Martin W. Kurz

The epidemiology of dementia associated with Parkinson disease

Several recent studies have shown that dementia is common in Parkinsons disease (PD), and that in some patients, cognitive impairment occurs even at the time of diagnosis. The point prevalence of dementia in PD is close to 30% and the incidence rate is increased 4-6 times as compared to controls. The cumulative prevalence is very high, at least 75% of PD patients who survive for more than 10 years will develop dementia. The mean time from onset of PD to dementia is approximately 10 years. However, there are considerable variations, and some patients develop dementia early in the disease course. Earlier onset of dementia is associated with more structural brain changes. The most established risk factors for early dementia are old age, severity of motor symptoms, in particular postural and gait disturbances, mild cognitive impairment and visual hallucinations. The genetic contributions to dementia are currently not clear and need to be explored in future studies.

The Epidemiology of Dementia Associated with Parkinson's Disease

Parkinsons disease (PD) is the second most common neurodegenerative illness after Alzheimers disease (AD). Cognitive impairment and dementia are common features in PD and characterized by a wide range of cognitive deficits distinct from those seen in AD. Mild cognitive impairment occurs even early in PD and is associated with shorter time to dementia. The purpose of this review is to present recent findings on clinical aspects of dementia in PD and to elucidate underlying clinical and neurobiological risk factors.

CSF amyloid-beta and tau proteins, and cognitive performance, in early and untreated Parkinson's Disease: the Norwegian ParkWest study

Background Alzheimers disease (AD) pathology is found in a considerable portion of patients with Parkinsons disease (PD), particularly those with early dementia (PDD). Altered cerebrospinal fluid (CSF) levels of amyloid-β (Aβ) and tau proteins have been found in PDD, with intermediate changes for Aβ42 in non-demented PD. The authors investigated whether AD-related CSF protein levels are altered and relate to neuropsychological performance in early, untreated PD. Methods CSF concentrations of Aβ42, Aβ40 and Aβ38 were measured by electrochemiluminiscene and levels of total tau (T-tau) and phosphorylated tau (P-tau) by ELISA in 109 newly diagnosed, unmedicated, non-demented, community-based PD patients who had undergone comprehensive neuropsychological testing, and were compared with those of 36 age-matched normal controls and 20 subjects with mild AD. Results PD patients displayed significant reductions in Aβ42 (19%; p=0.009), Aβ40 (15.5%; p=0.008) and Aβ38 (23%; p=0.004) but not T-tau (p=0.816) or P-tau (p=0.531) compared with controls. CSF Aβ42 reductions in PD were less marked than in AD (53%; p=0.002). Sequential regression analyses demonstrated significant associations between CSF levels of Aβ42 (β=0.205; p=0.019), Aβ40 (β=0.378; p<0.001) and Aβ38 (β=0.288; p=0.001) and memory impairment, but not executive-attentional or visuospatial dysfunction. Tau protein levels did not correlate with cognitive measures. Conclusion CSF Aβ levels are altered in a subset of patients with early PD and relate to memory impairment. Our study suggests that alterations in Aβ protein metabolism may contribute to the heterogeneity in pattern and course of cognitive decline associated with PD. Longitudinal studies are needed to clarify the clinical significance of CSF Aβ peptides as prognostic biomarkers in PD.

Cigarette smoking in Parkinson's disease: Influence on disease progression

Previous studies have shown an inverse association between smoking and the prevalence of Parkinsons disease (PD), suggesting that smoking may induce a biological protection against nigral neuronal damage. In 1993, we examined the frequency of cigarette smokers among 239 patients with PD and two control groups. In addition, the progression of parkinsonism and other clinical features were followed prospectively in smoking and nonsmoking PD patients over an 8‐year period. Mortality in the two PD groups was also examined. We found a 50% higher prevalence of smokers in the control groups than in patients with PD. In contrast, during the follow‐up period, there were no significant differences in progression of parkinsonism, cognitive impairment, and mood in smoking and nonsmoking patients with PD. Mortality was also similar in the two groups. The lack of influence on disease progression may indicate that cigarette smoking does not have a major neuroprotective effect in patients with already diagnosed PD.

APOE Alleles in Parkinson Disease and Their Relationship to Cognitive Decline: A Population-based, Longitudinal Study

Apolipoprotein E gene alleles have been linked to various cardiovascular and neurodegenerative disorders. There have been conflicting reports of associations between Apolipoprotein E alleles and Parkinson disease and Parkinson disease dementia. To investigate the role of Apolipoprotein E alleles in Parkinson disease and Parkinson disease dementia, we have determined Apolipoprotein E genotypes in a group of patients with Parkinson disease (n = 95) and compared them with those of healthy control participants (n = 73). Additionally, in 64 longitudinally followed patients with Parkinson disease, the allele types were correlated to development and progression of dementia and to time from onset of Parkinson disease to dementia using multivariate and survival analyses. The Apolipoprotein E e4e4 genotype was more common in patients with Parkinson disease (7.4%) than in healthy controls (1.4%; P = .03). No significant associations between the Apolipoprotein E genotype and development and progression of dementia or time to dementia were found. More studies with larger Parkinson disease samples are warranted.

Early Discriminatory Diagnosis of Dementia with Lewy Bodies The Emerging Role of CSF and Imaging Biomarkers

Background: The clinical diagnostic criteria for dementia with Lewy bodies (DLB) have a low sensitivity, and there are no generally accepted biomarkers to distinguish DLB from other dementias. Our aim was to identify biomarkers that may differentiate DLB from Alzheimer’s disease (AD). Method: We performed a systematic literature search for studies of EEG, imaging techniques and genetic and CSF markers that provide sensitivity and specificity in the identification of DLB. Results: The best evidence was for scintigraphy of the striatal dopamine transporter system using FP-CIT SPECT. Several small scintigraphy studies of cardiovascular autonomic function using metaiodobenzylguanidine SPECT have reported promising results. Studies exploring innovative techniques based on CSF have reported interesting findings for the combination of amyloid β (aβ) isoforms as well as α-synuclein, and there are interesting results emerging from preliminary studies applying proteomic techniques. Data from studies using structural MRI, perfusion SPECT, genetics and EEG studies show differences between DLB and AD but only at a group level. Conclusion: Several potential biomarkers for the differential diagnosis of probable DLB and AD have shown good diagnostic accuracy in the research setting. Data from large multicentre studies and from studies with autopsy confirmation exist for scintigraphy of the dopamine transporter system. Future studies should explore its value in possible DLB and for clinical management and health economics.

Depression in mild dementia: associations with diagnosis, APOE genotype and clinical features.

Depression is common in dementia, with important clinical implications. Few studies of depression in dementia with Lewy bodies are available, and the results are inconsistent.

Cerebrospinal fluid Aβ levels correlate with structural brain changes in Parkinson's disease.

ParkWest is a large Norwegian multicenter study of newly diagnosed drug‐naïve subjects with Parkinsons disease (PD). Cognitively normal PD subjects (PDCN) and PD subjects with mild cognitive impairment (PDMCI) from this cohort have significant hippocampal atrophy and ventricular enlargement, compared to normal controls. Here, we aimed to investigate whether the same structural changes are associated with cerebrospinal fluid (CSF) levels of amyloid beta (Aβ)38, Aβ40, Aβ42, total tau (t‐tau), and phosphorylated tau (p‐tau). We performed three‐dimensional radial distance analyses of the hippocampi and lateral ventricles using the MRI data from ParkWest subjects who provided CSF at baseline. Our sample consisted of 73 PDCN and 18 PDMCI subjects. We found significant associations between levels of all three CSF Aβ analytes and t‐tau and lateral ventricular enlargement in the pooled sample. In the PDCN sample, all three amyloid analytes showed significant associations with the radial distance of the occipital and frontal horns of the lateral ventricles. CSF Aβ38 and Aβ42 showed negative associations, with enlargement in occipital and frontal horns of the lateral ventricles in the pooled sample, and a negative association with the occipital horns in PDMCI. CSF Aβ levels in early PD correlate with ventricular enlargement, previously associated with PD dementia. Therefore, CSF and MRI markers may help identify PD patients at high risk for developing cognitive decline and dementia in the course of their illness. Contrary to Alzheimers disease, we found no associations between CSF t‐tau and p‐tau and hippocampal atrophy.

Tenecteplase versus alteplase for management of acute ischaemic stroke (NOR-TEST): a phase 3, randomised, open-label, blinded endpoint trial

BACKGROUND Tenecteplase is a newer thrombolytic agent with some pharmacological advantages over alteplase. Previous phase 2 trials of tenecteplase in acute ischaemic stroke have shown promising results. We aimed to investigate the safety and efficacy of tenecteplase versus alteplase in patients with acute stroke who were eligible for intravenous thrombolysis. METHODS This phase 3, randomised, open-label, blinded endpoint, superiority trial was done in 13 stroke units in Norway. We enrolled adults with suspected acute ischaemic stroke who were eligible for thrombolysis and admitted within 4·5 h of symptom onset or within 4·5 h of awakening with symptoms, or who were eligible for bridging therapy before thrombectomy. Patients were randomly assigned (1:1) to receive intravenous tenecteplase 0·4 mg/kg (to a maximum of 40 mg) or alteplase 0·9 mg/kg (to a maximum of 90 mg), via a block randomisation schedule stratified by centre of inclusion. Patients were not informed of treatment allocation; treating physicians were aware of treatment allocation but those assessing the primary and secondary endpoints were not. The primary outcome was excellent functional outcome defined as modified Rankin Scale (mRS) score 0-1 at 3 months. The primary analysis was an unadjusted and non-stratified intention-to-treat analysis with last observation carried forward for imputation of missing data. This study is registered with ClinicalTrials.gov, number NCT01949948. FINDINGS Between Sept 1, 2012, and Sept 30, 2016, 1107 patients met the inclusion criteria and seven patients were excluded because informed consent was withdrawn or eligibility for thrombolytic treatment was reconsidered. 1100 patients were randomly assigned to the tenecteplase (n=549) or alteplase (n=551) groups. The median age of participants was 77 years (IQR 64-79) and the median National Institutes of Health Stroke Scale score at baseline was 4 points (IQR 2-8). A final diagnosis other than ischaemic stroke or transient ischaemic attack was found in 99 (18%) patients in the tenecteplase group and 91 (17%) patients in the alteplase group. The primary outcome was achieved by 354 (64%) patients in the tenecteplase group and 345 (63%) patients in the alteplase group (odds ratio 1·08, 95% CI 0·84-1·38; p=0·52). By 3 months, 29 (5%) patients had died in the tenecteplase group compared with 26 (5%) in the alteplase group. The frequency of serious adverse events was similar between groups (145 [26%] in the tenecteplase group vs 141 [26%] in the alteplase group; p=0·74). INTERPRETATION Tenecteplase was not superior to alteplase and showed a similar safety profile. Most patients enrolled in this study had mild stroke. Further trials are needed to establish the safety and efficacy in patients with severe stroke and whether tenecteplase is non-inferior to alteplase. FUNDING Research Council of Norway.

Acute ischemic stroke--from symptom recognition to thrombolysis.

The understanding of stroke has changed in the recent years from rehabilitation to an emergency approach. We review existing data from symptom recognition to thrombolysis and identify challenges in the different phases of patient treatment.