Diagnostic Confusion Cleared? Early Alzheimer's Subtype Defined

Pauline Anderson

June 23, 2020

Dr David T. Jones

An early Alzheimer's disease (AD) subtype has been defined in new research that investigators say will lead to more rapid and accurate diagnosis of the condition.

In a new study, investigators describe a condition they call "progressive dysexecutive syndrome," a type of AD that affects organizing, planning, and other executive functions and strikes patients as early as their 40s.

Typical AD affects the hippocampus and episodic memory, whereas this syndrome appears to affect the parietal lobe and executive function, particularly working memory.

Patients with the disease wait an average of 3 years for an accurate diagnosis, but results of the new study should expedite this and lead to more rapid and appropriate management of the disorder, study investigator David Thomas Jones, MD, assistant professor of neurology and radiology, Mayo Clinic College of Medicine, Rochester, Minnesota, told Medscape Medical News.

"We can change patient outcomes by identifying this syndrome right away," he said, adding he wants to create greater awareness of the syndrome to "open clinicians' eyes" when assessing young patients with potential symptoms.

The article was published online May 27 in Brain Communications.

Diagnostic Confusion

Atypical frontal, dysexecutive/behavioral variants and early onset variants of AD have been reported before, but no diagnostic criteria exist for a progressive dysexecutive syndrome, said Jones.

The new single-center retrospective study included 55 patients, 62% female, who presented with cognitive dysfunction predominantly affecting executive functions. Behavioral symptoms were present in 29% of cases although these were not predominant.

The mean age at onset of cognitive symptoms in these cases was 53.8 years. Nearly all patients were currently seeking a second or third opinion regarding their diagnosis.

Some patients had been struggling at work or didn't understand why they could no longer perform their job, said Jones.

Using cerebrospinal fluid testing, neuroimaging, or autopsy data (two cases), researchers confirmed AD in all patients. They also had information from genetic testing for APOE allele status and/or autosomal dominant genes, and from neuropsychological testing.

Patients were diagnosed with the syndrome by a behavioral neurologist. The mean age at diagnosis was 57.2 years, which occurred approximately 3 years after symptom onset. This, said Jones, highlights the poor recognition of the syndrome and long diagnostic delays.

Clear related documentation was available in 39 cases and, of these, 32 were initially misdiagnosed. A total of 14 patients were diagnosed with a psychiatric disorder: eight with frontotemporal dementia, four with autoimmune dementia, two with a language AD variant, one with corticobasal syndrome, one with arsenic poisoning (despite relevant lab values being normal), one with a traumatic brain injury, and one with chemotherapy-related dementia.

"This just highlights the type of diagnostic confusion that exists with these patients," said Jones.

In 26 cases with genetic testing, 54% had at least one APOE ε4 allele. This, said Jones, is more than in the general population but less than in typical AD. "It suggests that there are factors other than typical genetics to explain the syndrome," he said.

Hippocampus Spared

Researchers did more detailed genetic testing in the five cases with family histories suggestive of possible contribution of autosomal dominant genes but none of these patients had genes that are causative in AD, said Jones.

With genes eliminated as a culprit, the main driver of the syndrome remains unclear, said Jones. However, he added, this new information means researchers will be better able to study the disease.

Amyloid PET was positive for all 22 participants who had imaging. The 20 participants who underwent tau PET were all positive, and the middle frontal and superior parietal lobes had the highest tau levels.

Two cases with autopsy data both showed a high level of AD neuropathologic change. "There was relative hippocampus sparing. There was not as much tau protein there relative to the frontal and parietal lobe," said Jones.

When physicians think of AD, the hippocampus usually comes to mind, but brain scans on these patients revealed a normal hippocampus, adding to the diagnostic confusion, Jones said.

He noted that some clinicians "erroneously" attribute executive function only to the frontal lobe.

"They don't realize that the parietal lobe is quite an important player in executive function. These cases really highlight that fact in that the heart of this disease is in the parietal lobe."

In the past, patients with this syndrome have been labeled with frontal AD although they "may or may not have a frontal lobe problem on imaging and usually don't have behavioral issues like you would see with frontal temporal dementia," said Jones.

"Nightmare Search" Eliminated?

This new study highlights the importance of executive brain networks in early onset dementia, defined as presenting before age 65, said Jones.

"We have shown in the past that tau protein actually accumulates specifically in this brain network, the working memory network, in younger-onset individuals."

Reducing the 3-year average time to properly diagnose these patients should go a long way to improving outcomes, said Jones

"That's 3 years of a diagnostic odyssey, of getting fired, feeling bad about yourself, not knowing what's going on, perhaps getting a wrong diagnosis and bad treatment like steroids, which have terrible side effects."

If the "nightmare" search for the correct diagnosis can be avoided, "that's always a good outcome to me," said Jones.

Although there's no cure for this — or any — type of AD, certain medications may slow the disease course, including cholinesterase inhibitors such as donepezil.

Lifestyle interventions such as optimal nutrition, physical activity, and social engagement may also help in dementia management.

Getting a prompt and accurate diagnosis can provide patients with some measure of relief so they receive disability and access support, said Jones.

Key Questions Remain

Future research should expand on the current findings to answer questions to determine those at greatest risk for the syndrome, its prevalence, and optimal treatment, said Jones.

There is already some suggestion that patients with AD who have hippocampal sparing do much better on cholinesterase inhibitors than other patients with dementia, said Jones.

"They potentially have more involvement of the area of the brain that produces that neurochemical — acetylcholine — and may have a particular deficit there that would make them more responsive to cholinesterase inhibitors."

Determining common characteristics among patients with the syndrome "is an active area of investigation," said Jones.

He noted, though, that some of the 55 cases in the current study had "technically challenging jobs" that "might tax working memory more than usual." However, it could just be that the symptoms become more prominent in these types of jobs, he added.

Clinicians are already welcoming this new information. Jones said that since the article was published, he has received several calls from colleagues with patients who appear to fit the diagnosis of progressive dysexecutive syndrome.

High-Quality Research

Commenting on the study for Medscape Medical News, Maria C. Carrillo, PhD, chief science officer, Alzheimer's Association, said it is "high quality" and conducted by "an excellent group of investigators."

"Early onset Alzheimer's is understudied, and although this one paper does not solve the issue of the delayed diagnosis in younger persons, which is a complex, multifactorial problem, it is one step forward to address this issue."

The Alzheimer's Association is participating in two studies focused on early onset AD. These include the 2-year observational Longitudinal Early-Onset Alzheimer's Disease Study (LEADS) and the New Imaging Dementia–Evidence for Amyloid Scanning (New IDEAS).

"The next challenge is to create, verify, and disseminate diagnostic criteria for the various forms of early onset Alzheimer's, and then ensure that clinics and research centers, both academic and non-academic, are able to recognize early onset disease of varying types, including [progressive dysexecutive syndrome]," said Carrillo

Jones and Carrillo have reported no relevant financial relationships.

Brain Comms. Published online May 27, 2020. Full text

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