Dementia with Lewy bodies: Impact of co-pathologies and implications for clinical trial design.

Dementia with Lewy bodies (DLB) is clinically defined by the presence of visual hallucinations, fluctuations, rapid eye movement (REM) sleep behavioral disorder, and parkinsonism. Neuropathologically, it is characterized by the presence of Lewy pathology. However, neuropathological studies have demonstrated the high prevalence of coexistent Alzheimer's disease, TAR DNA-binding protein 43 (TDP-43), and cerebrovascular pathologic cases. Due to their high prevalence and clinical impact on DLB individuals, clinical trials should account for these co-pathologies in their design and selection and the interpretation of biomarkers values and outcomes. Here we discuss the frequency of the different co-pathologies in DLB and their cross-sectional and longitudinal clinical impact. We then evaluate the utility and possible applications of disease-specific and disease-nonspecific biomarkers and how co-pathologies can impact these biomarkers. We propose a framework for integrating multi-modal biomarker fingerprints and step-wise selection and assessment of DLB individuals for clinical trials, monitoring target engagement, and interpreting outcomes in the setting of co-pathologies.

Prodromal Dementia With Lewy Bodies: Evolution of Symptoms and Predictors of Dementia Onset.

BACKGROUND: Research criteria for prodromal dementia with Lewy bodies (DLB) were published in 2020, but little is known regarding prodromal DLB in clinical settings. METHODS: We identified non-demented participants without neurodegenerative disease from the National Alzheimer's Coordinating Center Uniform Data Set who converted to DLB at a subsequent visit. Prevalence of neuropsychiatric and motor symptoms were examined up to 5 years prior to DLB diagnosis. RESULTS: The sample included 116 participants clinically diagnosed with DLB and 348 age and sex-matched (1:3) Healthy Controls. Motor slowing was present in approximately 70% of participants 3 years prior to DLB diagnosis. In the prodromal phase, 50% of DLB participants demonstrated gait disorder, 70% had rigidity, 20% endorsed visual hallucinations, and over 50% of participants endorsed REM sleep behavior disorder. Apathy, depression, and anxiety were common prodromal neuropsychiatric symptoms. The presence of 1+ core clinical features of DLB in combination with apathy, depression, or anxiety resulted in the greatest AUC (0.815; 95% CI: 0.767, 0.865) for distinguishing HC from prodromal DLB 1 year prior to diagnosis. The presence of 2+ core clinical features was also accurate in differentiating between groups (AUC = 0.806; 95% CI: 0.756, 0.855). CONCLUSION: A wide range of motor, neuropsychiatric and other core clinical symptoms are common in prodromal DLB. A combination of core clinical features, neuropsychiatric symptoms and cognitive impairment can accurately differentiate DLB from normal aging prior to dementia onset.

Selection of Normative Group Affects Rates of Mild Cognitive Impairment in Parkinson's Disease.

OBJECTIVE: The objective of this study was to examine the impact of different methods of standardizing cognitive data in the Parkinson's Progression Marker Initiative. METHODS: Cognitive data from 423 participants with Parkinson's disease were included (age = 61.7 [9.7], education = 15.6 [3.0]). Internal norms were calculated using the group mean and standard deviation of the healthy control group. Published norms were compared to the overall group mean of and to age-stratified norms from healthy controls for each neuropsychological test over 4 visits. Rates of mild cognitive impairment were calculated using established criteria. RESULTS: The use of internal norms resulted in lower standardized scores than published norms on all tests with the exception of memory and processing speed (P ≤ .001). Individuals were 1.5 to 2.1 times more likely to be diagnosed with mild cognitive impairment using internal norms than published norms. CONCLUSIONS: Standardization approaches with cognitive data are not interchangeable. Selection of a normative comparison group impacts research and clinical interpretations of cognitive data. © 2018 International Parkinson and Movement Disorder Society.

Neuropsychological Test Performance in Parkinsonism Without Dopaminergic Deficiency on [123I]-FP-CIT SPECT Imaging.

OBJECTIVES: To examine neuropsychological test performance among individuals clinically diagnosed with Parkinson's disease (PD) without evidence of dopaminergic deficiency on [123]I-CIT single photon emission computed tomography imaging. METHODS: Data were obtained from the Parkinson's Progression Marker Initiative. The sample included 59 participants with scans without evidence of dopaminergic deficiency (SWEDD), 412 with PD, and 114 healthy controls (HC). Tests included Judgment of Line Orientation, Letter-Number Sequencing, Symbol Digit Modalities, Hopkins Verbal Learning Test-Revised, and Letter and Category Fluency. Multivariate analysis of variance was used to compare standardized scores between the groups. RESULTS: There was a statistically significant difference in performances between the groups, F(14,1155)=5.04; p<.001; partial η2=.058. Pairwise comparisons revealed significant differences in Category Fluency between SWEDD (M=0.22; SD=1.08) and HC (M=0.86; SD=1.15) and in Symbol Digit Modalities Test performance between SWEDD (M=45.09; SD=11.54) and HC (M=51.75; SD=9.79). No significant differences between SWEDD and PD were found. Using established criteria, approximately one in four participants in the SWEDD and PD groups met criteria for mild cognitive impairment (MCI). CONCLUSIONS: Individuals with SWEDD demonstrate significantly worse mental processing speed and semantic fluency than HC. The neuropsychological test performances and rates of MCI were similar between the SWEDD group and PD groups, which may reflect a common pathology outside of the nigrostriatal pathway. (JINS, 2018, 24, 646-651).

Diagnostic Accuracy and Confidence in the Clinical Detection of Cognitive Impairment in Early-Stage Parkinson Disease.

BACKGROUND/AIMS: Mild cognitive impairment (MCI) is present in up to 34% of patients with early-stage Parkinson disease (PD); however, it is difficult to detect subtle impairment without objective cognitive testing. METHODS: Data were obtained from the Parkinson Progression Marker Initiative. All 341 participants were administered the Montreal Cognitive Assessment (MoCA) and a brief neuropsychological battery. Participants were classified as PD-MCI if MoCA was <26 or if they scored ≥1 standard deviation below the normative mean in 2 or more domains, based upon established criteria. The sensitivity/specificity for the clinical detection of PD-MCI was determined. RESULTS: Overall accuracy for clinical detection of PD-MCI was 67.4%. Although clinical determination was highly specific (96.3%; 95% confidence interval [CI]: 0.92-0.98), sensitivity was poor (32.0%; 95% CI: 0.25-0.40). CONCLUSION: Identifying MCI in early-stage PD based on clinical interview alone appears to be insufficient. The inclusion of objective cognitive tests allowing for normative sample comparisons is needed to increase the detection of cognitive impairment in this population.

Verbal Fluency in Parkinson's Patients with and without Bilateral Deep Brain Stimulation of the Subthalamic Nucleus: A Meta-analysis.

OBJECTIVES: Patients with Parkinson's disease often experience significant decline in verbal fluency over time; however, deep brain stimulation of the subthalamic nucleus (STN-DBS) is also associated with post-surgical declines in verbal fluency. The purpose of this study was to determine if Parkinson's patients who have undergone bilateral STN-DBS have greater impairment in verbal fluency compared to Parkinson's patients treated by medication only. METHODS: A literature search yielded over 140 articles and 10 articles met inclusion criteria. A total of 439 patients with Parkinson's disease who underwent bilateral STN-DBS and 392 non-surgical patients were included. Cohen's d, a measure of effect size, was calculated using a random effects model to compare post-treatment verbal fluency in patients with Parkinson's disease who underwent STN-DBS versus those in the non-surgical comparison group. RESULTS: The random effects model demonstrated a medium effect size for letter fluency (d=-0.47) and a small effect size for category fluency (d=-0.31), indicating individuals with bilateral STN-DBS had significantly worse verbal fluency performance than the non-surgical comparison group. CONCLUSIONS: Individuals with Parkinson's disease who have undergone bilateral STN-DBS experience greater deficits in letter and category verbal fluency compared to a non-surgical group.

Cognition in Patients With a Clinical Diagnosis of Parkinson Disease and Scans Without Evidence of Dopaminergic Deficit (SWEDD): 2-Year Follow-Up.

OBJECTIVE AND BACKGROUND: More than 10% of patients clinically diagnosed with Parkinson disease demonstrate normal dopamine uptake on dopamine transporter single-photon emission computed tomography (DaTscan), but little is known about how cognitive function differs between patients with dopamine deficiency on DaTscan and patients with scans without evidence of dopaminergic deficit (SWEDD). We compared the cognitive function of these two groups of patients over 2 years. METHODS: We retrospectively analyzed data obtained from the Parkinson's Progression Markers Initiative on 309 participants clinically diagnosed with idiopathic Parkinson disease who had scored in the normal range on the Montreal Cognitive Assessment at baseline and had completed 1- and 2-year follow-up visits. We compared the Montreal Cognitive Assessment scores at 1 and 2 years between the 42 participants with SWEDD and the 267 with dopamine deficiency. RESULTS: Mean cognitive scores did not differ significantly between groups at 1 year, but at 2 years the participants with SWEDD performed more poorly. At 2 years, 31% of the participants with SWEDD versus 15% of those with dopamine deficiency had statistically reliable cognitive impairment. CONCLUSIONS: This study provides evidence that some individuals clinically diagnosed with idiopathic Parkinson disease but with SWEDD demonstrate early cognitive decline. The results also suggest that recently diagnosed patients with SWEDD may be at even greater risk for cognitive decline than patients with DaTscan-confirmed early-stage Parkinson disease. While patients with SWEDD likely represent a heterogeneous group of etiologies, our results highlight the need to monitor these patients' cognitive function over time.

Differentiating Prodromal Dementia with Lewy Bodies from Prodromal Alzheimer's Disease: A Pragmatic Review for Clinicians.

This pragmatic review synthesises the current understanding of prodromal dementia with Lewy bodies (pDLB) and prodromal Alzheimer's disease (pAD), including clinical presentations, neuropsychological profiles, neuropsychiatric symptoms, biomarkers, and indications for disease management. The core clinical features of dementia with Lewy bodies (DLB)-parkinsonism, complex visual hallucinations, cognitive fluctuations, and REM sleep behaviour disorder are common prodromal symptoms. Supportive clinical features of pDLB include severe neuroleptic sensitivity, as well as autonomic and neuropsychiatric symptoms. The neuropsychological profile in mild cognitive impairment attributable to Lewy body pathology (MCI-LB) tends to include impairment in visuospatial skills and executive functioning, distinguishing it from MCI due to AD, which typically presents with impairment in memory. pDLB may present with cognitive impairment, psychiatric symptoms, and/or recurrent episodes of delirium, indicating that it is not necessarily synonymous with MCI-LB. Imaging, fluid and other biomarkers may play a crucial role in differentiating pDLB from pAD. The current MCI-LB criteria recognise low dopamine transporter uptake using positron emission tomography or single photon emission computed tomography (SPECT), loss of REM atonia on polysomnography, and sympathetic cardiac denervation using meta-iodobenzylguanidine SPECT as indicative biomarkers with slowing of dominant frequency on EEG among others as supportive biomarkers. This review also highlights the emergence of fluid and skin-based biomarkers. There is little research evidence for the treatment of pDLB, but pharmacological and non-pharmacological treatments for DLB may be discussed with patients. Non-pharmacological interventions such as diet, exercise, and cognitive stimulation may provide benefit, while evaluation and management of contributing factors like medications and sleep disturbances are vital. There is a need to expand research across diverse patient populations to address existing disparities in clinical trial participation. In conclusion, an early and accurate diagnosis of pDLB or pAD presents an opportunity for tailored interventions, improved healthcare outcomes, and enhanced quality of life for patients and care partners.

The Burden of Dementia Spectrum Disorders and Associated Comorbid and Demographic Features.

Dementia spectrum disorders (DSDs) are a major cause of mortality and disability worldwide. DSDs encompass a large group of medical conditions that all ultimately lead to major functional and cognitive decline and disability. Demographic and comorbid conditions that are associated with DSDs have significant prognostic and preventive implications. In this article, we will discuss the global and regional burden of DSDs and cover key demographic and clinical conditions linked with DSDs. In the absence of disease-modifying treatments, the role of primary prevention has become more prominent. Implementation of preventive measures requires an understanding of predisposing and exacerbating factors.

Sex differences in dementia with Lewy bodies: Focused review of available evidence and future directions.

In this review, we summarize the current knowledge on sex differences in dementia with Lewy bodies (DLB) relating to epidemiology, clinical features, neuropathology, biomarkers, disease progression, and caregiving. While many studies show a higher DLB prevalence in men, this finding is inconsistent and varies by study approach. Visual hallucinations may be more common and occur earlier in women with DLB, whereas REM sleep behavior disorder may be more common and occur earlier in men. Several studies report a higher frequency of parkinsonism in men with DLB, while the frequency of fluctuations appears similar between sexes. Women tend to be older, have greater cognitive impairment at their initial visit, and are delayed in meeting DLB criteria compared to men. Women are also more likely to have Lewy body disease with co-existing AD-related pathology than so-called "pure" Lewy body disease, while men may present with either. Research is mixed regarding the impact of sex on DLB progression. Biomarker and treatment research assessing for sex differences is lacking. Women provide the majority of caregiving in DLB but how this affects the caregiving experience is uncertain. Gaining a better understanding of sex differences will be instrumental in aiding future development of sex-specific strategies in DLB for early diagnosis, care, and drug development.

Clinical outcome measures in dementia with Lewy bodies trials: critique and recommendations.

The selection of appropriate outcome measures is fundamental to the design of any successful clinical trial. Although dementia with Lewy bodies (DLB) is one of the most common neurodegenerative conditions, assessment of therapeutic benefit in clinical trials often relies on tools developed for other conditions, such as Alzheimer's or Parkinson's disease. These may not be sufficiently valid or sensitive to treatment changes in DLB, decreasing their utility. In this review, we discuss the limitations and strengths of selected available tools used to measure DLB-associated outcomes in clinical trials and highlight the potential roles for more specific objective measures. We emphasize that the existing outcome measures require validation in the DLB population and that DLB-specific outcomes need to be developed. Finally, we highlight how the selection of outcome measures may vary between symptomatic and disease-modifying therapy trials.

Neuropsychological Test Performances and Depression in Early-Stage De Novo Parkinson's Disease.

OBJECTIVE: Evaluate neuropsychological test performance in depressed patients with early-stage Parkinson's disease. METHOD: Data from 422 participants from the Parkinson's Progression Marker Initiative were examined. The Geriatric Depression Scale-15 was used to categorize depressed and non-depressed participants. Neuropsychological tests measured verbal learning/memory, processing speed, visuospatial ability, verbal fluency, and working memory. Demographic and clinical variables were compared using independent samples t tests and chi-square analyses.Linear regression models were fit to adjust for age, years of education, and symptom duration. RESULTS: The non-depressed group (n = 280) was significantly older; t(246.08) = 2.25, p = .026 and had higher education; t(420) = 2.35, p = .019; and longer duration of PD symptoms; t(170.58) = -2.13, p = .035 than the depressed group (n = 142). The non-depressed group performed better on a working memory task than the depressed group, t(420) = 2.05, p = .041, but the results did not appear to be of clinical significance. There was no significant difference between other cognitive domains. The results were not influenced by age, education, or disease duration. CONCLUSIONS: Among patients with early-stage, untreated Parkinson's disease, depression does not appear to affect neuropsychological test performance. Clinicians should demonstrate caution in over-interpreting the influence of depression on cognition in this population.

Adherence to Pharmacotherapy in Patients With Parkinson's Disease Taking Three and More Daily Doses of Medication.

Background: Once-daily treatment formulation is associated with better adherence in comparison to more complex medication regimens. The study aimed to detect the extent of adherence to pharmacotherapy in Parkinson disease (PD) patients who take a minimum of three daily doses of drugs, and to identify factors associated with lower levels of adherence. Methods: The cohort was selected from non-demented PD patients. The 8-Item Morisky Medication Adherence Scale (MMAS-8), 8-Item Parkinson's Disease Questionnaire (PDQ-8), Geriatric Depression Scale (GDS), Non-Motor Symptom Assessment Scale (NMSS), 9-Item Wearing-off Questionnaire (WOQ-9), MDS-UPDRS III (motor examination), and IV (motor complications) scales were used in this study. Results: From a total of 124 subjects, 33.9% reported a high level of adherence, 29.8% reported a medium level of adherence, and 36.3% reported a low level of adherence to their pharmacotherapy. The level of non-adherence correlated with gender, longer disease duration, higher scores of PDQ-8, NMSS, WOQ-9, and MDS-UPDRS IV. Detailed analysis of NMSS demonstrated a correlation between the level of adherence and domains sleep/fatigue, mood/cognition, perceptual problems/hallucinations, attention/memory, and urinary symptoms. Independent risk factors for non-adherence were excessive daytime sleepiness, anhedonia, and forgetfulness. Conclusion: Non-adherence to more complicated medication regimens is frequent in PD patients and is associated with gender, longer PD duration, poorer quality of life, frequency and severity of non-motor symptoms, and more severe motor and non-motor fluctuations. Non-adherence was predicted by non-motor symptoms including fatigue, mood disturbances, and subjective cognitive complaints.

Rates of Abnormally Low TOPF Word Reading Scores in Individuals Failing Versus Passing Performance Validity Testing.

The present study examined the impact of performance validity test (PVT) failure on the Test of Premorbid Functioning (TOPF) in a sample of 252 neuropsychological patients. Word reading performance differed significantly according to PVT failure status, and number of PVTs failed accounted for 7.4% of the variance in word reading performance, even after controlling for education. Furthermore, individuals failing ≥2 PVTs were twice as likely as individuals passing all PVTs (33% vs. 16%) to have abnormally low obtained word reading scores relative to demographically predicted scores when using a normative base rate of 10% to define abnormality. When compared with standardization study clinical groups, those failing ≥2 PVTs were twice as likely as patients with moderate to severe traumatic brain injury and as likely as patients with Alzheimer's dementia to obtain abnormally low TOPF word reading scores. Findings indicate that TOPF word reading based estimates of premorbid functioning should not be interpreted in individuals invalidating cognitive testing.

Frontotemporal Lobe Degeneration as Origin of Scans Without Evidence of Dopaminergic Deficit.

The term scans without evidence of dopaminergic deficit (SWEDD) can be associated with any patient diagnosed at first with Parkinson's disease but with a negative dopamine transporter-single photon emission computed tomography (DaTSPECT), which does not confirm the presynaptic dopaminergic deficiency. Therefore, an alternative diagnosis should be sought to support parkinsonism as a clinical diagnosis. Parkinsonism is a well-known manifestation of frontotemporal lobar degeneration (FTLD), particularly frequent in those with positive DaTSPECT. Here, we reinforce previous observations that parkinsonism can be present in FTLD patients with negative DaTSPECT and therefore, FTLD may account for a percentage of patients with SWEDD. We gather the clinical observations supporting this hypothesis and describe a case report illustrating this idea. Studies suggest the result of DaTSPECT in FTLD may depend on the neuropathology and clinical subtype. However, most studies do not provide a clinical description of the clinical subtype or pathological features making the association between subtypes of FTLD and DaTSPECT results impossible at the moment. Further studies correlating clinical, neuropsychological, neuroimaging, genetic, and pathology findings are needed to better understand parkinsonism in FTLD.

DEVELOPMENT OF CLINICAL DEMENTIA RATING SCALE CUTOFF SCORES FOR PATIENTS WITH PARKINSON'S DISEASE.

BACKGROUND: The purpose of this study was to explore validity of the Clinical Dementia Rating Scale in measuring cognitive impairment among individuals with Parkinson's disease. The scale was created for use in patients with Alzheimer's disease and, to date, there have been no published studies examining if this tool is appropriate for patients with Parkinson's disease. METHODS: The data were obtained from the National Alzheimer's Coordinating Center database and included 490 subjects diagnosed with Parkinson's disease, further categorized as having Parkinson's disease dementia (n= 151), mild cognitive impairment (n= 186), or normal cognition (n = 153) by a treating physician. Sensitivity, specificity, positive predictive value and negative predictive values were calculated for the Clinical Dementia Rating Scale Global Score as well as the Sum of Boxes Score using existing cutoff scores. Finally, new cutoff scores were calculated using sensitivity and specificity values derived using Receiver Operating Characteristic curves. RESULTS: Sensitivity and specificity of the published Global Score cutoff scores for patients with dementia were .34 and .10, respectively. The newly calculated cutoff scores for patients with dementia yielded a sensitivity of .79 and a specificity of .96. The area under the curve was 0.92 (95% CI = 0.90-0.95). CONCLUSION: The CDR is a useful tool in identifying dementia in patients with Parkinson's disease when the cutoff scores are adjusted.