A genome-wide association study in multiple system atrophy.

OBJECTIVE: To identify genetic variants that play a role in the pathogenesis of multiple system atrophy (MSA), we undertook a genome-wide association study (GWAS). METHODS: We performed a GWAS with >5 million genotyped and imputed single nucleotide polymorphisms (SNPs) in 918 patients with MSA of European ancestry and 3,864 controls. MSA cases were collected from North American and European centers, one third of which were neuropathologically confirmed. RESULTS: We found no significant loci after stringent multiple testing correction. A number of regions emerged as potentially interesting for follow-up at p < 1 × 10-6, including SNPs in the genes FBXO47, ELOVL7, EDN1, and MAPT. Contrary to previous reports, we found no association of the genes SNCA and COQ2 with MSA. CONCLUSIONS: We present a GWAS in MSA. We have identified several potentially interesting gene loci, including the MAPT locus, whose significance will have to be evaluated in a larger sample set. Common genetic variation in SNCA and COQ2 does not seem to be associated with MSA. In the future, additional samples of well-characterized patients with MSA will need to be collected to perform a larger MSA GWAS, but this initial study forms the basis for these next steps.

Plasma phospholipids identify antecedent memory impairment in older adults.

Alzheimer's disease causes a progressive dementia that currently affects over 35 million individuals worldwide and is expected to affect 115 million by 2050 (ref. 1). There are no cures or disease-modifying therapies, and this may be due to our inability to detect the disease before it has progressed to produce evident memory loss and functional decline. Biomarkers of preclinical disease will be critical to the development of disease-modifying or even preventative therapies. Unfortunately, current biomarkers for early disease, including cerebrospinal fluid tau and amyloid-ß levels, structural and functional magnetic resonance imaging and the recent use of brain amyloid imaging or inflammaging, are limited because they are either invasive, time-consuming or expensive. Blood-based biomarkers may be a more attractive option, but none can currently detect preclinical Alzheimer's disease with the required sensitivity and specificity. Herein, we describe our lipidomic approach to detecting preclinical Alzheimer's disease in a group of cognitively normal older adults. We discovered and validated a set of ten lipids from peripheral blood that predicted phenoconversion to either amnestic mild cognitive impairment or Alzheimer's disease within a 2-3 year timeframe with over 90% accuracy. This biomarker panel, reflecting cell membrane integrity, may be sensitive to early neurodegeneration of preclinical Alzheimer's disease.

A combined effect of two Alzheimer's risk genes on medial temporal activity during executive attention in young adults.

A recent history of failed clinical trials suggests that waiting until even the early stages of onset of Alzheimer's disease may be too late for effective treatment, pointing to the importance of early intervention in young people. Early intervention will require markers of Alzheimer's risk that track with genotype but are capable of responding to treatment. Here, we sought to identify a functional MRI signature of combined Alzheimer's risk imparted by two genetic risk factors. We used a task of executive attention during fMRI in participants genotyped for two Alzheimer's risk alleles: APOE-ε4 and CLU-C. Executive attention is a sensitive indicator of the progression of Alzheimer's even in the early stages of mild cognitive impairment, but has not yet been investigated as a marker of Alzheimer's risk in young adults. Functional MRI revealed that APOE-ε4 and CLU-C had an additive effect on brain activity such that increased combined genetic risk was associated with decreased brain activity during executive attention, including in the medial temporal lobe, a brain area affected early in Alzheimer's pathogenesis.

Microglial activation and antioxidant responses induced by the Parkinson's disease protein α-synuclein.

Parkinson's disease (PD) is the second most common age-related neurodegenerative disorder typified by tremor, rigidity, akinesia and postural instability due in part to the loss of dopamine within the nigrostriatal system. The pathologic features of this disorder include the loss of substantia nigra dopamine neurons and attendant striatal terminals, the presence of large protein-rich neuronal inclusions containing fibrillar α-synuclein and increased numbers of activated microglia. Evidence suggests that both misfolded α-synuclein and oxidative stress play an important role in the pathogenesis of sporadic PD. Here we review evidence that α-synuclein activates glia inducing inflammation and that Nrf2-directed phase-II antioxidant enzymes play an important role in PD. We also provide new evidence that the expression of antioxidant enzymes regulated in part by Nrf2 is increased in a mouse model of α-synuclein overexpression. We show that misfolded α-synuclein directly activates microglia inducing the production and release of the proinflammatory cytokine, TNF-α, and increasing antioxidant enzyme expression. Importantly, we demonstrate that the precise structure of α-synuclein is important for induction of this proinflammatory pathway. This complex α-synuclein-directed glial response highlights the importance of protein misfolding, oxidative stress and inflammation in PD and represents a potential locus for the development of novel therapeutics focused on induction of the Nrf2-directed antioxidant pathway and inhibition of protein misfolding.

Parkinson's disease.

Parkinson's disease (PD) is the most common age-related motoric neurodegenerative disease initially described in the 1800's by James Parkinson as the 'Shaking Palsy'. Loss of the neurotransmitter dopamine was recognized as underlying the pathophysiology of the motor dysfunction; subsequently discovery of dopamine replacement therapies brought substantial symptomatic benefit to PD patients. However, these therapies do not fully treat the clinical syndrome nor do they alter the natural history of this disorder motivating clinicians and researchers to further investigate the clinical phenotype, pathophysiology/pathobiology and etiology of this devastating disease. Although the exact cause of sporadic PD remains enigmatic studies of familial and rare toxicant forms of this disorder have laid the foundation for genome wide explorations and environmental studies. The combination of methodical clinical evaluation, systematic pathological studies and detailed genetic analyses have revealed that PD is a multifaceted disorder with a wide-range of clinical symptoms and pathology that include regions outside the dopamine system. One common thread in PD is the presence of intracytoplasmic inclusions that contain the protein, α-synuclein. The presence of toxic aggregated forms of α-synuclein (e.g., amyloid structures) are purported to be a harbinger of subsequent pathology. In fact, PD is both a cerebral amyloid disease and the most common synucleinopathy, that is, diseases that display accumulations of α-synuclein. Here we present our current understanding of PD etiology, pathology, clinical symptoms and therapeutic approaches with an emphasis on misfolded α-synuclein.

α-Synuclein Alters Toll-Like Receptor Expression.

Parkinson's disease, an age-related neurodegenerative disorder, is characterized by the loss of dopamine neurons in the substantia nigra, the accumulation of α-synuclein in Lewy bodies and neurites, and neuroinflammation. While the exact etiology of sporadic Parkinson's disease remains elusive, a growing body of evidence suggests that misfolded α-synuclein promotes inflammation and oxidative stress resulting in neurodegeneration. α-Synuclein has been directly linked to microglial activation in vitro and increased numbers of activated microglia have been reported in an α-synuclein overexpressing mouse model prior to neuronal loss. However, the mechanism by which α-synuclein incites microglial activation has not been fully described. Microglial activation is governed in part, by pattern recognition receptors that detect foreign material and additionally recognize changes in homeostatic cellular conditions. Upon proinflammatory pathway initiation, activated microglia contribute to oxidative stress through release of cytokines, nitric oxide, and other reactive oxygen species, which may adversely impact adjacent neurons. Here we show that microglia are directly activated by α-synuclein in a classical activation pathway that includes alterations in the expression of toll-like receptors. These data suggest that α-synuclein can act as a danger-associated molecular pattern.

Proteomic analysis of peripheral leukocytes in Alzheimer's disease patients treated with divalproex sodium.

The molecular profiling of peripheral tissues, including circulating leukocytes, may hold promise in the discovery of biomarkers for diagnosing and treating neurodegenerative diseases, including Alzheimer's disease (AD). As a proof-of-concept, we performed a proteomics study on peripheral leukocytes from patients with AD both before and during treatment with divalproex sodium. Using two-dimensional gel electrophoresis and MALDI-TOF mass spectrometry, we identified 10 differentially expressed proteins: two up-regulated proteins, 14-3-3 protein epsilon and peroxiredoxin 2; and eight down-regulated proteins, actin-interacting protein, mitogen activated protein kinase 1, beta actin, annexin A1, glyceraldehyde 3-phosphate dehydrogenase, transforming protein RhoA, acidic leucine-rich nuclear phosphoprotein 32 family member B, and a currently unidentified protein. A subset was validated on both the transcript and protein levels in normal human peripheral blood mononuclear cell cultures treated with valproic acid. These proteins comprise a number of functional classes that may be important to the biology of AD and to the therapeutic action of valproate. These data also suggest the potential of using peripheral leukocytes to monitor pharmaceutical action for neurodegenerative diseases.

Gazing into the future: Parkinson's disease gene therapeutics to modify natural history.

PD gene therapy clinical trials have primarily focused on increasing the production of dopamine (DA) through supplemental amino acid decarboxylase (AADC) expression, neurotrophic support for surviving dopaminergic neurons (DAN) or altering brain circuitry to compensate for DA neuron loss. The future of PD gene therapy will depend upon resolving a number of important issues that are discussed in this special issue. Of particular importance is the identification of novel targets that are amenable to early intervention prior to the substantial loss of DAN. However, for the most part the etiopathogenesis of PD is unknown making early intervention a challenge and the development of early biomarker diagnostics imperative.

Reversal of misfolding: prion disease behavioral and physiological impairments recover following postnatal neuronal deletion of the PrP gene.

The prionoses are fatal neurodegenerative diseases caused by a pathogenic protein, PrP scrapie, that derives from misfolding of a normal form, PrP(c). These diseases progress through stages. A new study by Mallucci et al. in this issue of Neuron shows that prion disease may be reversed in mice by selective removal of the gene in neurons after early physiological, cognitive, and pathological features have developed.

Altered flurothyl seizure induction latency, phenotype, and subsequent mortality in a mouse model of juvenile neuronal ceroid lipofuscinosis/batten disease.

PURPOSE: Juvenile neuronal ceroid lipofuscinosis (JNCL), or Batten disease, is a pediatric neurodegenerative disease characterized by vision loss, seizure activity, cognitive decline, and premature death. Discovery of the Batten disease-related gene, CLN3, led to creation of a Cln3 protein-deficient mouse model (Cln3-/-), which recapitulates some of the histopathologic characteristics of the human condition. We hypothesized that lack of Cln3 would alter seizure-related behavioral parameters. METHODS: Using flurothyl gas inhalation, we examined seizure-induction latencies in Cln3-/- mice and wildtype (wt) controls at time points that represent late neonatal, immature, mature, and aged time points. We examined latency to first myoclonic jerk (LMJ), latency to loss of posture (LOP), and subsequent mortality. RESULTS: Our results demonstrate an age-dependent alteration of seizure-induction latencies in Cln3-/-. Immature Cln-/- mice aged 35-42 days had an increased latency to both LMJ and LOP compared with age-matched wt controls. There were no significant latency differences between Cln3-/- and wt at other time points examined. Mortality after generalized seizure was high in both Cln3-/- and wt animals at late neonatal and immature developmental stages. No mortality was seen in wt mice past maturity at 6 weeks. Mature and aged Cln3-/- animals retained a vulnerability to death after seizure activity. CONCLUSIONS: These results suggest that a deficiency of Cln3 protein in the Batten model mice may result in age-dependent alteration of the neuroanatomic and biochemical substrates involved in seizure propagation and recovery. This may be important in understanding seizures, neurodegeneration, and premature death in human Batten disease.