Detecting Non-cognitive Features of Prodromal Neurodegenerative Diseases

Abstract: Background: Prodromal Neurodegenerative Disease (ND) due to tauopathies such as Alzheimer’s Disease (AD) and Synucleinopathies (SN) such as Parkinson's Disease (PD) and Dementia with Lewy Bodies (DLB) present subtly. Although ND are considered cognitive disorders, in fact ND present with behavioral and even medical symptomatology years to decades prior to the onset of cognitive changes. Recognizing prodromal ND syndromes is a public health priority because ND is common, disabling and expensive. Diagnosing prodromal ND in real world clinical settings is challenging because ND of the same pathology can present with different symptoms in different people. Individual variability in nature and variability in nurture across the life course influence how ND pathology manifests clinically. The objective of this study was to describe how non-cognitive symptoms from behavioral, medical, neurological and psychiatric domains cluster in prodromal and early stages of ND. Methods: This was an observational study of patients receiving routine clinical care for memory disorders. All patients receiving a standardized evaluation including complete neurological history and examination and standardized brief neuropsychological testing. A Principal Component Analysis (PCA) considering emotion, motor, sensory and sleep factors was performed on the entire sample of patients in order to identify co-occurring symptom clusters. All patients received a consensus diagnosis adjudicated by at least two dementia experts. Patients were grouped into Cognitively Normal, Detectable Cognitive Impairment, and Mild Cognitive Impairment categories due to AD and/or PD/LBD or NOS pathology. Symptom cluster scores were compared between clinical diagnostic groups. Results: In this study 165 patients completed baseline neuropsychological testing and reported subjective measures of non-cognitive symptoms. Four syndrome specific symptom factors emerged and eight non-specific symptom factors. Symptoms of personality changes, paranoia, hallucinations, cravings, agitation, and changes in appetite grouped together into a cluster consistent with an “SN Non-motor Phenotype”. Appetite, walking, balance, hearing, increased falls, and dandruff grouped together into a cluster consistent with an “SN Motor Phenotype”. The Prodromal AD phenotype included symptoms of anxiety, irritability, apathy, sleep disturbance and social isolation. The fourth factor included symptoms of increased sweating, twitching, and tremor grouped into a cluster consistent with an Autonomic phenotype. Conclusions: Non-cognitive features can be reliably measured by self-report in busy clinical settings. Such measurement can be useful in distinguishing patients with different etiologies of ND. Better characterization of unique, prodromal, non-cognitive ND trajectories could improve public health efforts to modify the course of ND for all patients at risk.