Matt Hoffman

This article, "Amyloid ß and Tau Pathology Linked to Dementia With Lewy Bodies Phenotype," was originally published in NeurologyLive.

The 2 Alzheimer disease pathologic proteins—amyloid-ß and tau—are common in individuals with probable 

 (DLB) and associated with the clinical phenotype.

Alzheimer's disease pathologic changes are common in DLB and are associated with the clinical phenotype. Amyloid-β is associated with cognitive impairment and tau pathology is associated with a lower frequency of clinical features of DLB. These findings have important implications for diagnosis, prognosis, and disease monitoring, as well as for clinical trials targeting disease-specific proteins in DLB.

Ultimately, the investigators observed that amyloid-β co-occurred with tau pathology in 15% of probable DLB patients, implying that about that percentage of probable DLB patients fulfill the biologic definition of Alzheimer, likely with mixed Lewy body disease pathology.

Conducted by Daniel Ferreira, PhD, assistant professor of neurobiology, care sciences and society, Division of Clinical Geriatrics, Karolinska Institut, and Department of Radiology, Mayo Clinic, and colleagues, the study stratified patients by amyloid-β (A+) and tau (T+) biomarker positivity, which was determined by cerebrospinal fluid (CSF) amyloid-β 1-42 and phosphorylated tau testing. The assessment included 417 patients with DLB.

Those who were A-T- made up the largest subgroup in the study population (n = 162; 39%), followed by A+T- (n = 135; 32%), A+T+ (n = 64; 15%), and A-T+ (n = 56; 13%). This distribution of amyloid-ß and tau pathology was strongly modulated by age (

 <.001) with the percentage of groups with an A+ biomarker doubling with older age.

In total at age 55, the A+T+ group made up 8% of the cohort and the A+T- group made up 19%. At age 85, those groups consisted of 25% and 45% of the cohort, respectively.

In contrast, the percentage of the A-T- group decreased to a third with older age, to 61% at age 55 compared to 20% at age 85. The percentage of the A-T+ group remained relatively comparable across ages.

“The novelty of our study is that it demonstrates the frequency of amyloid-β and tau biomarkers and several influencing factors in probable DLB patients during life across a wide age range. In this context, we interpret A+T- as an Alzheimer’s pathologic change and A+T+ as AD, that is, AD likely concomitant to Lewy body disease pathology in this cohort,” Ferreira and colleagues wrote.

As well, the AT group distribution also varied according to sex (

<.001). APOE ε4 positive status for each group was as follows: A-T- (28%), A-T+ (50%), A+T- (59%), A+T+ (64%).

All told, 55% of the A+T+ were men compared with the A- groups (A-T- and A-T+), both of which consisted of 75% men. APOE ε4 carriers were more common ingroups who were A+ or T+ (A+T-, 59%; A-T+, 50%; A+T+, 64%) compared with the A-T- group (28%).

“When plotting sex and APOE versus age we observed that the percentage of A+T- and A+T+ seemed to increase in parallel with age in both men and women,” Ferreira et al. wrote. “In APOE ε4 carriers, we observed that the A+ groups achieved higher percentages at younger ages than in APOE ε4 non-carriers, which considerably reduced the percentage of A- groups over the age of 70 in APOE ε4 carriers.”

Of the tests the group ran for heterogeneity across centers, none were statistically significant except for Mini-Mental State Exam (MMSE) by APOE ε4 carrier status (

= .02). MMSE scores for the A-T- group was 23.6, the A-T+ group was 22.6, the A+T- group was 21.5, and for the A+T+ group was 20.3.

Those with 1 or 2 positive biomarkers tended to be older (

 <.05)compared with the A-T- group. Those differences in MMSE were found to be independent of age and associated with both the A+ and T+ biomarker positivity, with no significant interaction between A+ and T+ observed (

The percentage of A-T- decreased with age and A+ and T+ increased with age both in women and men. The A+ biomarker increased more in 

 ε4 carriers with age than in non-carriers and was the main predictor of lower cognitive performance when considered together with T+. As well, T+ was associated with a lower frequency of parkinsonism and probable rapid eye movement sleep behavior disorder.

“Our data from multiple sites across Europe and the United States indicate that amyloid-β pathology is common in probable DLB, increases with age, and contributes to global cognitive impairment,” Ferreira and colleagues concluded. “Tau pathology is relatively less common and when present it seems to influence Lewy body disease clinical phenotype with a lower frequency of clinical features of probable DLB.

“These data may help to advance our ability to distinguish the clinical phenotype associated to concomitant AD pathology in patients with probable DLB, with potential implications for diagnosis, prognosis, and disease monitoring, as well as for clinical trials targeting disease-specific proteins in DLB,” they wrote.

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The findings of this multicenter cohort may have implications for diagnosis, prognosis, and disease monitoring, as well as for clinical trials targeting disease-specific proteins in DLB.

Alzheimer Pathologic Changes Linked to Dementia With Lewy Bodies Phenotype

This article, "Transient Orthostatic Hypotension Appears Common in Parkinson Disease" was originally published in NeurologyLive.

New data shows transient orthostatic hypotension (tOH) is at least as common as classic orthostatic hypotension (cOH) in patients with 

 (PD) and occurs as an age-dependent phenomenon.

The new assessment included 173 patients with Parkinson and an age- and gender-matched control group of the same size, and uncovered that tOH occurred in 24% (n = 41) of those with Parkinson compared to 21% (n = 37) of controls (OR, 1.1; 95% CI, 0.6–2.0; 

 = .759), while cOH occurred in 19% (n = 32) and 0%, respectively, and 12% (n = 20) of those with Parkinson fulfilled OH criteria after a single minute of standing.

Notably, 40% (n = 69) of patients with Parkinson had a history of falls, 29% of which were due to syncope. PD patients with history of orthostatic intolerance and syncope had a more severe systolic BP fall and lower diastolic BP rise upon standing, most pronounced in the first 30 to 60 seconds.

“Transient blood pressure falls when changing to the upright position may be overlooked with bedside blood pressure measurements but contribute to orthostatic intolerance and syncope in Parkinson disease,” the authors, including Alessandra Fanciulli, MD, PhD, department of neurology, Medizinische Universität Innsbruck, wrote in conclusion. “Continuous non-invasive blood pressure monitoring upon standing may help identify a modifiable risk factor for syncope-related falls in parkinsonian patients.”

Pathological blood pressure regulation upon standing was observed in 41% (n = 71)of patients with Parkinson and 21% (n = 37) of controls. After adjustment for the total number of drugs, use of anti-hypotensive, anti-hypertensive and central nervous system-acting drugs other than dopaminergic medications, patients with Parkinson showed an OR of 2.0 (95% CI, 1.2–3.5; 

 = .013) for any form of orthostatic blood pressure dysregulation.

The researchers defined tOH as a systolic blood pressure fall of ≥20 mmHg or diastolic ≥10 mmHg resolving within the 1st minute upon standing, and cOH as a sustained systolic BP fall of ≥20 mmHg or diastolic ≥10 mmHg within 3 minutes upon standing. “In those with Parkinson, we reviewed the medical records of the 6 months preceding and following autonomic testing for a history of falls, syncope, and orthostatic intolerance,” they noted.

When comparing the Parkinson cohort with the age- and gender-matched patients with orthostatic intolerance but a negative neurological history, there were similar frequencies of initial OH (iOH), although delayed orthostatic blood pressure recovery was significantly more frequent in those with Parkinson than in controls (

In the 6 months following or prior to cardiovascular autonomic function testing, syncope was documented in 13% (n = 22) of patients with Parkinson, occurring upon standing in all but 2 patients and was associated with falls (

History of syncope was present in 17% of the Parkinson group who had an altered blood pressure regulation upon standing and in 10% of those without.

“Performing a standing test under continuous heart rate and blood pressure monitoring may thus help in identifying a modifiable cause of syncope-related falls in patients with a suggestive medical history,” the investigators wrote.

The frequency of syncope did not differ between PD patients diagnosed with tOH versus cOH at cardiovascular autonomic function testing (10% versus 23%, respectively).

Upon standing, those with Parkinson and a history of syncope showed lower absolute systolic blood pressure values after 30 seconds (

 = .016), as well as more severe systolic blood pressure falls, which were most pronounced after 30 seconds (

“To the best of our knowledge, this is the first study specifically investigating tOH in Parkinson,” the researchers said. “IOH40/20, as defined by the 2018 Guidelines for the Diagnosis and Management of Syncope of the European Society of Cardiology, occurred rarely. The observed frequency of delayed orthostatic blood pressure recovery was also lower than previously reported for the general aging population. Patients with Parkinson mostly showed milder transient orthostatic blood pressure changes, i.e., iOH20/10, but overall, tOH was at least as common as cOH in the present study.”

The group concluded by noting that in light of the frequency and potential impact on Parkinson-related symptoms, including tOH as an outcome measure in interventional trials targeting OH should be recommended.

Transient Orthostatic Hypotension Commonly Found in Parkinson Disease

This article, "Dementia-Related Psychosis Places Heavy Burden on Patients and Caretakers," was originally published in NeurologyLive.

New research shows laryngeal movement disorders could serve as a diagnostic biomarker for multiple system atrophy (MSA), which could help distinguish the disease from 

 following systematic assessments of laryngeal dysfunction identifying it as highly prevalent in this patient population.

Conducted by a group including Georg Ebersbach, MD, chief physician, Parkinson Clinic, Movement Disorders Hospital, Kliniken Beelitz GmbH, the study found that with flexible endoscopic evaluation of swallowing (FEES), 93% of patients (n = 53) with MSA demonstrated laryngeal dysfunction compared with only 1.8% of patients (n = 1) in the matched Parkinson cohort (

In total, the study included 57 patients with MSA and 57 patients with Parkinson disease. In the MSA group 43 patients presented with more than 1 laryngeal symptom on FEES.

“FEES is becoming increasingly available in neurology departments worldwide, and we therefore suggest that whenever MSA is suspected, patients should undergo a systematic and standardized endoscopic MSA‐FEES task protocol assessment of laryngeal function to improve diagnostic certainty of MSA and delineation from Parkinson, taking other clinical signs into account,” Ebersbach and colleagues concluded. “Furthermore, we suggest that endoscopic laryngeal findings, above all the occurrence of irregular arytenoid cartilages movements, should be implemented into the next revised diagnostic criteria for MSA.”


Of those with MSA, 43.9% (n = 25) showed clinically overt laryngeal dysfunction with inspiratory stridor, compared to none of the patients with Parkinson.

The investigators noted there was “considerable discrepancy” between overt clinical symptoms of laryngeal pathology and the abnormalities observed during the task protocol, which has been somewhat identified by prior literature in 2019 showing the difficultly in diagnosing inspiratory stridor in MSA.

Additionally, they pointed to the work of Ozawa et al. in 2010, showing that irregular arytenoid cartilages movements (iACM)—which investigators observed in 91.2% (n = 52) of those with MSA compared to 0% of the Parkinson cohort (sensitivity, 0.9; specificity, 1.0; 

 <.0001)—are likely to precede the clinical onset of inspiratory stridor, which might explain their observations of its occurrence of iACM without inspiratory stridor.

Ebersbach and colleagues observed that iACM were present at rest in 80.7% (n = 46) of the MSA group, and could be provoked in an additional 10.5% (n = 6) patients during a newly designed positioning task.

“Therefore, laryngeal function should be assessed as early as possible, even without clinical evidence of laryngeal motion abnormalities, when MSA is suspected,” Ebersbach and colleagues wrote. “To further support this recommendation, we performed a subgroup analysis and showed that laryngeal motion abnormalities are present as early as 1 year after disease onset.

The aforementioned analysis revealed that the frequency of laryngeal findings was independent of MSA phenotype (χ

 = 0.15) and a diagnostic level of certainty (χ

The MSA cohort did have some significant differences from the matched Parkinson cohort, coming with shorter disease duration (MSA: 4 years [interquartile range (IQR), 3–5]; Parkinson: 7 years [IQR, 5–10]; 

 <.0001), higher disease severity (MSA: Hoehn and Yahr stage, 4 [IQR, 3–4]; Parkinson: stage, 3 [IQR, 2–4]; 

 <.0001), and more physical impairment (MSA: Unified Parkinson's Disease Rating Scale motor score, 35.5 [IQR, 29.8–41.8]; Parkinson: motor score, 28 [IQR, 19–36]; 

Additional analysis showed that patients with MSA had higher rates of vocal fold motion impairment (75.4%; n = 43; At rest: 66.7% [n = 38]), paradoxical vocal fold motion (33.3%; n = 19), and vocal fold fixation (19.3%; n = 11). In comparison, 1 patient with Parkinson showed vocal fold motion impairment.

The investigators identified a number of unknowns that require further study, including if laryngeal abnormalities allow for delineation of MSA from 4R‐tauopathies, as well as in the debate around the underlying pathology of laryngeal symptoms in MSA.

“An international multicenter study under guidance of the Movement Disorders Society MSA study group is under way to collect longitudinal data on laryngopharyngeal findings in patients with MSA using the MSA‐FEES task protocol,” they wrote. “In addition, systematic laryngeal assessment with the FEES task protocol will also be performed in patients with 4R‐tauopathies and the results compared with patients with MSA and Parkinson.”

Considerable discrepancy found between overt clinical symptoms of laryngeal pathology and abnormalities observed during a task protocol.

Laryngeal Movement Disorders Distinguish MSA from Parkinson Disease

Data from a survey of patients with dementia-related psychosis and their care partners seeking to identify unmet needs in treatment and patient experience suggest that symptoms of visual hallucinations and paranoid delusions carry a high burden for both patients and their caretakers.

The data revealed that a number of patients were either not taking a treatment for their psychosis or their current therapy included adverse events and limited efficacy.

All in all, 42% of both patient and care partner respondents reported having no current treatment, with the reported agents being atypical antipsychotics, antidepressants, anxiolytics, and benzodiazepines.

The results were presented virtually at the 

Alzheimer’s Association International Conference (AAIC) 2020 annual meeting

 by Teresa Brandt, PhD, MCB, Executive Director of Regulatory Affairs, Acadia Pharmaceuticals.

The online survey included 212 patients (n = 26) and care partners (n = 186) who completed the survey on behalf of patients under their care, of which 16 partook in a qualitative interview (patients, n = 1; care partners, n = 15).

“The data shows people with dementia-related psychosis experience hallucinations and delusions that have a substantial burden on their lives,” Brandt said in a statement. “We are pleased to be a part of this patient-focused study as it is critical for the treatment triad of patients, caregivers and healthcare providers to better identify and understand these symptoms, and to incorporate the patient’s voice in drug development and evaluation.”

The most common symptoms reported by patients were visual hallucinations (89%), auditory hallucinations (54%), and a distortion of senses (54%).

Of those who reported recent visual hallucinations, 61% noted that they occurred weekly.

Additionally, the participants described an impact of dementia-related psychosis on their activities of daily living (75%), sleep (63%), family life (56%), and as well as safety concerns (56%).

The care partners, on the other hand, reported that paranoid delusions (76%), visual hallucinations (75%), and lack of trust for loved ones (52%) were the most common symptoms experienced by their patient partners. In total, 77% of the care partners reported paranoid delusions as occurring at least weekly.

“The symptoms of dementia-related psychosis can cause fear and anxiety, disrupting the lives of people living with dementia and their families,” said Virginia Biggar, Senior Director of Communities, UsAgainstAlzheimer’s, in a statement.

The survey participants noted that in many cases, their current treatment method was less than helpful, with a median visual analog scale (VAS) score of 2 out of 5 (patients: mean score, 2.33 [standard deviation (SD), 1.0]; care partners: mean score, 2.4 [SD, 1.3]).

The most common reason for discontinuation of a treatment—reported by 11 patients and 115 partners—was an adverse effect, reported by 27% and 31% of patients and partners, respectively.

The next most common reasons were physician recommendation (patients: 27%; care partners: 14%), and lack of symptom improvement (patients: 9%; care partners: 28%).

All told, when queried about what an ideal treatment would provide for them, patients and care partners ranked the ability to distinguish reality (patients: 35%; care partners: 49%) and overall symptom improvement (patients: 42%; care partners: 23%) as the most important benefits.

“The survey results show that many patients with dementia-related psychosis are unaware of what’s happening or how to communicate what they are experiencing. The findings highlight the need for caregivers and healthcare providers to be able to better recognize, report, and manage these symptoms,” Terry Frangiosa, lead investigator, A-LIST Insight Series, UsAgainstAlzheimer’s, said in a statement.

Additional data presented at AAIC 2020 suggest that a treatment may be on the way, with the results of the phase 3 HARMONY study demonstrating that treatment with pimavanserin produced a robust reduction in psychosis symptoms, irrespective of most likely clinical diagnosis of dementia subtype or baseline dementia severity.

 for such an indication, the application being supported by the HARMONY data. Its prescription drug user fee act (PDUFA) date was set for April 3, 2021.

In a pair of studies, 42% of patients and care partners reported having no current treatment.

Author | Matt Hoffman

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