Treatment of motor symptoms in Parkinson's disease. / Behandling av motoriske symptomer ved Parkinsons sykdom.

In recent years, the development of new therapies and improvements in our understanding of older therapies have led to changes in the management of Parkinson's disease. However, current Norwegian and international therapy recommendations present a range of different options as being equally viable. In this clinical review, we propose an updated algorithm for the medical treatment of motor symptoms in Parkinson's disease, based on evidence-based recommendations and our own personal experience and opinions.

A Case of Parkinson's Disease with No Lewy Body Pathology due to a Homozygous Exon Deletion in Parkin.

Parkinson's disease (PD) is a clinical diagnosis based on the presence of cardinal motor signs, good response to levodopa, and no other explanations of the syndrome. Earlier diagnostic criteria required autopsy for a definite diagnosis based on neuronal loss in the substantia nigra pars compacta (SNpc) and the presence of Lewy bodies and neurites. Here, we present a patient who developed parkinsonism around the age of 20, with an excellent response to levodopa who, at age 65, received bilateral STN deep brain stimulation (DBS). The patient died at age 79. The autopsy showed severe neuronal loss in the SN without any Lewy bodies in the brainstem or in the hemispheres. Genetic screening revealed a homozygous deletion of exon 3-4 in the Parkin gene. In this case report we discuss earlier described pathological findings in Parkin cases without Lewy body pathology, the current diagnostic criteria for PD, and their clinical relevance.

Genetic fine-mapping of the Iowan SNCA gene triplication in a patient with Parkinson's disease.

The "Iowa kindred," a large Iowan family with autosomal-dominant Parkinson's disease, has been followed clinically since the 1920s at the Mayo Clinic. In 2003, the genetic cause was determined to be a 1.7 Mb triplication of the alpha-synuclein genomic locus. Affected individuals present with an early-onset, severe parkinsonism-dementia syndrome. Here, we present a descendant of the Iowa kindred with novel, disease-associated non-motor findings of reduced heart rate variability, complete anosmia, and a rare skin condition called colloid milium. At autopsy, key neuropathological findings were compatible with diffuse Lewy body disease. Using high-resolution comparative genomic hybridization (CGH) array analysis to fine-map the genomic breakpoints, we observed two independent recombination events of the SNCA locus that resulted in a genomic triplication of twelve genes, including SNCA, and the disruption of two genes, HERC6 and CCSER1, at the genomic breakpoints. In conclusion, we provide further evidence that the mere two-fold overexpression of alpha-synuclein leads to a fulminant alpha-synucleinopathy with rapid progression and severe clinical and neuropathological features.

Impaired synaptic function is linked to cognition in Parkinson's disease.

OBJECTIVE: Cognitive impairment is frequent in Parkinson's disease, but the underlying mechanisms are insufficiently understood. Because cortical metabolism is reduced in Parkinson's disease and closely associated with cognitive impairment, and CSF amyloid-ß species are reduced and correlate with neuropsychological performance in Parkinson's disease, and amyloid-ß release to interstitial fluid may be related to synaptic activity; we hypothesize that synapse dysfunction links cortical hypometabolism, reduced CSF amyloid-ß, and presynaptic deposits of α-synuclein. We expect a correlation between hypometabolism, CSF amyloid-ß, and the synapse related-markers CSF neurogranin and α-synuclein. METHODS: Thirty patients with mild-to-moderate Parkinson's disease and 26 healthy controls underwent a clinical assessment, lumbar puncture, MRI, 18F-fludeoxyglucose-PET, and a neuropsychological test battery (repeated for the patients after 2 years). RESULTS: All subjects had CSF amyloid-ß 1-42 within normal range. In Parkinson's disease, we found strong significant correlations between cortical glucose metabolism, CSF Aß, α-synuclein, and neurogranin. All PET CSF biomarker-based cortical clusters correlated strongly with cognitive parameters. CSF neurogranin levels were significantly lower in mild-to-moderate Parkinson's disease compared to controls, correlated with amyloid-ß and α-synuclein, and with motor stage. There was little change in cognition after 2 years, but the cognitive tests that were significantly different, were also significantly associated with cortical metabolism. No such correlations were found in the control group. INTERPRETATION: CSF Aß, α-synuclein, and neurogranin concentrations are related to cortical metabolism and cognitive decline. Synaptic dysfunction due to Aß and α-synuclein dysmetabolism may be central in the evolution of cognitive impairment in Parkinson's disease.

Detecting At-Risk Alzheimer's Disease Cases.

While APOEɛ4 is the major genetic risk factor for Alzheimer's disease (AD), amyloid dysmetabolism is an initial or early event predicting clinical disease and is an important focus for secondary intervention trials. To improve identification of cases with increased AD risk, we evaluated recruitment procedures using pathological CSF concentrations of Aß42 (pAß) and APOEɛ4 as risk markers in a multi-center study in Norway. In total, 490 subjects aged 40-80 y were included after response to advertisements and media coverage or memory clinics referrals. Controls (n = 164) were classified as normal controls without first-degree relatives with dementia (NC), normal controls with first-degree relatives with dementia (NCFD), or controls scoring below norms on cognitive screening. Patients (n = 301) were classified as subjective cognitive decline or mild cognitive impairment. Subjects underwent a clinical and cognitive examination and MRI according to standardized protocols. Core biomarkers in CSF from 411 and APOE genotype from 445 subjects were obtained. Cases (both self-referrals (n = 180) and memory clinics referrals (n = 87)) had increased fractions of pAß and APOEɛ4 frequency compared to NC. Also, NCFD had higher APOEɛ4 frequencies without increased fraction of pAß compared to NC, and cases recruited from memory clinics had higher fractions of pAß and APOEɛ4 frequency than self-referred. This study shows that memory clinic referrals are pAß enriched, whereas self-referred and NCFD cases more frequently are pAß negative but at risk (APOEɛ4 positive), suitable for primary intervention.

Neuropsychological Profiles in Mild Cognitive Impairment due to Alzheimer's and Parkinson's Diseases.

BACKGROUND: Neuropsychological comparisons between patients with mild cognitive impairment due to Parkinson's disease (MCI-PD) and Alzheimer's disease (MCI-AD) is mostly based on indirect comparison of patients with these disorders and normal controls (NC). OBJECTIVE: The focus of this study was to make a direct comparison between patients with these diseases. METHODS: The study compared 13 patients with MCI-PD and 19 patients with MCI-AD with similar age, education and gender. The participants were recruited and assessed at the same university clinic with equal methods. RESULTS: The main finding was that on group level, MCI-AD scored significantly poorer on learning and memory tests than MCI-PD, whereas MCI-PD were impaired on 1 of 3 measures of executive functioning. CONCLUSION: MCI-AD performed poorer learning and memory tests, whereas MCI-PD only scored below the employed cut-off on one single executive test. In general, MCI-PD was noticeably less cognitively impaired than MCI-AD.

Hippocampal subfield atrophy in relation to cerebrospinal fluid biomarkers and cognition in early Parkinson's disease: a cross-sectional study.

Cognition is often affected early in Parkinson's disease (PD). Lewy body and amyloid ß (Aß) pathology and cortical atrophy may be involved. The aim of this study was to examine whether medial temporal lobe structural changes may be linked to cerebrospinal fluid (CSF) biomarker levels and cognition in early PD. PD patients had smaller volumes of total hippocampus, presubiculum, subiculum, CA2-3, CA4-DG, and hippocampal tail compared with normal controls (NCs). In the PD group, lower CSF Aß38 and 42 were significant predictors for thinner perirhinal cortex. Lower Aß42 and smaller presubiculum and subiculum predicted poorer verbal learning and delayed verbal recall. Smaller total hippocampus, presubiculum and subiculum predicted poorer visuospatial copying. Lower Aß38 and 40 and thinner perirhinal cortex predicted poorer delayed visual reproduction. In conclusion, smaller volumes of hippocampal subfields and subhippocampal cortex thickness linked to lower CSF Aß levels may contribute to cognitive impairment in early PD. Thirty-three early PD patients (13 without, 5 with subjective, and 15 with mild cognitive impairment) and NC had 3 T magnetic resonance imaging (MRI) scans. The MRI scans were post processed for volumes of hippocampal subfields and entorhinal and perirhinal cortical thickness. Lumbar puncture for CSF biomarkers Aß38, 40, 42, total tau, phosphorylated tau (Innogenetics), and total α-synuclein (Meso Scale Diagnostics) were performed. Multiple regression analyses were used for between-group comparisons of the MRI measurements in the NC and PD groups and for assessment of CSF biomarkers and neuropsychological tests in relation to morphometry in the PD group.

Changes to Intermediary Metabolites in Sporadic and LRRK2 Parkinson's Disease Demonstrated by Proton Magnetic Resonance Spectroscopy.

Background. Parkinson's disease (PD) remains a clinical diagnosis and biomarkers are needed to detect the disease as early as possible. Genetically determined PD provides an opportunity for studying metabolic differences in connection with disease development. Objectives. To study the levels of intermediary metabolites in cerebrospinal fluid (CSF) from patients with PD, either of sporadic type or in carriers of the LRRK2 p.G2019S mutation. Methods. Results from patients with sporadic PD or LRRK2-PD were compared with asymptomatic LRRK2 mutation carriers and healthy control individuals. CSF was analysed by proton MR spectroscopy ((1)H-MRS) giving reliable results for 16 intermediary metabolites. Partial least squares discriminant analysis (PLS-DA) was applied to study group differences. Results. PLS-DA distinguished PD patients from healthy individuals based on the metabolites identified in CSF, with 2-hydroxybutyrate, glutamine, and dimethyl sulphone largely contributing to the separations. Conclusion. Speculatively, all three metabolites could alter concentration in response to metabolic changes connected with neurodegeneration; glutamine as a means of removing excess nitrogen from brain, dimethyl sulphone as an anti-inflammatory agent, and 2-hydroxybutyrate in connection with altered glutathione metabolism. Potentially, (1)H-MRS is a promising tool for identifying novel biomarkers for PD.

Hippocampal complex atrophy in poststroke and mild cognitive impairment.

To investigate putative interacting or distinct pathways for hippocampal complex substructure (HCS) atrophy and cognitive affection in early-stage Alzheimer's disease (AD) and cerebrovascular disease (CVD), we recruited healthy controls, patients with mild cognitive impairment (MCI) and poststroke patients. HCSs were segmented, and quantitative white-matter hyperintensity (WMH) load and cerebrospinal fluid (CSF) amyloid-ß concentrations were determined. The WMH load was higher poststroke. All examined HCSs were smaller in amyloid-positive MCI than in controls, and the subicular regions were smaller poststroke. Memory was reduced in amyloid-positive MCI, and psychomotor speed and executive function were reduced in poststroke and amyloid-positive MCI. Size of several HCS correlated with WMH load poststroke and with CSF amyloid-ß concentrations in MCI. In poststroke and amyloid-positive MCI, neuropsychological function correlated with WMH load and hippocampal volume. There are similar patterns of HCS atrophy in CVD and early-stage AD, but different HCS associations with WMH and CSF biomarkers. WMHs add to hippocampal atrophy and the archetypal AD deficit delayed recall. In line with mounting evidence of a mechanistic link between primary AD pathology and CVD, these additive effects suggest interacting pathologic processes.

Amyloid-ß and α-synuclein cerebrospinal fluid biomarkers and cognition in early Parkinson's disease.

INTRODUCTION: Cognitive impairment in early Parkinson's disease (PD) is common and distinct from early Alzheimer's disease. Predictors and mechanisms are only partially known, but α-synuclein, amyloid-ß and tau dysmetabolism may be involved. Our aim was to study associations between cerebrospinal fluid biomarkers (CSF) and cognition in non-dementia PD compared to normal controls (NC) and non-PD patients with mild cognitive impairment (MCI non-PD). METHODS: Patients were classified as having normal, subjective or mild cognitive impairment after cognitive screening. CSF levels of total α-synuclein (t-α-syn), amyloid-ß (Aß) 38, 40 and 42, total tau (T-tau) and phosphorylated tau (P-tau) were measured in 34 NC, 31 early, non-dementia PD and 28 MCI non-PD patients. A well validated neuropsychological test battery was administered. RESULTS: In the PD group, 13 had normal cognition, 4 had subjective and 14 mild cognitive impairment. PD patients had significantly lower CSF biomarker levels of t-α-syn, Aß38, 40 and 42, T-tau and P-tau compared to NC. Compared to MCI non-PD, t-α-syn, Aß38 and 40, T-tau and P-tau were also lower, while Aß42 was significantly higher in the PD group. Aß38 and 40 correlated strongly with t-α-syn levels in PD. Lower Aß42 was associated with decreased verbal learning, delayed verbal recall and response inhibition in PD. CONCLUSION: While Aß38, 40 and t-α-syn levels are strongly correlated, only lower Aß42 was associated with reduced cognitive functions in early PD, mainly connected to medial temporal lobe-based cognitive functions.

Ataxia with vitamin e deficiency in norway.

OBJECTIVE: Ataxia with vitamin E deficiency (AVED) is a rare autosomal recessive neurological disorder which usually starts in childhood. The clinical presentation is very similar to Friedreich ataxia, most patients have progressive truncal and extremity ataxia, areflexia, positive Babinski sign, dysarthria and sensory neuropathy. METHODS: We made an inquiry to our colleagues in Norway, we included information from a prevalence study published southern Norway and added data from our own known case. RESULTS: A newly published prevalence study of hereditary ataxias (total of 171 subjects) found only one subject with AVED in Southeast Norway. We describe two more patients, one from the Central part and one from the Northern part of Norway. All 3 cases had age of onset in early childhood (age of 4-5 years) and all experienced gait ataxia and dysarthria. The genetic testing confirmed that they had pathogenic mutations in the α-tocopherol transfer protein gene (TTPA). All were carriers of the non-sense c.400C > T mutation, one was homozygous for that mutation and the others were compound heterozygous, either with c.358G > A or c.513_514insTT. The homozygous carrier was by far the most severely affected case. CONCLUSIONS: We estimate the occurrence of AVED in Norway to be at least 0.6 per million inhabitants. We emphasize that all patients who develop ataxia in childhood should be routinely tested for AVED to make an early diagnosis for initiating treatment with high dose vitamin E to avoid severe neurological deficits.

Elevated levels of cerebrospinal fluid α-synuclein oligomers in healthy asymptomatic LRRK2 mutation carriers.

Mutations in the leucine-rich repeat kinase 2 gene are the most common cause of autosomal dominant Parkinson's disease (PD). To assess the cerebrospinal fluid (CSF) levels of α-synuclein oligomers in symptomatic and asymptomatic leucine-rich repeat kinase 2 mutation carriers, we used enzyme-linked immunosorbent assays (ELISA) to investigate total and oligomeric forms of α-synuclein in CSF samples. The CSF samples were collected from 33 Norwegian individuals with leucine-rich repeat kinase 2 mutations: 13 patients were clinically diagnosed with PD and 20 patients were healthy, asymptomatic leucine-rich repeat kinase 2 mutation carriers. We also included 35 patients with sporadic PD (sPD) and 42 age-matched healthy controls. Levels of CSF α-synuclein oligomers were significantly elevated in healthy asymptomatic individuals carrying leucine-rich repeat kinase 2 mutations (n = 20; P < 0.0079) and in sPD group (n = 35; P < 0.003) relative to healthy controls. Increased α-synuclein oligomers in asymptomatic leucine-rich repeat kinase 2 mutation carriers showed a sensitivity of 63.0% and a specificity of 74.0%, with an area under the curve of 0.66, and a sensitivity of 65.0% and a specificity of 83.0%, with an area under the curve of 0.74 for sPD cases. An inverse correlation between CSF levels of α- synuclein oligomers and disease severity and duration was observed. Our study suggests that quantification of α-synuclein oligomers in CSF has potential value as a tool for PD diagnosis and presymptomatic screening of high-risk individuals.

Progressive multifocal leukoencephalopathy in an immunocompetent patient?

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is a rapidly progressive, potentially fatal, demyelinating disease affecting immunosuppressed patients. PML is rarely reported in cases with no underlying disease or immunosuppression-associated condition. CASE REPORT: We present a 72-year-old previously healthy woman who developed a progressive neurological condition affecting the entire nervous system which led to her death within 5 months. PML was diagnosed at autopsy. CONCLUSION: PML should be considered in patients with progressive neurological disorders involving the white matter, even in the absence of previous immunomodulatory treatment or immunosuppression.

Subclinical signs in LRRK2 mutation carriers.

BACKGROUND: Several non-motor features have been reported to precede the motor signs of Parkinson's disease (PD) by several years. However, the time of onset of non-motor and motor symptoms is still debated. Healthy individuals carrying a PD-related mutation are candidates for studying the earliest disease signs. OBJECTIVES: To describe clinically healthy family members of PD patients carrying a LRRK2 mutation (LRRK2-PD). METHODS: A total of 47 family members of LRRK2-PD patients were included in the present study and were screened for the p.G2019S and p.N1437H substitutions in the LRRK2 gene. A standardized case report form was filled out in each case, including general medical evaluation, neurological examination with UPDRS, an olfaction test, mood, sleep and cognitive questionnaires. RESULTS: Thirty-two study participants were positive, and 15 were negative for a LRRK2 mutation. Higher UPDRS motor scores, more frequent reports of urinary problems, and fewer hours of sleep were found in mutation carriers compared to non-carriers. The mutation carriers with UPDRS ≥8 were all aged over 50 years, had shorter overall sleeping hours, more frequent urinary and constipation problems, higher mood scores and body mass index. Deterioration of olfaction was not detected in either group. CONCLUSION: Healthy LRRK2 mutation carriers presented subclinical parkinsonian motor and non-motor signs in the apparent absence of olfactory loss. Longitudinal studies will determine whether these changes precede alterations detectable by neuroimaging.

Mitochondrial impairment in patients with Parkinson disease with the G2019S mutation in LRRK2.

OBJECTIVE: The LRRK2(G2019S) mutation is the most common identifiable cause for Parkinson disease (PD), but the underlying mechanisms leading to neuronal cell death remain largely unclear. Impaired mitochondrial function and morphology have been described in different in vivo and in vitro model systems of early-onset PD (EOPD) as well as in EOPD patient tissue. The aim of our study was to assess mitochondrial function and morphology in LRRK2(G2019S) mutant patient tissue to determine whether impaired mitochondrial function and morphology are shared features in early-onset and late-onset PD. METHODS: Skin biopsies were taken from 5 patients with PD with the LRRK2(G2019S) mutation. Assessment of mitochondrial membrane potential and intracellular ATP levels as well as substrate-linked mitochondrial ATP production assays were all carried out on 3 independent cell preparations per patient. Results were compared to 5 age-matched controls. Mitochondrial elongation and interconnectivity was assessed using previously published methods. RESULTS: Both mitochondrial membrane potential and total intracellular ATP levels were decreased in the G2019S mutation carriers. Subsequently undertaken mitochondrial ATP production assays suggested that the observed reduction is at least partially due to impaired mitochondrial function. Mitochondrial elongation and interconnectivity were increased in the LRRK2(G2019S) patient cohort. CONCLUSION: Our results provide evidence for impaired mitochondrial function and morphology in LRRK2(G2019S) mutant patient tissue. Further studies are required to determine whether the impaired mitochondrial function is due to increased LRRK2 kinase activity or other mechanisms such as LRRK2 haploinsufficiency.

Novel pathogenic LRRK2 p.Asn1437His substitution in familial Parkinson's disease.

Genealogical investigation of a large Norwegian family (F04) with autosomal dominant parkinsonism has identified 18 affected family members over four generations. Genetic studies have revealed a novel pathogenic LRRK2 mutation c.4309 A>C (p.Asn1437His) that co-segregates with disease manifestation (LOD = 3.15, θ = 0). Affected carriers have an early age at onset (48 ± 7.7 SD years) and are clinically asymmetric and levodopa responsive. The variant was absent in 623 Norwegian control subjects. Further screening of patients from the same population identified one additional affected carrier (1 of 692) with familial parkinsonism who shares the same haplotype. The mutation is located within the Roc domain of the protein and enhances GTP-binding and kinase activity, further implicating these activities as the mechanisms that underlie LRRK2-linked parkinsonism.

Genealogical studies in LRRK2-associated Parkinson's disease in central Norway.

The most common mutation related to Parkinson's disease (PD) is the p.G2019S mutation in the LRRK2 gene. Global population frequencies and crude estimates of haplotype conservation suggest most carriers are related. A total of 671 Norwegian PD patients and 215 of their family members were screened for the LRRK2 p.G2019S mutation. Twenty-one PD cases and 44 family members were positive for the mutation and all could be traced back to 10 different families. A genealogical study employed data from the Norwegian National Family Record Centre, local parish registers and population censuses. A common ancestor couple (living between 1580 and 1650) was found in six families, and two other families were associated by intermarriage. The remaining two families could not be traced back to either of these ancestors, though chromosome 12q12 haplotype analysis showed p.G2019S carriers shared alleles for 15 markers in the LRRK2 region. The study provides support for a common ancestor in Norwegian families with LRRK2 p.G2019S parkinsonism. The mutation was probably introduced to Norway through tradesmen from Europe. The extended pedigree that now links modern day carriers may help in mapping penetrance modifiers.

Biomarkers: Parkinson disease with dementia and dementia with Lewy bodies.

Dementia is a common feature in Parkinson disease (PD), the time of onset determining how patients are classified. Those patients where dementia develops prior to parkinsonism or during the first year of disease are designated as having dementia with Lewy bodies (DLB). In those where dementia develops over a year after the onset of motor signs, the condition is known as Parkinson's disease with dementia (PDD). While this seems at first sight to be a definitive way to distinguish these conditions, reality is rather different. The overlap between them is considerable, and there is much uncertainty associated with patients who have both motor symptoms and early cognitive impairment. The diagnosis is still based on medical history and clinical evaluation. It is not even certain that they can be accurately distinguished at autopsy. For this reason, the data concerning these entities have been reviewed, to examine various markers employed or measured in clinical, neuropathological, neuroimaging, and biochemical investigations. The concept of PDD and DLB being separate conditions is comparatively new, and the most promising tools with which to separate them at present are cerebrospinal fluid (CSF) markers and positron emission tomography (PET) scanning that indicate increased amyloid-beta burden in DLB compared to PDD. However as yet there are no markers that unequivocally distinguish between PDD and DLB.