Detecting Non-cognitive Features of Prodromal Neurodegenerative Diseases
Authors: Seifan Alon , Ganzer Christine A. , Ryon Krista , Lin Michael , Mahmudur Rahman , Adolfo Henriquez , Shih Cindy , Jacobs Alan R. , Greenwald Molly , Isaacson Richard S. 
Published: February 2019

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.

Conclusion:
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.