, has been with the team since October 2019. Follow him on Twitter 

Marco Meglio

Results from 2 prospective, open-label, longitudinal, phase 3 studies demonstrated that patients with an advanced Alzheimer disease (AD) tau pattern, measured by flortaucipir (Tauvid), are at a higher risk of clinically meaningful deterioration.

The researchers also found that interpreting flortaucipir positron emission tomography (PET) scans using an FDA-approved, clinically applicable visual interpretation method could provide helpful information regarding anticipated clinical decline in the management of patients being assessed for causes of cognitive impairment. Senior author Mark A. Mintun, MD, president, Avid Radiopharmaceuticals, and colleagues collected data on 364 cognitively impaired participants with a range of demographic characteristics and clinical presentations similar to patients seen in a clinical practice setting over 18 months.

Pooling Study 1 (NCT02016560) and Study 2 (NCT03901105) data, 240 participants had an advanced and 124 participants had a nonadvanced AD flortaucipir scan pattern. At the end of the study period, 70% of the advanced group had a clinical dementia rating (CDR) sum of box (CDR-SB) score increase of 1 point or more, compared to 46% of those with a nonadvanced AD pattern scan experiencing the same event (risk ratio [RR], 1.40; 95% CI, 1.11-1.76; 

 = .005). Overall, the adjusted mean CDR-SB changes were 2.28 and 0.98 for advanced and nonadvanced AD pattern groups, respectively (

In both studies, participants’ clinical progression was measured with the CDR scale, including both CDR-SB and CDR-Global, the Mini Mental State Examination (MMSE), 11-item version of the Alzheimer Disease Assessment Scale-Cognitive subscale (ADAS-Cog11), and Functional Activities Questionnaire (FAQ).

The History of Exercise Interventions to Prevent Alzheimer Disease

In addition to the aforementioned changes in CDR-SB, researchers also saw similar statistically significant RRs for the other assessments. At the 18-month follow-up adjusted mean changes were –4.13 vs 1.27 (

<.001) for advanced compared to nonadvanced AD patterns, respectively.

Among the 3 different scan patterns, the moderate AD pattern occurred the least frequently in both studies. Mintun and colleagues also found an association of clinical progression by scan patterns (advanced > moderate > negative AD pattern) after pooling data.

The inter-reader consistency for flortaucipir scan visual interpretation was high in both Study 1 and 2 (94.5% and 91.4% agreement rate), resulting in homogenous findings similar to that observed for majority reads. Hazard ratio (HR) values from the analyses of CDR-SB event ranged from 1.49 to 1.70 in Study 1, and the corresponding RR values ranged from 1.25 to 1.46 in Study 2.

The researchers also found that impairment severity level at baseline was positively associated with participants’ clinical progression. Regardless of tau status, the study population had CDR-SB deteriorate from 0.51 to 3.61 points ranging from the healthiest to the most impaired MMSE baseline level.

Study 1 had a total of 159 participants that had flortaucipir scans that passed quality control. Of them, 64% were amyloid-beta positive (Aß+), 41% were apolipoprotein E (APOE) ε4 carriers, and 78 (49%) had an advanced, 11 (7%) had a moderate, and 70 (44%) had a negative AD pattern. Among Study 1 participants, compared with the Aß- group, the Aß+/advanced AD pattern group showed significantly greater CDR-SB progression (mean change, 1.99 vs 0.72; 

 = .02), whereas the Aß+/nonadvanced group progressed similarly to the Aß- group (0.86 vs 0.72; 

In Study 2, otherwise known as AMARANTH, all participants were Aß+ per enrollment criteria, and 69% were APOE ε4 carriers. A total of 162 (79%) participants had an advanced AD pattern, 15 (7.3%) had a moderate AD pattern, and 28 (13.7%) had a negative AD pattern.

Lu M, Pontecorvo MJ, Devous MD, et al. Aggregated tau measured by visual interpretation of flortaucipir positron emission tomography and the associated risk of clinical progression of mild cognitive impairment and Alzheimer disease. 

Published online February 15, 2021. doi: 10.1001/jamaneurol.2020.5505

Articles

At 18-month follow-up, 70% of those with an advanced Alzheimer disease pattern had 1 point or more increase in CDR-SB, an event predefined as clinically meaningful deterioration. 

Advanced Alzheimer Flortaucipir Pattern Associated With Increased Risk of Clinical Progression

Autoimmune encephalitis represents a complex category of disease with diverse immunological associations and clinical manifestations, including multiple sclerosis (MS). At 

, February 25–27, Divyanshu Dubey, MBBS, presented an invited talk on autoimmune encephalitis as part of a larger session of speakers focused on the spectrum of other non-MS diseases.

Dubey, an assistant professor of neurology at 

, touched upon recent research that found the prevalence and incidence of autoimmune encephalitis to be similar to infectious encephalitis, as well as noting the overall increase in prevalence. He also noted that gaining a better recognition of the clinical and paraclinical features associated with the condition could become critical for inpatient and outpatient neurology practice.

Dubey discussed his presentation, some of the major topics surrounding autoimmune encephalitis research, and why there has been steady momentum within the field over the past few years.

Can you provide some background on your presented talk and why you chose to specifically focus on this subject?

: This was an invited talk. ACTRIMS Forum asked me to talk about the clinical update on autoimmune encephalitis. It’s a topic of interest. Lately, a lot of research has been done in the area, especially the sheer number of biomarkers has expanded in the last few years. More and more people are interested in knowing about autoimmune encephalitis given it’s a treatable condition if diagnosed early. We have treatment options which can actually reverse the condition. Therefore, my talk is (was) going to be mostly about the clinical presentations of various autoimmune encephalitis and the various antibodies associated with them. That includes the ones that have been here for about 10 years, and the new ones which have been discovered in the past few years and then also understand their limitations, antibodies, and how to interpret them in terms of their specificity and sensitivity.

What is driving the sudden interest to research on autoimmune encephalitis?

I think it’s partly related to the fact that there was this big group of encephalitis cases where we tried to find and infection and could not. We did not nearly have an answer for why these patients were developing encephalitis, encephalopathy, or seizures. From some of the initial work done in Europe, Sloan Kettering, and here at Mayo Clinic, we were able to establish this area and the testing protocols for discovering and finding these antibodies. Over time, what we’ve seen is an exponential growth in the number of these antibodies, which has been like a chain reaction or a vicious circle, where discovery of more of these biomarkers has got more people interested in this area and has ultimately led to more input from researchers and clinicians. Additionally, the discovery of these patients and detection of these antibodies has helped improve our understanding about this field.

What value does discussing the spectrum of these sorts of non-MS inflammatory CNS diseases bring towards the MS field and the specialists and researchers within it?

Firstly, as we talk about the prevalence and epidemiology of these conditions, we have a better understanding and recognize that these are not as rare as we once thought they were. Secondly, MS is diagnosis of exclusion. We have to rule out some of the other things which look like MS, and many of the patients I see in autoimmune neurology clinic are initially diagnosed with MS and then they are treated with MS drugs and don’t get better. Then they are sent to use for a second opinion, we utilize our antibody panels and clinical judgment, and end up finding out they have something else. It is extremely important to understand the clinical radiological presentations of these non-MS inflammatory disorders, even for those who practice primarily in the field of MS. Therefore, inclusion of these non-MS topics is crucial for an MS focus.

Is there anything else that you'd like to mention about your presentation? Or about the meeting in general?

I would just like to highlight that we are learning that these non-MS inflammatory conditions such as autoimmune encephalitis are not as uncommon and rare as we once thought they were. Again, giving an example of an epidemiology study we did here in Homestead County, which estimated incidence and prevalence, we found autoimmune encephalitis to be as common as non-infectious encephalitis. Learning about these conditions and how to treat them is going to be important for our neurology practice, both inpatient as well as outpatient.

The assistant professor of neurology at Mayo Clinic discussed his presented talk at ACTRIMS Forum 2021 on autoimmune encephalitis.

Understanding the Momentum in the Autoimmune Encephalitis Research Community

This is 2-part interview. To view part 1, 

One of the more profound trends within the Alzheimer disease (AD) community over the past decade has been the growth in research on using lifestyle interventions, specifically exercise, as a way to improve cognition and reduce the risks of the disease. Exercise has been universally known as a pillar of health, but the specifics of prescribing it as a preventive option have been unknown to date.

A newly initiated study dubbed CYCLE-AD (Cycling to Cease or Limit the Effects of Alzheimer Disease), headed by a group of Cleveland Clinic researchers, is designed to assess the disease-modifying effects of a high-intensity exercise intervention aimed specifically at sedentary elders with the 

allele. Subjects in the exercise arm will undergo this training 3 times a week for 18 months using the Peloton home cycling system.

Stephen Rao, PhD, and Jay Alberts, PhD, co-principal investigators of the trial, stopped by to discuss the reasons for choosing the cycling intervention and the history leading up to this choice. The second half of their interview touches on the objectives of the trial and the significance if it proves successful, as well as the decision to specifically look at patients between ages 65 and 80 years.

What made you choose cycling? Are there specific types of exercise that may be more prone to altering cognitive onset?

As you mentioned there are a lot of data out there with different types of exercise interventions from aerobic to anaerobic strength training, stretching, etc. That is leading to this situation where we don’t know what to prescribe very well. Our rationale for this exercise came from some very positive studies we’ve had in Parkinson disease in terms of showing improvements and delaying some of the progression of Parkinson disease. The reason I’m a fan of the cycling is that it is safe to begin with. Again, we were instructing patients with Parkinson disease to exercise at a relatively high intensity and these patients already have postural and gait dysfunction. In a home environment, it makes it a little bit difficult to deploy, just because of safety.

The Peloton platform is nice because we can see what rides people are doing, the intensity of the rides, the heart rate, and it’s all packaged into data for us to analyze. Is there anything magical about cycling? Probably not. But I do think there are some interesting things about it from a cyclical movement perspective and a repetitive perspective that depending on the neurological disease, may actually be important in terms of priming different areas of the brain for either remodeling or slowing of progression.

At some point, Dr. Alberts and I had actually considered doing another project where we looked at more low impact type of exercise. We may still do that in the future.

Let’s say the study is successful, would looking at a younger population be the next goal? Where else would you like to go with your research?

The reason we study 65- to 80-year-olds is because they’re the most vulnerable age group when it comes to this particular genetic risk factor. The risk factor we’re looking at is the apolipoprotein E, or APOE. If you looked at younger people, you wouldn’t see anything because they’re not already starting to show Alzheimer changes. If you’re looking at older people, it turns out that if you make it to 80 and you don’t have Alzheimer disease, the genetic risk factor goes back to the general population. We’re trying to hit a specific sweet spot in terms of age of people who are intact but are at risk because of their age and genetic risk factor, to start showing atrophy of the brain and also try to show that they will have a deterioration in their cognition.

There is that fundamental question, ‘is the neuroprotective effects occurring?’ Is this because a person has been exercising most of their life on a consistent basis and that’s why we’re seeing the effects? Or is it possible the reverse the effects more acutely. That is the goal of the CYCLE-AD project. Can we affect something using short-term intervention that can be impacted in a relatively short duration? If we’re successful in that, it’s going to open the doors for all kinds of other projects in terms of expanding this on a larger scale. I think it will make a difference.

What we did notice, by the way, is that people who are not at genetic risk, did not show any differences on how much exercise they do. Now that’s not to say that exercise isn’t good for everybody, it’s just that people who aren’t at risk didn’t show any Alzheimer changes during the ages of 65 and 80 years, which is not all that surprising since they didn’t have the genetic risk factor. That’s why we concluded that exercise has a very specific effect for people who are genetically at risk.

How much has been achieved in terms of the progression of Alzheimer disease by researching lifestyle choices?

The big problem is that we don’t identify people who start getting the changes early enough. One of the thing Dr. Alberts and I have been working on very carefully is developing assessment tools that can be used in primary care so that we can actually measure cognition when people come in for their annual wellness visits, which is prescribed by Medicare. That problem is that people don’t get diagnosed until they have Alzheimer disease. But there’s a period before that called mild cognitive impairment that can precede as much as 3 to 5 years before you actually get the diagnosis. Then there are people who are have subtle cognitive changes as much as 5 to 7 years before they’re diagnosed. They’re not labeled as having mild cognitive impairment, but they have subtle changes.

If we can identify those people early on, that will make a huge difference in terms of prevention. We’re using the genetic risk factor, but there are other factors that can cause people to experience cognitive dysfunction, which may be the earliest stages of Alzheimer disease. For example, hypertension and having elevated cholesterol levels, having diabetes that’s not well controlled are all factors. Especially if someone is starting to show some cognitive decline, these are all ripe for preventive techniques. Through exercises, prescriptions of exercise, changes in diet, and all that. That’s where the field is moving, mainly in the direction of prevention.

The duo from Cleveland Clinic discussed the reasons for choosing cycling as part of their newly initiated clinical trial, as well as what has been observed for home-based exercise interventions. 

provide Class II evidence that tumor necrosis factor receptor 1 (TNF-TNFR1) signaling inhibition is not associated with the risk or age at onset of Parkinson disease (PD).

Lead author Xioying Kang, MPH, BSc, department of medical epidemiology and biostatistics, Karolinka Institut, and colleagues found that TNF-TNFR1 signaling inhibition was not estimated to affect PD risk (odds ratio [OR] per 10% lower circulating C-reactive protein [CRP], 0.99; 95% CI, 0.91–1.08) or age at onset (0.13 years later onset; 95% CI, –0.66 to 0.92). To the authors’ knowledge, this was the first Mendelian randomization (MR) study to address whether exposure to TNF inhibitors affect PD.

"Human genetics provides valuable guidance for therapeutic programs because the chances of successful drug development are substantially improved when genetic evidence links a drug’s target to an indication for therapeutic use,” Kang et al wrote. “Hence, our findings should be considered as part of discourse on the repurposing potential of TNF inhibitors for PD prevention and treatment, particularly if/when selective inhibitors of TNF-TNFR1 signaling become available.”

A total of 23 single nucleotide polymorphisms (SNPs) in the vicinity of the gene 

which encodes TNFR1, the principal effector of pro-inflammatory signaling following TNF agonism were present in the CRP data (genome-wide association studies [GWAS], n = 204,402). The effects of TNF-TNFR1 inhibition were estimated for PD risk (Ncases/controls = 37,688/981,372) and age at PD onset (n = 28,568) using GWAS data from the International Parkinson’s Disease Genomics Consortium and 23andMe, Inc.

Phase 1b Study of Investigational Parkinson Disease Agent YTX-7739 Announced

Researchers found, however, that genetically-indexed inhibition of TNF-TNFR1 signaling was predicted to reduce the risk of Crohn disease (OR, 0.75; 95% CI, 0.65–0.86) and ulcerative colitis (OR, 0.84; 95% CI, 0.74–0.97), and increased the risk of multiple sclerosis (MS; OR, 1.57; 95% CI, 1.36–1.81), as the authors noted was expected.

In secondary analyses, the more liberal linkage disequilibrium (LD) clumping yielded 4 correlated SNPs associated with CRP at false discovery rate-corrected (

<.05), 1 of which was not associated with either white blood cell count (WBC; 

 = .95) and was therefore removed. The other 3 variants were associated with all 3 inflammatory markers for secondary MR models.

Using adapted inverse variance weighting (IVW) methodology to account for correlations between the variants, MR estimates based on the 3 SNPs remained consistent with the main results that neither PD risk nor age at onset were predicted to be affected by TNF-TNFR1 blockade.

Kang and colleagues also found that there were no associations of the genotypes of implicated functional variant (rs1800693) with PD risk (OR, 1.00 per TNF-inhibiting allele; 95% CI, 0.98–1.02) or age at onset (0.05 years of increase per TNF-inhibiting allele; 95% CI, –0.13 to 0.24), despite strong associations of this SNP with other inflammatory traits.

Kang X, Ploner A, Pederson NL, et al. Tumor necrosis factor inhibition and Parkinson disease. 

Published online February 19, 2021. doi: 10.1212/WNL.0000000000011630

Genetically-index TNF-TNFR1 signaling blockade predicted reduced risk of Crohn disease and ulcerative colitis, and increased multiple sclerosis risk. 

Marco Meglio

Articles

Advanced Alzheimer Flortaucipir Pattern Associated With Increased Risk of Clinical Progression

Understanding the Momentum in the Autoimmune Encephalitis Research Community

The History of Exercise Interventions to Prevent Alzheimer Disease

Tumor Necrosis Factor Signaling Inhibition Fails to Prevent or Delay Parkinson Disease