PGRN Manifesting as Parkinson's Disease: Counseling and Treatment Implications.

Olfactory proteotyping: towards the enlightenment of the neurodegeneration

Background and Purpose: Brain-derived neurotrophic factor (BDNF) levels have been reported to play an important role in driving neuroprotection in people with neurologic disorders, and levels of BDNF are known to increase in response to physical activity. Moreover, the level of BDNF produced is also affected by BDNF genotype. It is not known, however, whether one’s BDNF genotype interacts with physical activity throughout life to affect a neuroprotective response in people with Parkinson’s disease (PD). Therefore, the purpose of this study was to determine if BDNF genotype interacts with lifetime self-reported physical activity levels to affect disease severity and progression as determined by measures of gait, balance, and PD motor function. Methods: Included in the study were 28 individuals with idiopathic PD. DNA collected from buccal cells was used to determine BDNF genotype. Self-report measures included a modified version of the Lifetime Physical Activity Questionnaire (LPAQ), the Fear of Falling Avoidance Behavior Questionnaire (FFABQ), and the Activities-Specific Balance Confidence scale (ABC), as well as demographic information. Tester- administered measures included the Mini-Balance Evaluations Test (MiniBESTest), a gait and balance performance battery, and the Movement Disorder Society – Unified Parkinson’s Disease Rating Scale III (MDS-UPDRS-III), an observational assessment of motor function. Results: There was not a significant interaction between BDNF genotype and self-reported history of physical activity on measures of gait and balance in individuals with PD. There was also no interaction between BDNF genotype and history of physical activity on age of PD onset or severity of disease. Discussion: Preliminary results did not reveal any differential effects of BDNF genotype and history of physical activity effecting gait and balance, age of disease onset, or disease severity in individuals with PD. While all of the analyses are currently underpowered due to sample size, there were trends to indicate that there may be some validity to the original hypotheses. Data collection for this study is ongoing.

Chapter 20 Neuropathological hallmarks of Alzheimer's and Parkinson's diseases

The risk of developing levodopa-associated dyskinesia is known to vary inversely with the age of Parkinson's disease onset. This study quantifies dyskinesia risks for different Parkinson's onset ages in a patient population treated at the Parkinson's Disease Research, Education, and Clinical Center at the San Francisco Veterans Affairs Medical Center. Medical records were reviewed to determine age of Parkinson's onset, medication history, and dyskinesia onset. Dyskinesia risks were determined by using Kaplan-Meier analysis. Cox proportional hazard models were used to compare age groups and to perform multivariate modeling. This study included 109 patients with Parkinson's, 105 of whom had onset of symptoms after 1989. At 5 years of levodopa treatment, the dyskinesia risk for patients with onset age 40-49 was 70%, decreasing to 42% for onset ages 50-59, 33% for onset ages 60-69, and 24% for onset ages 70-79. Pairwise comparisons between the 40-49 age group and the other age groups were statistically significant in time-to-event models. After 5 years of levodopa treatment, dyskinesia risks became uniformly high regardless of age of onset. These results suggest it is appropriate to use different baseline dyskinesia risks in clinical decision-making for patients on the basis of their ages of onset. However, the most significant difference occurs between ages 40-49 and ages 50-79, and if more than 5 years of levodopa therapy are anticipated, dyskinesia risk may have less utility when deciding upon Parkinson's therapy. Drug studies for Parkinson's disease should also take age of Parkinson's onset into account when analyzing dyskinesia outcomes.

The observation of neurofibrillary tangles (NFTs) without associated amyloid-beta (Aβ) in the brains of cognitively normal and cognitively impaired elderly individuals has, for many years, been a source of discussion and controversy. The term "primary age-related tauopathy" (PART) was introduced in 2014 and consensus guidelines for the condition were published [1]. The clinical manifestations of PART have been described (see [2] for review). A recent molecular imaging study suggested that mesial temporal tau load is associated with a decline in cognitive performance in those with no Aβ pathology [3].

Verbal fluency in Alzheimer's disease, Parkinson's disease, and major depression

Alcohol use disorder is associated with higher risks of Alzheimer's and Parkinson's diseases: A study of US insurance claims data.

Alzheimer's disease (AD) and Parkinson's disease (PD) are the most prevalent neurodegenerative diseases, affecting millions and costing billions each year in the United States alone. Despite tremendous progress in developing therapeutics that manage the symptoms of these two diseases, the scientific community has yet to develop a treatment that effectively slows down, inhibits, or cures neurodegeneration. To gain a better understanding of the current therapeutic frontier for the treatment of AD and PD, we provide a review on past and present therapeutic strategies for these two major neurodegenerative disorders in the clinical trial process. We briefly recap currently US Food and Drug Administration‐approved therapies, and then explore trends in clinical trials across the variables of therapy mechanism of disease intervention, administration route, use of delivery vehicle, and outcome measures, across the clinical phases over time for “Drug” and “Biologic” therapeutics. We then present the success rate of past clinical trials and analyze the intersections in therapeutic approaches for AD and PD, revealing the shift in clinical trials away from therapies targeting neurotransmitter systems that provide symptomatic relief, and towards anti‐aggregation, anti‐inflammatory, anti‐oxidant, and regeneration strategies that aim to inhibit the root causes of disease progression. We also highlight the evolving distribution of the types of “Biologic” therapies investigated, and the slowly increasing yet still severe under‐utilization of delivery vehicles for AD and PD therapeutics. We then briefly discuss novel preclinical strategies for treating AD and PD. Overall, this review aims to provide a succinct overview of the clinical landscape of AD and PD therapies to better understand the field's therapeutic strategy in the past and the field's evolution in approach to the present, to better inform how to effectively treat AD and PD in the future.

Impulse control disorders (ICDs) are common in patients with Parkinson's disease (PD) and strongly linked with dopaminergic medication.1 Given that dopamine agonists (DAs) are the main risk factor, ICDs have only been studied in disorders that are treated with these medications. Restless legs syndrome, prolactinoma, and fibromyalgia have all been shown to have an increased risk for ICDs compared with healthy controls (HC).2 However, patients without DAs can also develop ICDs, and there are several case reports of ICDs in other chronic neurological conditions without dopaminergic medications,1, 2 suggesting that ICDs could be a relevant neuropsychiatric symptom also in other chronic neurological disorders. Dystonia is a chronic movement disorder that is not considered a dopamine-dependent nor is treated with dopaminergic medications (with rare exceptions). Similar to PD, though, dystonia is associated with a high burden of neuropsychiatric comorbidity, including for example, depression, anxiety, and sleep disorders, which have been shown to increase the risk of substance use disorders in patients with dystonia.3, 4 These neuropsychiatric symptoms are also common comorbidities of ICDs.1 However, ICDs in dystonia have not been studied. The aim of this study was to investigate if dystonia is associated with ICDs by directly comparing ICD prevalence in dystonia with that of HC and patients with PD with DAs (PD + DA) and without DAs (PD − DA). ICDs were evaluated using the Questionnaire for Impulsive-Compulsive Disorders (QUIP) using a survey e-mailed personally to the members of the Finnish Movement Disorders Association, as described previously.5 Altogether, 98 patients with dystonia, 498 patients with PD (317 PD + DA, 181 PD − DA) and 119 HC provided sufficient information to be included in the study (Table S1). Full methodological details can be found in the Supplementary Material. Prevalence of positive screens for ICDs in dystonia (20.4%) did not differ from HC (21.8%, P = 0.87) or PD − DA (26.0%, P = 0.38), but was significantly lower than in PD + DA (33.8%, P = 0.02) Fig. 1, Table S1). In the multiple regression analysis, ICDs were independently associated with PD + DA compared with HC (odds ratio [OR], 1.70 [95% confidence interval, CI, 1.02–2.84]; P = 0.04), younger age (OR, 1.51 [95% CI, 1.26–1.80] for 10-year decrease; P < 0.001), and male sex (OR, 2.23 [95% CI, 1.56–3.20]; P < 0.001), but not with dystonia (OR, 0.92 [95% CI, 0.48–1.78]; P = 0.80) (Table S2–S4). Our results shown that the prevalence of ICDs in dystonia is comparable with HC and PD − DA, but less common than in patients with PD + DA. Our findings support the view that ICDs are linked with dopaminergic treatment, and not with chronic neurological conditions in general. The limitations of this study include the use of QUIP, which as a screening instrument is associated with false positives. In addition, the sample size could be considered low for estimating the prevalence of ICDs in dystonia. However, our aim was not to estimate the actual prevalence of ICDs but to investigate whether dystonia is associated with increased ICD risk. As the proportion of patients with ICDs in dystonia was slightly lower than in PD − DA or controls, it is highly unlikely that the lack of detecting an increased ICD risk in dystonia would be a sample size issue. This study was supported by the Finnish Parkinson Foundation. We express our gratitude to the staff of the Finnish Movement Disorders Association for their invaluable assistance during the study. (1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique. A.H.: 1A, 1C, 2A, 2B, 3A E.J.: 1A, 1C, 2A, 2B, 2C, 3B J.J.: 1A, 1B, 1C, 2A, 2C, 3A Annu Huovinen has received a grant from the Finnish Parkinson Foundation. Elina Jaakkola has received a grant from the Finnish Parkinson Foundation. Juho Joutsa has received lecturer honoraria from Lundbeck; research grants from the Finnish Medical Foundation, Sigrid Juselius Foundation, Instrumentarium Research Foundation, Finnish Foundation for Alcohol Studies, University of Turku, private donation, and Turku University Hospital (Finnish governmental research funding); and conference travel support from Abbvie. The data can be shared upon reasonable request, subject to institutional and national regulations Appendix S1 Supporting Information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Abnormal Mitochondrial Morphology in Sporadic Parkinson's and Alzheimer's Disease Cybrid Cell Lines

A study was undertaken to examine the neuropathological substrates of cognitive dysfunction and dementia in Parkinson disease (PD). One hundred forty patients with a clinical diagnosis of PD and either normal cognition or onset of dementia 2 or more years after motor symptoms (PDD) were studied. Patients with a clinical diagnosis of dementia with Lewy bodies were excluded. Autopsy records of genetic data and semiquantitative scores for the burden of neurofibrillary tangles, senile plaques, Lewy bodies (LBs), and Lewy neurites (LNs) and other pathologies were used to develop a multivariate logistic regression model to determine the independent association of these variables with dementia. Correlates of comorbid Alzheimer disease (AD) were also examined. Niney-two PD patients developed dementia, and 48 remained cognitively normal. Severity of cortical LB (CLB)/LN pathology was positively associated with dementia (p < 0.001), with an odds ratio (OR) of 4.06 (95% confidence interval [CI], 1.87-8.81), as was apolipoprotein E4 (APOE4) genotype (p = 0.018; OR, 4.19; 95% CI, 1.28-13.75). A total of 28.6% of all PD cases had sufficient pathology for comorbid AD, of whom 89.5% were demented. The neuropathological diagnosis of PDD+AD correlated with an older age of PD onset (p = 0.001; OR, 1.12; 95% CI, 1.04-1.21), higher CLB/LN burden (p = 0.037; OR, 2.48; 95% CI, 1.06-5.82), and cerebral amyloid angiopathy severity (p = 0.032; OR, 4.16; 95% CI, 1.13-15.30). CLB/LN pathology is the most significant correlate of dementia in PD. Additionally, APOE4 genotype may independently influence the risk of dementia in PD. AD pathology was abundant in a subset of patients, and may modify the clinical phenotype. Thus, therapies that target α-synuclein, tau, or amyloid β could potentially improve cognitive performance in PD.

Frontotemporal dementia (FTD) is the second most frequent type of neurodegenerative dementias. Mutations in the progranulin gene (GRN, PGRN) were recently identified in FTDU-17, an FTD subtype characterized by ubiquitin-immunoreactive inclusions and linkage to chromosome 17q21. We looked for PGRN mutations in a large series of 210 FTD patients (52 familial, 158 sporadic) to accurately evaluate the frequency of PGRN mutations in both sporadic and familial FTD, and FTD with associated motoneuron disease (FTD-MND), as well as to study the clinical phenotype of patients with a PGRN mutation. We identified nine novel PGRN null mutations in 10 index patients. The relative frequency of PGRN null mutations in FTD was 4.8% (10/210) and 12.8% (5/39) in pure familial forms. Interestingly, 5/158 (3.2%) apparently sporadic FTD patients carried a PGRN mutation, suggesting the possibility of de novo mutations or incomplete penetrance. In contrast, none of the 43 patients with FTD-MND had PGRN mutations, supporting that FTDU-17 and FTD-MND are genetically distinct. The clinical phenotype of PGRN mutation carriers was particular because of the wide range in onset age and the frequent occurrence of early apraxia (50%), visual hallucinations (30%), and parkinsonism (30%) during the course of the disease. This study supports that PGRN null mutations represent a more frequent cause of FTD than MAPT mutations (4.8% vs. 2.9%) but are not responsible for FTD-MND. It also demonstrates that half of the patients with a PGRN mutation in our series had no apparent family history of dementia. Taking this into account, genetic testing should be now considered more systematically, even in patients without obvious familial history of FTD.

One striking observation in Parkinson’s disease (PD) is the remarkable gender difference in incidence and prevalence of the disease. Data on gender differences with regard to disease onset, motor and non-motor symptoms, and dopaminergic medication are limited. Furthermore, whether estrogen status affects disease onset and progression of PD is controversially discussed. In this retrospective single center study, we extracted clinical data of 226 ambulatory PD patients and compared age of disease onset, disease stage, motor impairment, non-motor symptoms, and dopaminergic medication between genders. We applied a matched-pairs design to adjust for age and disease duration. To determine the effect of estrogen-related reproductive factors including number of children, age at menarche, and menopause on the age of onset, we applied a standardized questionnaire and performed a regression analysis. The male to female ratio in the present PD cohort was 1.9:1 (147 men vs. 79 women). Male patients showed increased motor impairment than female patients. The levodopa equivalent daily dose was increased by 18.9% in male patients compared to female patients. Matched-pairs analysis confirmed the increased dose of dopaminergic medication in male patients. No differences were observed in age of onset, type of medication, and non-motor symptoms between both groups. Female reproductive factors including number of children, age at menarche, and age at menopause were positively associated with a delay of disease onset up to 30 months. The disease-modifying role of estrogen-related outcome measures warrants further clinical and experimental studies targeting gender differences, specifically hormone-dependent pathways in PD.

Neuropsychological and motor deficits in Parkinson's disease that may contribute to driving impairment were examined in a cohort study comparing patients with Parkinson's disease (PD) to patients with Alzheimer's disease (AD) and to healthy elderly controls. Nondemented individuals with Parkinson's disease [Hoehn & Yahr (H&Y) stage I-III], patients with Alzheimer's disease [Clinical Demetia Rating scale (CDR) range 0-1], and elderly controls, who were actively driving, completed a neuropsychological battery and a standardized road test administered by a professional driving instructor. On-road driving ability was rated on number of driving errors and a global rating of safe, marginal, or unsafe. Overall, Alzheimer's patients were more impaired drivers than Parkinson's patients. Parkinson's patients distinguished themselves from other drivers by a head-turning deficiency. Drivers with neuropsychological impairment were more likely to be unsafe drivers in both disease groups compared to controls. Compared to controls, unsafe drivers with Alzheimer's disease were impaired across all neuropsychological measures except finger tapping. Driving performance in Parkinson's patients was related to disease severity (H&Y), neuropsychological measures [Rey Osterreith Complex Figure (ROCF), Trails B, Hopkins Verbal List Learning Test (HVLT)-delay], and specific motor symptoms (axial rigidity, postural instability), but not to the Unified Parkinson Disease Rating Scale (UPDRS) motor score. Multifactorial measures (ROCF, Trails B) were useful in distinguishing safe from unsafe drivers in both patient groups.

Dear Sirs, Hereditary spastic paraplegias (HSPs) are clinically and genetically heterogeneous. Pure forms are characterized primarily by progressive spasticity and weakness of the lower limbs. Complicated forms, however, involve neuronal systems other than corticospinal tracts, namely peripheral nerves, and sensory or cerebellar pathways [2]. At least 52 loci and 31 causative genes are known, and thus a gene-by-gene diagnostic approach is becoming impractical. For the 19 autosomal dominant forms (AD-HSPs), 11 genes are known, with SPG4 being by far the most common subtype (40–45 % AD-HSP cases) [4]. The vast heterogeneity in HSP makes a genetic diagnosis difficult and expensive. Many research groups have used gene panels or targeted sequencing but the rapid growth and frequent identification of new genes makes this difficult. We studied a female patient presenting familial spastic paraplegia with sensory axonal neuropathy, compatible with AD inheritance (Fig. 1a). At the age of 10 years she developed problems walking and subsequently had many surgical procedures on her feet. After a pregnancy at the age of 42, she became more tired and walking slowed down with more pain. She has significant spasticity and sensory symptoms in her feet, burning, redness, occasionally whiteness, and she is often in extreme pain and discomfort. Both brain and spinal cord MRI scans were normal. She was started on l-DOPA (Co-Careldopa 25/100 mg tds), as one of the differential diagnoses was dopamine responsive dystonia, which was very helpful for her spasms and sensory symptoms in her feet. Additionally, she had bladder urgency and skin features to suggest autonomic dysfunction, and her gait was typical of spastic paraplegia. Her daughter reported early problems presenting at the age of 19, with pain in her feet and in the back of her legs, spasticity, cramps and sensory symptoms. Her gait showed a slight inversion of the right foot on walking. Interestingly, the daughter had tried l-DOPA in the form of Co-Careldopa 25/100 mg with benefit to her spasticity similar to her mother. The proband’s mother was also thought to have feet problems, with cold and stiff painful feet as well as abnormal sensation but her presentation was late in her mid-50s with very slow deterioration. Fig. 1 a Pedigree of a UK family with spastic paraplegia. The arrow points to the proband. Black and white symbols indicate affected and unaffected individuals, respectively. b Electropherograms illustrating the novel KIAA0196 missense variant (c.677T > C, ... Although whole-exome sequencing is still expensive, and not everywhere available, it has been shown to be a useful tool for the diagnosis of complicated HSP [1]. Using this approach, we identified a novel KIAA0196 missense variant in the proband (c.677T>C, p.I226T). By Sanger sequencing, her daughter was shown to have the same variant (Fig. 1b). This variant is predicted as damaging by SIFT, is located in a conserved residue (Fig. 1c), and is not present in more than 200 in-house exomes or in public databases, such as dbSNP, 1000 Genomes Project, and the Exome Variant server (http://evs.gs.washington.edu/EVS/). The KIAA0196 gene (MIM#610657) is responsible for SPG8 (MIM#603563), a rare AD-HSP, and encodes for strumpellin, a protein that participates in the WASH complex, acting at the interface between actin regulation and endosomal membrane dynamics [5]. There are only two reports of mutations in this gene [3, 8], one of them recently published in this journal. Overall, there are seven SPG8 families, usually with pure phenotypes, and four pathogenic mutations identified worldwide (Table 1). Our pedigree is compatible with an AD-HSP, and the variant we found in the KIAA0196 gene, segregating with the phenotype, is most likely causing HSP. The response to l-DOPA is interesting and may suggest an overlap of the functional pathway of KIAA0196 and dopamine. Although the knowledge of the underlying mutation does not change the therapeutic strategy, it is valuable on what concerns genetic counseling. We therefore identified the eighth SPG8 family and the fifth mutation by making use of next-generation sequencing. Furthermore, we report a complicated phenotype, with an earlier onset than those previously reported (Table 1), also expanding the clinical spectrum of SPG8. Table 1 Mutations in the KIAA0196 gene identified in HSP families