M.S. Okun, MD; M.R. DeLong, MD; J. Hanfelt, PhD; M. Gearing, PhD; and A. Levey, MD, PhD.
From the Department of Neurology (Dr. Okun), University of Florida, Gainesville; and Departments of Neurology (Drs. DeLong and Levey), Biostatistics (Dr. Hanfelt), and Pathology and Laboratory Medicine (Dr. Gearing), Emory University, Atlanta, GA.
Received February 20, 2003. Accepted in final form October 13, 2003.
Address correspondence and reprint requests to Dr. M.S. Okun, Movement Disorders Program, University of Florida McKnight Brain Institute, Rm. L3-100, Department of Neurology, 100 S. Newell Dr., 3rd fl., PO Box 100236, Gainesville, FL 32610; e-mail: okun@neurology.ufl.edu.
Abstract
Background: Testosterone deficiency, a treatable condition commonly seen in aging men, has been linked to Parkinson disease (PD) and Alzheimer disease (AD). In normal subjects, low testosterone levels are associated with cognitive and neuropsychiatric symptoms, yet the relationship between testosterone levels and cognitive function in PD and AD remains unclear.
Objective: To examine the relationship of testosterone levels to age and cognitive function in PD and AD.
Methods: Plasma testosterone levels were determined in men enrolled in a clinical registry of subjects with PD and AD, and neuropsychological testing was performed on subjects who consented. Testosterone levels in men with PD were compared with those in men with AD. In both groups, the relationship between testosterone levels and neuropsychological test scores was analyzed, adjusting for age and education.
Results: Linear regression analysis revealed that testosterone levels decreased with age in male PD patients (p < 0.03) and male AD patients (p < 0.07). The rate of decline was similar for the two groups. In PD patients, lower testosterone levels were associated with poorer performance on Trails B Seconds (p < 0.02).
Conclusions: There is a similar age-related decline in plasma testosterone levels in men with either PD or AD. Previously described associations between low testosterone levels and frontal lobe dysfunction in normal aged men, together with these results, suggest that the hormonal deficiency may act as a “second hit” to impair cognitive function in neurodegenerative disease.
Recent studies have revealed a link between testosterone and neurodegenerative diseases,1,2 yet hormonal influences on dementia risk and neurodegenerative disease treatment and progression are still poorly understood. Estrogen has received the most attention, based on reports of increased Alzheimer disease (AD) risk in estrogen-deficient postmenopausal women.3-7 However, emerging evidence has linked testosterone deficiency to Parkinson disease (PD) and AD,1,2,7-11 and it has been shown that some nonmotor symptoms of PD may respond to testosterone replacement therapy. Moreover, testosterone deficiency, which in normal subjects is associated with cognitive and neuropsychiatric symptoms, might act as a “second hit” and exacerbate symptoms when superimposed in PD, AD, and other neurodegenerative disorders. As testosterone deficiency is common in aging men, despite the availability of hormone replacement,12 clarification of the relationship between testosterone and cognition in neurodegenerative disorders is critical to address this potentially important and treatable risk factor.
Methods
Men with symptoms of cognitive, behavioral, or motor dysfunction were referred to the Emory University Department of Neurology for evaluation. Patients (and guardians) who agreed and signed an informed consent were entered into an institutional review board-approved Clinical Registry in Neurology and Alzheimer’s Disease Center Registry involving subjects recruited from the Movement Disorders and Cognitive Disorders Clinics. Sixty- eight male PD and 50 male AD patients were studied. The diagnosis of PD was made by neurologic examination as well as by adherence to standard criteria for the diagnosis of idiopathic PD, including the presence of two of three cardinal symptoms of PD in the absence of relevant exclusion criteria.13 The diagnosis of AD was made by adhering to Diagnostic and Statistical Manual of Mental Disorders (3rd. rev. ed.) criteria and by consensus conference among the behavioral neurologists and neuropsychologists. Diagnosis of dementia in PD patients was made by neurologic and neuropsychological examination in addition to appropriate laboratory and imaging studies. Eight of the 68 PD patients had evidence of dementia. Plasma samples were drawn from all 118 patients, and selective cognitive testing was performed on those patients who agreed. Plasma free and total testosterone levels were determined at a commercial laboratory (Quest Diagnostics). Neuropsychological measures included Boston Naming (alternate items), Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) Naming, CERAD Word List Learning and Delayed Recall Memory Savings, Clinical Dementia Rating (Total) (CDR), Mattis Dementia Rating Scale (DRS) Total Score, Mattis Dementia Rating Scale Memory Subscale, Geriatric Depression Scale, Letter Fluency, Mini-Mental State Examination (MMSE), Wechsler Memory Scale III (WMS-III) Backward Digit Span, WMS-III Forward Digit Span, WMS revised (WMS-R) Backward Digit Span, WMS-R Forward Digit Span, and Trail Making A and B.
Testosterone levels in men with PD were compared with those in men with AD, and a multiple linear regression model was utilized to examine whether testosterone levels in PD and AD patients varied with age. The relationship between testosterone levels and neuropsychological test scores was also analyzed in both patient groups
Results
Testosterone levels did not differ significantly between the PD and AD patient groups (table 1). Linear regression analysis indicated that testosterone levels decreased with age in male PD patients (p = 0.03) and male AD patients (p = 0.07) (figure; table 2). In men with PD, testosterone levels declined by an estimated 65.9 ng/mL (95% CI, 7.5 to 124.3 ng/mL) per every 10 years of age. In male AD patients, testosterone levels dropped by 60.1 ng/mL (95% CI, —4 to 124.6 ng/mL) per every 10 years of age. The rate of decline of testosterone was not different in PD and AD patients (p = 0.42). Comparison with the Baltimore Longitudinal Study of elderly community-dwelling men14 revealed that the rate of decline in testosterone levels in our PD (65.9 ng/mL) and AD (60.1 ng/mL) groups was somewhat greater than that seen in the Baltimore aging study where there was an estimated drop of 35 ng/mL per every 10 years of age (PD vs community; p = 0.30; AD vs community; p = 0.45).
Table 1. Characteristics of 118 male patients with a diagnosis of PD or AD
Table 2. Relationship between age and testosterone levels (T) in men with PD or AD
Figure 1. Linear regression analysis indicated that testosterone levels decreased with age in men with Parkinson disease (PD) (p = 0.03). A similar tendency was noted in male Alzheimer disease (AD) patients (p = 0.07)
To determine the effects of testosterone deficiency on cognition in subjects with neurodegenerative disease, we analyzed the relationship between testosterone levels and performance on several neuropsychological measures (table 3). Neither MMSE (p = 0.14), DRS Total score (p = 0.14), nor DRS Memory Subscale (p = 0.21) was related to testosterone level in PD or AD patients. However, PD patients with lower testosterone levels performed more poorly on Trails B Seconds (p = 0.02), after adjusting for age and education. None of the p values reported above were adjusted for multiple comparisons. Hence, the above results should be interpreted with caution, and larger studies will be needed to confirm our observations.
Table 3. Relationship between testosterone levels and cognitive function, adjusted for age and education
Discussion
There is little information about testosterone’s relationship to PD, AD, and other neurodegenerative disorders in humans.1,2,7-11 In the current study, we found no significant difference in the rate of decline of testosterone levels in our PD and AD patients compared with that in an elderly population without neurodegenerative diseases or dementia.14 A larger sample size will be needed to confirm this observation.
Symptoms of testosterone deficiency overlap with those of PD, AD, and other neurodegenerative disorders and include memory loss, depression, anxiety, irritability, insomnia, and sexual dysfunction.1,11,15,16 However, there is little information about the role of testosterone on cognition and other symptoms in PD and AD patients. In the current study, there was no correlation between neuropsychological test scores and testosterone levels. Two small studies on PD showed lower levels of testosterone in men with PD as well as responsiveness of nonmotor and some cognitive symptoms to treatment with testosterone.1,2 We are aware of a single case report11 and one small cross-sectional study of 39 men with AD.16 In the latter study, the AD patients had lower levels of total serum testosterone than control subjects, independent of potential confounds such as age and other risk factors. Thus, low testosterone levels may be a co-morbid feature of PD and AD in men. A larger prospective longitudinal study is needed to confirm our results and to clarify the role of testosterone in neurodegenerative diseases.
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