Patients experiencing memory problems often come to neurologist David Jones, MD, for second opinions. They repeat questions and sometimes misplace items. Their primary care clinician has suggested they may have Alzheimer’s disease or something else.
In many cases, Dr. Jones, a neurologist with Mayo Clinic in Rochester, Minnesota, performs a series of investigations and finds the patient instead has a different type of neurodegenerative syndrome, one that progresses slowly, seems limited chiefly to loss of memory, and which tests show affects only the limbic system.
The news of diagnosis can be reassuring to patients.
“Memory problems are not always Alzheimer’s disease,” Dr. Jones said. “It’s important to broaden the differential diagnosis and seek diagnostic clarity and precision for patients who experience problems with brain functioning later in life.”
Dr. Jones and colleagues recently published clinical criteria for what they call limbic-predominant amnestic neurodegenerative syndrome (LANS).
Various underlying etiologies are known to cause degeneration of the limbic system, the most frequent being a buildup of deposits of the TAR DNA-binding protein 43 (TDP-43) protein referred to as limbic-predominant, age-related TDP-43 encephalopathy neuropathological change (LATE-NC). LATE-NC first involves the amygdala, followed by the hippocampus, and then the middle frontal gyrus, and is found in about 40% of autopsied brains in people over age of 85 years.
By contrast, amnestic syndromes originating from neocortical degeneration are largely caused by neuropathological changes from Alzheimer’s disease and often present with non-memory features.
Criteria for LANS
Broken down into core, standard, and advanced features
Core clinical features:
The patient must present with a slow, amnestic, predominant neurodegenerative syndrome — an insidious onset with gradual progression over 2 or more years — without another condition that better accounts for the clinical deficits.
Standard supportive features:
1. Older age at evaluation.
- Most patients are at least the age of 75 years. Older age increases the likelihood that the amnestic syndrome is caused by degeneration of the limbic system.
2. Mild clinical syndrome.
- A diagnosis of mild cognitive impairment or mild amnestic dementia (ie, a score of ≤ 4 on the Clinical Dementia Rating Sum of Boxes [CDR-SB]) at the first visit.
3. Hippocampal atrophy out of proportion to syndrome severity.
- Hippocampal volume was smaller than expected on MRI, compared with the CDR-SB score.
4. Mildly impaired semantic memory.
Advanced supportive features:
1.Limbic hypometabolism and absence of neocortical degenerative pattern on fludeoxyglucose-18-PET imaging.
2. Low likelihood of significant neocortical tau pathology.
Dr. Jones and colleagues also classified a degree of certainty for LANS to use when making a diagnosis. Those with the highest likelihood meet all core, standard, and advanced features.
Patients with a high likelihood of having LANS meet core features, at least three standard features and one advanced feature; or meet core features, at least two standard features as well as two advanced features. Those with a moderate likelihood meet core features and at least three standard features or meet core features and at least two standard features and one advanced feature. Those with a low likelihood of LANS meet core features and two or fewer standard features.
To develop these criteria, the group screened 218 autopsied patients participating in databases for the Mayo Clinic Study of Aging and the multicenter Alzheimer’s Disease Neuroimaging Initiative. They conducted neuropathological assessments, reviewed MRI and PET scans of the brains, and studied fluid biomarkers from samples of cerebrospinal fluid.
In LANS, the neocortex exhibits normal function, Dr. Jones said. High-level language functions, visual spatial functions, and executive function are preserved, and the disease stays mild for many years. LANS is highly associated with LATE, for which no biomarkers are yet available.
The National Institute on Aging in May 2023 held a workshop on LATE, and a consensus group was formed to publish criteria to help with the diagnosis. Many LANS criteria likely will be in that publication as well, Dr. Jones said.
Several steps lay ahead to improve the definition of LANS, the authors wrote, including conducting prospective studies and developing clinical tools that are sensitive and specific to its cognitive features. The development of in vivo diagnostic markers of TDP-43 pathology is needed to embed LANS into a disease state driven by LATE-NC, according to Dr. Jones’ group. Because LANS is newly defined, clinical trials are needed to determine the best treatments.