippocampal complex, but only when the extent of hippocampal atrophy is taken into consideration.

BACKGROUND: Amyloid senile plaques and tau neurofibrillary tangles are neuropathological hallmarks of Alzheimer's disease that accumulate in the cortical regions of the brain in persons with mild cognitive impairment who are at risk for Alzheimer's disease. Noninvasive methods to detect these abnormal proteins are potentially useful in developing surrogate markers for drug discovery and diagnostics. METHODS: We enrolled 83 volunteers with self-reported memory problems who had undergone neurologic and psychiatric evaluation and positron-emission tomography (PET). On the basis of cognitive testing, 25 volunteers were classified as having Alzheimer's disease, 28 as having mild cognitive impairment, and 30 as having no cognitive impairment (healthy controls). PET was performed after injection of 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile (FDDNP), a molecule that binds to plaques and tangles in vitro. All subjects also underwent 2-deoxy-2-[F-18]fluoro-D-glucose (FDG) PET, and 72 underwent magnetic resonance imaging (MRI). RESULTS: Global values for FDDNP-PET binding (average of the values for the temporal, parietal, posterior cingulate, and frontal regions) were lower in the control group than in the group with mild cognitive impairment (P<0.001), and the values for binding in the group with mild cognitive impairment were lower than in the group with Alzheimer's disease (P<0.001). FDDNP-PET binding differentiated among the diagnostic groups better than did metabolism on FDG-PET or volume on MRI. CONCLUSIONS: FDDNP-PET scanning can differentiate persons with mild cognitive impairment from those with Alzheimer's disease and those with no cognitive impairment. This technique is potentially useful as a noninvasive method to determine regional cerebral patterns of amyloid plaques and tau neurofibrillary tangles.

CONTEXT: Amyloid senile plaques and tau neurofibrillary tangles are neuropathological hallmarks of Alzheimer disease that accumulate in the brains of people without dementia years before they develop dementia. Positron emission tomography (PET) scans after intravenous injections of 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile (FDDNP), which binds to plaques and tangles in vitro, demonstrate increased cerebral binding in patients with Alzheimer disease compared with cognitively intact controls. Here we investigated whether known risk factors for Alzheimer disease and dementia are associated with FDDNP-PET binding. OBJECTIVE: To determine if impaired cognitive status, older age, apolipoprotein E-4 (APOE-4) genetic risk for Alzheimer disease, family history of dementia, and less education are associated with increased regional cerebral FDDNP-PET binding. DESIGN: Cross-sectional clinical study. SETTING: A university research institute. PARTICIPANTS: Volunteer sample of 76 middle-aged and older persons without dementia (mean age, 67 years) including 36 with mild cognitive impairment. Of the 72 subjects with genetic data, 34 were APOE-4 carriers. MAIN OUTCOME MEASURES: The FDDNP-PET signal in brain regions of interest, including medial and lateral temporal, posterior cingulate, parietal, and frontal. RESULTS: For all regions studied, cognitive status was associated with increased FDDNP binding (P <.02 to .005). Older age was associated with increased lateral temporal FDDNP binding. Carriers of APOE-4 demonstrated higher frontal FDDNP binding than noncarriers. In the mild cognitive impairment group, age was associated with increased medial and lateral temporal FDDNP binding, and APOE-4 carriers had higher medial temporal binding than noncarriers. CONCLUSIONS: Impaired cognitive status, older age, and APOE-4 carrier status are associated with increased brain FDDNP-PET binding in persons without dementia, consistent with previous clinical and postmortem studies associating these risk factors with amyloid plaque and tau tangle accumulation. Stratifying subject groups according to APOE-4 carrier status, age, and cognitive status may therefore be an informative strategy in future clinical trials using FDDNP-PET.

Amyloid plaques and tau neurofibrillary tangles, the pathological hallmarks of Alzheimer's disease (AD), begin accumulating in the healthy human brain decades before clinical dementia symptoms can be detected. There is great interest in how this pathology spreads in the living brain and its association with cognitive deterioration. Using MRI-derived cortical surface models and four-dimensional animation techniques, we related cognitive ability to positron emission tomography (PET) signal from 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile ([(18)F]FDDNP), a molecular imaging probe for plaques and tangles. We examined this relationship at each cortical surface point in 23 older adults (10 cognitively intact, 6 with amnestic mild cognitive impairment, 7 with AD).[(18)F]FDDNP-PET signal was highly correlated with cognitive performance, even in cognitively intact subjects. Animations of [(18)F]FDDNP signal growth with decreased cognition across all subjects (http://www.loni.ucla.edu/ approximately thompson/FDDNP/video.html) mirrored the classic Braak and Braak trajectory in lateral temporal, parietal, and frontal cortices. Regions in which cognitive performance was significantly correlated with [(18)F]FDDNP signal include those that deteriorate earliest in AD, suggesting the potential utility of [(18)F]FDDNP for early diagnosis.

OBJECTIVE: The authors explored whether positron emission tomography (PET) with 2-(1-{6-[(2-[fluorine-18]fluoroethyl)(methyl) amino]-2-naphthyl} ethylidene)malononitrile (FDDNP), a molecule that binds to plaques and tangles in vitro, might identify homogeneous subgroups of persons in middle-aged and older persons with mild cognitive impairment (MCI) or normal cognition. PARTICIPANTS: Fifty-six subjects (MCI, N = 29; normal cognition, N = 27). MEASUREMENTS: FDDNP-PET scans were performed. Logan parametric images were produced using cerebellum as a reference region, and relative distribution volumes were obtained for regions of interest (ROIs) known to accumulate plaques and tangles in Alzheimer disease (AD). Cluster analysis was used to identify subgroups of subjects according to FDDNP signal distribution. Once the FDDNP clusters were identified, the authors then characterized the clusters also with respect to diagnosis and cognitive test performances and conducted analyses on cluster differences in these variables. RESULTS: The authors identified three FDDNP clusters: high signal in lateral temporal and posterior cingulate ROIs (high temporal-posterior cingulate HT/PC); low signal in all ROIs (low global [LG] cluster); high frontal and parietal signal with intermediate temporal and posterior cingulate signal (HF/PA). Most MCI subjects belonged to the HT/PC and HF/PA clusters, whereas most cognitively normal subjects were in the LG cluster. On cognitive tests, the HT/PC and the HF/PA clusters performed significantly worse than LG but did not significantly differ from each other. CONCLUSIONS: This approach may be useful in identifying potential high-risk imaging cluster patterns. Longitudinal follow-up would be performed to determine the association of these subgroups with diagnostic and functional outcome.

OBJECTIVES: Amyloid senile plaques and tau neurofibrillary tangles are neuropathologic hallmarks of Alzheimer disease, which may be associated with mild cognitive impairment (MCI) or mood and anxiety symptoms years before the dementia diagnosis. To address this issue, the authors obtained positron emission tomography (PET) scans after intravenous injections of 2-(1-{6-[(2-[fluorine-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile (FDDNP), a molecule that binds to amyloid plaques and neurofibrillary tangles, to determine whether symptoms of depression and anxiety in nondemented subjects were associated with increased FDDNP-PET binding values. METHODS: Forty-three middle-aged and elderly volunteers received clinical and FDDNP-PET assessments. Subjects were nondemented--23 of them were diagnosed with MCI and 20 were cognitively normal. Subjects with a diagnosis of major depression or an anxiety disorder were excluded. Correlations between standardized measures of depressive and anxiety symptoms and regional FDDNP binding values were calculated. RESULTS: The MCI and comparison subjects did not differ by the depression and anxiety scores. In the MCI group, depression scores correlated with lateral temporal and trait anxiety scores correlated with posterior cingulate FDDNP binding. In the comparison group, depression scores correlated with medial temporal, and trait anxiety scores correlated with medial temporal and frontal FDDNP binding. DISCUSSION: This is the first report to demonstrate a relationship between the severity of depression and anxiety symptoms and FDDNP binding values in nondemented middle age and older individuals. The results suggest a relationship between relatively mild mood symptoms and biomarkers of cerebral amyloid and tau deposition and vary according to degree of cognitive impairment. The presence of MCI may signify different pathophysiological mechanisms underlying mood and anxiety symptoms.

Objective: Because anti-inflammatory drugs may delay cognitive decline and influence brain metabolism in normal aging, the authors determined the effects of the cyclooxygenase-2 inhibitor, celecoxib, on cognitive performance and regional cerebral glucose metabolism in nondemented volunteers with mild age-related memory decline. Design: Randomized, double-blind, placebo-controlled, parallel group trial with 18-months of exposure to study medication. Setting: University research institute. Participants: Eighty-eight subjects, aged 40-81 years (mean: 58.7, SD: 8.9 years) with mild self-reported memory complaints but normal memory performance scores were recruited from community physician referrals, media coverage, and advertising. Forty subjects completed the study. Interventions: Daily celecoxib dose of 200 or 400 mg, or placebo. Main Outcome Measures: Standardized neuropsychological test battery and statistical parametric mapping (SPM) of FDG-PET scans performed during mental rest. Results: Measures of cognition showed significant between-group differences in executive functioning (F [1, 30]= 5.06, p = 0.03) and language/semantic memory (F [1, 31]= 6.19, p = 0.02), favoring the celecoxib group compared with the placebo group. Concomitantly, FDG-PET scans demonstrated bilateral metabolic increases in prefrontal cortex in the celecoxib group in the vicinity of Brodmann's areas 9 and 10, but not in the placebo group. SPM analyses of the PET data pooled by treatment arm corresponded to a 6% increase in activity over pretreatment levels (p <0.01, after adjustment for multiple comparisons). Conclusions: These results suggest that daily celecoxib use may improve cognitive performance and increase regional brain metabolism in people with age-associated memory decline.

This work focuses on the development of specific substrates for estrogen sulfotransferase (SULT1E1) to produce molecular imaging probes for this enzyme. SULT1E1 is a key enzyme in estrogen homeostasis, playing a central role in the prevention and development of human disease. In vitro sulfation assays showed alkyl and aryl substitutions to a fused heterocyclic system modeled after beta-naphthol (betaN), based on compounds that interact with the estrogen receptor, rendered several molecules with enhanced specificity for SULT1E1 over SULT1A1*1, SULT1A1*2, SULT1A3, and SULT2A1. Several 6-hydroxy-2-arylbenzothiazoles tested demonstrated excellent affinity-V(max)/K(m) ratios-and specificity for SULT1E1. K(m) values ranged from 0.12-2.36 muM. A strong correlation was observed between polarity of the 4'-sustituent on the 2-aryl moiety (Hammett sigma(p)) and the log(V(max)/K(m))(r = 0.964). Substrate sensitivity is influenced by the acidity of the 6-phenolic group demonstrated by correlating its (1)H NMR chemical shift (delta(OH)) with the log(V(max)/K(m))(r = 0.963). Acidity is mediated by the electron withdrawing capacity of the 4'-substituent outlined by the correlation of the C-2 (13)C NMR chemical shift (delta(C2)) with the log(V(max)/K(m))(r = 0.987). 2-[4-(Methylamino)phenyl]-6-hydroxybenzothiazole (2b) was radiolabeled with carbon-11 ((11)C-(2b)) and used in vivo for microPET scanning and tissue metabolite identification. High PET signal was paralleled with the presence of radiolabeled (11)C-(2b)-6-O-sulfate and the SULT1E1 protein detected by western blot. Because this and other members of this family presenting specificity for SULT1E1 can be labeled with carbon-11 or fluorine-18, in vivo assays of SULT1E1 functional activity are now feasible in humans.

Head movement during a PET scan (especially a dynamic scan) can affect both the qualitative and the quantitative aspects of an image, making it difficult to accurately interpret the results. The primary objective of this study was to develop a retrospective image-based movement correction (MC) method and evaluate its implementation on dynamic 2-(1-{6-[(2-(18)F-fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile ((18)F-FDDNP) PET images of cognitively intact controls and patients with Alzheimer's disease (AD). METHODS: Dynamic (18)F-FDDNP PET images, used for in vivo imaging of beta-amyloid plaques and neurofibrillary tangles, were obtained from 12 AD patients and 9 age-matched controls. For each study, a transmission scan was first acquired for attenuation correction. An accurate retrospective MC method that corrected for transmission-emission and emission-emission misalignments was applied to all studies. No restriction was assumed for zero movement between the transmission scan and the first emission scan. Logan analysis, with the cerebellum as the reference region, was used to estimate various regional distribution volume ratio (DVR) values in the brain before and after MC. Discriminant analysis was used to build a predictive model for group membership, using data with and without MC. RESULTS: MC improved the image quality and quantitative values in (18)F-FDDNP PET images. In this subject population, no significant difference in DVR value was observed in the medial temporal (MTL) region of controls and patients with AD before MC. However, after MC, significant differences in DVR values in the frontal, parietal, posterior cingulate, MTL, lateral temporal (LTL), and global regions were seen between the 2 groups (P < 0.05). In controls and patients with AD, the variability of regional DVR values (as measured by the coefficient of variation) decreased on average by more than 18% after MC. Mean DVR separation between controls and patients with AD was higher in frontal, MTL, LTL, and global regions after MC. Group classification by discriminant analysis based on (18)F-FDDNP DVR values was markedly improved after MC. CONCLUSION: The streamlined and easy-to-use MC method presented in this work significantly improves the image quality and the measured tracer kinetics of (18)F-FDDNP PET images. The proposed MC method has the potential to be applied to PET studies on patients having other disorders (e.g., Down syndrome and Parkinson's disease) and to brain PET scans with other molecular imaging probes.

Abstract In vivo amyloid PET imaging was carried out on six symptomatic and asymptomatic carriers of PRNP mutations associated with the Gerstmann-Sträussler-Scheinker (GSS) disease, a rare familial neurodegenerative brain disorder demonstrating prion amyloid neuropathology, using 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile ([F-18]FDDNP). 2-Deoxy-2-[F-18]fluoro-d-glucose PET ([F-18]FDG) and magnetic resonance imaging (MRI) scans were also performed in each subject. Increased [F-18]FDDNP binding was detectable in cerebellum, neocortex and subcortical areas of all symptomatic gene carriers in close association with the experienced clinical symptoms. Parallel glucose metabolism ([F-18]FDG) reduction was observed in neocortex, basal ganglia and/or thalamus, which supports the close relationship between [F-18]FDDNP binding and neuronal dysfunction. Two asymptomatic gene carriers displayed no cortical [F-18]FDDNP binding, yet progressive [F-18]FDDNP retention in caudate nucleus and thalamus was seen at 1- and 2-year follow-up in the older asymptomatic subject. In vitro FDDNP labeling experiments on brain tissue specimens from deceased GSS subjects not participating in the in vivo studies indicated that in vivo accumulation of [F-18]FDDNP in subcortical structures, neocortices and cerebellum closely related to the distribution of prion protein pathology. These results demonstrate the feasibility of detecting prion protein accumulation in living patients with [F-18]FDDNP PET, and suggest an opportunity for its application to follow disease progression and monitor therapeutic interventions.

Beta amyloid plaques, neurofibriilary tangles, and impaired glucose metabolism are among the most prevalent pathological characteristics of Alzheimer's disease (AD). However, separate visualization of these three AD-related pathologies in living humans has not been conducted. Here, we show that positron emission tomography (PET) imaging using the three radiotracers (11)C-Pittsburgh compound B (PIB), 2-(1-{6-[(2-(18)F-fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene) malononitrile (FDDNP), and 2-[18F]fluoro-2-deoxy-D-glucose (FDG), in the same subjects, with and without AD, can provide valuable information on the pathological patterns of the distribution of tracers for amyloid plaque, neurofibriilary tangle, and glucose hypometabolism in AD. Voxel-based analysis of PIB-PET in patients with AD compared with normal control subjects showed that patients with AD have highly significant PIB retention in brain regions known to have high amyloid plaque deposition (e.g., frontal, parietal, temporal, and posterior cingulate/precuneus cortices). In contrast, voxel-based analysis of FDDNP-PET showed significantly high FDDNP binding in some brain regions known to have high tangle accumulation in patients with AD compared with age-matched normal subjects (e.g., entorhinal cortex, inferior temporal gyrus, and secondary visual cortex). In addition, because FDDNP binds both plaques and tangles but PIB binds plaques specifically, we examined subtracted PET data (FDDNP minus PIB) acquired from the same patients with AD using an SPM analysis. We found that the hippocampal formation was the most significant brain region in the voxel mapping of FDDNP minus PIB in the same patients with AD. Voxel-based analysis of FDG-PET in the same subjects revealed that brain regions with glucose hypometabolism in patients with AD overlap with regions of high PIB binding. In conclusion, PET imaging using these three radiotracers in the same subjects may contribute toward developing and testing disease-modifying drugs targeting amyloid pathology, tau pathology, and/or energy metabolism.

In 2006, TAR DNA-binding protein 43 (TDP-43), a highly conserved nuclear protein, was identified as the major disease protein in amyotrophic lateral sclerosis (ALS) and in the most common variant of frontotemporal lobar degeneration (FTLD), FTLD-U, which is characterized by cytoplasmic inclusions that stain positive for ubiquitin but negative for tau and alpha-synuclein. Since then, rapid advances have been made in our understanding of the physiological function of TDP-43 and the role of this protein in neurodegeneration. These advances link ALS and FTLD-U (now designated FTLD-TDP) to a shared mechanism of disease. In this Review, we summarize the current evidence regarding the normal function of TDP-43 and the TDP-43 pathology observed in FTLD-TDP, ALS, and other neurodegenerative diseases wherein TDP-43 pathology co-occurs with other disease-specific lesions (for example, with amyloid plaques and neurofibrillary tangles in Alzheimer disease). Moreover, we discuss the accumulating data that support our view that FTLD-TDP and ALS represent two ends of a spectrum of primary TDP-43 proteinopathies. Finally, we comment on the importance of recent advances in TDP-43-related research to neurological practice, including the new opportunities to develop better diagnostics and disease-modifying therapies for ALS, FTLD-TDP, and related disorders exhibiting TDP-43 pathology.

Intense multidisciplinary research has provided detailed knowledge of the molecular pathogenesis of Alzheimer disease (AD). This knowledge has been translated into new therapeutic strategies with putative disease-modifying effects. Several of the most promising approaches, such as amyloid-beta immunotherapy and secretase inhibition, are now being tested in clinical trials. Disease-modifying treatments might be at their most effective when initiated very early in the course of AD, before amyloid plaques and neurodegeneration become too widespread. Thus, biomarkers are needed that can detect AD in the predementia phase or, ideally, in presymptomatic individuals. In this Review, we present the rationales behind and the diagnostic performances of the core cerebrospinal fluid (CSF) biomarkers for AD, namely total tau, phosphorylated tau and the 42 amino acid form of amyloid-beta. These biomarkers reflect AD pathology, and are candidate markers for predicting future cognitive decline in healthy individuals and the progression to dementia in patients who are cognitively impaired. We also discuss emerging plasma and CSF biomarkers, and explore new proteomics-based strategies for identifying additional CSF markers. Furthermore, we outline the roles of CSF biomarkers in drug discovery and clinical trials, and provide perspectives on AD biomarker discovery and the validation of such markers for use in the clinic.

In Alzheimer disease (AD), which is the most common cause of dementia, the underlying disease pathology most probably precedes the onset of cognitive symptoms by many years. Thus, efforts are underway to find early diagnostic markers as well as disease-modifying treatments for this disorder. PET enables various brain systems to be monitored in living individuals. In patients with AD, PET can be used to investigate changes in cerebral glucose metabolism, various neurotransmitter systems, neuroinflammation, and the protein aggregates that are characteristic of the disease, notably the amyloid deposits. These investigations are helping to further our understanding of the complex pathophysiological mechanisms that underlie AD, as well as aiding the early and differential diagnosis of the disease in the clinic. In the future, PET studies will also be useful for identifying new therapeutic targets and monitoring treatment outcomes. Amyloid imaging could be useful as early diagnostic marker of AD and for selecting patients for anti-amyloid-beta therapy, while cerebral glucose metabolism could be a suitable PET marker for monitoring disease progression. For the near future, multitracer PET studies are unlikely to be used routinely in the clinic for AD, being both burdensome and expensive; however, such studies are very informative in a research context.

Structural imaging based on magnetic resonance is an integral part of the clinical assessment of patients with suspected Alzheimer dementia. Prospective data on the natural history of change in structural markers from preclinical to overt stages of Alzheimer disease are radically changing how the disease is conceptualized, and will influence its future diagnosis and treatment. Atrophy of medial temporal structures is now considered to be a valid diagnostic marker at the mild cognitive impairment stage. Structural imaging is also included in diagnostic criteria for the most prevalent non-Alzheimer dementias, reflecting its value in differential diagnosis. In addition, rates of whole-brain and hippocampal atrophy are sensitive markers of neurodegeneration, and are increasingly used as outcome measures in trials of potentially disease-modifying therapies. Large multicenter studies are currently investigating the value of other imaging and nonimaging markers as adjuncts to clinical assessment in diagnosis and monitoring of progression. The utility of structural imaging and other markers will be increased by standardization of acquisition and analysis methods, and by development of robust algorithms for automated assessment.

We report on the current state of in vivo amyloid imaging. Although this technique is less than a decade old, a wealth of information is emerging as the initial clinical studies are being reported. Imaging of patients with Alzheimer's disease has allowed quantitative exploration of the natural history of amyloid deposition and its relationship to neurodegeneration. Amyloid imaging also shows significant promise in the differential diagnosis of mild cognitive impairment or atypical dementias. However, amyloid detection may be of greatest utility in healthy elderly persons; consistent with prior autopsy studies, a significant proportion of asymptomatic individuals display increased levels of amyloid by in vivo imaging. Understanding the relationship between this pathology and future cognitive status has significant implications for the application of disease-modifying medications in the "preclinical" phase of disease. Given the considerable clinical experience compared with other tracers, this review focuses on the literature involving Pittsburgh compound B positron emission tomography.

The introduction of biological markers in the clinical management of Alzheimer's disease (AD) will not only improve diagnosis relating to early detection of neuropathology with underlying molecular mechanisms, but also provides tools for the assessment of objective treatment benefits. In this review, we identify a number of in vivo neurochemistry and neuroimaging techniques, which can reliably assess aspects of physiology, pathology, chemistry, and neuroanatomy of AD, and hold promise as meaningful biomarkers in the early diagnostic process, as well as for the tracking of disease-modifying pharmacological effects. These neurobiological measures appear to relate closely to pathophysiological, neuropathological, and clinical data, such as hyperphosphorylation of tau, abeta metabolism, lipid peroxidation, pattern and rate of atrophy, loss of neuronal integrity, and functional and cognitive decline, as well as risk of future decline. As a perspective, the important role of biomarkers in the development of innovative drug treatments for AD and the related regulatory process is discussed.

At the Sixth Annual Mild Cognitive Impairment Symposium in Miami Beach, Florida, a multidisciplinary group of experts from the Alzheimer's disease (AD) community met to discuss the current status of AD intervention trials and future plans for designing trials of prodromal AD and/or mild cognitive impairment. There is no agreement regarding a single pathogenic mechanism to be targeted, although a consensus seems to be emerging that effective treatment will require attacking multiple targets. These targets include beta amyloid (Ass) aggregates (including different isoforms and different aggregation species), neurofibrillary tangles composed of hyperphosphorylated tau, neuronal and synaptic loss, and mechanisms that contribute to Ass deposition-induced inflammation and immune dysregulation. Vascular disease, which is very common in the elderly, also appears to be a contributor to AD pathogenesis and might be modifiable through pharmacologic and lifestyle interventions to reduce the impact of conditions such as hypertension and metabolic syndrome. Potential disease-modifying approaches that were discussed, including pharmacologic agents that target Abeta, immunotherapy to eliminate plaques in the brain, passive immunotherapy, and secretase inhibitors. Nonpharmacologic approaches included stimulation of endogenous bone marrow cells, which can enter the brain and remove amyloid deposits, and cognitive and exercise training. Innovative trial designs are required that will allow a drug's effectiveness to be determined efficiently in the transition from normal to mild cognitive impairment to probable AD. This might be achieved through the use of various forms of imaging and measurement of biochemical markers in the blood or cerebrospinal fluid, as well as measures that assess very early cognitive and behavioral changes. In the absence of effective treatments for AD, clinicians are faced with a dilemma about why, when, and how to disclose the diagnosis to patients and their family members and/or caregivers. The issues were discussed from multiple perspectives by a panel that included a lay representative, neurologist, psychiatrist, primary care physician, and a psychosocial researcher.

Alzheimer's disease (AD) is an incurable neurodegenerative disorder that produces cognitive impairments that increase in severity as the disease progresses. The clinical symptoms are related to the presence of neuritic plaques and neurofibrillary tangles in the cerebral cortex which represent the pathophysiological hallmarks of AD. The debilitating nature of the disease can result in clinical burden for the patient, emotional strain for those that care for patients with Alzheimer's, and significant financial burden to society. The goals of current treatments, such as cholinesterase inhibitors and N-methyl-D-aspartate receptor antagonist, are to reduce the severity or slow the progression of cognitive symptoms. Although these treatments have demonstrated modest clinical benefit, they are unable to prevent, prohibit, or reverse the underlying pathophysiology of AD. Considerable progress has been made toward the development of disease-modifying treatments. Treatments currently under development mainly target the production, aggregation, and removal of existing amyloid beta-peptide aggregates which are believed to instigate the overall development of the neuropathology. Additional strategies that target tau pathology are being studied to promote neural protection against AD pathology. The current research has continued to expand our knowledge toward the development of disease modifying Alzheimer's therapies; however, no specific treatment strategy capable of demonstrating empirical efficacy and safety has yet to emerge.

Amyloid plaques and tau neurofibrillary tangles, the pathological hallmarks of Alzheimer's disease (AD), begin accumulating in the healthy human brain decades before clinical dementia symptoms can be detected. There is great interest in how this pathology spreads in the living brain and its association with cognitive deterioration. Using MRI-derived cortical surface models and four-dimensional animation techniques, we related cognitive ability to positron emission tomography (PET) signal from 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile ([(18)F]FDDNP), a molecular imaging probe for plaques and tangles. We examined this relationship at each cortical surface point in 23 older adults (10 cognitively intact, 6 with amnestic mild cognitive impairment, 7 with AD).[(18)F]FDDNP-PET signal was highly correlated with cognitive performance, even in cognitively intact subjects. Animations of [(18)F]FDDNP signal growth with decreased cognition across all subjects (http://www.loni.ucla.edu/ approximately thompson/FDDNP/video.html) mirrored the classic Braak and Braak trajectory in lateral temporal, parietal, and frontal cortices. Regions in which cognitive performance was significantly correlated with [(18)F]FDDNP signal include those that deteriorate earliest in AD, suggesting the potential utility of [(18)F]FDDNP for early diagnosis.