Corticotropin-releasing hormone as a candidate biomarker for parkinsonian disorders

Accepted September 14, 1998. From the Neuropharmacology Unit, Defense and Veterans Head Injury Program, Henry M. Jackson Foundation, and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland; Veterans Administration Medical Center GRECC, Bedford, Massachusetts; and Departments of Neurology and Pathology, Boston University Medical School, Boston, Massachusetts. Address correspondence to Dr. Litvan, Neuropharmacology Unit, Defense and Veterans Head Injury Program, Henry M. Jackson Foundation, NINDS, NIH, Federal Building, Room 714, 7550 Wisconsin Avenue, Bethesda, MD 20892-9130; e-mail: litvan1@helix.nih.gov Copyright q 1999 American Psychiatric Press, Inc. Clinicopathologic Case Report

The value of neurofilament light chain (NfL) levels as a biomarker for the diagnosis and differential diagnosis in patients with Parkinson's disease (PD) and atypical parkinsonian syndromes (APS) remains controversial. Furthermore, few studies have directly compared NfL levels among specific APS categories. This study aimed to compare cerebrospinal fluid (CSF) and blood NfL levels among PD, APS, other PD-related disorders, and controls, as well as rank NfL levels across these groups. PubMed, Embase, Web of Science, and the Cochrane Library were searched from the inception up to November 1st, 2024, to identify eligible studies reporting CSF or blood NfL concentrations in PD, PD dementia (PDD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), dementia with Lewy bodies (DLB), corticobasal syndrome (CBS), vascular parkinsonism (VP), essential tremor (ET), idiopathic rapid eye movement sleep behavior disorder (iRBD), and controls. The Bayesian approach was utilized to estimate the standardized mean difference (SMD) and the associated 95% credible intervals (CrIs) of NfL levels. The surface under the cumulative ranking curve (SUCRA) was employed to evaluate the ranking probabilities of NfL levels. Subgroup analysis and meta-regression were conducted to explore the sources of heterogeneity. The present network meta-analysis (NMA) included 78 studies with 13,120 participants (4050 controls, 5021 PD, 191 PDD, 1173 MSA, 887 PSP, 1254 DLB, 319 CBS, 160 ET, 65 iRBD, and 0 VP). Of these, the NMA of CSF NfL included 34 studies with 6,013 participants, while the NMA of blood NfL included 49 studies with 7,787 participants. Both CSF and blood NfL levels were significantly elevated in patients with PD and APS compared to controls. Compared to PD patients, CSF NfL levels were significantly elevated in MSA (SMD 1.85; 95% CrI 1.55-2.15), CBS (1.42; 1.08-1.75), PSP (1.35; 1.06-1.64), and DLB 0.52; 0.20-0.85) patients. Similarly, blood NfL levels were significantly higher in patients with MSA (1.36; 1.02-1.71), PDD (1.19; 0.65-1.72), PSP (1.15; 0.77-1.54), CBS (0.92; 0.11-1.72), and DLB (0.63; 0.14-1.12) compared to PD. Among APS, CSF NfL levels in MSA patients were significantly higher than those in PSP, DLB, and CBS patients, while blood NfL levels in MSA patients were significantly higher only compared to DLB. In both CSF and blood NfL, MSA patients exhibited the highest probability of ranking first for NfL level elevations (CSF: SUCRA = 0.998; blood: SUCRA = 0.925). Age significantly influenced the SMD of the comparison between MSA and PD in CSF NfL (β = -0.15; p = 0.016). CSF and blood NfL levels in PD and APS are higher than those in controls, and all APS categories show higher levels than PD, suggesting that NfL levels may serve as a potential biomarker for the differential diagnosis between PD and APS. However, caution is warranted when using NfL as a diagnostic biomarker for PD. Significant differences in NfL levels are also observed between certain APS categories. Patients with MSA exhibit the highest NfL levels among PD and related disorders.

Haloperidol in the Treatment of Agitation and Psychosis of Lewy Body Dementia after Failure of Second Generation Antipsychotic: Case Report and Literature Review

Long‐term cognitive and motor decline across the spectrum of Lewy body disease

MOLECULAR PERTURBATIONS IN SYNUCLEINOPATHY DISORDERS: INSIGHTS FROM PRE-CLINICAL TO HUMAN NEUROPATHOLOGY

Background: Effective therapies for dementia with Lewy bodies (DLB) and Parkinson's disease (PD) dementia will require accurate diagnosis and an understanding of the contribution of distinct molecular pathologies to these diseases. We seek to use imaging biomarkers to improve diagnostic accuracy and to clarify the contribution of molecular species to cognitive impairment in DLB and PD. Summary: We have performed cross-sectional and prospective cohort studies in subjects with DLB, PD with normal cognition, PD with mild cognitive impairment and PD with dementia, contrasted with Alzheimer's disease (AD) and healthy control subjects (HCS). Subjects underwent formal neurological examination, detailed neuropsychological assessments, MRI and PET scans with the radioligands altropane (a dopamine transporter, DAT) and Pittsburgh compound B (PiB; β-amyloid). Putamen DAT concentrations were similar in DLB and PD and differentiated them from HCS and AD. Decreased caudate DAT concentration related to functional impairment in DLB but not PD. PiB uptake was greatest in DLB. However, cortical PiB retention was common in PD and predicted cognitive decline. PET imaging of tau aggregates holds promise both to clarify the contribution of tau to cognitive decline in these diseases and to differentiate DLB and PD from the parkinsonian tauopathies. Key Messages: Together, DAT and amyloid PET imaging discriminate DLB from PD and from other disease groups and identify pathological processes that contribute to their course. Multimodal PET imaging has the potential to increase the diagnostic accuracy of DLB and PD in the clinic, improve cohort uniformity for clinical trials, and serve as biomarkers for targeted molecular therapies.

Previous Cochrane reviews have considered the use of cholinesterase inhibitors in both Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB). The clinical features of DLB and PDD have much in common and are distinguished primarily on the basis of whether or not parkinsonism precedes dementia by more than a year. Patients with both conditions have particularly severe deficits in cortical levels of the neurotransmitter acetylcholine. Therefore, blocking its breakdown using cholinesterase inhibitors may lead to clinical improvement. To assess the efficacy, safety and tolerability of cholinesterase inhibitors in dementia with Lewy bodies (DLB), Parkinson's disease with dementia (PDD), and cognitive impairment in Parkinson's disease falling short of dementia (CIND-PD) (considered as separate phenomena and also grouped together as Lewy body disease). The trials were identified from a search of ALOIS, the Specialised Register of the Cochrane Dementia and Cognitive Improvement Group (on 30 August 2011) using the search terms Lewy, Parkinson, PDD, DLB, LBD. This register consists of records from major healthcare databases (MEDLINE, EMBASE, PsycINFO, CINAHL) and many ongoing trial databases and is updated regularly.Reference lists of relevant studies were searched for additional trials. Randomised, double-blind, placebo-controlled trials assessing the efficacy of treatment with cholinesterase inhibitors in DLB, PDD and cognitive impairment in Parkinson's disease (CIND-PD). Data were extracted from published reports by one review author (MR). The data for each 'condition' (that is DLB, PDD or CIND-PD) were considered separately and, where possible, also pooled together. Statistical analysis was conducted using Review Manager version 5.0. Six trials met the inclusion criteria for this review, in which a total of 1236 participants were randomised. Four of the trials were of a parallel group design and two cross-over trials were included. Four of the trials included participants with a diagnosis of Parkinson's disease with dementia (Aarsland 2002a; Dubois 2007; Emre 2004; Ravina 2005), of which Dubois 2007 remains unpublished. Leroi 2004 included patients with cognitive impairment and Parkinson's disease (both with and without dementia). Patients with dementia with Lewy bodies (DLB) were included in only one of the trials (McKeith 2000).For global assessment, three trials comparing cholinesterase inhibitor treatment to placebo in PDD (Aarsland 2002a; Emre 2004; Ravina 2005) reported a difference in the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) score of -0.38, favouring the cholinesterase inhibitors (95% CI -0.56 to -0.24, P < 0.0001).For cognitive function, a pooled estimate of the effect of cholinesterase inhibitors on cognitive function measures was consistent with the presence of a therapeutic benefit (standardised mean difference (SMD) -0.34, 95% CI -0.46 to -0.23, P < 0.00001). There was evidence of a positive effect of cholinesterase inhibitors on the Mini-Mental State Examination (MMSE) in patients with PDD (WMD 1.09, 95% CI 0.45 to 1.73, P = 0.0008) and in the single PDD and CIND-PD trial (WMD 1.05, 95% CI 0.42 to 1.68, P = 0.01) but not in the single DLB trial.For behavioural disturbance, analysis of the pooled continuous data relating to behavioural disturbance rating scales favoured treatment with cholinesterase inhibitors (SMD -0.20, 95% CI -0.36 to -0.04, P = 0.01).For activities of daily living, combined data for the ADCS and the Unified Parkinson's Disease Rating Scale (UPDRS) activities of daily living rating scales favoured treatment with cholinesterase inhibitors (SMD -0.20, 95% CI -0.38 to -0.02, P = 0.03).For safety and tolerability, those taking a cholinesterase inhibitor were more likely to experience an adverse event (318/452 versus 668/842; odds ratio (OR) 1.64, 95% CI 1.26 to 2.15, P = 0.0003) and to drop out (128/465 versus 45/279; OR 1.94, 95% CI 1.33 to 2.84, P = 0.0006). Adverse events were more common amongst those taking rivastigmine (357/421 versus 173/240; OR 2.28, 95% CI 1.53 to 3.38, P < 0.0001) but not those taking donepezil (311/421 versus 145/212; OR 1.24, 95% CI 0.86 to 1.80, P = 0.25). Parkinsonian symptoms in particular tremor (64/739 versus 12/352; OR 2.71, 95% CI 1.44 to 5.09, P = 0.002), but not falls (P = 0.39), were reported more commonly in the treatment group but this did not have a significant impact on the UPDRS (total and motor) scores (P = 0.71). Fewer deaths occurred in the treatment group than in the placebo group (4/465 versus 9/279; OR 0.28, 95% CI 0.09 to 0.84, P = 0.03). The currently available evidence supports the use of cholinesterase inhibitors in patients with PDD, with a positive impact on global assessment, cognitive function, behavioural disturbance and activities of daily living rating scales. The effect in DLB remains unclear. There is no current disaggregated evidence to support their use in CIND-PD.

Objective: Parkinson’s disease (PD) has significant clinical overlaps with atypical parkinsonism syndromes (APS), which have a poorer treatment response and a more aggressive course than PD. We aimed to identify plasma biomarkers to differentiate PD from APS.Methods: Plasma samples (n = 204) were obtained from healthy controls and from patients with PD, dementia with Lewy bodies (DLB), multiple system atrophy, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), or frontotemporal dementia (FTD) with parkinsonism (FTD-P) or without parkinsonism. We measured plasma levels of α-synuclein, total tau, p-Tau181, and amyloid beta 42 (Aβ42) by immunomagnetic reduction-based immunoassay.Results: Plasma α-synuclein level was significantly increased in patients with PD and APS when compared with controls and FTD without parkinsonism (p < 0.01). Total tau and p-Tau181 were significantly increased in all disease groups compared to controls, especially in patients with FTD (p < 0.01). A multivariate and receiver operating characteristic curve analysis revealed that a cut-off value for Aβ42 multiplied by p-Tau181 for discriminating patients with FTD from patients with PD and APS was 92.66 (pg/ml)2, with an area under the curve (AUC) of 0.932. An α-synuclein cut-off of 0.1977 pg/ml could separate FTD-P from FTD without parkinsonism (AUC 0.947). In patients with predominant parkinsonism, an α-synuclein cut-off of 1.388 pg/ml differentiated patients with PD from those with APS (AUC 0.87).Conclusion: Our results suggest that integrated plasma biomarkers improve the differential diagnosis of PD from APS (PSP, CBD, DLB, and FTD-P).

This article summarizes the underlying biology and current diagnostic and treatment strategies for the cognitive and neuropsychiatric features of Parkinson disease (PD) and dementia with Lewy bodies (DLB). Cognitive impairment and neuropsychiatric symptoms have been increasingly recognized in PD and DLB, leading to improved diagnosis and treatment strategies. While PD is most associated with and diagnosed by the presence of motor symptoms, nonmotor symptoms can often be the most debilitating for patients. Neuropsychiatric symptoms are highly prevalent nonmotor features and include cognitive impairment, depression, anxiety, psychosis, impulse control disorders, and apathy. Neuropsychiatric symptoms can be difficult to recognize and diagnose in patients with PD, in part because of comorbidity and symptom overlap with core PD features. Treatment strategies are a combination of pharmacologic and nonpharmacologic interventions used in the general population and those specific to PD. DLB is a clinical dementia syndrome, often with similar cognitive, behavioral, autonomic, and motor features as PD. Moreover, DLB has shared underlying pathophysiology with PD, as both are associated with postmortem findings of α-synuclein neuropathology at autopsy and have shared genetic risk and prodromal symptoms. DLB is clinically differentiated from PD by the presenting features of cognitive impairment in DLB, compared with the variable onset of cognitive impairment occurring 1 year or more after established motor onset in PD. Thus, diagnosis and treatment of cognitive impairment and neuropsychiatric symptoms in DLB are similar to that of PD and have important implications for maintaining patient independence and providing support for caregivers because motor, cognitive, and neuropsychiatric symptoms have an additive effect on patient functional disability. A careful history and physical examination are often needed to accurately diagnose and treat the heterogeneous cognitive and behavioral symptoms of PD and DLB. Accurate diagnosis and treatment of neuropsychiatric symptoms and cognitive impairment in PD and DLB are important, as these are a considerable source of patient disability and caregiver burden.

The Role of NAC in Amyloidogenesis in Alzheimer's Disease

Objective To investigate the clinical features in patients with Parkinson disease with dementia (PDD) and dementia with lewy bodies (DLB), in order to provide evidence for clinical diagnosis. Methods 36 patients with DLB and 24 patients with PDD were collected in department of neurology of our hospital from March 2015 to December 2017. The severity of motor symptoms, cognitive function, and mental behavior symptoms were compared between the two groups. Results The course of disease in DLB group was significantly shorter than that in PDD group [(2.13±1.98)d vs.(5.65±3.59)d]. The scores of UPDRSⅢ and tremor in DLB group were lower than those in PDD group [(26.73±11.61) vs.(37.16±13.73), (2.59±1.83) vs.(5.15±3.59)], but the score of posture and gait disorder in DLB group was higher than that in PDD group [(9.16±1.64) vs.(6.35±2.48)] (P<0.05). The scores of MMSE, MoCA, and CDT in DLB group were lower than those in PDD group (P<0.05). The rates of illusion and emotional instability in DLB group were higher than those in PDD group, the rates of apathy, depression, anxiety, and sleep disorders in DLB group were lower than those in PDD group (P<0.05). Conclusion Cognitive impairment is more progressive in DLB patients compared with PDD patients. Hallucinations and emotional instability are more common in DLB patients, but depression, anxiety, and sleep disorders are more common in PDD patients. Key words: Dementia with lewy bodies; Parkinson disease with dementia; Clinical features

Parkinsonian disorders consist mostly of Parkinson’s disease (PD); other forms are relatively rare, although dementia with Lewy bodies (DLB) seems to be, after Alzheimer’s disease, one of the most common causes of dementia. Atypical parkinsonisms (other than idiopathic PD) include progressive supranuclear palsy (PSP), multiple system atrophy (MSA), corticobasal degeneration (CBD) and DLB. In addition to parkinsonism symptoms the most characteristic features of these disorders, sometimes called parkinsonism-plus syndromes, are cerebellar ataxia in MSA, apraxia in CBD, gaze palsy in PSP or early in the course of dementia in DLB, and minimal, sometimes moderate (in MSA or PSP) or complete lack (in CBD) of response to L-dopa therapy. When appraising the condition, it is vital to separate it from those conditions that mimic the appearance of PD, but that are caused by another underlying pathology. Because of the lack of biological markers, differential diagnosis has to be based mostly on clinical findings. Nevertheless, neuroimaging studies, utilizing MRI, SPECT and PET examinations, seem to be helpful in establishing diagnosis. Nuclear medicine uses different tracers, specific for the dopamine transporting system or dopamine receptor ligands, which makes it possible to differentiate presynaptic dopaminergic system involvement (seen in PD) from pre- and postsynaptic involvement in MSA or PSP. Highly asymmetric tracer uptake reflects the asymmetry of cortical-subcortical atrophy and is characteristic for CBD. All of these conditions are accompanied by different psychiatric problems. In PD, depression is the most common, followed by dementia and psychosis at late stages. In PSP, subcortical dementia is typical with frontal behavior. Dementia is less frequent and late in CBD, but usually is the first or early symptom in DLB, followed by parkinsonian features. Functional neuroimaging may be useful for assessment of the preclinical period of PD (with potential early neuroprotective therapy), the rate of progression (evaluation of the influence of drugs and stereotaxic surgery on disease progression), the role of different structures in late complications (dyskinesias, fluctuations), and differential diagnosis of PD with essential tremor and atypical parkinsonian disorders. These techniques may also be helpful for investigation of pathogenesis and pathology underlying the non-motor symptoms of PD and atypical parkinsonisms as depression, dementia and psychosis. This review summarizes recent applications of SPECT, PET, but also MRI in the study of parkinsonian disorders, in terms of differential diagnosis and understanding concomitant neuropsychiatric phenomena.

Redefining Bradykinesia.

Differentiating Alzheimer’s disease from dementia with Lewy bodies and Parkinson’s disease with (+)-[ 11C]dihydrotetrabenazine positron emission tomography

Sirs: Dementia with Lewy bodies (DLB) is clinically characterized by fluctuating cognitive impairment, visual hallucinations and parkinsonism [4]. It is the second most common neurodegenerative disease that causes dementia after Alzheimer’s disease (AD). One of the most distinct pathologic features in the brains of DLB patients is the prominent loss of nigrostriatal dopaminergic neurons similar to that in the brains of Parkinson’s disease (PD) patients. The previous SPECT and PET studies have shown that the assessment of nigrostriatal dopaminergic functions is useful in distinguishing between DLB and AD patients [2, 6]. In the present study, we measured the CSF levels of homovanillic acid (HVA), a major dopamine metabolite, in DLB and AD patients. We report here that the assessment of CSF HVA levels is also a possible marker for distinguishing DLB patients from AD patients. Although Weiner et al. [7] previously reported that CSF HVA levels in DLB patients were lower than those in AD patients, the number of samples was small (DLB, n = 8) and they did not show the normal control levels of CSF HVA. Sixty-five patients with PD without dementia (32 men and 33 women, 74.5 ± 5.6 years, mean ± SD), 14 patients with DLB (8 men and 6 women, 74.0 ± 7.8 years), 53 patients with AD (23 men and 30 women, 77.1 ± 6.8 years) and 34 normal control subjects (16 men and 18 women, 76.9 ± 6.4 years) were examined. There were no significant differences in age and gender among the four groups. The clinical diagnosis of DLB was based on the criteria of the consortium on DLB international workshop [4]. All the patients with DLB had at least two of the three core features of DLB (fluctuating cognition, recurrent visual hallucinations, and spontaneous parkinsonism). CT or MRI of the heads of these patients showed no focal brain lesions, including those of cerebrovascular disease. Thus, they were diagnosed as having probable DLB. The clinical diagnosis of AD was based on the NINCDS-ADRDA criteria [5]. The mean Mini-Mental State Examination (MMSE) scores (mean ± SD) were 15.1 ± 5.4 (5 to 23) in the DLB group and 16.1 ± 5.1 (0 to 23) in the AD group. The difference in MMSE scores between the two groups was not significant. The mean Hoehn and Yahr scores were 2.08 ± 0.56 in the PD group and 2.13 ± 0.64 in the DLB group. All the AD patients had no apparent extrapyramidal signs and could walk unassisted. After informed consent was obtained, CSF samples were collected from the patients by lumbar puncture. None of the patients took any antiparkinsonian drugs, neuroleptics, or antidepressants when the lumbar puncture was performed. Three milliliters of CSF was used for routine examination, and an additional 2 ml was stored at –70 °C until analysis. The CSF HVA levels were measured by injection of 80 μl of CSF into a high-performance liquid chromatography (HPLC) system equipped with 16 electrochemical sensors (CEAS Model 5500, ESA, Bedford, MA, USA). The mean CSF HVA values were compared by ANOVA with post hoc Scheffe’s analyses. The study protocol was reviewed and approved by the ethics committee of Tokyo Metropolitan Geriatric Hospital. CSF HVA levels were 37.1 ± 14.4 ng/ml in the control group, 14.5 ± 7.3 ng/ml in the PD group, 10.9 ± 9.0 ng/ml in the DLB group and 22.0 ± 10.9 ng/ml in the AD group (Fig. 1). CSF HVA levels were lower in the PD, DLB and AD groups than in the control subjects (p< 0.001, ANOVA). CSF HVA levels in the DLB and PD groups were much lower than those in the AD group (p< 0.01, ANOVA). The difference in CSF HVA levels between the PD and DLB groups was not significant. The cutoff value of 12.6 ng/ml could distinguish the DLB patients from the AD patients with a sensitivity of 78.6 % and a specificity of 79.2 %. We demonstrated a prominent reduction in CSF HVA levels in DLB patients. This finding is compatible with the pathological features that nigrostriatal dopaminergic neurons are severely degenerated in the DLB brain. As previously reported, CSF HVA levels were also lower in AD patients than in the control subjects [1]. However, CSF HVA levels in DLB patients were much lower than those in AD patients. The analysis of CSF HVA levels may be useful in distinguishing DLB patients from AD patients. Recently, we have shown that CSF Aβ42 levels are decreased and CSF tau levels are normal in DLB patients [3]. Although our results should be confirmed by postmortem examination, decreased As42, normal tau and decreased HVA levels may be the characteristic CSF features of DLB. LETTER TO THE EDITORS