By Harini Sarva, MD
Synopsis: This large study of patients with cognitive impairment-assessed cerebrospinal fluid biomarkers, positron emission tomography imaging, and cognitive tests showed that those with evidence of both Alzheimer’s and Lewy body pathologies had greater cognitive dysfunction and faster progression than those with either pathology alone.
Source: Silva-Rodriguez J, Labrador-Espinosa MA, Zhang L, et al. The effect of Lewy body (co-)pathology on the clinical and imaging phenotype of amnestic patients. Brain. 2025; Jan 31. doi: 10.1093/brain/awaf037. [Online ahead of print].
A total of 865 patients from the Alzheimer’s Disease Neuroimaging Initiative with clinical diagnoses of amnestic mild cognitive impairment (MCI; 661 patients) or Alzheimer’s disease (AD) dementia (211 patients) with cerebrospinal fluid (CSF) and fluorodeoxyglucose positron emission tomography (FDG-PET) data were evaluated for underlying pathology and speed of progression of cognitive impairment. Based on the evaluations, 335 patients were classified as having only AD pathology, 158 patients were classified as having both AD and Lewy body (LB) pathologies, 68 patients were classified as having only LB pathology, and 304 patients had neither.
Patients with neither pathology were younger in age. The two groups with AD pathology had no differences in apolipoprotein E (APOE) e4 positivity, but the group with LB only and the group with neither pathology were less frequent carriers of APOE e4. Those with both pathologies had more global cognitive impairment than those with solely AD pathology. Those with solely LB pathology had fewer memory impairments and more executive function and visuospatial dysfunction on cognitive testing.
The patients with AD pathology alone and mixed pathologies had similar hypometabolic patterns in the temporoparietal lobes as seen on FDG-PET, whereas those with solely LB pathology had a distinct dementia with Lewy bodies hypometabolic pattern affecting the posterior-occipital region. Those without any pathology had mild hypometabolism limited to the medial temporal lobe. Those with mixed pathologies had significantly faster rates of cognitive decline compared to those with either pathology alone. The group with only LB pathology had a slower cognitive progression affecting primarily visuospatial and executive domains compared to the two groups with AD pathology.
Although there was no higher risk of developing hallucinations among all the groups with any pathology, those with distinct posterior-occipital hypometabolism pattern on FDG-PET had a higher likelihood of developing hallucinations. Regarding diagnosis, those patients with solely LB pathology had their diagnosis changed from probable AD to dementia due to other etiology.
Commentary
Accurate diagnosis of dementia type prior to autopsy is extremely challenging. CSF assays and FDG-PET aid in diagnosis. With greater establishment of co-pathologies in patients with neurodegenerative diseases, correct diagnosis, appropriate treatments, and precise prognostication are challenging. Patients in this study who were clinically diagnosed with amnestic MCI or AD had their cause of dementia changed to another diagnosis when CSF and PET studies suggested that only LB pathology was present.
Those with both pathologies with this testing had greater global cognitive dysfunction and faster progression than those with either pathology alone. However, without access to CSF analysis and FDG-PET, accurate diagnosis in many individuals remains difficult. This limits the development of effective therapeutics through clinical trials.
Patients with inaccurate clinical diagnoses may be incorrectly funneled into clinical studies and negatively affect results. Greater use of available biomarkers for accurate diagnosis is vital for improving clinical care, developing effective therapeutics, and selecting appropriate patients for clinical trials.
Harini Sarva, MD, is Assistant Professor of Clinical Neurology, Weill Cornell Medical College.
This large study of patients with cognitive impairment-assessed cerebrospinal fluid biomarkers, positron emission tomography imaging, and cognitive tests showed that those with evidence of both Alzheimer’s and Lewy body pathologies had greater cognitive dysfunction and faster progression than those with either pathology alone.
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