- Email: [email protected]
Taste in dementing diseases and Parkinsonism
Journal of the Neurological Sciences 248 (2006) 177 – 184 www.elsevier.com/locate/jns
Taste in dementing diseases and Parkinsonism C.J.G. Lang a,*, T. Leuschner a, K. Ulrich a, C. Sto¨ßel a, J.G. Heckmann a, T. Hummel b b
a Neurological Unit, University of Erlangen-Nuremberg, Germany Smell and Taste Laboratory; Ear, Nose and Throat Unit, University of Dresden, Germany
Available online 12 June 2006
Abstract Like with many sensory abilities a reduction of taste and smell occurs during aging. Since there are hints to an additional reduction in dementing diseases, we assessed 52 patients, 26 women and 26 men, who were presented to a memory clinic, using the Sniffin’ Sticks, Whole Mouth and Taste Strip Tests. While smoking, alcohol consumption, intake of drugs and sex exerted only minor impact, age and the severity of cognitive impairment were of major importance. There was a moderate but significant correlation between the severity of dementia, taste and smell, even if the age effect was partialled out. Notably, patients with Parkinson syndrome showed worse taste and smell abilities than those without. Here the differences were indeed marked enough to play a possible role in making the diagnosis. This exploratory study confirms a mild reduction of gustatory function in dementing diseases over and beyond that of normal aging which – in addition to a reduction of smell – seems to be especially marked in Parkinson syndromes. D 2006 Elsevier B.V. All rights reserved. Keywords: Taste; Gustation; Smell; Olfaction; Dementia; Alzheimer’s disease; Parkinson’s disease
1. Introduction
2. Physiology and pathophysiology
Taste and smell are senses which, although transmitting less information than seeing and hearing, are nonetheless very important for everyday life. While disorders of smell are relatively well assessed with regard to their central representation and involvement in cerebral diseases, this does not hold true for disorders of taste. In addition, taste disorders are neither always reported spontaneously nor are they very common—at least when compared with impairments of other sensory domains. This has led to the situation that our knowledge of taste disorders in neurological diseases – e.g. in stroke or dementing conditions – has remained modest at best. Information on this topic, even in more extensive neurological textbooks is relatively sparse [1].
Besides sensory afferents via the trigeminal nerve, gustatory fibers reach the brain stem via the VIIth, IXth and Xth cerebral nerves extending to the ipsilateral nucleus tractus solitarii (NTS) of the medulla oblongata, the central tegmentum, posteromedial ventral thalamic nucleus, and finally the cortex probably crossing at the midbrain level. Gustatory and olfactory information converge in the caudal orbitofrontal cortex. Other central structures dealing with the processing of gustatory information are the amygdala, anterior gyrus cinguli and insular cortex. In animal experiments bilateral lesions of these structures or of the prefrontal cortex inhibit the association of taste and smell. In humans, disorders of taste have been described after bilateral paramedian thalamic infarction [2]. Recently the cerebral representations of taste perception have even been made visible by neuroimaging techniques. These central components of gustatory processing render it plausible that several brain diseases – depending on their localization and extent – may impair the sense of taste. It has been shown that acetylcholine is important for gustation [3,4] and that the adrenergic system plays an additional role [5,6].
* Corresponding author. Neurologische Universita¨tsklinik Schwabachanlage 6 91054 Erlangen, Germany. Tel.: +49 9131 8534339; fax.: +49 9131 8536596. E-mail address: [email protected] (C.J.G. Lang). 0022-510X/$ - see front matter D 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2006.05.020
178
C.J.G. Lang et al. / Journal of the Neurological Sciences 248 (2006) 177 – 184
Age is associated with a decline of the sense of taste [7 –11] which may additionally be impaired by smoking and a number of drugs [1,12 –20]. It seems that there are no essential differences in gustation between men and women; women, however, more often seek medical consultation, at least in Japan. Especially interesting for our considerations are observations which point to an involvement of taste disorders in dementing conditions like Alzheimer and Creutzfeldt – Jakob disease, frontotemporal degeneration, and other non-Alzheimer dementias [11,21 –25]. All of them may induce changes of appetite, food preferences and eating habits [26]. The multimodal memory impairment which is characteristic for the dementias may lead to an impairment of taste memory [3,4]. The administration of zinc gluconate was proposed as a treatment [1,27]. The assessment of taste can be performed in different ways. The most costly, namely gustatory evoked potentials, has proved itself to be not very reliable [28]. The Whole Mouth Test (WMT, [29]), where a taste solution is sprayed into the oral cavity, or the Taste Strip Test (TST, [30]), where the patient licks at a strip of cardboard which is saturated with a taste solution in different concentrations, are substantially more simple to apply in everyday practice. These tests usually only cover the classical four qualities sweet, sour, bitter, and salty and do not include the recently described umami taste [1,31]. The aim of the present pilot study was to do quantitative taste testing in an unselected sample of patients being referred to a memory clinic and to evaluate the relation with the underlying diseases and with the degree of cognitive impairment. In particular is was hypothesized that taste is compromised in patients with dementing disorders – especially Alzheimer’s and Parkinson’s disease– compared to nondemented individuals, similarly as it has been shown for smell.
3. Materials and methods We assessed 52 patients, 26 women and 26 men, 50 right- and 2 left-handed, who had been presented to the memory clinic of the neurological outpatient department of the University of Erlangen for the evaluation of dementia respectively cognitive decline. 24 suffered from dementia of the Alzheimer type according to research criteria (DSMIV), 5 of them with an additional vascular component and one with an additional Parkinson syndrome. 28 had a dementia of the non-Alzheimer type, i. e. Pick’s disease or frontal brain degeneration (2), cerebrovascular disease (10), Lewy body dementia (3), hydrocephalus (3), Parkinson’s disease (6), and one a multi-system atrophy, corticobasal degeneration, tick-borne encephalitis, and multiple sclerosis. 24 had finished eight to nine years of schooling (elementary school), six at least 10 years of schooling, and 22 had completed high school (at least 13 years of
schooling). There were only three smokers. 39 claimed to drink no alcohol, the remainder conceded between one and three drinks a day (bottle of beer or glass of wine). A control group was gathered using patients with minor strokes or vascular risk factors without stroke; it was comparable in regard to sex (26 women, 26 men), age (t-test, P = .709), handedness (47 right-handed, 5 lefthanded), schooling (t-test, P = .265), alcohol consumption (t-test, P = .119), drug intake (10 took no drugs, 42 took drugs; v 2, P = .080), and drugs potentially influencing taste (13 no, 39 yes; v 2, P = .641). They differed in regard to the MMSE (see Table 1) and smoking (13 smokers, 39 nonsmokers; v 2, P = .014). Epidemiological data are summarized in Table 1. After in-depth information about the test procedure and obtaining informed consent, history was taken, the MMSE [32] performed, smell assessed using the Sniffin’ Sticks Test (SST [33], 12-stick version [8-stick version for the first two patients whose results were multiplied by 12/8 = 1.5]), and taste using the Whole Mouth (WMT) and the Taste Strip Tests (TST [30]). All tests apply a forced-choice paradigm. Testing was done in a well-ventilated room, the patients were allowed to rinse their mouth with tap water according to their needs. Nobody terminated the procedure prematurely, although everybody was explicitly told to feel free to do so. Each patient was capable to understand the instructions and to perform the required tasks properly. In more severe cases (MMSE < 15 points) a relative was available who also consented but was not present during testing. Due to some patients’ inability to position the taste strips exactly over one half of the tongue, only sum values were considered which comprised both sides. All drugs taken were listed and evaluated for their potential to induce taste impairments [1,13,34,35]. 10 patients took no drugs that were contained in these lists. Only three patients took no medication, the rest took up to 13 different drugs. The significance level was set at P .05. Statistical calculations were performed using a commercially available software (SPSS\).
Table 1 Demographic data
Patients Age (years) Disease duration (days) Years of schooling MMSE (points) Controls Age (years) Years of schooling MMSE (points)
Mean
Median
S.D.
Range
71.90 1000 10.35 22.38***
74.5 741 10 23
10.03 950 2.34 4.84
43 – 91 2 – 4021 8 – 13 8 – 30
71.19 9.85 28.56
71.50 8 29
9.36 2.21 1.73
43 – 89 8 – 13 23 – 30
MMSE = Mini-Mental Status Examination, S.D. = standard deviation, ***= significant difference on the P = .000 level (Mann – Whitney U-test).
C.J.G. Lang et al. / Journal of the Neurological Sciences 248 (2006) 177 – 184
4. Results The TST results were significantly different from controls ( P = .036, Mann –Whitney U-test), as were those for the the WMT and SST ( P = .000) (Fig. 1). Patients taking pharmaceuticals that were likely to influence taste had somewhat lower WMT (2.95 T 1.04 vs. 3.60 T 0.70) and TST (17.64 T 6.35 vs. 20.00 T 5.75) scores, the differences, however, not being significant (Mann – Whitney U-test, P = .067 for the WMT; P = .377 for the TST). The SST yielded somewhat better results for the latter group (7.40 T 2.80, P = .216), too. This signified that a drug influence was present but could be regarded as rather minor. When smoking and drinking were considered in combination, they exerted no significant influence (Mann – Whitney U-test, P = .293 to .712), neither on smell nor on taste. Smokers/drinkers and non-smokers/nondrinkers did also not differ in regard to their MMSE scores ( P = .905).
179
As regards different taste qualities, sweet was recognized best in both taste tests (Friedman ANOVA, P = .029 for the WMT and .000 for the TST), sour worst (see Fig. 2). Remarkably, sweet strips were even marginally better recognized by patients than by controls (Mann –Whitney U-test, P = .403 [not significant]). Sex exerted no significant influence on either test (Mann –Whitney U-test, P = .071 to .755). Therefore, the tests and taste qualities were not evaluated separately. A comparison between Alzheimer and non-Alzheimer patients was deemed feasible since age, disease duration, schooling, alcohol/nicotine consumption, and MMSE were equal. There were, however, slightly more women (N = 16) among Alzheimer patients than among non-Alzheimer patients (N = 10, v 2-test, P = .052, not significant). Neither smell nor taste were found to be significantly different between these groups (Mann – Whitney U-test, P = .196 to .638), although Alzheimer patients differed from controls with regard to the SST (Mann – Whitney U-test, P = .000)
Fig. 1. Comparison between patients and controls in regard to their results on the Whole Mouth Test (WMT), Taste Strip Test (TST), and Sniffin’ Sticks Test (SST).
180
C.J.G. Lang et al. / Journal of the Neurological Sciences 248 (2006) 177 – 184
Fig. 2. Mean and standard deviation (S.D.) of the four different taste qualities on the Whole Mouth Test (WMT) and the Taste Strip Test (TST).
Fig. 3. Patients with Parkinson syndromes were inferior to the remainder of the patient sample for three taste qualities on the Whole Mouth Test (WMT) and on the Taste Strip Test (TST).
C.J.G. Lang et al. / Journal of the Neurological Sciences 248 (2006) 177 – 184 Table 2 Correlational analysis
MMSE Age Schooling Disease duration
WMT total
TST total
SST total
.358** .233 .077 .120
.434** .237 .113 .252
.395** .401** .036 .143
Correlations between the Mini-Mental Status Examination (MMSE), the Taste Strip Test (TST), the Sniffin’ Sticks Test (SST) and the Whole Mouth Test (WMT). Given are nonparametric correlation coefficients (Spearman’s q). **P < 0.01.
and WMT ( P = .000), but not the TST ( P = .201). Finally patients with (N = 10, 6 Parkinson patients, one with an additional Alzheimer’s dementia and 3 with Lewy body dementia) or without (N = 42) Parkinson syndrome were compared. They did not differ in regard to any of the control parameters including MMSE, but in their smell and taste abilities (Mann – Whitney U-test, P = .024 to .047), Parkinsonians persistently scoring lower values than non-Parkin-
181
sonians (Fig. 3). The main differences were on WMT sour (Mann – Whitney U-test, P = .007), and on TST salty ( P = .011). They also differed from controls in all three sensory tests (Mann –Whitney U-test, P = .000 to .004). 4.1. Correlational analysis In order to determine which parameters could possibly influence taste and smell, we did nonparametric correlational statistics. The most salient results are listed in Table 2. There was no impact of daily alcohol consumption on taste or smell. The small number of smokers prohibited a meaningful correlation. Years of schooling and disease duration correlated neither with smell nor taste. There was a significant correlation between SST and TST (q = .381, P < 0.01) as well as between SST and WMT (q = .408, P < 0.01). The interrelation between WMT and TST was even higher (q = .561, P < 0.01) as might be expected. There was a moderate but significant correlation between dementia severity as measured by the MMSE, taste (q = .358 to .434,
Fig. 4. Scatter diagrams with regression lines for the correlation between the Mini Mental Status Examination (MMSE) and the Whole Mouth Test (WMT, above left), the Taste Strip Test (TST, above right), and the Sniffin’ Sticks Test (SST, below).
182
C.J.G. Lang et al. / Journal of the Neurological Sciences 248 (2006) 177 – 184
P = .009 to .001), and smell (q = .395, P = .004) (Fig. 4). The correlations for Alzheimer patients were q = .305, P = .148 (SST); q = .444, P = .030 (WMT); and q = .519, P = .009 (TST), respectively. The correlations held true even when the effect of age was partialled out (r = .276 to .353, P .050). None of the correlations with these target variables was significant in the control group ( P .284).
5. Discussion In a sample of 20 probable Alzheimer patients Broggio et al. [21] found disturbances on three levels of gustatory processing, namely discriminative resp. perceptive, gnostic resp. associative, and gustatory-verbal. Associative disturbances were already present in mildly impaired patients. However, there were some methodological discrepancies between their study and ours. The French group chose everyday taste probes which may stimulate both taste and smell. But a reduction of smell is well known in Alzheimer patients. There are hints concerning a disturbance of taste bud innervation [25] and to a reduced taste memory in persons-atrisk [24]. The impairment of gustatory abilities seems to vary on one hand with the chemical structure of the substance, on the other hand to be characteristic for the dementias in general exceeding that of the influence of age [23]. We only assessed taste at the discriminative –perceptive level. Following our intention we made sure that any associative-gnostic or verbal elements were reduced to a minimum. The response sheet contained only four pure taste qualities to be chosen from in verbal and pictorial form without any further hints. Taking this into account a separation as good as that reported by the French authors was not to be expected. We wanted to assess taste abilities without giving olfactory hints using a newly developed paper Taste Strip Test (TST [30]) offering four tastes in four different intensities in an unselected sample of patients presented to a memory clinic. We assessed altogether 52 patients whose mean age was approximately 70 years, who had suffered from their diseases for a mean of almost 3 years, presented with some 10 years of schooling and obtaining a mean MMSE score of slightly below 23, therefore being on the margin of what is usually used as cut-off value for demented and non-demented persons. Half of the patients were diagnosed with Alzheimer’s dementia and were compared to the remaining non-Alzheimer patients. All our patients could follow the instructions well and perform the testing in a valid fashion as is indicated by the accompanying MMSE results and their behavior during the test sessions. Rarely a patient tried to smell at a taste strip before he or she put it into his mouth. Schooling or disease duration did not influence the results. These were good preconditions for testing the influence of dementing diseases. When we compared all patients with a matched control group, patients scored worse on the SST, WMT, and
TST. While Alzheimer patients did not differ from controls on the TST, Parkinson patients did. There was a certain but nonsignificant difference between those who took drugs which are potentially harmful for taste and those who did not. There were no differences between drinkers and nondrinkers, smokers and nonsmokers. It has been claimed that that male smokers between the age of 30 and 50 years had significantly lower (!) taste thresholds than non-smokers in electrogustometric testing of the soft palate [9]. This notwithstanding male smokers in their third decade seemed to recognize bitter worse than non-smokers [29]. This age segment, however, was scarcely represented in our study. Only after the age of 60 [9] or 70 [29] there is a rather steep increase in threshold value. We found no significant differences between men and women: women were able to identify only slightly more taste strips than men. There are no highly consistent or predictable sex differences in regard to chemosensory perception [34,35]. Some studies yielded clues as to a lower taste threshold in women which was explained by their socially determined greater role in the preparation of food and the consequent learning effect. The menstruation cycle also seems to play a role in gustation but can be disregarded in our study. Notably, the quality sour was not identified very well in the WMT and the TST by men and women alike. This could be a specific trait of both tests which is, however, contradicted by the results in normal controls. Other researchers found a reduced sour threshold only in women beyond the age of 20, while the results for salty and bitter were ambiguous [18,19]. This sweet/sour dissociation could mean that patients need less sweeteners and are more likely to tolerate sour ingredients in their food, like vinegar. There was a correlation between taste/smell and dementia even when the influence of age was partialled out; it was, however, moderate. It is therefore not to be anticipated that this type of taste testing will help in clinically diagnosing individual patients. This, however, also holds true for smell testing. When Parkinson patients were compared to the remainder and their respective controls, they scored lower for all three types of sensory testing. While a reduced sense of smell is well known in Parkinson disease [33], the notion that Parkinson patients could differ from patients with other potentially dementing diseases concerning their taste abilities, has, to our knowledge not been reported so far. The influence of antiparkinson drugs, however, cannot be ruled out. A recent study [36] found out that perceived intensity, pleasantness, and identification of sucrose, quinine, citric acid, or sodium chloride samples did not differ between Parkinson patients and controls, a finding not supported by our data. It stated the surprising finding that electrogustometric thresholds were significantly lower in Parkinsonians. More research is needed to resolve this apparent contradiction.
C.J.G. Lang et al. / Journal of the Neurological Sciences 248 (2006) 177 – 184
Summing up, the most salient results from this preliminary pilot study of taste are that an unselected sample of patients suffering from various dementing diseases scores less well than matched controls, women did not display significantly better gustatory abilities than men, the quality of sour is somewhat less readily identified than others, while sweet is recognized best, there is a moderate but significant correlation between the degree of cognitive impairment and taste as well as smell, taste did not significantly depend on drug intake, smoking, alcohol consumption, schooling or disease duration, and Alzheimer patients did not differ from non-Alzheimer patients in regard to their taste and smell abilities, but patients with Parkinson syndromes did. Even the very simple WMT correlated with dementia severity. The TST allowed for one-sided testing which, however, was not relevant for this study, but is an advantage in testing peripheral or unilateral cerebral lesions [37]. A direct comparison between patients and controls yielded lower TST results for the former. TST and WMT correlated significantly with each other and with the MMSE, the WMT only a little less so. The finding that Parkinsonians exhibit less gustatory and olfactory abilities than patients with other degenerative or dementing disorders is intriguing but requires further research, preferably in unmedicated subjects. The clinical usefulness of taste testing seems to be limited at present. Nevertheless, the finding of a taste (and smell) impairment over and beyond the influence of cognitive impairment and age, in a group of patients suffering from dementing diseases and especially from Parkinson syndromes adds a new facet to our understanding and should nurture considerations as to include sensory testing in the work-up of the dementias.
Acknowledgments We are very much indebted to Ms. Monica Hinrichs (now Mayer) and Daniela Tuffner, Dipl-Psych, who were instrumental in collecting the data. We also would like to express our gratitude to Ms. Patricia Heron for improving the English.
References [1] Heckmann JG, Heckmann SM, Lang CJ, Hummel T. Neurological aspects of taste disorders. Arch Neurol 2003;60:667 – 71. [2] Tohyama J, Kanazawa O, Akasaka N, Kamimura T. A case of bilateral thalamic infarction in childhood with the sensory disturbance and the sensory loss of taste. No To Hattatsu 2004;36:65 – 9 [in Japanese]. [3] Ramirez-Lugo L, Miranda MI, Escobar ML, Espinosa E, BermudezRattoni F. The role of cortical cholinergic pre- and post-synaptic receptors in taste memory formation. Neurobiol Learn Mem 2003;79:184 – 93. [4] Miranda MI, Ferreira G, Ramirez-Lugo L, Bermudez-Rattoni F. Role of cholinergic system on the construction of memories: taste memory encoding. Neurobiol Learn Mem 2003;80:211 – 22.
183
[5] Miranda MI, LaLumiere RT, Buen TV, Bermudez-Rattoni F, McGaugh JL. Blockade of noradrenergic receptors in the basolateral amygdala impairs taste memory. Eur J Neurosci 2003;18: 2605 – 10. [6] Herness S, Zhao FL, Kaya N, Lu SG, Shen T, Sun XD. Adrenergic signalling between rat taste receptor cells. J Physiol 2002;543:601 – 14. [7] Kaneda H, Maeshima K, Goto N, Kobayakawa T, Ayabe-Kanamura S, Saito S. Decline in taste and odor discrimination abilities with age, and relationship between gustation and olfaction. Chem Senses 2000;25: 331 – 7. [8] Leopold DA, Bartoshuk L, Doty RL, Jafek B, Smith DV, Snow JB. Aging of the upper airway and the senses of taste and smell. Otolaryngol Head Neck Surg 1989;100:287 – 9. [9] Nakazat M, Endo S, Yoshimura I, Tomita H. Influence of aging on electrogustometry thresholds. Acta Otolaryngol Suppl 2002;546: 16 – 26. [10] Schiffman SS. Perception of taste and smell in elderly persons. Crit Rev Food Sci Nutr 1993;33:17 – 26. [11] Schiffman SS. Taste and smell losses in normal aging and disease. JAMA 1997;278:1357 – 62. [12] Schiffman SS, Zervakis J. Taste and smell perception in the elderly: effect of medications and disease. Adv Food Nutr Res 2002;44: 247 – 346. [13] Tomita H, Yoshikawa T. Drug-related taste disturbances. Acta Otolaryngol Suppl 1999;546:116 – 21. [14] Ackerman BH, Kasbekar N. Disturbances of taste and smell induced by drugs. Pharmacotherapy 1997;17:482 – 96. [15] Doty RL, Philip S, Reddy K, Kerr KL. Influences of antihypertensive and antihyperlipidemic drugs on the senses of taste and smell: a review. J Hypertens 2003;21:1805 – 13. [16] Schiffman SS. Changes in taste and smell: drug interactions and food preferences. Nutr Rev 1994;52:S11 – 4. [17] Schiffman SS, Graham BG, Suggs MS, Sattely-Miller EA. Effect of psychotropic drugs on taste responses in young and elderly persons. Ann N Y Acad Sci 1998;855:732 – 7. [18] Schiffman SS, Zervakis J, Suggs MS, Budd KC, Iuga L. Effect of tricyclic antidepressants on taste responses in humans and gerbils. Pharmacol Biochem Behav 2000;65:599 – 609. [19] Schiffman SS, Zervakis J, Suggs MS, Shaio E, Sattely-Miller EA. Effect of medications on taste: example of amitriptyline HCl. Physiol Behav 1999;66:183 – 91. [20] Schiffman SS, Zervakis J, Westall HL, Graham BG, Metz A, Bennett JL, et al. Effect of antimicrobial and anti-inflammatory medications on the sense of taste. Physiol Behav 2000;69:413 – 24. [21] Broggio E, Pluchon C, Ingrand P, Gil R. E´tude du gout dans la maladie d’Alzheimer. Rev Neurol (Paris) 2001;157:409 – 13. [22] Reuber M, Al-Din AS, Baborie A, Chakrabarty A. New variant Creutzfeldt – Jakob disease presenting with loss of taste and smell. J Neurol Neurosurg Psychiatry 2001;71:412 – 3. [23] Schiffman SS, Clark CM, Warwick ZS. Gustatory and olfactory dysfunction in dementia: not specific to Alzheimer’s disease. Neurobiol Aging 1990;11:597 – 600. [24] Schiffman SS, Graham BG, Sattely-Miller EA, Zervakis J, WelshBohmer K. Taste, smell and neuropsychological performance of individuals at familial risk for Alzheimer’s disease. Neurobiol Aging 2002;23:397 – 404. [25] Yamagishi M, Takami S, Getchell TV. Innervation in human taste buds and its decrease in Alzheimer’s disease patients. Acta Otolaryngol 1995;115:678 – 84. [26] Ikeda M, Brown J, Holland AJ, Fukuhara R, Hodges JR. Changes in appetite, food preference, and eating habits in frontotemporal dementia and Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2002;73: 371 – 6. [27] Heckmann SM, Hujoel P, Habiger S, Friess W, Wichmann M, Heckmann JG, Hummel T. Zinc gluconate in the treatment of dysgeusia — a randomized clinical trial. J Dent Res 2005;84: 35 – 8 [Erratum in: J Dent Res 2005;84:382].
184
C.J.G. Lang et al. / Journal of the Neurological Sciences 248 (2006) 177 – 184
[28] Ikui A. A review of objective measures of gustatory function. Acta Otolaryngol Suppl 2002;546:60 – 8. [29] Yamauchi Y, Endo S, Yoshimura I. A new whole-mouth gustatory test procedure. II. Effects of aging, gender and smoking. Acta Otolaryngol Suppl 2002;546:49 – 59. [30] Mu¨ller C, Kallert S, Renner B, Stiassny K, Temmel AFP, Hummel T, et al. Quantitative assessment of gustatory function in a clinical context using impregnated ‘‘taste strips’’ made from filter paper. Rhinology 2003;41:2 – 6. [31] de Araujo IE, Kringelbach ML, Rolls ET, Hobden P. Representation of umami taste in the human brain. J Neurophysiol 2003;90:313 – 9. [32] Kessler J, Markowitsch HJ, Denzler P. Mini-Mental-Status-Test MMST. Go¨ttingen’ Beltz; 1990.
[33] Daum RF, Sekinger B, Kobal G, Lang CJG. Riechpru¨fung mit ‘‘sniffin_ sticks‘‘ zur klinischen Diagnostik des Morbus Parkinson. Nervenarzt 2000;71:643 – 50. [34] Schiffman SS. Taste and smell in disease. Part 1. N Engl J Med 1983;308:1275 – 9. [35] Schiffman SS. Taste and smell in disease. Part 2. N Engl J Med 1983;308:1337 – 43. [36] Sienkiewicz-Jarosz H, Scinska A, Kuran W, Ryglewicz D, Rogowski A, Wrobel E, et al. Taste responses in patients with Parkinson’s disease. J Neurol Neurosurg Psychiatry 2005;76:40 – 6. [37] Heckmann JG, Sto¨ssel C, Lang CJG, Neundo¨rfer B, Tomandl B, Hummel T. Taste disorders in acute stroke. A prospective observational study on taste disorders in 102 stroke patients. Stroke 2005;36:1690 – 4.
Taste in dementing diseases and Parkinsonism C.J.G. Lang a,*, T. Leuschner a, K. Ulrich a, C. Sto¨ßel a, J.G. Heckmann a, T. Hummel b b
a Neurological Unit, University of Erlangen-Nuremberg, Germany Smell and Taste Laboratory; Ear, Nose and Throat Unit, University of Dresden, Germany
Available online 12 June 2006
Abstract Like with many sensory abilities a reduction of taste and smell occurs during aging. Since there are hints to an additional reduction in dementing diseases, we assessed 52 patients, 26 women and 26 men, who were presented to a memory clinic, using the Sniffin’ Sticks, Whole Mouth and Taste Strip Tests. While smoking, alcohol consumption, intake of drugs and sex exerted only minor impact, age and the severity of cognitive impairment were of major importance. There was a moderate but significant correlation between the severity of dementia, taste and smell, even if the age effect was partialled out. Notably, patients with Parkinson syndrome showed worse taste and smell abilities than those without. Here the differences were indeed marked enough to play a possible role in making the diagnosis. This exploratory study confirms a mild reduction of gustatory function in dementing diseases over and beyond that of normal aging which – in addition to a reduction of smell – seems to be especially marked in Parkinson syndromes. D 2006 Elsevier B.V. All rights reserved. Keywords: Taste; Gustation; Smell; Olfaction; Dementia; Alzheimer’s disease; Parkinson’s disease
1. Introduction
2. Physiology and pathophysiology
Taste and smell are senses which, although transmitting less information than seeing and hearing, are nonetheless very important for everyday life. While disorders of smell are relatively well assessed with regard to their central representation and involvement in cerebral diseases, this does not hold true for disorders of taste. In addition, taste disorders are neither always reported spontaneously nor are they very common—at least when compared with impairments of other sensory domains. This has led to the situation that our knowledge of taste disorders in neurological diseases – e.g. in stroke or dementing conditions – has remained modest at best. Information on this topic, even in more extensive neurological textbooks is relatively sparse [1].
Besides sensory afferents via the trigeminal nerve, gustatory fibers reach the brain stem via the VIIth, IXth and Xth cerebral nerves extending to the ipsilateral nucleus tractus solitarii (NTS) of the medulla oblongata, the central tegmentum, posteromedial ventral thalamic nucleus, and finally the cortex probably crossing at the midbrain level. Gustatory and olfactory information converge in the caudal orbitofrontal cortex. Other central structures dealing with the processing of gustatory information are the amygdala, anterior gyrus cinguli and insular cortex. In animal experiments bilateral lesions of these structures or of the prefrontal cortex inhibit the association of taste and smell. In humans, disorders of taste have been described after bilateral paramedian thalamic infarction [2]. Recently the cerebral representations of taste perception have even been made visible by neuroimaging techniques. These central components of gustatory processing render it plausible that several brain diseases – depending on their localization and extent – may impair the sense of taste. It has been shown that acetylcholine is important for gustation [3,4] and that the adrenergic system plays an additional role [5,6].
* Corresponding author. Neurologische Universita¨tsklinik Schwabachanlage 6 91054 Erlangen, Germany. Tel.: +49 9131 8534339; fax.: +49 9131 8536596. E-mail address: [email protected] (C.J.G. Lang). 0022-510X/$ - see front matter D 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2006.05.020
178
C.J.G. Lang et al. / Journal of the Neurological Sciences 248 (2006) 177 – 184
Age is associated with a decline of the sense of taste [7 –11] which may additionally be impaired by smoking and a number of drugs [1,12 –20]. It seems that there are no essential differences in gustation between men and women; women, however, more often seek medical consultation, at least in Japan. Especially interesting for our considerations are observations which point to an involvement of taste disorders in dementing conditions like Alzheimer and Creutzfeldt – Jakob disease, frontotemporal degeneration, and other non-Alzheimer dementias [11,21 –25]. All of them may induce changes of appetite, food preferences and eating habits [26]. The multimodal memory impairment which is characteristic for the dementias may lead to an impairment of taste memory [3,4]. The administration of zinc gluconate was proposed as a treatment [1,27]. The assessment of taste can be performed in different ways. The most costly, namely gustatory evoked potentials, has proved itself to be not very reliable [28]. The Whole Mouth Test (WMT, [29]), where a taste solution is sprayed into the oral cavity, or the Taste Strip Test (TST, [30]), where the patient licks at a strip of cardboard which is saturated with a taste solution in different concentrations, are substantially more simple to apply in everyday practice. These tests usually only cover the classical four qualities sweet, sour, bitter, and salty and do not include the recently described umami taste [1,31]. The aim of the present pilot study was to do quantitative taste testing in an unselected sample of patients being referred to a memory clinic and to evaluate the relation with the underlying diseases and with the degree of cognitive impairment. In particular is was hypothesized that taste is compromised in patients with dementing disorders – especially Alzheimer’s and Parkinson’s disease– compared to nondemented individuals, similarly as it has been shown for smell.
3. Materials and methods We assessed 52 patients, 26 women and 26 men, 50 right- and 2 left-handed, who had been presented to the memory clinic of the neurological outpatient department of the University of Erlangen for the evaluation of dementia respectively cognitive decline. 24 suffered from dementia of the Alzheimer type according to research criteria (DSMIV), 5 of them with an additional vascular component and one with an additional Parkinson syndrome. 28 had a dementia of the non-Alzheimer type, i. e. Pick’s disease or frontal brain degeneration (2), cerebrovascular disease (10), Lewy body dementia (3), hydrocephalus (3), Parkinson’s disease (6), and one a multi-system atrophy, corticobasal degeneration, tick-borne encephalitis, and multiple sclerosis. 24 had finished eight to nine years of schooling (elementary school), six at least 10 years of schooling, and 22 had completed high school (at least 13 years of
schooling). There were only three smokers. 39 claimed to drink no alcohol, the remainder conceded between one and three drinks a day (bottle of beer or glass of wine). A control group was gathered using patients with minor strokes or vascular risk factors without stroke; it was comparable in regard to sex (26 women, 26 men), age (t-test, P = .709), handedness (47 right-handed, 5 lefthanded), schooling (t-test, P = .265), alcohol consumption (t-test, P = .119), drug intake (10 took no drugs, 42 took drugs; v 2, P = .080), and drugs potentially influencing taste (13 no, 39 yes; v 2, P = .641). They differed in regard to the MMSE (see Table 1) and smoking (13 smokers, 39 nonsmokers; v 2, P = .014). Epidemiological data are summarized in Table 1. After in-depth information about the test procedure and obtaining informed consent, history was taken, the MMSE [32] performed, smell assessed using the Sniffin’ Sticks Test (SST [33], 12-stick version [8-stick version for the first two patients whose results were multiplied by 12/8 = 1.5]), and taste using the Whole Mouth (WMT) and the Taste Strip Tests (TST [30]). All tests apply a forced-choice paradigm. Testing was done in a well-ventilated room, the patients were allowed to rinse their mouth with tap water according to their needs. Nobody terminated the procedure prematurely, although everybody was explicitly told to feel free to do so. Each patient was capable to understand the instructions and to perform the required tasks properly. In more severe cases (MMSE < 15 points) a relative was available who also consented but was not present during testing. Due to some patients’ inability to position the taste strips exactly over one half of the tongue, only sum values were considered which comprised both sides. All drugs taken were listed and evaluated for their potential to induce taste impairments [1,13,34,35]. 10 patients took no drugs that were contained in these lists. Only three patients took no medication, the rest took up to 13 different drugs. The significance level was set at P .05. Statistical calculations were performed using a commercially available software (SPSS\).
Table 1 Demographic data
Patients Age (years) Disease duration (days) Years of schooling MMSE (points) Controls Age (years) Years of schooling MMSE (points)
Mean
Median
S.D.
Range
71.90 1000 10.35 22.38***
74.5 741 10 23
10.03 950 2.34 4.84
43 – 91 2 – 4021 8 – 13 8 – 30
71.19 9.85 28.56
71.50 8 29
9.36 2.21 1.73
43 – 89 8 – 13 23 – 30
MMSE = Mini-Mental Status Examination, S.D. = standard deviation, ***= significant difference on the P = .000 level (Mann – Whitney U-test).
C.J.G. Lang et al. / Journal of the Neurological Sciences 248 (2006) 177 – 184
4. Results The TST results were significantly different from controls ( P = .036, Mann –Whitney U-test), as were those for the the WMT and SST ( P = .000) (Fig. 1). Patients taking pharmaceuticals that were likely to influence taste had somewhat lower WMT (2.95 T 1.04 vs. 3.60 T 0.70) and TST (17.64 T 6.35 vs. 20.00 T 5.75) scores, the differences, however, not being significant (Mann – Whitney U-test, P = .067 for the WMT; P = .377 for the TST). The SST yielded somewhat better results for the latter group (7.40 T 2.80, P = .216), too. This signified that a drug influence was present but could be regarded as rather minor. When smoking and drinking were considered in combination, they exerted no significant influence (Mann – Whitney U-test, P = .293 to .712), neither on smell nor on taste. Smokers/drinkers and non-smokers/nondrinkers did also not differ in regard to their MMSE scores ( P = .905).
179
As regards different taste qualities, sweet was recognized best in both taste tests (Friedman ANOVA, P = .029 for the WMT and .000 for the TST), sour worst (see Fig. 2). Remarkably, sweet strips were even marginally better recognized by patients than by controls (Mann –Whitney U-test, P = .403 [not significant]). Sex exerted no significant influence on either test (Mann –Whitney U-test, P = .071 to .755). Therefore, the tests and taste qualities were not evaluated separately. A comparison between Alzheimer and non-Alzheimer patients was deemed feasible since age, disease duration, schooling, alcohol/nicotine consumption, and MMSE were equal. There were, however, slightly more women (N = 16) among Alzheimer patients than among non-Alzheimer patients (N = 10, v 2-test, P = .052, not significant). Neither smell nor taste were found to be significantly different between these groups (Mann – Whitney U-test, P = .196 to .638), although Alzheimer patients differed from controls with regard to the SST (Mann – Whitney U-test, P = .000)
Fig. 1. Comparison between patients and controls in regard to their results on the Whole Mouth Test (WMT), Taste Strip Test (TST), and Sniffin’ Sticks Test (SST).
180
C.J.G. Lang et al. / Journal of the Neurological Sciences 248 (2006) 177 – 184
Fig. 2. Mean and standard deviation (S.D.) of the four different taste qualities on the Whole Mouth Test (WMT) and the Taste Strip Test (TST).
Fig. 3. Patients with Parkinson syndromes were inferior to the remainder of the patient sample for three taste qualities on the Whole Mouth Test (WMT) and on the Taste Strip Test (TST).
C.J.G. Lang et al. / Journal of the Neurological Sciences 248 (2006) 177 – 184 Table 2 Correlational analysis
MMSE Age Schooling Disease duration
WMT total
TST total
SST total
.358** .233 .077 .120
.434** .237 .113 .252
.395** .401** .036 .143
Correlations between the Mini-Mental Status Examination (MMSE), the Taste Strip Test (TST), the Sniffin’ Sticks Test (SST) and the Whole Mouth Test (WMT). Given are nonparametric correlation coefficients (Spearman’s q). **P < 0.01.
and WMT ( P = .000), but not the TST ( P = .201). Finally patients with (N = 10, 6 Parkinson patients, one with an additional Alzheimer’s dementia and 3 with Lewy body dementia) or without (N = 42) Parkinson syndrome were compared. They did not differ in regard to any of the control parameters including MMSE, but in their smell and taste abilities (Mann – Whitney U-test, P = .024 to .047), Parkinsonians persistently scoring lower values than non-Parkin-
181
sonians (Fig. 3). The main differences were on WMT sour (Mann – Whitney U-test, P = .007), and on TST salty ( P = .011). They also differed from controls in all three sensory tests (Mann –Whitney U-test, P = .000 to .004). 4.1. Correlational analysis In order to determine which parameters could possibly influence taste and smell, we did nonparametric correlational statistics. The most salient results are listed in Table 2. There was no impact of daily alcohol consumption on taste or smell. The small number of smokers prohibited a meaningful correlation. Years of schooling and disease duration correlated neither with smell nor taste. There was a significant correlation between SST and TST (q = .381, P < 0.01) as well as between SST and WMT (q = .408, P < 0.01). The interrelation between WMT and TST was even higher (q = .561, P < 0.01) as might be expected. There was a moderate but significant correlation between dementia severity as measured by the MMSE, taste (q = .358 to .434,
Fig. 4. Scatter diagrams with regression lines for the correlation between the Mini Mental Status Examination (MMSE) and the Whole Mouth Test (WMT, above left), the Taste Strip Test (TST, above right), and the Sniffin’ Sticks Test (SST, below).
182
C.J.G. Lang et al. / Journal of the Neurological Sciences 248 (2006) 177 – 184
P = .009 to .001), and smell (q = .395, P = .004) (Fig. 4). The correlations for Alzheimer patients were q = .305, P = .148 (SST); q = .444, P = .030 (WMT); and q = .519, P = .009 (TST), respectively. The correlations held true even when the effect of age was partialled out (r = .276 to .353, P .050). None of the correlations with these target variables was significant in the control group ( P .284).
5. Discussion In a sample of 20 probable Alzheimer patients Broggio et al. [21] found disturbances on three levels of gustatory processing, namely discriminative resp. perceptive, gnostic resp. associative, and gustatory-verbal. Associative disturbances were already present in mildly impaired patients. However, there were some methodological discrepancies between their study and ours. The French group chose everyday taste probes which may stimulate both taste and smell. But a reduction of smell is well known in Alzheimer patients. There are hints concerning a disturbance of taste bud innervation [25] and to a reduced taste memory in persons-atrisk [24]. The impairment of gustatory abilities seems to vary on one hand with the chemical structure of the substance, on the other hand to be characteristic for the dementias in general exceeding that of the influence of age [23]. We only assessed taste at the discriminative –perceptive level. Following our intention we made sure that any associative-gnostic or verbal elements were reduced to a minimum. The response sheet contained only four pure taste qualities to be chosen from in verbal and pictorial form without any further hints. Taking this into account a separation as good as that reported by the French authors was not to be expected. We wanted to assess taste abilities without giving olfactory hints using a newly developed paper Taste Strip Test (TST [30]) offering four tastes in four different intensities in an unselected sample of patients presented to a memory clinic. We assessed altogether 52 patients whose mean age was approximately 70 years, who had suffered from their diseases for a mean of almost 3 years, presented with some 10 years of schooling and obtaining a mean MMSE score of slightly below 23, therefore being on the margin of what is usually used as cut-off value for demented and non-demented persons. Half of the patients were diagnosed with Alzheimer’s dementia and were compared to the remaining non-Alzheimer patients. All our patients could follow the instructions well and perform the testing in a valid fashion as is indicated by the accompanying MMSE results and their behavior during the test sessions. Rarely a patient tried to smell at a taste strip before he or she put it into his mouth. Schooling or disease duration did not influence the results. These were good preconditions for testing the influence of dementing diseases. When we compared all patients with a matched control group, patients scored worse on the SST, WMT, and
TST. While Alzheimer patients did not differ from controls on the TST, Parkinson patients did. There was a certain but nonsignificant difference between those who took drugs which are potentially harmful for taste and those who did not. There were no differences between drinkers and nondrinkers, smokers and nonsmokers. It has been claimed that that male smokers between the age of 30 and 50 years had significantly lower (!) taste thresholds than non-smokers in electrogustometric testing of the soft palate [9]. This notwithstanding male smokers in their third decade seemed to recognize bitter worse than non-smokers [29]. This age segment, however, was scarcely represented in our study. Only after the age of 60 [9] or 70 [29] there is a rather steep increase in threshold value. We found no significant differences between men and women: women were able to identify only slightly more taste strips than men. There are no highly consistent or predictable sex differences in regard to chemosensory perception [34,35]. Some studies yielded clues as to a lower taste threshold in women which was explained by their socially determined greater role in the preparation of food and the consequent learning effect. The menstruation cycle also seems to play a role in gustation but can be disregarded in our study. Notably, the quality sour was not identified very well in the WMT and the TST by men and women alike. This could be a specific trait of both tests which is, however, contradicted by the results in normal controls. Other researchers found a reduced sour threshold only in women beyond the age of 20, while the results for salty and bitter were ambiguous [18,19]. This sweet/sour dissociation could mean that patients need less sweeteners and are more likely to tolerate sour ingredients in their food, like vinegar. There was a correlation between taste/smell and dementia even when the influence of age was partialled out; it was, however, moderate. It is therefore not to be anticipated that this type of taste testing will help in clinically diagnosing individual patients. This, however, also holds true for smell testing. When Parkinson patients were compared to the remainder and their respective controls, they scored lower for all three types of sensory testing. While a reduced sense of smell is well known in Parkinson disease [33], the notion that Parkinson patients could differ from patients with other potentially dementing diseases concerning their taste abilities, has, to our knowledge not been reported so far. The influence of antiparkinson drugs, however, cannot be ruled out. A recent study [36] found out that perceived intensity, pleasantness, and identification of sucrose, quinine, citric acid, or sodium chloride samples did not differ between Parkinson patients and controls, a finding not supported by our data. It stated the surprising finding that electrogustometric thresholds were significantly lower in Parkinsonians. More research is needed to resolve this apparent contradiction.
C.J.G. Lang et al. / Journal of the Neurological Sciences 248 (2006) 177 – 184
Summing up, the most salient results from this preliminary pilot study of taste are that an unselected sample of patients suffering from various dementing diseases scores less well than matched controls, women did not display significantly better gustatory abilities than men, the quality of sour is somewhat less readily identified than others, while sweet is recognized best, there is a moderate but significant correlation between the degree of cognitive impairment and taste as well as smell, taste did not significantly depend on drug intake, smoking, alcohol consumption, schooling or disease duration, and Alzheimer patients did not differ from non-Alzheimer patients in regard to their taste and smell abilities, but patients with Parkinson syndromes did. Even the very simple WMT correlated with dementia severity. The TST allowed for one-sided testing which, however, was not relevant for this study, but is an advantage in testing peripheral or unilateral cerebral lesions [37]. A direct comparison between patients and controls yielded lower TST results for the former. TST and WMT correlated significantly with each other and with the MMSE, the WMT only a little less so. The finding that Parkinsonians exhibit less gustatory and olfactory abilities than patients with other degenerative or dementing disorders is intriguing but requires further research, preferably in unmedicated subjects. The clinical usefulness of taste testing seems to be limited at present. Nevertheless, the finding of a taste (and smell) impairment over and beyond the influence of cognitive impairment and age, in a group of patients suffering from dementing diseases and especially from Parkinson syndromes adds a new facet to our understanding and should nurture considerations as to include sensory testing in the work-up of the dementias.
Acknowledgments We are very much indebted to Ms. Monica Hinrichs (now Mayer) and Daniela Tuffner, Dipl-Psych, who were instrumental in collecting the data. We also would like to express our gratitude to Ms. Patricia Heron for improving the English.
References [1] Heckmann JG, Heckmann SM, Lang CJ, Hummel T. Neurological aspects of taste disorders. Arch Neurol 2003;60:667 – 71. [2] Tohyama J, Kanazawa O, Akasaka N, Kamimura T. A case of bilateral thalamic infarction in childhood with the sensory disturbance and the sensory loss of taste. No To Hattatsu 2004;36:65 – 9 [in Japanese]. [3] Ramirez-Lugo L, Miranda MI, Escobar ML, Espinosa E, BermudezRattoni F. The role of cortical cholinergic pre- and post-synaptic receptors in taste memory formation. Neurobiol Learn Mem 2003;79:184 – 93. [4] Miranda MI, Ferreira G, Ramirez-Lugo L, Bermudez-Rattoni F. Role of cholinergic system on the construction of memories: taste memory encoding. Neurobiol Learn Mem 2003;80:211 – 22.
183
[5] Miranda MI, LaLumiere RT, Buen TV, Bermudez-Rattoni F, McGaugh JL. Blockade of noradrenergic receptors in the basolateral amygdala impairs taste memory. Eur J Neurosci 2003;18: 2605 – 10. [6] Herness S, Zhao FL, Kaya N, Lu SG, Shen T, Sun XD. Adrenergic signalling between rat taste receptor cells. J Physiol 2002;543:601 – 14. [7] Kaneda H, Maeshima K, Goto N, Kobayakawa T, Ayabe-Kanamura S, Saito S. Decline in taste and odor discrimination abilities with age, and relationship between gustation and olfaction. Chem Senses 2000;25: 331 – 7. [8] Leopold DA, Bartoshuk L, Doty RL, Jafek B, Smith DV, Snow JB. Aging of the upper airway and the senses of taste and smell. Otolaryngol Head Neck Surg 1989;100:287 – 9. [9] Nakazat M, Endo S, Yoshimura I, Tomita H. Influence of aging on electrogustometry thresholds. Acta Otolaryngol Suppl 2002;546: 16 – 26. [10] Schiffman SS. Perception of taste and smell in elderly persons. Crit Rev Food Sci Nutr 1993;33:17 – 26. [11] Schiffman SS. Taste and smell losses in normal aging and disease. JAMA 1997;278:1357 – 62. [12] Schiffman SS, Zervakis J. Taste and smell perception in the elderly: effect of medications and disease. Adv Food Nutr Res 2002;44: 247 – 346. [13] Tomita H, Yoshikawa T. Drug-related taste disturbances. Acta Otolaryngol Suppl 1999;546:116 – 21. [14] Ackerman BH, Kasbekar N. Disturbances of taste and smell induced by drugs. Pharmacotherapy 1997;17:482 – 96. [15] Doty RL, Philip S, Reddy K, Kerr KL. Influences of antihypertensive and antihyperlipidemic drugs on the senses of taste and smell: a review. J Hypertens 2003;21:1805 – 13. [16] Schiffman SS. Changes in taste and smell: drug interactions and food preferences. Nutr Rev 1994;52:S11 – 4. [17] Schiffman SS, Graham BG, Suggs MS, Sattely-Miller EA. Effect of psychotropic drugs on taste responses in young and elderly persons. Ann N Y Acad Sci 1998;855:732 – 7. [18] Schiffman SS, Zervakis J, Suggs MS, Budd KC, Iuga L. Effect of tricyclic antidepressants on taste responses in humans and gerbils. Pharmacol Biochem Behav 2000;65:599 – 609. [19] Schiffman SS, Zervakis J, Suggs MS, Shaio E, Sattely-Miller EA. Effect of medications on taste: example of amitriptyline HCl. Physiol Behav 1999;66:183 – 91. [20] Schiffman SS, Zervakis J, Westall HL, Graham BG, Metz A, Bennett JL, et al. Effect of antimicrobial and anti-inflammatory medications on the sense of taste. Physiol Behav 2000;69:413 – 24. [21] Broggio E, Pluchon C, Ingrand P, Gil R. E´tude du gout dans la maladie d’Alzheimer. Rev Neurol (Paris) 2001;157:409 – 13. [22] Reuber M, Al-Din AS, Baborie A, Chakrabarty A. New variant Creutzfeldt – Jakob disease presenting with loss of taste and smell. J Neurol Neurosurg Psychiatry 2001;71:412 – 3. [23] Schiffman SS, Clark CM, Warwick ZS. Gustatory and olfactory dysfunction in dementia: not specific to Alzheimer’s disease. Neurobiol Aging 1990;11:597 – 600. [24] Schiffman SS, Graham BG, Sattely-Miller EA, Zervakis J, WelshBohmer K. Taste, smell and neuropsychological performance of individuals at familial risk for Alzheimer’s disease. Neurobiol Aging 2002;23:397 – 404. [25] Yamagishi M, Takami S, Getchell TV. Innervation in human taste buds and its decrease in Alzheimer’s disease patients. Acta Otolaryngol 1995;115:678 – 84. [26] Ikeda M, Brown J, Holland AJ, Fukuhara R, Hodges JR. Changes in appetite, food preference, and eating habits in frontotemporal dementia and Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2002;73: 371 – 6. [27] Heckmann SM, Hujoel P, Habiger S, Friess W, Wichmann M, Heckmann JG, Hummel T. Zinc gluconate in the treatment of dysgeusia — a randomized clinical trial. J Dent Res 2005;84: 35 – 8 [Erratum in: J Dent Res 2005;84:382].
184
C.J.G. Lang et al. / Journal of the Neurological Sciences 248 (2006) 177 – 184
[28] Ikui A. A review of objective measures of gustatory function. Acta Otolaryngol Suppl 2002;546:60 – 8. [29] Yamauchi Y, Endo S, Yoshimura I. A new whole-mouth gustatory test procedure. II. Effects of aging, gender and smoking. Acta Otolaryngol Suppl 2002;546:49 – 59. [30] Mu¨ller C, Kallert S, Renner B, Stiassny K, Temmel AFP, Hummel T, et al. Quantitative assessment of gustatory function in a clinical context using impregnated ‘‘taste strips’’ made from filter paper. Rhinology 2003;41:2 – 6. [31] de Araujo IE, Kringelbach ML, Rolls ET, Hobden P. Representation of umami taste in the human brain. J Neurophysiol 2003;90:313 – 9. [32] Kessler J, Markowitsch HJ, Denzler P. Mini-Mental-Status-Test MMST. Go¨ttingen’ Beltz; 1990.
[33] Daum RF, Sekinger B, Kobal G, Lang CJG. Riechpru¨fung mit ‘‘sniffin_ sticks‘‘ zur klinischen Diagnostik des Morbus Parkinson. Nervenarzt 2000;71:643 – 50. [34] Schiffman SS. Taste and smell in disease. Part 1. N Engl J Med 1983;308:1275 – 9. [35] Schiffman SS. Taste and smell in disease. Part 2. N Engl J Med 1983;308:1337 – 43. [36] Sienkiewicz-Jarosz H, Scinska A, Kuran W, Ryglewicz D, Rogowski A, Wrobel E, et al. Taste responses in patients with Parkinson’s disease. J Neurol Neurosurg Psychiatry 2005;76:40 – 6. [37] Heckmann JG, Sto¨ssel C, Lang CJG, Neundo¨rfer B, Tomandl B, Hummel T. Taste disorders in acute stroke. A prospective observational study on taste disorders in 102 stroke patients. Stroke 2005;36:1690 – 4.