Studies of the mutant gene in Huntington's disease, and for eight related neurodegenerative disorders, have identified polyglutamine (polyQ) expansions as a basis for cellular toxicity. This finding has led to a disease hypothesis that protein aggregation and cellular dysfunction can occur at a threshold of approximately 40 glutamine residues. Here, we test this hypothesis by expression of fluorescently tagged polyQ proteins (Q29, Q33, Q35, Q40, and Q44) in the body wall muscle cells of Caenorhabditis elegans and show that young adults exhibit a sharp boundary at 35-40 glutamines associated with the appearance of protein aggregates and loss of motility. Surprisingly, genetically identical animals expressing near-threshold polyQ repeats exhibited a high degree of variation in the appearance of protein aggregates and cellular toxicity that was dependent on repeat length and exacerbated during aging. The role of genetically determined aging pathways in the progression of age-dependent polyQ-mediated aggregation and cellular toxicity was tested by expressing Q82 in the background of age-1 mutant animals that exhibit an extended lifespan. We observed a dramatic delay of polyQ toxicity and appearance of protein aggregates. These data provide experimental support for the threshold hypothesis of polyQ-mediated toxicity in an experimental organism and emphasize the importance of the threshold as a point at which genetic modifiers and aging influence biochemical environment and protein homeostasis in the cell.T he folding and maintenance of proteins in their native conformation is essential to cellular function. Disruption of protein-folding homeostasis, leading to the appearance of protein aggregates, is associated with an increasing number of human diseases (1, 2). A prototypical class of these disorders, composed of at least eight progressive neurodegenerative diseases including Huntington's disease, is associated with genes containing (CAG) n trinucleotide repeats encoding polyglutamine (polyQ) tracts in otherwise unrelated proteins (3, 4). Expression of expanded polyQ, with or without flanking sequences, is sufficient to recapitulate the pathological features of the diseases in multiple model systems, supporting a central role for the expansion in the etiology of these disorders (5-7).Molecular genetic studies have established that huntingtin alleles from normal chromosomes contain fewer than 30-34 CAG repeats, whereas those from affected chromosomes contain more than 35-40 repeats (8, 9). These observations have led to the suggestion of a 35-40-residue threshold at which the disease gene products are converted to a proteotoxic state. Analysis of patient databases has established a strong inverse correlation between repeat length and age of onset (9-11). However, both this correlation and disease penetrance are much weaker for repeats of 42 or fewer residues (12), suggesting that substantial variation in the behavior of polyQ-containing proteins can exist at near-threshold repeat lengths, which influences the course ...

The correlation between longevity and stress resistance observed in long-lived mutant animals suggests that the ability to sense and respond to environmental challenges could be important for the regulation of life span. We therefore examined the role of heat shock factor (HSF-1), a master transcriptional regulator of stress-inducible gene expression and protein folding homeostasis, in the regulation of longevity. Down-regulation of hsf-1 by RNA interference suppressed longevity of mutants in an insulin-like signaling (ILS) pathway that functions in the nervous system of Caenorhabditis elegans to influence aging. hsf-1 was also required for temperature-induced dauer larvae formation in an ILS mutant. Using tissue-specific expression of wild-type or dominant negative HSF-1, we demonstrated that HSF-1 acts in multiple tissues to regulate longevity. Down-regulation of individual molecular chaperones, transcriptional targets of HSF-1, also decreased longevity of long-lived mutant but not wild-type animals. However, suppression by individual chaperones was to a lesser extent, suggesting an important role for networks of chaperones. The interaction of ILS with HSF-1 could represent an important molecular strategy to couple the regulation of longevity with an ancient genetic switch that governs the ability of cells to sense and respond to stress. INTRODUCTIONStudies in a variety of organisms have identified single gene mutations that influence life span (Guarente and Kenyon, 2000). These mutations are pleiotropic and are correlated with resistance to a variety of environmental stresses, including UV radiation, oxidizing conditions, and heat shock (Larsen, 1993;Lithgow et al., 1995;Murakami and Johnson, 1996;Finkel and Holbrook, 2000). We have observed previously that the age-dependent aggregation of polyglutamine proteins was suppressed in long-lived age-1 mutant animals (Morley et al., 2002), suggesting that longevity can be associated with protection not only against exogenously imposed environmental stress but also to biochemical stress associated with expression of misfolded and aggregationprone proteins. Moreover, these observations suggest that genes that regulate aging are coupled to cellular systems that act to restore protein homeostasis and prevent damage in response to a diverse array of stresses. Alternatively, stress resistance could be a secondary pleiotropic consequence of many cellular processes that are altered in longlived animals. The observation of hormesis, wherein organisms exposed to sublethal insults become long-lived, however, suggests that activation of stress responses could be sufficient to extend life span (Lithgow et al., 1995;Cypser and Johnson, 2002). Additionally, forward genetic screens to identify stress resistant mutants have been used effectively as strategies to directly isolate long-lived animals (Muänoz and Riddle, 2003). Although cell-protective factors, including antioxidants and molecular chaperones, have been implicated in these processes (Finkel and Holbrook, 2000), how and ...

Objective: To report the rates and predictors of progression from normal cognition to either mild cognitive impairment (MCI) or dementia using standardized neuropsychological methods.Methods: A prospective cohort of patients diagnosed with Parkinson disease (PD) and baseline normal cognition was assessed for cognitive decline, performance, and function for a minimum of 2 years, and up to 6. A panel of movement disorders experts classified patients as having normal cognition, MCI, or dementia, with 55/68 (80.9%) of eligible patients seen at year 6. Kaplan-Meier curves and Cox proportional hazard models were used to examine cognitive decline and its predictors. Results:We enrolled 141 patients, who averaged 68.8 years of age, 63% men, who had PD on average for 5 years. The cumulative incidence of cognitive impairment was 8.5% at year 1, increasing to 47.4% by year 6. All incident MCI cases had progressed to dementia by year 5. In a multivariate analysis, predictors of future decline were male sex (p 5 0.02), higher Unified Parkinson's Disease Rating Scale motor score (p # 0.001), and worse global cognitive score (p , 0.001).Conclusions: Approximately half of patients with PD with normal cognition at baseline develop cognitive impairment within 6 years and all new MCI cases progress to dementia within 5 years. Our results show that the transition from normal cognition to cognitive impairment, including dementia, occurs frequently and quickly. Certain clinical and cognitive variables may be useful in predicting progression to cognitive impairment in PD. Nonmotor symptoms are common in Parkinson disease (PD), 1 including mild cognitive impairment (MCI) and dementia (PDD).2 Up to 80% of patients with PD develop dementia long-term, 3 and 20%-30% of patients with PD without dementia meet criteria for MCI. 4 Both PD-MCI and PDD impact negatively on patient quality of life, cost of care, and caregiver burden. 5,6 Longitudinal reports on patients with early PD-MCI show that more than 25% will develop dementia within 3 years, 7 and MCI at disease onset increases risk for development of dementia. 8Another study reported that up to 50% of patients with early PD developed cognitive decline within 5 years, 9 although the sample size was relatively small and lack of cognitive impairment at baseline was defined by Mini-Mental State Examination score only.Structural MRI, and plasma and CSF biomarkers, are associated with cognitive functioning and predict future cognitive decline in PD.1 However, many biomarkers are invasive, costly, and done mainly at academic centers conducting research. Demographic and clinical factors such as age, 10 motor subtypes, 11 and early visuospatial, language, and fluency deficits 12,13 have also been shown to predict future cognitive decline. However, to our knowledge, no research has focused on those patients defined as having normal cognition (NC) at baseline, which allows for examination of the course of cognitive decline from its clinical onset.

Olfactory dysfunction is common in Parkinson's disease (PD) and often predates the diagnosis by years, reflecting early deposition of Lewy pathology, the histologic hallmark of PD, in the olfactory bulb. Clinical tests are available that allow for the rapid characterization of olfactory dysfunction, including tests of odor identification, discrimination, detection, and recognition thresholds, memory, and tests assessing the build-up of odor intensity across increasing suprathreshold stimulus concentrations. The high prevalence of olfactory impairment, along with the ease and low cost of assessment, has fostered great interest in olfaction as a potential biomarker for PD. Hyposmia may help differentiate PD from other causes of parkinsonism, and may also aid in the identification of ''pre-motor'' PD due to the early pathologic involvement of olfactory pathways. Olfactory function is also correlated with other non-motor features of PD and may serve as a predictor of cognitive decline. In this article, we summarize the existing literature on olfaction in PD, focusing on the potential for olfaction as a biomarker for early or differential diagnosis and prognosis.

Background The role of genetic factors in cognitive decline associated with Parkinson's disease is unclear. We examined whether variations in apolipoprotein E, microtubule-associated protein tau or catechol-O-methytransferase genotypes are associated with cognitive decline in Parkinson's disease. Methods We performed a prospective cohort study of 212 patients with a clinical diagnosis of Parkinson's disease. The primary outcome was change in Mattis Dementia Rating Scale version 2 score. Linear mixed-effects models and survival analysis were used to test for associations between genotypes and change in cognitive function over time. Results The ε4 allele of apoliporotein E was associated with more rapid decline (loss of 2.9 (95% CI, 1.7–4.1) more points/year, p<0.001) in total score and an increased risk of a ≥10 pointdrop during the follow-up period (HR 2.8, 95% CI 1.4–5.4, p=0.003). Microtubule-associated protein tau haplotype and catechol-O-methytransferase genotype were associated with measures of memory and attention, respectively, over the entire followup period but not with the overall rate of cognitive decline. Conclusion These results confirm and extend previously described genetic associations with cognitive decline in Parkinson's disease and imply that individual genes may exert effects on specific cognitive domains or at different disease stages. Carrying at least one apolipoprotein E ε4 allele is associated with more rapid cognitive decline in Parkinson's disease, supporting the idea of a component of shared etiology between Parkinson's disease dementia and Alzheimer disease. Clinically, these results suggest genotyping can provide information about the risk of future cognitive decline for Parkinson's disease patients.

These results suggest that significant neurodegeneration and cellular dysfunction precede LP in the SN, challenging the pathogenic role of LP in PD and the assumption that ILBD always represents preclinical PD.

As the need for PD subspecialty care increases, innovative patient-centered solutions to overcoming barriers to access, such as video telehealth, will be invaluable to patients and may provide high patient satisfaction.

SUMMARYProlonged status epilepticus (SE) can be refractory to conventional interventions, with high rates of subsequent morbidity and mortality. A high fat, low protein, low carbohydrate ketogenic diet (KD) has been used successfully to treat intractable epilepsy. However, its possible role in prolonged SE has not been well described. We report successful use of the KD in two adult patients with prolonged nonconvulsive SE (NCSE) refractory to multiple other interventions. Our observations suggest induction of ketosis may be a novel strategy to safely and effectively treat status in adults even after weeks to months of refractory seizures. Although there are few data regarding the use of the ketogenic diet in the treatment of adult epilepsy syndromes, it may be an option for the treatment of adults with refractory, prolonged SE.