Is the functional decline of Parkinson's disease similar to the functional decline of Alzheimer's disease?

Since many Parkinson's disease (PD) subjects develop dementia, we determined whether the correlation between functional and cognitive decline seen in Alzheimer's disease (AD) is seen in PD. Seventy-five PD subjects with and without dementia and 103 AD/MCI subjects underwent the Functional Assessment Staging (FAST), the Global Deterioration Scale (GDS), the UPDRS motor portion, and the MMSE. In AD/MCI subjects, changes in FAST and GDS scores correlated with MMSE (rho=-0.814, P<0.001; rho=-0.840, P<0.001, respectively). In PD subjects, the FAST and GDS also correlated with MMSE (rho=-0.675, P<0.001; rho=-0.647, P<0.001, respectively). The UPDRS correlated with the GDS and FAST more closely in PD than in AD. Similar to AD, functional declines in PD correlates with cognitive decline and may be influenced by motor disability in PD.     

How valid is the clinical diagnosis of Parkinson's disease in the community?

BACKGROUND: Many patients diagnosed with Parkinson's disease are later found to have an erroneous diagnosis, often only when they come to necropsy; conversely, many patients with Parkinson's disease in the community remain undiagnosed. OBJECTIVE: To assess the validity of a clinical diagnosis of parkinsonism in the general population according to strict published criteria. METHODS: As part of a population based study on the prevalence of Parkinson's disease in London, all patients were identified with a diagnosis of parkinsonism, tremor with onset over age 50 years, or who had ever received antiparkinsonian drugs. All patients who agreed to participate were diagnosed according to strict clinical diagnostic criteria, after a detailed neurological interview and examination and discussion of the findings with examination of their video recordings. Follow up information was obtained over a period of at least one year, and atypical cases were reviewed at the end of the study. RESULTS: A diagnosis of probable Parkinson's disease was confirmed in 83% of patients with this diagnosis, including three (2%) in whom atypical features were found that were insufficient to discard a diagnosis of Parkinson's disease. Two additional patients (2%) were found to have possible Parkinson's disease. However, in 15% of patients the diagnosis was unequivocally rejected. Conversely, 13 patients who had previously not been diagnosed with Parkinson's disease (19%) were found to have this disorder. CONCLUSIONS: At least 15% of patients with a diagnosis of Parkinson's disease in the population do not fulfil strict clinical criteria for the disease, and approximately 20% of patients with Parkinson's disease who have already come to medical attention have not been diagnosed as such.     

Patterns of α-synuclein pathology in incidental cases and clinical subtypes of Parkinson's disease

Parkinson's disease (PD) is characterized by a gradual accumulation of neuropathology that may begin many years before a clinical diagnosis can be made using currently accepted criteria. Here, we first review the prevalence of α-synuclein neuropathology in elderly and discuss its clinical relevance in Parkinson patients. Subsequently, the results of a retrospective study focussing on the distribution of neuropathology in Parkinson patients with a tremor-dominant (TD), non-tremordominant (NTD) or rapid disease progression (RDP) subtype are presented. The study population recruited by the Netherlands Brain bank consisted of 149 non-neurological donors, 26 donors with incidental Lewy body disease (iLBD) and 111 Parkinson patients. In total, 89% of these cases could be classified in accordance with the Braak staging when taking into account the severity of α-synuclein pathology and adding an amygdala-predominant category of synucleinopathy. The pathological progression seemed to be non-linear. Interestingly, a strong correlation between neuronal loss and α-synuclein pathology was observed in the substantia nigra in Braak stages 3-6 (P < 0.01). However, there was no correlation between Hoehn & Yahr and Braak stages. Neuropathological progression may, however, vary between subtypes as cortical Lewy body load and Braak stages were higher in patients with NTD compared to TD and Alzheimer pathology was more prevalent in RDP patients. Recognition of clinical subtypes in neuropathological studies is essential to identify selective vulnerability to protein accumulation that may determine the clinical phenotype in PD.     

Do prothrombotic factors influence clinical phenotype of severe haemophilia? A review of the literature

There is considerable variability in bleeding patterns of severe haemophilia (<1% factor VIII). Knowledge of the contribution of thrombophilic factors in these patterns may improve individually tailored treatment strategies. We reviewed the literature regarding the relation between prothrombotic factors and clinical phenotype of severe haemophilia. Medline and EMBASE were searched for relevant articles. 9369 articles published between 1963 and September 2003 were screened and seven relevant papers were retrieved. Each of these reported on a different combination of thrombophilic factors. Presence of the factor V Leiden mutation appears to decrease the severity of severe haemophilia most consistently. Findings on other thrombophilic factors were inconclusive. There is a clear need for additional research on potential determinants of phenotypes of severe haemophilia before such knowledge can be translated into individual care for severe haemophilia patients with confidence.     

Can the emotional connotation of concepts modulate the lexico-semantic deficits in Alzheimer's disease?

Semantic memory impairments are a common symptom of Alzheimer's disease (AD) and may occur at a relatively early stage. These disturbances can be evidenced by a hyperpriming effect (greater semantic priming in AD patients than in controls). Up till now, very few studies of semantic memory have included emotionally charged concepts. Our aim was therefore to study the semantic processing of such concepts, as opposed to neutral ones, in early AD. Given that emotional processes are relatively preserved at the beginning of the disease compared with other cognitive functions, we expected that an emotional connotation would influence the spreading activation of words and affect some of the impairments in semantic processing. We administered a semantic priming task (lexical decision task) implicitly assessing semantic memory to 26 patients with AD and 26 normal controls. Primes and targets either had a semantic relationship (e.g. tiger-lion), a semantic and emotional (positive or negative) relationship (e.g. slap-smack) or no relationship at all (e.g. chair-horse), or else belonged to a word-nonword condition (e.g. window-inuly). Compared with controls, the patients showed pathological hyperpriming effects in all conditions, especially in the emotional conditions. Hyperpriming implies a deterioration in specific attributes, as it is difficult to tell two concepts apart once their distinctive attributes have been lost. These results suggest that emotional concepts, like neutral ones, lose some of their distinctive attributes in early AD, and as the emotional processes are preserved, there is greater similarity between close emotional concepts than between close neutral concepts.     

Can estrogen play a significant role in the prevention of Alzheimer's disease?

In women the abrupt decline estrogen levels at menopause may be associated with cognitive deficits and increased risk for Alzheimer's disease (AD); estrogen replacement therapy may reduce this risk. Animal studies indicate that estrogen modulates neurotransmitter systems, regulates synaptogenesis, and is neuroprotective. These beneficial effects occur in brain areas critical to cognitive function and involved in AD. Reduced estrogen levels can compromise neuronal function and survival. Estrogen replacement therapy can reverse cognitive deficits associated with low estrogen levels and may reduce the risk of AD. However, clinical trials for estrogen replacement in the treatment of AD have produced ambiguous results. Initial, small, open-label and double blind clinical trials indicated improved cognitive function in women with AD. Recent large trials failed to show a beneficial effect for long-term estrogen replacement for women with AD. There are several variables that could affect these results, such as genetic factors, time between estrogen loss and replacement, extent and types of AD pathology, and other environmental and health factors. Presently large prospective studies are being conducted as the National Institutes of Health in the Women's Health Initiative and the Preventing Postmenopausal Memory Loss and Alzheimer's with Replacement Estrogens studies to provide a better assessment of the role of estrogen for age related health issues, including dementia.     

Apathy: a complex symptom specific to the clinical pattern of presentation of Parkinson's disease?

There is currently no consensus on the nosological position of apathy in clinical practice, although many different articles indicate that apathy is a common, behavioral disturbance in the general Parkinson's disease (PD) population, often related to severe motor symptoms, hypothesizing that the dysfunction of the nigrostriatal pathway may play an important role in its pathophysiology. However, not all patients with PD become apathetic, indicating that apathy should not entirely be considered a dopamine-dependent syndrome in PD. The aim of this study was to examine the prevalence and clinical correlates of apathy in a representative community-based sample of patients within 2 variants of the PD: akinetic-rigid type and tremor-dominant type. Specifically, we wanted to investigate whether these 2 variants of PD would present with apathy as a primary behavioral disorder and whether apathy could be associated with different cognitive and behavioral disorders. Apathy is present in both the groups but significantly more evident in the akinetic-rigid group associated with frontal impairment but not related to motor impairment or depression. We discuss the results, starting with anatomical and physiological brain studies.     

Which factors influence therapeutic decisions in Parkinson's disease?

Development of dyskinesia is a common phenomenon during the long-term course of Parkinson's disease. During the last few years, some but not all pathogenetic mechanisms causing dyskinesias in PD have become better understood. Severity of Parkinson's disease and levodopa dosing are the main clinical risk factors. Most concepts underline the significance of pulsatile D1-receptor stimulation for the development of dyskinesias. The interactions between D1- and D2-mediated STR-Gpi pathways and colocalized neuropeptides are important but not fully understood. Glutamatergic overactivity might also be a significant pathogenetic factor. According to these pathophysiological concepts, therapeutic strategies focus mainly on continuous postsynaptic DA-receptor stimulation by long-acting DA-agonists or highly selective D2-agonists. Another strategy is the use of NMDA antagonists.     

Can mouse models mimic sporadic Alzheimer's disease?

Alzheimer's disease(AD) is a progressive neurodegenerative disorder and the most common form of dementia worldwide. As age is the main risk factor, 97% of all AD cases are of sporadic origin, potentiated by various risk factors associated with life style and starting at an age 60 years. Only 3% of AD cases are of genetic origin caused by mutations in the amyloid precursor protein or Presenilins 1 or 2, and symptoms already start at an age 30 years. In order to study progression of AD, as well as therapeutic strategies, mouse models are state-of-the-art. So far many transgenic mouse models have been developed and used, with mutations in the APP or presenilin or combinations(3×Tg, 5×Tg). However, such transgenic mouse models more likely mimic the genetic form of AD and no information can be given how sporadic forms develop. Several risk genes, such as Apolipoprotein E4 and TREM-2 enhance the risk of sporadic AD, but also many risk factors associated with life style(e.g., diabetes, hypercholesterolemia, stress) may play a role. In this review we discuss the current situation regarding AD mouse models, and the problems to develop a sporadic mouse model of AD.     

Can we prevent Alzheimer's disease? Secondary “prevention” trials in Alzheimer's disease

Current research including the basic biology of Alzheimer's disease (AD) provides a foundation to explore whether our current state of knowledge is sufficient to initiate prevention studies and allow us to believe prevention of AD is possible. Current research and recently revised criteria for the diagnosis of AD by the National Institutes on Aging and the Alzheimer's Association suggest a continuum of disease from preclinical asymptomatic to symptomatic Alzheimer's dementia. In light of these revised criteria, the possibility of secondary prevention and even primary prevention is under discussion. The Alzheimer's Association Research Roundtable convened a meeting to discuss the rationale and feasibility of conducting secondary prevention trials in AD.