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1.  C9orf72 immunohistochemistry in Alzheimer's disease 
Mutation in chromosome 9 open reading frame 72 (C9orf72) is a major genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), referred to as C9FTD/ALS. The function of the protein is currently unknown, and the pathomechanism of C9FTD/ALS remains to be elucidated. The study by Satoh and colleagues in the previous issue of Alzheimer's Research & Therapy presents important new findings on C9orf72 protein expression in neurodegenerative disorders along with characterization of C9orf72 antibodies.
PMCID: PMC3580394  PMID: 23014271
2.  Assessment of psychiatric changes in C9ORF72 frontotemporal dementia 
Recent neuroimaging evidence highlights cerebellar atrophy as one feature of frontotemporal dementia (FTD) with C9ORF72 mutation. Interestingly, C9ORF72 patients do not present with classic cerebellar symptoms, such as ataxia, but have instead a higher incidence of psychiatric changes compared to sporadic FTD. To date there exists no objective tool to assess such psychiatric changes due to cerebellar dysfunction. In the previous edition of Alzheimer's Research & Therapy, Downey and colleagues present a novel task, including a new apparatus, that targets such psychiatric disturbances. In the task participants are required to make self-other attributions, which have been shown to be dependent on the cerebellum in functional neuroimaging in healthy subjects. The data Downey and colleagues present on a case of C9ORF72 compared to four age-matched controls reveal that the patient shows impaired judgement only for other induced actions. These findings highlight the sensitivity of such a simple task to tap into potential cerebellar dysfunction in C9ORF72. Future studies are needed to now to determine whether this task is mediated solely via the cerebellum and is disease specific to C9ORF72. Nevertheless, this study is an important first step in the development of cerebellar-specific tasks tapping into psychiatric dysfunction, which will inform future diagnosis and disease management of patients with cerebellar dysfunction, and in particular C9ORF72.
PMCID: PMC3580458  PMID: 23269019
3.  Resistant to amyloid-β or just waiting for disease to happen? 
The post-mortem finding of abundant intracerebral accumulation of amyloid-β (Aβ) in the cerebral cortex of some people who develop minimal neurofibrillary pathology and remain cognitively intact until death (so-called pathological aging, or PA) challenges the orthodox view of the pathogenesis of Alzheimer's disease (AD). This issue of Alzheimer's Research & Therapy reports a study by Moore and colleagues, of the McKnight Brain Institute (Gainesville, FL, USA) and the Mayo Clinic College of Medicine (Jacksonville, FL, USA), who have performed the most detailed analysis to date of the levels and types of Aβ that accumulate in such cases. Although the levels of the different forms of Aβ in prefrontal cortex from patients with AD tended to be higher than those from patients with PA, the authors found extensive overlap between the two groups and suggest that PA is likely to represent a prodromal stage of AD. It is also possible that the quantity of Aβ is less important than the extent to which it accumulates intraneuronally or that some people are resistant to its effects - perhaps because of genetically determined differences in the inflammatory and astrocytic reactions to Aβ. The study emphasizes the continuing importance of careful human clinical and post-mortem studies in elucidating the pathogenesis of this disease.
PMCID: PMC3506933  PMID: 22643124
4.  Does a prion-like mechanism play a major role in the apparent spread of α-synuclein pathology? 
Parkinson's disease, the most common movement disorder, results in an insidious reduction for patients in quality of life and ability to function. A hallmark of Parkinson's disease is the brain accumulation of neuronal cytoplasmic inclusions comprised of the protein α-synuclein. The presence of α-synuclein brain aggregates is observed in several neurodegenerative diseases, including dementia with Lewy bodies and Lewy body variant of Alzheimer's disease. These disorders, as a group, are termed synucleinopathies. Mounting evidence indicates that α-synuclein amyloid pathology may spread during disease progression by a prion-like (self-templating alteration in protein conformation) mechanism. Clear in vitro and cell culture data demonstrate that amyloidogenic α-synuclein can readily induce the conversion of other α-synuclein molecules into this conformation. Some data from experimental mouse studies and autopsied brain analyses also are consistent with the notion that a self-promoting process of α-synuclein amyloid inclusion formation may lead to a progressive spread of disease in vivo. However, as pointed out in this review, there are alternative explanations and interpretations for these findings. Therefore, from a therapeutic perspective, it is critical to determine the relative importance and contribution of α-synuclein prionlike spread in disease before embarking on elaborate efforts to target this putative pathogenic mechanism.
PMCID: PMC3580457  PMID: 23245350
5.  NF-κB-regulated, proinflammatory miRNAs in Alzheimer's disease 
Abundant neurochemical, neuropathological, and genetic evidence suggests that a critical number of proinflammatory and innate immune system-associated factors are involved in the underlying pathological pathways that drive the sporadic Alzheimer's disease (AD) process. Most recently, a series of epigenetic factors - including a select family of inducible, proinflammatory, NF-κB-regulated small noncoding RNAs called miRNAs - have been shown to be significantly elevated in abundance in AD brain. These upregulated miRNAs appear to be instrumental in reshaping the human brain transcriptome. This reorganization of mRNA speciation and complexity in turn drives proinflammatory and pathogenic gene expression programs. The ensuing, progressively altered immune and inflammatory signaling patterns in AD brain support immunopathogenetic events and proinflammatory features of the AD phenotype. This report will briefly review what is known concerning NF-κB-inducible miRNAs that are significantly upregulated in AD-targeted anatomical regions of degenerating human brain cells and tissues. Quenching of NF-κB-sensitive inflammatory miRNA signaling using NF-κB-inhibitors such as the polyphenolic resveratrol analog trans-3,5,4'-trihydroxystilbene (CAY10512) may have some therapeutic value in reducing inflammatory neurodegeneration. Antagonism of NF-κB-inducing, and hence proinflammatory, epigenetic and environmental factors, such as the neurotrophic herpes simplex virus-1 and exposure to the potent neurotoxin aluminum, are briefly discussed. Early reports further indicate that miRNA neutralization employing anti-miRNA (antagomir) strategies may hold future promise in the clinical management of this insidious neurological disorder and expanding healthcare concern.
PMCID: PMC3580456  PMID: 23217212
6.  Treatment implications of C9ORF72 
Frontotemporal dementia (FTD) is a common dementia syndrome in patients under the age of 65 years with many features overlapping with amyotrophic lateral sclerosis (ALS). The link between FTD and ALS has been strengthened by the discovery that a hexanucleotide repeat expansion in a non-coding region of the C9ORF72 gene causes both familial and sporadic types of these two diseases. As we begin to understand the pathophysiological mechanisms by which this mutation leads to FTD and ALS (c9FTD/ALS), new targets for disease-modifying therapies will likely be unveiled. Putative C9ORF72 expansion pathogenic mechanisms include loss of C9ORF72 protein function, sequestration of nucleic acid binding proteins due to expanded hexanucleotide repeats, or a combination of the two. New animal models and other research tools informed by work in other repeat expansion neurodegenerative diseases such as the spinocerebellar ataxias will help to elucidate the mechanisms of C9ORF72-mediated disease. Similarly, re-examining previous studies of drugs developed to treat ALS in light of this new mutation may identify novel FTD treatments. Ultimately, research consortiums incorporating animal models and well-characterized clinical populations will be necessary to fully understand the natural history of the c9FTD/ALS clinical phenotypes and identify biomarkers and therapeutic agents that can cure the most common form of genetically determined FTD and ALS.
PMCID: PMC3580455  PMID: 23186535
7.  Neuroimaging features of C9ORF72 expansion 
Hexanucleotide expansion intronic to chromosome 9 open reading frame 72 (C9ORF72) has recently been identified as the most common genetic cause of both familial and sporadic amyotrophic lateral sclerosis and of frontotemporal dementia with or without concomitant motor neuron disease. Given the common frequency of this genetic aberration, clinicians seek to identify neuroimaging hallmarks characteristic of C9ORF72-associated disease, both to provide a better understanding of the underlying degenerative patterns associated with this mutation and to enable better identification of patients for genetic screening and diagnosis. A survey of the literature describing C9ORF72 neuroimaging thus far suggests that patients with this mutation may demonstrate symmetric frontal and temporal lobe, insular, and posterior cortical atrophy, although temporal involvement may be less than that seen in other mutations. Some studies have also suggested cerebellar and thalamic involvement in C9ORF72-associated disease. Diffuse cortical atrophy that includes anterior as well as posterior structures and subcortical involvement thus may represent unique features of C9ORF72.
PMCID: PMC3580454  PMID: 23153366
8.  Potential sources of interference on Abeta immunoassays in biological samples 
Therapeutic products that depend on the use of an in vitro diagnostic biomarker test to confirm their effectiveness are increasingly being developed. Use of biomarkers is particularly meaningful in the context of selecting the patient population where the therapeutic treatment is believed to be efficacious (patient enrichment). Currently available 'research-use-only' assays for Alzheimer's disease diagnosis all suffer from non-analyte and analyte-specific interferences. The impact of these interferences on the outcome of the assays is not well understood. The confounding factors are hampering correct value determination in biological samples and are intrinsic to the assay concept, the assay design, the presence in the sample of heterophilic antibodies and auto-antibodies, or might be the result of the therapeutic approach. This review focuses on the importance of assay interferences and considers how these might be minimized with the final aim of making the assays more acceptable as in vitro diagnostic biomarker tests for theranostic use.
PMCID: PMC3580396  PMID: 23082750
9.  Dementia: a global health priority - highlights from an ADI and World Health Organization report 
Alzheimer's Disease International is the worldwide federation of Alzheimer associations that represent people with dementia and their families. Alzheimer's Disease International has commissioned a number of World Alzheimer Reports since 2009 and was involved in the recently launched report Dementia: A Public Health Priority by the World Health Organization. From these reports, we can learn about the growing impact of Alzheimer's disease and other dementias on our societies and the need to take action. Developing national Alzheimer plans is a key tool for this action.
PMCID: PMC3580397  PMID: 22995353
10.  Championing of dementia in England 
Dementia is starting to attract attention following decades of comparative neglect relative to other disease areas. England has been at the forefront of this sea change as one of the first countries in the world to develop a National Dementia Strategy (in 2009). Events leading up to the publication of this strategy and since will be examined here together with a glimpse at the international landscape.
PMCID: PMC3580393  PMID: 22967371
11.  Alzheimer's disease diagnostic criteria: practical applications 
Alzheimer's disease (AD) can be identified prior to the occurrence of dementia by using biomarkers. Three phases of AD are recognized: an asymptomatic biomarker-positive phase, a phase with positive biomarkers and mild cognitive deficits, and a dementia phase. Codification of these phases was first accomplished in 2007 by an International Work Group (IWG) led by Bruno Dubois. The definitions relevant to the approach were further clarified in 2010. In 2011, the National Institute on Aging/Alzheimer's Association (NIA/AA) established three work groups to develop definitions and criteria for these three phases of AD. The criteria of the IWG and those of the NIA/AA have many similarities and important differences. The two sets of criteria concur in recognizing the onset of AD prior to dementia. The three phases of AD described in both sets of criteria embrace the same clinical entities but with different terminologies and emphases. IWG criteria emphasize a single clinico-biological approach that includes all symptomatic phases of AD and uses the same diagnostic framework across the spectrum of symptomatic disease; the NIA/AA criteria apply different diagnostic approaches to the three phases. Biomarkers are an integrated and required part of the IWG criteria and are optional in the NIA/AA approach. Both sets of criteria have substantial strengths, but new information demonstrates shortcomings that can be addressed in future revisions of the criteria. These new criteria have profound implications, including greatly increasing the number of people identified as suffering from AD and increasing the time that patients will spend with knowledge of the presence of the disease.
PMCID: PMC3580392  PMID: 22947665
12.  Apolipoprotein E, amyloid-ß clearance and therapeutic opportunities in Alzheimer's disease 
Alzheimer's disease (AD) is a progressive neurodegenerative disease characterised by extracellular amyloid-ß (Aß) and intraneuronal tau protein brain pathologies. The most significant risk factor for non-familial AD is the presence of the E4 isoform of the cholesterol transporter apolipoprotein E (apoE). Despite extensive basic research, the exact role of apoE in disease aetiology remains unclear. Correspondingly, therapeutic targeting of apoE in AD is at an early preclinical stage. In this review, I discuss the key interactions of apoE and Aß pathology, the current progress of preclinical animal models and the caveats of existing therapeutic approaches targeting apoE. Finally, novel Alzheimer's genetics and Aß-independent disease mechanisms are highlighted.
PMCID: PMC3506946  PMID: 22929359
13.  Expanding the genetics of amyotrophic lateral sclerosis and frontotemporal dementia 
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized clinically by rapidly progressive paralysis leading ultimately to death from respiratory failure. It is now recognized that ALS and frontotemporal lobar degeneration (FTLD) form a clinical spectrum of disease with overlapping clinical, pathological and genetic features. This past year, the genetic causes of ALS have expanded to include mutations in the genes OPTN, VCP, and UBQLN2, and the hexanucleotide repeat expansion in C9ORF72. The C9ORF72 repeat expansion solidifies the notion that ALS and FTLD are phenotypic variations of a disease spectrum with a common molecular etiology. Furthermore, the C9ORF72 expansion is the genetic cause of a substantial portion of apparently sporadic ALS and FTLD cases, showing that genetics plays a clear role in sporadic disease. Here we describe the progress made in the genetics of ALS and FTLD, including a detailed look at how new insights brought about by C9ORF72 have both broadened and unified current concepts in neurodegeneration.
PMCID: PMC3506944  PMID: 22835154
14.  Cognitive and behavioral features of c9FTD/ALS 
Numerous kindreds with familial frontotemporal dementia or amyotrophic lateral sclerosis or both have been linked to chromosome 9 (c9FTD/ALS), and an expansion of the GGGGCC hexanucleotide repeat in the non-coding region of chromosome 9 open reading frame 72 (C9ORF72) was identified in the summer of 2011 as the pathogenic mechanism. An avalanche of papers on this disorder is in progress, and a relatively distinctive phenotype is taking form. In this review, we present an illustrative case and summarize the demographic, inheritance, clinical, and behavioral aspects and presumed pathologic underpinnings of c9FTD/ALS on the basis of the available data on more than 250 patients with frontotemporal lobar degeneration syndromes, parkinsonism, or ALS or a combination of these disorders.
PMCID: PMC3506943  PMID: 22817642
15.  Genetic counseling for FTD/ALS caused by the C9ORF72 hexanucleotide expansion 
Frontotemporal degeneration (FTD) and amyotrophic lateral sclerosis (ALS) are related but distinct neurodegenerative diseases. The identification of a hexanucleotide repeat expansion in a noncoding region of the chromosome 9 open reading frame 72 (C9ORF72) gene as a common cause of FTD/ALS, familial FTD, and familial ALS marks the culmination of many years of investigation. This confirms the linkage of disease to chromosome 9 in large, multigenerational families with FTD and ALS, and it promotes deeper understanding of the diseases' shared molecular FTLD-TDP pathology. The discovery of the C9ORF72 repeat expansion has significant implications not only for familial FTD and ALS, but also for sporadic disease. Clinical and pathological correlates of the repeat expansion are being reported but remain to be refined, and a genetic test to detect the expansion has only recently become clinically available. Consequently, individuals and their families who are considering genetic testing for the C9ORF72 expansion should receive genetic counseling to discuss the risks, benefits, and limitations of testing. The following review aims to describe genetic counseling considerations for individuals at risk for a C9ORF72 repeat expansion.
PMCID: PMC3506941  PMID: 22808918
16.  Supporting clinical research in the NHS in England: the National Institute for Health Research Dementias and Neurodegenerative Diseases Research Network 
Clinical research is best done when aligned with clinical care - that is, when the patient can be identified, recruited and, in many instances, researched in parallel with the delivery of clinical service. However, to achieve this effectively requires identification of the additional cost to the National Health Service clinical support services and the development of an appropriately skilled workforce. The National Institute for Health Research (NIHR) Cancer Research Network demonstrated the value of dedicated research support in terms of the number of patients recruited into clinical trials. Building on this model, the NIHR in England funded the Dementias and Neurodegenerative Diseases Research Network (DeNDRoN). DeNDRoN is now in its sixth year and has established a geographically widespread network of research support staff and research leadership managed by a central coordinating centre. Success can already be measured by a significant increase in the number of patients entering studies and the speed with which both commercial and noncommercial studies are completed. There are also early indications that the network will result in improved patient outcomes.
PMCID: PMC3506937  PMID: 22769969
17.  Ayurvedic medicinal plants for Alzheimer's disease: a review 
Alzheimer's disease is an age-associated, irreversible, progressive neurodegenerative disease that is characterized by severe memory loss, unusual behavior, personality changes, and a decline in cognitive function. No cure for Alzheimer's exists, and the drugs currently available to treat the disease have limited effectiveness. It is believed that therapeutic intervention that could postpone the onset or progression of Alzheimer's disease would dramatically reduce the number of cases in the next 50 years. Ayurvedic medicinal plants have been the single most productive source of leads for the development of drugs, and over a hundred new products are already in clinical development. Indeed, several scientific studies have described the use of various Ayurvedic medicinal plants and their constituents for treatment of Alzheimer's disease. Although the exact mechanism of their action is still not clear, phytochemical studies of the different parts of the plants have shown the presence of many valuable compounds, such as lignans, flavonoids, tannins, polyphenols, triterpenes, sterols, and alkaloids, that show a wide spectrum of pharmacological activities, including anti-inflammatory, anti-amyloidogenic, anti-cholinesterase, hypolipidemic, and antioxidant effects. This review gathers research on various medicinal plants that have shown promise in reversing the Alzheimer's disease pathology. The report summarizes information concerning the phytochemistry, biological, and cellular activities and clinical applications of these various plants in order to provide sufficient baseline information that could be used in drug discovery campaigns and development process, thereby providing new functional leads for Alzheimer's disease.
PMCID: PMC3506936  PMID: 22747839
18.  Phenotypic differences between apolipoprotein E genetic subgroups: research and clinical implications 
With the recent interest in Alzheimer's disease course modification and earlier, even preclinical, intervention, questions have arisen regarding the potentially confounding impact of apolipoprotein E (APOE) genotype on study design, therapeutic outcomes, and even clinical practice. APOE e4 carriers have a faster rate of cognitive decline both preclinically and during the mild cognitive impairment (MCI) stage, and a higher burden of cerebrovascular amyloid that may be the basis for the observed gene-dose-related increased frequency of immunomodulatory therapy-induced meningoencephalitis and cerebral microhemorrhages. To date, this has impacted study design in some research trials but not clinical practice.
PMCID: PMC3506934  PMID: 22694803
19.  Plasma lipoprotein-associated phospholipase A2 activity in Alzheimer's disease, amnestic mild cognitive impairment, and cognitively healthy elderly subjects: a cross-sectional study 
Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a circulating enzyme with pro-inflammatory and oxidative activities associated with cardiovascular disease and ischemic stroke. While high plasma Lp-PLA2 activity was reported as a risk factor for dementia in the Rotterdam study, no association between Lp-PLA2 mass and dementia or Alzheimer's disease (AD) was detected in the Framingham study. The objectives of the current study were to explore the relationship of plasma Lp-PLA2 activity with cognitive diagnoses (AD, amnestic mild cognitive impairment (aMCI), and cognitively healthy subjects), cardiovascular markers, cerebrospinal fluid (CSF) markers of AD, and apolipoprotein E (APOE) genotype.
Subjects with mild AD (n = 78) and aMCI (n = 59) were recruited from the Memory Clinic, University Hospital, Basel, Switzerland; cognitively healthy subjects (n = 66) were recruited from the community. Subjects underwent standardised medical, neurological, neuropsychological, imaging, genetic, blood and CSF evaluation. Differences in Lp-PLA2 activity between the cognitive diagnosis groups were tested with ANOVA and in multiple linear regression models with adjustment for covariates. Associations between Lp-PLA2 and markers of cardiovascular disease and AD were explored with Spearman's correlation coefficients.
There was no significant difference in plasma Lp-PLA2 activity between AD (197.1 (standard deviation, SD 38.4) nmol/min/ml) and controls (195.4 (SD 41.9)). Gender, statin use and low-density lipoprotein cholesterol (LDL) were independently associated with Lp-PLA2 activity in multiple regression models. Lp-PLA2 activity was correlated with LDL and inversely correlated with high-density lipoprotein (HDL). AD subjects with APOE-ε4 had higher Lp-PLA2 activity (207.9 (SD 41.2)) than AD subjects lacking APOE-ε4 (181.6 (SD 26.0), P = 0.003) although this was attenuated by adjustment for LDL (P = 0.09). No strong correlations were detected for Lp-PLA2 activity and CSF markers of AD.
Plasma Lp-PLA2 was not associated with a diagnosis of AD or aMCI in this cross-sectional study. The main clinical correlates of Lp-PLA2 activity in AD, aMCI and cognitively healthy subjects were variables associated with lipid metabolism.
PMCID: PMC3580460  PMID: 23217243
20.  Whether, when and how chronic inflammation increases the risk of developing late-onset Alzheimer's disease 
Neuropathological studies have revealed the presence of a broad variety of inflammation-related proteins (complement factors, acute-phase proteins, pro-inflammatory cytokines) in Alzheimer's disease (AD) brains. These constituents of innate immunity are involved in several crucial pathogenic events of the underlying pathological cascade in AD, and recent studies have shown that innate immunity is involved in the etiology of late-onset AD. Genome-wide association studies have demonstrated gene loci that are linked to the complement system. Neuropathological and experimental studies indicate that fibrillar amyloid-β (Aβ) can activate the innate immunity-related CD14 and Toll-like receptor signaling pathways of glial cells for pro-inflammatory cytokine production. The production capacity of this pathway is under genetic control and offspring with a parental history of late-onset AD have a higher production capacity for pro-inflammatory cytokines. The activation of microglia by fibrillar Aβ deposits in the early preclinical stages of AD can make the brain susceptible later on for a second immune challenge leading to enhanced production of pro-inflammatory cytokines. An example of a second immune challenge could be systemic inflammation in patients with preclinical AD. Prospective epidemiological studies show that elevated serum levels of acute phase reactants can be considered as a risk factor for AD. Clinical studies suggest that peripheral inflammation increases the risk of dementia, especially in patients with preexistent cognitive impairment, and accelerates further deterioration in demented patients. The view that peripheral inflammation can increase the risk of dementia in older people provides scope for prevention.
PMCID: PMC3506930  PMID: 22647384
21.  Simulations of symptomatic treatments for Alzheimer's disease: computational analysis of pathology and mechanisms of drug action 
A substantial number of therapeutic drugs for Alzheimer's disease (AD) have failed in late-stage trials, highlighting the translational disconnect with pathology-based animal models.
To bridge the gap between preclinical animal models and clinical outcomes, we implemented a conductance-based computational model of cortical circuitry to simulate working memory as a measure for cognitive function. The model was initially calibrated using preclinical data on receptor pharmacology of catecholamine and cholinergic neurotransmitters. The pathology of AD was subsequently implemented as synaptic and neuronal loss and a decrease in cholinergic tone. The model was further calibrated with clinical Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog) results on acetylcholinesterase inhibitors and 5-HT6 antagonists to improve the model's prediction of clinical outcomes.
As an independent validation, we reproduced clinical data for apolipoprotein E (APOE) genotypes showing that the ApoE4 genotype reduces the network performance much more in mild cognitive impairment conditions than at later stages of AD pathology. We then demonstrated the differential effect of memantine, an N-Methyl-D-aspartic acid (NMDA) subunit selective weak inhibitor, in early and late AD pathology, and show that inhibition of the NMDA receptor NR2C/NR2D subunits located on inhibitory interneurons compensates for the greater excitatory decline observed with pathology.
This quantitative systems pharmacology approach is shown to be complementary to traditional animal models, with the potential to assess potential off-target effects, the consequences of pharmacologically active human metabolites, the effect of comedications, and the impact of a small number of well described genotypes.
PMCID: PMC3580459  PMID: 23181523
22.  Recent Alzheimer's disease research highlights 
PMCID: PMC3506929  PMID: 22594696
23.  Long-term benefit from deep brain stimulation of the subthalamic nucleus: is it for everyone? 
Although deep brain stimulation (DBS) has revolutionized our approach to therapy for patients with advanced Parkinson's disease, many questions remain. Should DBS be instituted earlier in the course of the disease? Why do some patients show striking improvements whereas others show limited benefit even when lead locations appear to be similar? Why can some patients markedly reduce medications whereas others cannot? What is the optimal target site for DBS and how does it work? One question that has long been asked but only recently become addressable is how long the therapeutic effect of DBS can be sustained in the face of what is still a progressive, neurodegenerative disease? A recent article by Castrioto and colleagues, 'Ten-year outcome of subthalamic stimulation in Parkinson disease', seeks to address this question. The authors report significant improvement at 10 years following the onset of subthalamic nucleus DBS in the off UPDRS (Unified Parkinson's Disease Rating Scale) III total motor score, tremor and bradykinesia subscores, UPDRS II meds on and off scores, and UPDRS IV dyskinesia and motor fluctuation score as well as a significant reduction in the levodopa equivalent daily dose when compared with baseline. Does this finally answer our question of the longevity of DBS? I would suggest not. The article by Castrioto and colleagues provides evidence that some patients can expect improvement for 10 years or longer. However, the young age of onset for patients in this study (average of less than 40 years) combined with a substantial loss of patients to follow-up (23 out of 41) likely leads to a data set that was biased in favor of better long-term outcomes, making it unlikely that the data from this study can be applied to the majority of older patients undergoing DBS, who are more likely to follow a more progressive course. Thus, the present findings are encouraging for some but are not likely to be predictive for all or even for most of the patients currently undergoing this procedure. In spite of these problems, one cannot help but be encouraged by the results of a study that was done early in the course of implementing DBS and that shows continued improvement for patients as long as 10 years following implantation.
PMCID: PMC3506928  PMID: 22574875
24.  Examining the mechanisms that link β-amyloid and α-synuclein pathologies 
β-amyloid (Aβ) and α-synuclein (α-syn) are aggregation-prone proteins typically associated with two distinct neurodegenerative disorders: Alzheimer's disease (AD) and Parkinson's disease. Yet α-syn was first found in association with AD plaques several years before being linked to Parkinson's disease or Lewy body formation. Nowadays, a large subset of AD patients (~50%) is well recognized to co-exhibit significant α-syn Lewy body pathology. Unfortunately, these AD Lewy body variant patients suffer from additional symptoms and an accelerated disease course. Basic research has begun to show that Aβ and α-syn may act synergistically to promote the aggregation and accumulation of each other. While the exact mechanisms by which these proteins interact remain unclear, growing evidence suggests that Aβ may drive α-syn pathology by impairing protein clearance, activating inflammation, enhancing phosphorylation, or directly promoting aggregation. This review examines the interactions between Aβ and α-syn and proposes potential mechanistic links between Aβ accumulation and α-syn pathogenesis.
PMCID: PMC4054672  PMID: 22546279
25.  Oral curcumin for Alzheimer's disease: tolerability and efficacy in a 24-week randomized, double blind, placebo-controlled study 
Curcumin is a polyphenolic compound derived from the plant Curcuma Long Lin that has been demonstrated to have antioxidant and anti-inflammatory effects as well as effects on reducing beta-amyloid aggregation. It reduces pathology in transgenic models of Alzheimer's disease (AD) and is a promising candidate for treating human AD. The purpose of the current study is to generate tolerability and preliminary clinical and biomarker efficacy data on curcumin in persons with AD.
We performed a 24-week randomized, double blind, placebo-controlled study of Curcumin C3 Complex® with an open-label extension to 48 weeks. Thirty-six persons with mild-to-moderate AD were randomized to receive placebo, 2 grams/day, or 4 grams/day of oral curcumin for 24 weeks. For weeks 24 through 48, subjects that were receiving curcumin continued with the same dose, while subjects previously receiving placebo were randomized in a 1:1 ratio to 2 grams/day or 4 grams/day. The primary outcome measures were incidence of adverse events, changes in clinical laboratory tests and the Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) at 24 weeks in those completing the study. Secondary outcome measures included the Neuropsychiatric Inventory (NPI), the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) scale, levels of Aβ1-40 and Aβ1-42 in plasma and levels of Aβ1-42, t-tau, p-tau181 and F2-isoprostanes in cerebrospinal fluid. Plasma levels of curcumin and its metabolites up to four hours after drug administration were also measured.
Mean age of completers (n = 30) was 73.5 years and mean Mini-Mental Status Examination (MMSE) score was 22.5. One subject withdrew in the placebo (8%, worsened memory) and 5/24 subjects withdrew in the curcumin group (21%, 3 due to gastrointestinal symptoms). Curcumin C3 Complex® was associated with lowered hematocrit and increased glucose levels that were clinically insignificant. There were no differences between treatment groups in clinical or biomarker efficacy measures. The levels of native curcumin measured in plasma were low (7.32 ng/mL).
Curcumin was generally well-tolerated although three subjects on curcumin withdrew due to gastrointestinal symptoms. We were unable to demonstrate clinical or biochemical evidence of efficacy of Curcumin C3 Complex® in AD in this 24-week placebo-controlled trial although preliminary data suggest limited bioavailability of this compound.
Trial registration Identifier: NCT00099710.
PMCID: PMC3580400  PMID: 23107780

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