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Serum Leptin Levels and Cognition in Parkinson's Disease Patients.


There is some evidence about decreased neurotrophin production and signaling in the brain playing a role in the unknown mechanism of neurodegeneration in Parkinson's disease (PD) (1,2,3). Leptin is a growth factor that is synthesized and released from adipocytes and plays a principal role in food intake and body weight. There are leptin receptors in the hypothalamic, thalamic, and extra-thalamic brain regions, such as the cortex, hippocampus, brainstem, and cerebellum (1,4). Two functionally distinct groups of dopaminergic neurons are rich in leptin receptor expression in the brain (1,5,6): one is the medial group located in the ventral tegmental area, which is known to help food intake and reward pathways, while the other is the lateral group, namely the dopaminergic neurons of the substantia nigra pars compacta, which are involved in the modulation of peripheral motor control and, specifically PD (1,5,6).

Learning and memory are functions of the hippocampus, and long-term potentiation, a type of plasticity, takes place in this area. Some studies have reported that the direct administration of leptin into the hippocampus improves learning and memory (7,8). Moreover, low leptin levels have been discovered in Alzheimer disease (AD) patients (9). There are some important pathways in the brain that utilize dopamine other than just the nigrostriatal and tubuloinfindubular pathway, namely the mesocortical and mesolimbic pathways that link the ventral tegmental area of the midbrain to the prefrontal cortex and to the limbic area, respectively. In PD, the nigrostriatal pathway and the other two abovementioned patients can be affected. Although there are some studies in the literature about the relationship among weight loss, body fat mass, and satiety with blood leptin levels in PD patients (10,11,12), there is no study investigating the relationship between cognition and blood leptin levels in PD.

Therefore, in the present study, we aimed to investigate the relationship between blood leptin levels and the cognitive state of Turkish PD patients using the validated form of the Montreal Cognitive Assessment Scale in Turkey (MoCA-TR).


Thirty patients with the diagnosis of idiopathic PD according to the United Kingdom PD society brain bank criteria (13) and 30 healthy controls with similar demographic features were enrolled into the study. The subjects were recruited from the outpatient clinic of movement disorders at Erenkoy Education and Research Hospital for Neurological and Psychiatric Disorders in Istanbul, Turkey PD patients were evaluated by the Unified Parkinson's disease rating scale (UPDRS) and the Hoehn and Yahr scale (HY) for the stage and the severity of the disease. The daily dose of dopaminergic medications taken by the patient was recorded as the L-dopa equivalent daily dose (LEDD, mg/day) (14). Patients who were unable to ambulate; those with systemic illnesses, such as diabetes, thyroid disease, and neoplasia; those with psychiatric diseases (psychosis and severe depression), which can interfere with the cognitive test performance; those using any medication that may affect body weight, namely some antidepressants, antipsychotics, antihistamines, corticosteroids, diabetes medications; and those who had major dietary restrictions were excluded. None of the patients presented with nausea or anorexia due to dopaminergic medication, and none changed their dietary habits throughout the whole study. None of the subjects had undergone surgical treatment for PD. The controls subjects did not have any past or present neurological, psychiatric, or metabolic disorders that are known to cause an impairment to cognition. Any subjects using medication that may affect body weight and that involved major dietary restrictions were excluded.

At baseline, all the patients had their standing height and weight measurements taken using a standard scale. Each patient's body mass index (BMI) was then calculated as the weight (in kilograms) divided by the square of their height (in meters) and classified as normal (<25), overweight (25-29), or obese ([greater than or equal to]30). At baseline, the waist circumference (WC) (in centimeters) was measured at the level of maximum indentation over the abdomen.

On the day of the neurological examination and the body measurements, a 5 mL fasting blood sample was obtained from each patient between the times of 08.00 and 11.00 am. Serum was separated and stored at -80[degrees]C until analysis. Leptin concentrations were analyzed by DIAsource ImmunoAssays Human Leptin ELISA kit (DIAsource, Louvain-la-Neuve, Belgium) by an investigator who was blinded to the clinical criteria. This ELISA sandwiches human leptin between two monoclonal antibodies reacting against different epitopes on the leptin molecule.

The cognitive status of all the subjects was evaluated using the MoCA-TR scale. Selekler et al. (15) translated the MoCA-TR test in 2010 to Turkish, which had some cultural and linguistic changes from the original form. It was also validated with Parkinson's disease (PD) in Turkey (16). MoCA-TR is a 30 point scale in which a higher score indicates better cognition, and scores under 21 indicate a cognitive dysfunction in the Turkish PD population (16). PD patients were on dopamineric treatment during the study and evaluated in their 'on' state.

This study was approved by the Institutional Review Board and informed written consent was obtained from all subjects.

Statistical Analyses

All statistical analyses were was performed using the Statistical Package for the Social Sciences (IBM SPSS Statistics, New York, USA) version 20. The independent sample t-test and Yates chi-square test were used for the between-group comparisons. Correlations between serum leptin and body weight, BMI, and UPDRS were performed using Spearman's rank correlation coefficient (r). All the p values were two-sided and the level of statistical significance was set at p<0.05.


The mean age of the patients and controls were 59.37 [+ or -] 9.27 and 58.50 [+ or -] 9.85, respectively Five PD patients and eight controls were women (Table 1). The mean HY stage of the patients was 2.2 [+ or -] 0.9. Ten patients were at Hoehn-Yahr stage I, nine were at stage 2, eight were at stage 3, and three were at stage 4. The daily total dopaminergic dose of the patients was 777 [+ or -] 408 mg.

Although the WC of the patients were significantly higher than the controls (p=0.03), there was not any statistically significant difference between BMI of PD patients and the controls (p=0.246). Further, leptin levels did not differ between PD patients and the controls (p=0.209), but PD patients had significantly lower MoCA-TR scores than the control subjects (p=0.037).

In PD patients, leptin levels were significantly correlated with weight (r=0.417, p=0.022), waist circumference (r=0.522, p=0.003), and BMI (r=0.63I, p=0.00I) measurements (Table 2), but there was no correlation between MoCA-TR scores and leptin levels (r=0.020, p=0.916) (Table 2). There was no significant relationship between leptin levels and UPDRS III or the total scores (r=-0.59, p=0.750; r=-0.75, p=0.69), respectively. Also, the duration of the disease and the dose of dopaminergic treatment was not correlated with leptin levels (r=0.104, p=0.585 and r=0.19, p=0.30, respectively).

In the control group, there was no correlation of leptin levels with body composition measurements or MoCA-TR scores (Table 2).


In the present study, the blood leptin levels of PD patients were similar to normal controls, and they were not associated with cognition, as assessed by MoCA-TR, or the degree of motor or functional impairment, as assessed by UPDRS, or disease duration.

There are several reports in the literature evaluating leptin levels and its relationship with weight in PD patients (10,11,12,17). Lorefalt et al. (11) found that leptin was correlated with body fat mass both in PD patients and in the controls, and they found the lower leptin values in weight-losing PD patients could be related to their decreased body fat mass (11).

Evidente et al. (12) found that mean serum leptin concentrations were lower in PD patients with weight loss than in weight stable patients, but this did not reach statistical significance. They concluded that unintended weight loss in PD patients is unlikely to be due to abnormal serum leptin concentrations (12). In our study we could not find any statistically significant difference between the BMI of the patients and of the controls, but leptin levels were significantly correlated with weight, WC, and BMI in PD patients.

In two studies, it was shown that injecting leptin into the hippocampus directly improved learning and memory performance (8,18). In addition, the structure of some brain regions, such as the midbrain, the hippocampus, and the hindbrain, was shown to be altered by leptin (19,20,21,22). Also the neuroprotective actions of leptin have been reported in some studies (23,24). Paz-Filho et al. (25) reported that the substitution of leptin in a leptin-deficient child not only improved the metabolic parameters but also had a markedly positive effect on neurocognitive development (25). Because of these recent reports about leptin and its association with cognition, especially in AD, the absence of its beneficial effects in the central nervous system would suggest a predisposition to cognitive impairment (26). Although Power et al. (9) found lower serum leptin levels in patients with AD and vascular dementia, more recently Teunissen et al. (27) reported that serum leptin levels were not altered in a population of relatively young AD or vascular dementia patients (mean age 60) compared to healthy subjects and were not related to cognitive decline in that age group. In the sample we presented here, similarly, the blood leptin levels of PD patients were not lower than the control subjects and there was no statistically significant difference in blood leptin levels of PD patients and the controls.

Parkinson's disease patients had lower MoCA-TR scores than controls, but leptin levels were not associated with cognition. In two other prospective studies, higher leptin levels were associated with a lower risk of dementia or cognitive impairment (28,29). Al Hazzouri et al. (30) hypothesized that higher leptin would be associated with slower rates of cognitive decline in aging Mexican Americans and found that a higher baseline leptin level was associated with better cognitive function over time for females and males without central obesity, as measured by waist circumference. Leptin and insulin were found to have a modulation effect on the hippocampal function. The regulation of appetite and energy expenditure by leptin occurs by inhibiting serotonin synthesis and releasing it in brainstem neurons. This is suggested as leptin receptors were found also in brainstem serotoninergic neurons. Leptin receptor mRNA expression has been demonstrated in substantia nigra (31). Leptin has been shown to increase tyrosine hydroxylase content and the regulation of dopamine transporter activity (32). Therefore, leptin was shown to be able to modulate the mesolimbic dopaminergic system (32,33).

To the best of our knowledge, there is no prior study in the literature investigating the relationship between leptin levels and cognition in PD patients. However our study has some limitations. First, leptin levels may be subject to diurnal variation, although the blood samples were taken during fasting in the morning at the same time for all patients. Second, this is a cross sectional study with a small sample size. Third, our study group had a relatively low age and more than half of the patients were at a relatively early stage of the disease. Leptin levels might be lower in patients with more advanced PD and those with cognitive dysfunction.

In conclusion, cumulative data from our study and also from previous reports suggest that the relationship between leptin levels and cognition in neurodegenerative diseases such as AD and PD is still open to debate. We think that additional longitudinal studies in different larger populations need to be conducted to confirm the role of leptin as a biomarker or as a possible treatment regimen for neurodegenerative disorders in the future.

Ethics Committee Approval: Ethics committee approval was received for this study from the ethics committee of Erenkoy Research and Training Hospital for Neurological and Psychiatric Disorders.

Informed Consent: Written informed consent was obtained from patients who participated in this study.

Peer-review: Externally peer-reviewed.

Author Contributions: Concept--G.K.; Design--G.K.; Supervision --G.K.; Resources--G.K.; Materials--G.K., B.O.; Data Collection and/or Processing--B.O.; Analysis and/or Interpretation--G.K., B.O.; Literature Search--G.K.; Writing Manuscript--G.K.; Critical Review--G.K., B.O.; Other--G.K., B.O.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study has received no financial support.


(1.) Weng Z, Signore AP Gao Y Wang S, Zhang F Hastings T Leptin protects against 6-hidroxydopamine-induced dopaminergic cell death via Mitogen-activated protein kinase signaling. J Biol Chem 2007; 282:3479-3491. [CrossRef]

(2.) Cowen T. Selective vulnerability in adult and ageing mammalian neurons. Auton Neurosci 2002; 96:20-24. [CrossRef]

(3.) Enwere E, Shingo T, Gregg C, Fujikawa H, Ohta S, Weiss S. Aging results in reduced epidermal growth factor receptor signaling, diminished olfactory neurogenesis, and deficits in fine olfactory discrimination. J Neurosci 2004; 24:8354-8365. [CrossRef]

(4.) Harvey J. Leptin regulation of neuronal excitability and cognitive function. Curr Opin Pharmacol 2007; 7:643-647. [CrossRef]

(5.) Elmquist JK, Bjorbaek C, Ahima RS, Flier JS, Saper CB. Distributions of leptin receptor mRNA isoforms in the rat brain. J Comp Neurol 1998; 395:535-547. [CrossRef]

(6.) Figlewicz DP Evans SB, Murphy J, Hoen M, Baskin DG. Expression of receptors for insulin and leptin in the ventral tegmental area/substantia nigra (VTA/SN) of the rat. Brain Res 2003; 964:107-115. [CrossRef]

(7.) Farr SA, Banks WA, Morley JE. Effects of leptin on memory processing. Peptides 2006; 27:1420-1425. [CrossRef]

(8.) Oomuro Y, Hori N, Shiraishi T, Fukunaga K, Takeda H, Tsuji M, Matsumiya T, Ishibashi M, Aou S, Li XL, Kohno D, Uramura K, Sougawa H, Yada T Wayner MJ, Sasaki K. Leptin facilitates learning and memory performance and enhances hippocampal CAI long-term potentiation nad CaMK II phosphorylation in rats. Peptides 2006; 27:2738-2749. [CrossRef]

(9.) Power DA, Noel J, Collins R, O'Neill D. Circulating leptin levels and weight loss in Alzheimer's disease patients. Dement Geriatr Cogn Disord 2001; 12:167-170. [CrossRef]

(10.) Aziz NA, Pijl H, Frolich M, Roelfsema F, Roos RA. Leptin, adiponectin and resistin secretion and diurnal rhythmicity are unaltered in Parkinson's disease. Mov Disord 2011; 26:760-761. [CrossRef]

(11.) Lorefalt B, Toss G, Granerus AK. Weight loss, body fat mass and leptin in Parkinson's disease. Mov Disord 2009; 24:885-890. [CrossRef]

(12.) Evidente VGH, Caviness JN, Adler CH, Gwinn-Hardy KA, Pratley RE. Serum leptin concentrations and satiety in Parkinson's disease patients with and without weight loss. Mov Disord 2001; 16:924-927. [CrossRef]

(13.) Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson's disease. A clinico-pathological study of 100 cases. JNNP 1992; 55:181-184.

(14.) Tomlinson CL, Stowe R, Patel S, Rick C, Gray R, Clarke CE. Systematic review of levodopa dose equivalency reporting in Parkinson's disease. Mov Disord 2010; 25:2649-2653. [CrossRef]

(15.) Selekler K, Cangoz B, Uluc S. Power of discrimination of Montreal cognitive assessment (MoCA) scale in Turkish patients with mild cognitive impairment and Alzheimer's disease. Turk J Geriatr 2010; 13:166-171.

(16.) Ozdilek B, Kenangil G. Validation of the Turkish version of the Montreal Cognitive Assessment Scale (MoCA-TR) in patients with Parkinson's disease. Clin Neuropsychol 2014; 28:333-343. [CrossRef]

(17.) Markaki E, Ellul J, Kefalopopoulou Z, Trachani E, Theodoropoulou A, Kyriazopoulou V, Constantoyannis C. The role of ghrelin, neuropeptide Y and leptin peptides in weight gain after deep brain stimulation for Parkinson's disease. Stereotact Funct Neurosurg 2012; 90:104-112. [CrossRef]

(18.) Farr SA, Banks WA, Morley JE. Effects of leptin on memory processing. Peptides 2006; 27:1420-1425. [CrossRef]

(19.) Fulton S, Pissios P, Manchon RP, Stiles L, Frank L, Pothos EN, Maratos-Flier E, Flier JS. Leptin regulation of the mesoaccumbens dopamine pathway. Neuron 2006; 5I:811-822. [CrossRef]

(20.) Hommel JD, Trinko R, Sears RM, Sears RM, Georgescu D, Liu ZW, Gao XB, Thurmon JJ, Marinelli M, DiLeone RJ. Leptin receptor signaling in midbrain dopamin neurons regulates feeding. Neuron 2006; 5I:801-810. [CrossRef]

(21.) Lu XY, Kim CS, Frazer A, Zhang W. Leptin: a potential novel antidepressant. Proc Natl Acad Sci USA 2006; 103:1593-1598. [CrossRef]

(22.) Hayes MR, Skibicka KP Leichner TM, Guarnieri DJ, DiLeone RJ, Bence KK, Grill HJ. Endogeneus leptin signaling in the caudal nucleus tractus solitarius and area postrema is required for energy balance regulation. Cell Metab 2010; 11:77-83. [CrossRef]

(23.) Morrison CD. Leptin signaling in brain: a link between nutrition and cognition? Biochim Biophys Acta 2009; 1792:401-408.

(24.) Zhang F Wang S, Signore AP Chen J. Neuroprotective effects of leptin against ischemic injury induced by oxygen-glucose deprivation and transient cerebral ischemia. Stroke 2007; 38:2329-2336. [CrossRef]

(25.) Paz-Filho GJ, Babikian T, Asarnow R, Delibasi T, Esposito K, Erol HK, Wong ML, Licinio J. Leptin replacement improves cognitive development. PloS One 2008; 3:e-3098.

(26.) Paz-Filho G, Wong ML, Licinio J. The procognitive effects of leptin in the brain and their clinical implications. Int J Clin Pract 2010; 63:1808-1812. [CrossRef]

(27.) Teunissen CE, van der Flier WM, Scheltens P, Duits A, Wijnstok N, Nijpels G, Dekker JM, Blankenstein MA, Heijboer AC. Serum Leptin is not altered nor related to cognitive decline in Alzheimer's disease. J Alzheimers Dis 2015; 44:809-813.

(28.) Holden KF Lindquist K, Tylavsky FA, Rosano C, Harris TB, Yaffe K; Health ABC study. Serum leptin level and cognition in the elderly: findings from the Health ABC study. Neurobiol Aging 2009; 30:1483-1489. [CrossRef]

(29.) Lieb W, Beiser AS, Vasan RS, Tan ZS, Au R, Harris TB, Roubenoff R, Auerbach S, DeCarli C, Wolf PA, Seshadri S. Association of plasma leptin levels with incident Alzheimer disease and MRI measures of brain aging. JAMA 2009; 302:2565-2572. [CrossRef]

(30.) Al Hazzouri AZ, Haan MN, Whitmer RA, Yaffe K, Neuhaus J. Central obesity, leptin and cognitive decline: The Sacramento Area Latino Study on Aging. Dement Geriatr Cogn Disord 2012; 33:400-409. [CrossRef]

(31.) Folch J, Pedros I, Patraca I, Sureda F Junyent F Beas-Zarate C, Verdaguer E, Pallas M, Auladell C, Camins A. Neuroprotective and anti-aging role of leptin. J Mol Endocrinol 2012; 49:149-156. [CrossRef]

(32.) Scott MM, Lachey JL, Sternson SM, Lee CE, Elias CF Friedman JM, Elmquist JK Leptin targets in the mouse brain. J Comp Neurol 2009; 514:518-532. [CrossRef]

(33.) Bjorbaek C, Kahn BB. Leptin signaling in the central nervous system and the periphery. Recent Prog Hor Res 2004; 59:305-331. [CrossRef]


Clinic of Neurology, Erenkoy Research and Training Hospital for Neurologic and Psychiatric Disorders, istanbul, Turkey

Correspondence Address: Gulay Kenangil, Erenkoy Ruh ve Sinir Hastaliklari Egitim ve Arastirma Hastanesi, Noroloji Klinigi, istanbul, Turkiye


Received: 03.04.2015 Accepted: 27.08.2015

DOI: 10.5152/npa.2016.113
Table 1. Demographic features, leptin levels, MoCA-TR scores, and body
measurements of PD patients and the healthy controls

(n=60)              Patients                Controls
                    (n=30)                  (n=30)
                     n           %            n        %

Female               5         16.7           8      26.7
Male                25         83.3          22      73.3

                    Mean [+ or -] SD        Mean [+ or -] SD

Age (years)          59.37 [+ or -] 9.21    58.50 [+ or -] 9.85
Education (years)     7.87 [+ or -] 3.92     9.47 [+ or -] 4.62
BW (kg)              80.10 [+ or -] 13.86   76.63 [+ or -] 11.66
WC (cm)             104.83 [+ or -] 10.59   98.47 [+ or -] 11.57
BMI (kg/[m.sup.2])   28.87 [+ or -] 4.52    27.69 [+ or -] 3.09
HY score              2.2 [+ or -] 0.9      -
LEDD (mg/day)       777 [+ or -] 408        -
UPDRS III scores     13.63 [+ or -] 8.15    -
UPDRS Total scores   28.26 [+ or -] 18.49   -
Leptin (ng/mL)        4.13 [+ or -] 3.61     3.12 [+ or -] 2.43
MoCA-TR scores       21.93 [+ or -] 5.37    24.50 [+ or -] 3.77



Female              (a)0.347

Age (years)         (b)0.726
Education (years)   (b)0.154
BW (kg)             (b)0.299
WC (cm)             (b)0.030 (*)
BMI (kg/[m.sup.2])  (b)0.246
HY score             -
LEDD (mg/day)        -
UPDRS III scores     -
UPDRS Total scores   -
Leptin (ng/mL)      (b)0.209
MoCA-TR scores      (b)0.037 (*)

(a) Chi-square test, independent groups t-test, (*) p<0.05.
SD: standard deviation; BW: body weight; WC: waist circumference; BMI:
body mass index; MoCA-TR: Turkish version of the Montreal cognitive
assessment scale; UPDRS: the Unified Parkinson's Disease Rating Scale;
HY: Hoehn and Yahr; LEDD: L-dopa equivalent daily dose.

Table 2. The correlation of leptin levels with body measurements,
UPDRS, and MoCA-TR in PD patients and controls

Subjects (n=60)      BW          WC          BMI         MoCA-TR   UPDRS

Leptin levels    r  0.417       0.522        0.631         0.020  -0.059
of patients
(n=30)           p  0.022 (*)   0.003 (**)   0.001 (**)    0.916   0.755
Leptin levels    r  0.089       0.340        0.235         0.097
of controls
(n=30)           p  0.639       0.066        0.210         0.610

Subjects (n=60)   UPDRS

Leptin levels    -0.075
of patients
(n=30)            0.694
Leptin levels
of controls

Spearman correlation analysis, (*) p<0.05, (**) p<0.01. BW: body
weight; WC: waist circumference; BMI: body mass index; MoCA-TR: Turkish
version of the Montreal cognitive assessment scale.
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Title Annotation:Research Article
Author:Kenangil, Gulay; Ozdjlek, Betul
Publication:Archives of Neuropsychiatry
Date:Sep 1, 2016
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