Brainstem pathology and non-motor symptoms in PD

Parkinson`s disease (PD) is considered a multisystem disorder involving dopaminergic, noradrenergic. serotoninergic. and cholinergic systems, characterized by motor and non-motor symptoms. The causes of the non-motor symptoms in PD are multifactorial and unlikely to be explained by single lesions However, several evidence link them to damage of specific brainstem nuclei Numerous brainstem nuclei are engaged in fundamental homeostatic mechanisms, including gastrointestinal regulation, pain perception, mood control, and sleep-wake cycles In addition, these nuclei are locally interconnected in a complex manner and are subject to supraspinal control. The objective of this review is to provide a better overview of the current knowledge about the consequences of the involvement of specific brainstem nuclei to the most prevalent non-motor symptoms occurring in PD The multidisciplinary efforts of research directed to these non-nigral brainstem nuclei, in addition to the topographical and chronological spread of the disease - especially in the prodromal stages of PD. are discussed (C) 2009 Elsevier B V. All rights reserved

Consensus neuropathological diagnosis of common dementia syndromes: testing and standardising the use of multiple diagnostic criteria

The aim of this study was to assess the variation between neuropathologists in the diagnosis of common dementia syndromes when multiple published protocols are applied. Fourteen out of 18 Australian neuropathologists participated in diagnosing 20 cases (16 cases of dementia, 4 age-matched controls) using consensus diagnostic methods. Diagnostic criteria, clinical synopses and slides from multiple brain regions were sent to participants who were asked for case diagnoses. Diagnostic sensitivity, specificity, predictive value, accuracy and variability were determined using percentage agreement and kappa statistics. Using CERAD criteria, there was a high inter-rater agreement for cases with probable and definite Alzheimer's disease but low agreement for cases with possible Alzheimer's disease. Braak staging and the application of criteria for dementia with Lewy bodies also resulted in high inter-rater agreement. There was poor agreement for the diagnosis of frontotemporal dementia and for identifying small vessel disease. Participants rarely diagnosed more than one disease in any case. To improve efficiency when applying multiple diagnostic criteria, several simplifications were proposed and tested on 5 of the original 210 cases. Inter-rater reliability for the diagnosis of Alzheimer's disease and dementia with Lewy bodies significantly improved. Further development of simple and accurate methods to identify small vessel lesions and diagnose frontotemporal dementia is warranted.

Clinical diagnosis of 80 cases of dementia in a university hospital

OBJECTIVE: This study aims to estimate the prevalence of dementia subtypes and to assess the socio-demographic data of patients attending the outpatient clinic of dementia at Hospital das Clínicas from January 2008 to December 2009, in the city of Goiânia-GO, Brazil. METHODS: Procedures provided for diagnosis included physical and neurological examination, laboratory tests, neuroimaging and DSM-IV. The functional capacity and level of cognitive deficit were assessed by Pfeffer Functional Activities Questionnaire (Pfeffer-FAQ) and Mini-Mental State Examination (MMSE), respectively. RESULTS: Eighty patients met the criteria for dementia. The mean age was 63.48 (± 16.85) years old, the schooling was 3.30 (± 3.59) years old, the MMSE was 13.89 (± 7.79) and Pfeffer 17.73 (± 9.76). The Vascular Dementia (VD; 17.5%) was the most frequent cause of dementia, followed by Lewy body dementia (LBD) and Alzheimer's disease (AD) (12.25%). CONCLUSION: Considering entire sample and only the elderly over 60 years, VD, AD and LBD are the most common subtypes observed at both groups. Further epidemiological studies are necessary to confirm such rates, which may have a considerable impact on the organization and planning of healthcare services in our country.

Myocardial MIBG scintigraphy: a useful clinical tool? : A retrospective study in 50 parkinsonian patients.

Meta-iodbenzylguanidine scintigraphy (MIBG scintigraphy) shows reduced uptake in idiopathic Parkinson's disease (IPD), idiopathic REM sleep behavior disorder (IRBD) and Lewy body dementia (LBD), but not in other parkinsonian or dementia syndromes. We retrospectively reevaluated 50 patients. Concordance rate between last clinical diagnosis and scintigraphy diagnosis was only given in two-thirds of the patients. Confounding factors were: decreasing heart/mediastinum ratio (HMR) with progressive age, higher HMR in women and possibly interference with antihypertensive medication. Standardization of the methods and precise clinical guidelines are warranted for better clinical use.

Familial frontotemporal dementia with ubiquitin inclusion bodies and without motor neuron disease.

Frontotemporal dementia (FTD) is the second most common degenerative dementia after Alzheimer's disease and its Lewy body variant. Clinical pathology can be subdivided in three main neuropathological subtypes: frontal lobe dementia, Pick's disease and FTD with motor neuron disease (MND), all characterised by distinct histological features. Until recently the presence of ubiquitin-positive intraneuronal inclusions in the dentate gyrus, and the temporal and frontal cortex was usually associated with the MND type. Such inclusions were also observed in a few sporadic cases of FTD without or with parkinsonism (FTDP) in the absence of MND. We present here clinical, neuropathological and immunohistochemical data about a Swiss FTD family with FTDP-like features but without MND. Spongiosis and mild gliosis were observed in the grey matter. No neurofibrillary tangles, Pick bodies, Lewy bodies, senile plaques or prion-positive signals were present. However, ubiquitin-positive intracytoplasmic inclusions were detected in various structures but predominantly in the dentate gyrus. These observations support the existence of a familial form of FTDP with ubiquitin-positive intracytoplasmic inclusions (Swiss FTDP family).

CSF biomarkers for the differential diagnosis of Alzheimer's disease: A large-scale international multicenter study.

INTRODUCTION: The aim of this study was to test the diagnostic value of cerebrospinal fluid (CSF) beta-amyloid (Aβ1-42), phosphorylated tau, and total tau (tau) to discriminate Alzheimer's disease (AD) dementia from other forms of dementia. METHODS: A total of 675 CSF samples collected at eight memory clinics were obtained from healthy controls, AD dementia, subjective memory impairment, mild cognitive impairment, vascular dementia, Lewy body dementia (LBD), fronto-temporal dementia (FTD), depression, or other neurological diseases. RESULTS: CSF Aβ1-42 showed the best diagnostic accuracy among the CSF biomarkers. At a sensitivity of 85%, the specificity to differentiate AD dementia against other diagnoses ranged from 42% (for LBD, 95% confidence interval or CI = 32-62) to 77% (for FTD, 95% CI = 62-90). DISCUSSION: CSF Aβ1-42 discriminates AD dementia from FTD, but shows significant overlap with other non-AD forms of dementia, possibly reflecting the underlying mixed pathologies.

Utilidad de la electromiografía de esfínter anal en el diagnóstico diferencial de la atrofia multisistémica: una revisión de la literatura

La atrofia multisistémica (AMS) es una enfermedad degenerativa caracterizada por disautonomías y síntomas extrapiramidales. El diagnóstico diferencial con otros parkinsonismos es difícil, por lo cual se requiere una ayuda paraclínica para soportar el diagnóstico clínico. La degeneración del núcleo de Onuf, exclusiva en esta enfermedad, podría sugerir que la presencia de denervación en el esfínter anal podría ser tomada en cuenta como criterio diagnóstico de AMS. Se realizó una revisión sistemática con el fin de determinar la utilidad de la electromiografía de esfínter anal (EMG-EA) en el diagnóstico diferencial de AMS contra otros parkinsonismos. Se incluyeron 17 estudios que analizaron los resultados de EMG-EA en pacientes con AMS. De éstos, 11 de estudios fueron analíticos y compararon pacientes con AMS y otros parkinsonismos. Los 6 estudios restantes fueron descriptivos. La duración de los potenciales de unidad motora (PUM) es significativamente mayor en pacientes con AMS comparados con otros parkinsonismos, y utilizando un punto de corte > 13 ms muestra características operativas que hacen a este parámetro potencialmente útil. Solo un estudio encontró diferencias significativas en el porcentaje de PUM polifásicos, el cual tuvo una sensibilidad y especificidad clínicamente útil cuando el punto de corte es mayor a 60%. El resto de los estudios no reportan diferencias estadísticamente significativas entre parkinsonismos. La literatura disponible apunta a la potencial utilidad de la EMG-EA en el diagnóstico diferencial de la AMS de otros parkinsonismos; sin embargo es necesario conducir más estudios para solventar las limitaciones metodológicas existentes.

Multicenter Analysis of Glucocerebrosidase Mutations in Parkinson`s Disease

Background Recent studies indicate an increased frequency of mutations in the gene encoding glucocerebrosidase (GBA), a deficiency of which causes Gaucher`s disease, among patients with Parkinson`s disease. We aimed to ascertain the frequency of GBA mutations in an ethnically diverse group of patients with Parkinson`s disease. Methods Sixteen centers participated in our international, collaborative study: five from the Americas, six from Europe, two from Israel, and three from Asia. Each center genotyped a standard DNA panel to permit comparison of the genotyping results across centers. Genotypes and phenotypic data from a total of 5691 patients with Parkinson`s disease (780 Ashkenazi Jews) and 4898 controls (387 Ashkenazi Jews) were analyzed, with multivariate logistic-regression models and the Mantel-Haenszel procedure used to estimate odds ratios across centers. Results All 16 centers could detect two GBA mutations, L444P and N370S. Among Ashkenazi Jewish subjects, either mutation was found in 15% of patients and 3% of controls, and among non-Ashkenazi Jewish subjects, either mutation was found in 3% of patients and less than 1% of controls. GBA was fully sequenced for 1883 non-Ashkenazi Jewish patients, and mutations were identified in 7%, showing that limited mutation screening can miss half the mutant alleles. The odds ratio for any GBA mutation in patients versus controls was 5.43 across centers. As compared with patients who did not carry a GBA mutation, those with a GBA mutation presented earlier with the disease, were more likely to have affected relatives, and were more likely to have atypical clinical manifestations. Conclusions Data collected from 16 centers demonstrate that there is a strong association between GBA mutations and Parkinson`s disease.

Orthostatic hypotension in Parkinson's disease: association with cognitive decline?

BACKGROUND Orthostatic hypotension is common in Lewy body disorders and may be related to disease progression and the spread of Lewy body pathology. We therefore hypothesize that PD patients with orthostatic hypotension (OH) have a different cognitive profile compared to PD patients without OH. METHODS This cross-sectional study included 175 PD patients. Blood pressure (BP) was measured with a validated digital blood pressure monitor and patients with a systolic BP drop of > or =20 mmHg or a systolic pressure of <90 mm Hg after standing were considered to have OH. Cognition was assessed using MMSE extended by a selection of computerized cognitive tests focusing on reaction time, sustained attention, working memory and episodic verbal and visual memory. RESULTS Eighty-seven (49.7%) of the PD patients had OH. These patients were significantly more impaired in sustained attention and visual episodic memory compared to PD patients without OH. CONCLUSION We conclude that there are differences in the neuropsychological performance of patients with PD and OH, supporting the hypothesis that OH might be a marker for disease progression and cognitive decline in PD.

Latrepirdine stimulates autophagy and reduces accumulation of α-synuclein in cells and in mouse brain

Latrepirdine (Dimebon; dimebolin) is a neuroactive compound that was associated with enhanced cognition, neuroprotection and neurogenesis in laboratory animals, and has entered phase II clinical trials for both Alzheimer's disease and Huntington's disease (HD). Based on recent indications that latrepirdine protects cells against cytotoxicity associated with expression of aggregatable neurodegeneration-related proteins, including Aβ42 and γ-synuclein, we sought to determine whether latrepirdine offers protection to Saccharomyces cerevisiae. We utilized separate and parallel expression in yeast of several neurodegeneration-related proteins, including α-synuclein (α-syn), the amyotrophic lateral sclerosis-associated genes TDP43 and FUS, and the HD-associated protein huntingtin with a 103 copy-polyglutamine expansion (HTT gene; htt-103Q). Latrepirdine effects on α-syn clearance and toxicity were also measured following treatment of SH-SY5Y cells or chronic treatment of wild-type mice. Latrepirdine only protected yeast against the cytotoxicity associated with α-syn, and this appeared to occur via induction of autophagy. We further report that latrepirdine stimulated the degradation of α-syn in differentiated SH-SY5Y neurons, and in mouse brain following chronic administration, in parallel with elevation of the levels of markers of autophagic activity. Ongoing experiments will determine the utility of latrepirdine to abrogate α-syn accumulation in transgenic mouse models of α-syn neuropathology. We propose that latrepirdine may represent a novel scaffold for discovery of robust pro-autophagic/anti-neurodegeneration compounds, which might yield clinical benefit for synucleinopathies including Parkinson's disease, Lewy body dementia, rapid eye movement (REM) sleep disorder and/or multiple system atrophy, following optimization of its pro-autophagic and pro-neurogenic activities.

The dementia cognitive fluctuation scale, a new psychometric test for clinicians to identify cognitive fluctuations in people with dementia.

OBJECTIVES Cognitive fluctuation (CF) is a common feature of dementia and a core diagnostic symptom for dementia with Lewy bodies (DLB). CF remains difficult to accurately and reliably detect clinically. This study aimed to develop a psychometric test that could be used by clinicians to facilitate the identification of CF and improve the recognition and diagnosis of DLB and Parkinson disease, and to improve differential diagnosis of other dementias. METHODS We compiled a 17-item psychometric test for identifying CF and applied this measure in a cross-sectional design. Participants were recruited from the North East of England, and assessments were made in individuals' homes. We recruited people with four subtypes of dementia and a healthy comparison group, and all subjects were administered this pilot scale together with other standard ratings. The psychometric properties of the scale were examined with exploratory factor analysis. We also examined the ability of individual items to identify CF to discriminate between dementia subtypes. The sensitivity and specificity of discriminating items were explored along with validity and reliability analyses. RESULTS Participants comprised 32 comparison subjects, 30 people with Alzheimer disease, 30 with vascular dementia, 29 with DLB, and 32 with dementia associated with Parkinson disease. Four items significantly discriminated between dementia groups and showed good levels of sensitivity (range: 78.6%-80.3%) and specificity (range: 73.9%-79.3%). The scale had very good levels of test-retest (Cronbach's alpha: 0.82) and interrater (0.81) reliabilities. The four items loaded onto three different factors. These items were: 1) marked differences in functioning during the daytime; 2) daytime somnolence; 3) daytime drowsiness; and 4) altered levels of consciousness during the day. CONCLUSIONS We identified four items that provide valid, sensitive, and specific questions for reliably identifying CF and distinguishing the Lewy body dementias from other major causes of dementia (Alzheimer disease and vascular dementia).

Transgenic mice carrying a human mutant superoxide dismutase transgene develop neuronal cytoskeletal pathology resembling human amyotrophic lateral sclerosis lesions.

Mutations in the human Cu,Zn superoxide dismutase gene (SOD1) are found in 20% of kindreds with familial amyotrophic lateral sclerosis. Transgenic mice (line G1H) expressing a human SOD1 containing a mutation of Gly-93 --> Ala (G93A) develop a motor neuron disease similar to familial amyotrophic lateral sclerosis, but transgenic mice (line N1029) expressing a wild-type human SOD1 transgene do not. Because neurofilament (NF)-rich inclusions in spinal motor neurons are characteristic of amyotrophic lateral sclerosis, we asked whether mutant G1H and/or N1029 mice develop similar NF lesions. NF inclusions (i.e., spheroids, Lewy body-like inclusions) were first detected in spinal cord motor neurons of the G1H mice at 82 days of age about the time these mice first showed clinical evidence of disease. Other neuronal intermediate filament proteins (alpha-internexin, peripherin) also accumulated in these spheroids. The onset of accumulations of ubiquitin immunoreactivity in the G1H mice paralleled the emergence of vacuoles and NF-rich spheroids in neurons, but they did not colocalize exclusively with spheroids. In contrast, NF inclusions were not seen in the N1029 mice until they were 132 days old, and ubiquitin immunoreactivity was not increased in the N1029 mice even at 199 days of age. Astrocytosis in spinal cord was associated with a marked increase in glial fibrillary acidic protein immunoreactivity in the G1H mice, but not in the N1029 mice. Finally, comparative studies revealed a striking similarity between the cytoskeletal pathology in the G1H transgenic mice and in patients with amyotrophic lateral sclerosis. These findings link a specific SOD1 mutation with alterations in the neuronal cytoskeleton of patients with amyotrophic lateral sclerosis. Thus, neuronal cytoskeletal abnormalities may be implicated in the pathogenesis of human familial amyotrophic lateral sclerosis.

Phosphorylated α-synuclein-immunoreactive retinal neuronal elements in Parkinson's disease subjects

Visual symptoms are relatively common in Parkinson's disease (PD) and optical coherence tomography has indicated possible retinal thinning. Accumulation of aggregated α-synuclein is thought to be a central pathogenic event in the PD brain but there have not as yet been reports of retinal synucleinopathy. Retinal wholemounts were prepared from subjects with a primary clinicopathological diagnosis of PD (N = 9), dementia with Lewy bodies (DLB; N = 3), Alzheimer's disease (N = 3), progressive supranuclear palsy (N = 2) as well as elderly normal control subjects (N = 4). These were immunohistochemically stained with an antibody against α-synuclein phosphorylated at serine 129, which is a specific molecular marker of synucleinopathy. Phosphorylated α-synuclein-immunoreactive (p-syn IR) nerve fibers were present in 7/9 PD subjects and in 1/3 DLB subjects; these were sparsely distributed and superficially located near or at the inner retinal surface. The fibers were either long and straight or branching, often with multiple en-passant varicosities along their length. The straight fibers most often had an orientation that was radial with respect to the optic disk. Together, these features are suggestive of either retinopetal/centrifugal fibers or of ganglion cell axons. In one PD subject there were sparse p-syn IR neuronal cell bodies with dendritic morphology suggestive of G19 retinal ganglion cells or intrinsically photosensitive ganglion cells. There were no stained nerve fibers or other specific staining in any of the non-PD or non-DLB subjects. It is possible that at least some of the observed visual function impairments in PD subjects might be due to α-synucleinopathy.

Prevalence of mixed neuropathologies in autopsied older adults and associations with clinical disease progression

Thesis (Ph.D.)--University of Washington, 2016-06