- Email: [email protected]
Estrogen replacement therapy and frontotemporal dementia
Maturitas 45 (2003) 83 /88 www.elsevier.com/locate/maturitas
Estrogen replacement therapy and frontotemporal dementia Andrew J. Levine a,*, Linda Hewett b a
Neuropsychiatric Institute, University of California Los Angeles, 760 Westwood Plaza, Room C8-747, Los Angeles, CA 90024-1759, USA b San Francisco-Alzheimer’s Disease Research Center, University of California, San Francisco, CA, USA Received 28 May 2002; received in revised form 18 February 2003; accepted 4 March 2003
Abstract Objective: To examine the relationship between estrogen replacement therapy (ERT) and frontotemporal dementia (FTD). Methods: We examined the files of thirty female patients diagnosed with FTD at the University of California, San Francisco (UCSF)-Alzheimer’s Disease Research Center in Fresno between the years of 1994 and 1999. Twentyone patients (70%) were found to have been taking ERT at the time of their evaluation. This was compared with an estimate of estrogen use in a similar cohort from the general population (24%). Results: Chi-square (x2) analysis found this number to be significantly greater than estimates from the general population significant (x2[df /1, N /30] / 34.803, P B/0.01). Conclusions: Three potential explanations for the findings are put forth, including an intriguing neurobiological relationship between estradiol and tau, the complex protein implicated in the etiology of FTD. # 2003 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Estrogen replacement; Frontotemporal; Dementia
1. Introduction The current paper describes findings of a recent exploration into the frequency of estrogen replacement therapy (ERT) usage among women diagnosed with Frontotemporal dementia (FTD). The usefulness of ERT in the prevention of certain neurodegenerative diseases has been of great interest during the past decade and a half. Alzheimer’s disease (AD) is the most common form of neurodegenerative disease, and has been the most extensively studied with regards to ERT.
* Corresponding author. E-mail address: [email protected] (A.J. Levine).
AD usually has an onset after the age of 65 and is characterized by early memory loss, thought to be due to the selective early neuropathological changes in the mesial temporal lobes. Large epidemiological studies have consistently shown that women who take ERT have a lowered risk of developing AD (see [1,2] for reviews). This is further evidenced when the ratio of men and women who develop AD is examined. Women, who develop AD with up to twice the frequency of men even when the higher number of women in the at-risk elderly population is taken into consideration [3], slowly lose the ability to produce adequate amounts of a particular endogenous estrogen, 17 beta-estradiol, during perimenopause. Men also have small amounts of estrogen circulating
0378-5122/03/$ - see front matter # 2003 Elsevier Science Ireland Ltd. All rights reserved. doi:10.1016/S0378-5122(03)00142-7
84
A.J. Levine, L. Hewett / Maturitas 45 (2003) 83 /88
through their bodies and are physiologically capable of converting testosterone into estrogen. Though the cause of AD is uncertain, at least five neuroprotective mechanisms have been identified through which estrogen may act to prevent or delay the disease. 17 beta-estradiol has direct restorative action on nerve cells, including neuronal arborization and increasing the number of synapses [4,5], and has been found to induce and increase the activity of choline acetyltransferase, the rate-limiting enzyme for acetylcholine synthesis [6]. It modulates the effects of nerve growth factor and other factors such as brain-derived neurotropic factor [7], and has been shown to have anti-oxidant effects, protecting neurons against oxidative damage induced by beta-amyloid as well as other oxidants such as hydrogen peroxide and glutamate [8]. Finally, estrogen has been found to increase the expression of the antiapoptotic protein Bcl-XL in rat brains [9]. Although there has been an abundance of research into the relationship between ERT and AD, the relationship between ERT and another common neurodegenerative disease, FTD, has not been specifically examined. FTD is the most common form of a group of related neurodegenerative diseases that primarily affect the frontal and/or temporal lobes. The others include semantic dementia (SD) and progressive nonfluent aphasia (PA). In addition, there may be an associated amyotrophic form of motor neuron disease [10]. Collectively, these have been called frontotemporal lobar degenerative diseases, or FTLD [11], and they are believed to account for an estimated 20% of dementia cases with presenile onset [10]. Furthermore, genetic studies have identified a number of families who have autosomal dominant disorders, many of which are clinically and pathologically related to FTD. Because these disorders often involve some form of motor disturbance or subcortical pathology, and since about half have been found linked to mutations in a specific region of chromosome 17, they are termed FTD with Parkinsonism linked to chromosome 17 (FTDP-17). The subjects used in the current paper were diagnosed according to the criteria put forth by the Lund and Manchester Groups [12]. Clinically, the hallmarks of this
disease typically include a presenile onset and early changes in social conduct and personality. Behavioral changes vary, and may consist of disinhibition, loss of insight, inertia, apathy, neglect of personal hygiene, and lack of concern for others. Cognitively, there is early loss of ‘‘frontal’’ and ‘‘executive’’ abilities, such as abstract thinking and problem solving, while memory functioning is well preserved. The frontotemporal involvement of the disease is further evidenced by hypoperfusion of these areas as seen on SPECT and atrophy seen on MRI and CT scans. Although the common areas of neuropathological change are the frontal and anterior temporal lobes, the specific type of lesions found varies. There are three general patterns seen [10]. The most common is loss of large cortical nerve cells and microvacuolation. Another consists of Pick type inclusion bodies with widespread gliosis, as well as enlarged neurons in some cases. The third type is typically seen in patients with motor neuron disease and lobar degeneration, and consists of loss of large cortical nerve cells, microvacuolation, and gliosis. As with AD, the exact cause of FTD is unknown. A complex protein called tau is highly suspected of being a primary player in the pathogenesis of some types of FTD. Tau is in fact a conglomerate of microtubule associated proteins (MAPS) derived from a single gene on chromosome 17. It is involved in microtubule support within neurons, although exactly how its dysfunction leads to neurodegeneration is unclear. Tau may also have other roles within the brain, though these have not been confirmed [13]. Most, if not all, FTDP-17 families have tau deposits in their brains [13]. Linkage analysis studies have identified 26 kindreds that have FTD heritable disorders [14]. Of these, approximately half are linked to chromosome 17. Investigation into the role of tau, as well as further genetic studies of families with FTDP-17 illness, will hopefully shed more light on the etiology of FTD over the next few years. It may be of no surprise that the relationship between ERT and FTD has not been examined. First, while the drop of 17 beta-estradiol in postmenopausal women is believed to be related
A.J. Levine, L. Hewett / Maturitas 45 (2003) 83 /88
to the fact that they develop AD twice as often as men, the rates of developing FTD are equal in men and women, suggesting that a drop in estrogen does not increase one’s risk of developing FTD. Second, the average age of onset of symptoms for FTD has been found to be around 50 years in some studies, when the average woman is going through perimenopause. Therefore, one would not expect a drop in estrogen to be associated with FTD, since the disease process likely starts some time before the actual time symptom’s surface. Whether or not estrogen’s use is associated with FTD, risk remains to be clarified. The current exploratory study, therefore, is an attempt to add to our knowledge of possible preventative or etiological factors associated with FTD.
85
usage rate in those women living in the Western United States. Greatest rates of use were found among those in Caucasian women (26%) in the 50/59 (39%) age range who were living in the Southern or Midwest regions, and who had completed some college (31%). The typical woman in our sample was Caucasian, 70-year-old at the time of their evaluation, and with an education of approximately 12 years. Rates of estimated population use based on this source were compared with the observed rate of use among the FTD group using a Chi-square (x2) analysis. The characteristics of the women in the current study are illustrated in the table below Table 1.
3. Results 2. Methods Patient files of all females diagnosed with FTD at the UCSF Alzheimer’s Disease Research Center (UCSF-ADRC) since 1994 were reviewed. These patients were self-referred, physician-referred, referred by social and community agencies, or referred by friends and family. Patients had undergone an extensive, multifaceted evaluation. This evaluation included physical examination, neurological examination including CT or MRI scan of the brain, neuropsychological testing, laboratory tests, and thorough review of medical and family history. Patients were diagnosed according to criteria put forth by the Lund and Manchester groups [12]. Total number of patients was 30. The subject’s charts were reviewed to assess for estrogen use at the times of their evaluations. Estimates of estrogen use for women in the general population vary according to different studies, ranging from as low as 5% to as high as 59.8%, depending on such factors as socioeconomic status, occupation ethnicity, and education [15 /18]. For the purposes of the current study, we chose to use a national estimate of 24% from The Commonwealth Fund study [19]. In that study, based on a national survey that included 2010 women, it was found that peak estrogen use occurs between 50 and 59 years of age, with a decline in those over 60. They also found a relatively lower
Seventy percent (70%) of the women (21 of 30) diagnosed with FTD at the UCSF-ADRC between the years of 1994 and 2000 were on ERT at the time of their evaluation. When compared with the estimated use among healthy individuals of a similar age cohort (24%) in a x2 analysis, this difference was found to be significant (x2[df /1, N /30] /34.803, P B/0.01). To ensure that this finding was not simply a result of sampling bias at the UCSF-ADRC, we used frequencies of estrogen use among women diagnosed with probable Alzheimer’s disease (AD) that were obtained for another study (Levine and Battista, unpublished data). The records of 100 such women, evaluated during the same period, were examined, and revealed a 20% (20 of 99) rate of estrogen use at the time of initial evaluation. This finding indicates a slightly lower rate of estrogen use in the Alzheimer’s cohort as compared with the healthy population estimate, congruent with the lowered risk of AD among estrogen users found in previous studies [1,2]. More importantly, it Table 1
Education Age of onset Age at evaluation
Mean
Minimum
Maximum
11.95 64.95 70
7 46 51
20 87 91
86
A.J. Levine, L. Hewett / Maturitas 45 (2003) 83 /88
strengthens the finding of significantly heightened incidence of estrogen use among those diagnosed with FTD.
4. Discussion The findings of the current study indicate that a relationship exists between ERT use and the diagnosis of FTD. The direction of this relationship is not supportive of a preventative effect. In fact, the evidence here indicates a high correlation between estrogen use and the development of FTD. The fact that a greater rate of ERT use was found in those diagnosed with FTD is quite compelling. Although the current exploratory study is admittedly small, the findings should be investigated further in larger studies. Three hypotheses are now put forward that may help to explain the findings and to give direction for future research. 1) Diagnostic accuracy of neurodegenerative diseases has been the focus of numerous studies [20,21]. With regards to the current findings, it may be that estrogen use results in an atypical symptom presentation in those that in fact have AD. Numerous past studies of estrogen receptor distribution in animals, and more recent studies of the distribution in humans (Goka and Chang, unpublished data), have shown that the hippocampus is densely populated with estrogen receptors, and therefore, a candidate for the neuroprotective effects of estradiol. This area is among those first affected in AD, and is believed to be associated with the learning and short-term memory loss that are hallmark symptoms of early AD. It is not unreasonable to conceive that estrogen may protect areas in which there are dense estrogen receptors (e.g. hippocampus), while the disease process progresses in other areas, thereby resulting in an atypical symptom presentation where memory is not primarily affected. Findings of another study from this center support this hypothesis (Levine and Battista, manuscript submitted). However, it is a long leap from neurobiology
to clinical symptomology, especially in a disease with such global neuropathological changes. Furthermore, recent research has found that it is, in fact, FTD that often gets misclassified as AD [21]. In that study, the diagnostic criteria used for the differential diagnosis of FTD, AD, and other dementias were found to result in frequent misdiagnoses of FTD. Specifically, the NINCDS-ADRDA criteria for AD [22] were often fulfilled by those eventually verified as having FTD on post-mortem examination. Finally, even if it were possible that AD patients taking ERT present differently, the extensive, multifaceted evaluation performed at the UCSF-ADRC is unlikely to have misdiagnosed enough patients to account for the present findings. However, the possibility of misdiagnosis should not be dismissed. 2) Estrogen’s beneficial effects on mood have been well documented [23 /25]. As the initial symptoms of FTD can appear as mood disturbance such as depression [26], it may be that physicians prescribe ERT to women with FTD more often than those with AD or those in the general population. One significant limitation of the current study is that information regarding our patients’ hormone replacement use at the time of symptom onset was not available. As our databases become more comprehensive, this variable will ideally be accounted for in future studies. 3) The prime suspect in the pathogenesis of some forms of FTD is tau. Tau deposits are the major component of neurofibrillary tangles and of the other unusual pathological features of some FTDs, such as Pick bodies [27]. Tau is actually a collection of MAPs expressed from a single gene on chromosome 17, and it comes in six known isoforms [13]. At least twelve mutations in the tau gene have been identified and linked with various FTDP-17 disorders. Some have hypothesized that each mutation may result in a different clinical disease. In support of this idea, differences in the neuropathological sequelae of different mutations have been identified [13]. Most, if not all, FTDP-17 disorders show tau deposits on
A.J. Levine, L. Hewett / Maturitas 45 (2003) 83 /88
neuropathological examination, though not all involve a mutated form. The tau mutations found thus far account for only a small percentage of FTD cases, suggesting that faulty tau is not a direct cause of these diseases. In fact, one researcher has found that no phenotypic abnormalities are seen in a strain of mice that lack the tau gene altogether [28]. They suggested that the disease process may not be due to mutated tau being unable to carry out its usual functions, but rather the disruption of binding of tau, due to mutations or other reasons, leads to an excessive buildup of the compound, which results in disruption of cellular function. Others have suggested that over production of any one of the six tau isoforms may result in an accumulation of tau, which could polymerize into filaments, again disrupting cellular functioning [13]. Furthermore, these authors found that the expression of the tau isoforms can be cell-type specific. Therefore, should a misbalance of tau or the overproduction of any of the tau isoforms occur, whether mutated or not, this may result in the accumulation of tau and the disruption of cellular functioning, and this can occur in specific cell types. In 1991, it was found that the in-vitro administration of estrogen, specifically estradiol beta-17, to embryonic hypothalamic neurons of rats resulted in a selective 3-fold increase of tau levels over those observed in control cells [29]. This was found for cells that had already differentiated as well. The expression of other MAPs did not increase with estrogen. Furthermore, other forms of estrogen used in the study did not result in a significant increase of tau. Recall that it is 17 betaestradiol that ERT replaces. It is not inconceivable, therefore, that the administration of exogenous estrogen may result in a significant increase of tau expression. In prone individuals (e.g. those with mutated tau) this increase could result in the accumulation of tau to levels that may result in the dysfunction of specific neuronal populations, which in turn may be related to the greater percentage of women diagnosed with FTD observed here. If this relationship between tau and
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estrogen is also present in humans, these findings suggest that ERT may be contra-indicated in those with early FTD symptoms, family history of FTD, or a known tau mutation.
References [1] Brinton RD, Yamazaki RS. Advances and challenges in the prevention and treatment of Alzheimer’s disease. Pharmaceutical Research 1998;15(3):386 /98. [2] Monk D, Brodaty H. Use of estrogens for the prevention and treatment of Alzheimer’s disease. Dementia and the Geriatric Cognitive Disorders 2000;11:1 /10. [3] Jorm AF, Korten AE, Henderson AS. The prevalence of dementia: a quantitative integration of the literature. Acta Psychiatrica Scandinavica 1987;76(5):465 /79. [4] Brinton RD, Tran J, Profitt P, Kahil M. 17 Beta-estradiol increases the growth and survival of cultured cortical neurons. Neurochemical Research 1997;22:1339 /51. [5] Gould E, Woolley CS, Frankfurt M, McEwen BS. Gonadal steroids regulate dendritic spine density in hippocampal pyramidal cells in adulthood. The Journal of Neuroscience 1990;10(4):1286 /91. [6] Luine VN. Estradiol increases acetyltransferase activity in specific basal forebrain nuclei and projection areas of the female rat brain. Experimental Neurology 1985;89:484 / 90. [7] Rabbani O, Panickar KS, Rajakumar G, King MA, Bodar N, Meyer E, Simpkins J. 17 Beta-estradiol attenuates fimbrial lesion-induced decline of ChAT-immunoreactive neurons in the rat medial septum. Experimental Neurology 1997;146:179 /86. [8] Behl C, Skutella T, Lezoualc’h F, Post A, Widmann M, Newton CJ. Neuroprotection against oxidative stress by estrogens: structure /activity relationship. Molecular Pharmacology 1997;51:535 /41. [9] Pike CJ. Estrogen modulates neuronal Bcl-XL expression and beta-amyloid-induced apoptosis: Relevance to Alzheimer’s disease. Journal of Neurochemistry 1999;72:1552 / 63. [10] Neary D, Snowden JS, Mann DMA. Classification and description of frontotemporal dementias. Annals of the New York Academy of Sciences 2000;920:46 /51. [11] Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, Black S, et al. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 1998;51:1546 /54. [12] The Lund and Manchester Groups. Consensus statement. Clinical and neuropathological criteria for frontotemporal dementia, Journal of Neurology Neurosurgery and Psychiatry 1994;57(4):416 /8. [13] Giasson BI, Wilson CA, Trojanowski JQ, Lee VM-Y. Tau and alpha-synuclein dysfunction in neurodegenerative diseases. In: Chesselet M-F, Totowa NJ, editors. Con-
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A.J. Levine, L. Hewett / Maturitas 45 (2003) 83 /88 temporary clinical neuroscience: molecular mechanisms of neurodegenerative diseases. Humana Press, 1991:151 /76. Wilhelmsen KC, Clark LN, Miller BL, Geschwind DH. Tau mutations in frontotemporal dementia. Dementia and Geriatric Cognitive Disorders 1999;10(1):88 /92. Groenveld FPMJ, Boreman FP, Barensten R, Dokter HJ, Drogendijk AC, Hoes AW. Determinants of first prescription of hormone replacement therapy. A follow-up study among 1689 women aged 45 /60 years. Maturitas 1995;20:81 /9. McNagny S. Personal use of postmenopausal hormone replacement therapy by women physicians in the United States. Annals of Internal Medicine 1997;127:1093 /6. Harris R, Laws A, Reddy V, King A, Haskell W. Are women using postmenopausal estrogens: a community survey. American Journal of Public Health 1990;80:1266 /8. Johannes C, Crawford S, Posner J, Mckinlay S. Longitudinal patterns and correlates of hormone replacement therapy use in middle aged women. American Journal of Epidemiology 1994;140:439 /52. Falik M, Collins K. Women’s health; the commonwealth fund study. Baltimore: Johns Hopkins Press, 1996. Duara R, Barker W, Luis CA. Frontotemporal dementia and Alzheimer’s disease: differential diagnosis. Dementia and Geriatric Cognitive Disorders 1999;10(1):37 /42. Varma AR, Snowden JS, Lloyd JJ, Talbot PR, Mann DM, Neary D. Evaluation of the NINCDS-ADRDA criteria in the differentiation of Alzheimer’s disease and frontotemporal dementia. Journal of Neurology Neurosurgery and Psychiatry 1999;66(2):184 /8.
[22] Tierney MC, Fisher RH, Lewis AJ, Zorzitto ML, Snow WG, Reid DW. The NINCDS-ADRDA work group criteria for the clinical diagnosis of probable Alzheimer’s disease: a clinicopathological study of 57 cases. Neurology 1988;38:359 /64. [23] Sherwin BB, Gelfand MM. Sex steroids and effect in the surgical menopause: a double-blind, cross-over study. Psychoneuroendocrinology 1985;10:325 /35. [24] Smith RNJ, Studd JWW. Estrogens and depression in women. In: Lobo R, editor. Treatment of the postmenopausal woman: basic and clinical aspects. New York: Raven Press, 1994. [25] Zweifel JE, O’Brien WH. A meta-analysis of the effects of hormone replacement therapy upon depressed mood. Psychoneuroednocrinology 1997;22(3):189 /212. [26] Lynch T, Sano M, Marder KS, Bell KL, Foster NL, Defendini RF. Clinical characteristics of a family with chromosome 17-linked disinhibition /dementia / parkinsonism /amyotrophy complex. Neurology 1994;44(10):1878 /84. [27] Spillantini MG, Bird TD, Ghetti B. Frontotemporal dementia and Parkinsonism linked to chromosome 17: a new group of tauopathies. Brain Pathology 1998;8(2):387 / 402. [28] Hardy J. Pathways to primary neurodegenerative disease. Mayo Clinic Proceedings 1999;74:835 /7. [29] Ferreira A, Caceres A. Estrogen-enhanced neurite growth: evidence for a selective induction of tau and stable microtubules. The Journal of Neuroscience 1991;11(2):392 /400.
Estrogen replacement therapy and frontotemporal dementia Andrew J. Levine a,*, Linda Hewett b a
Neuropsychiatric Institute, University of California Los Angeles, 760 Westwood Plaza, Room C8-747, Los Angeles, CA 90024-1759, USA b San Francisco-Alzheimer’s Disease Research Center, University of California, San Francisco, CA, USA Received 28 May 2002; received in revised form 18 February 2003; accepted 4 March 2003
Abstract Objective: To examine the relationship between estrogen replacement therapy (ERT) and frontotemporal dementia (FTD). Methods: We examined the files of thirty female patients diagnosed with FTD at the University of California, San Francisco (UCSF)-Alzheimer’s Disease Research Center in Fresno between the years of 1994 and 1999. Twentyone patients (70%) were found to have been taking ERT at the time of their evaluation. This was compared with an estimate of estrogen use in a similar cohort from the general population (24%). Results: Chi-square (x2) analysis found this number to be significantly greater than estimates from the general population significant (x2[df /1, N /30] / 34.803, P B/0.01). Conclusions: Three potential explanations for the findings are put forth, including an intriguing neurobiological relationship between estradiol and tau, the complex protein implicated in the etiology of FTD. # 2003 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Estrogen replacement; Frontotemporal; Dementia
1. Introduction The current paper describes findings of a recent exploration into the frequency of estrogen replacement therapy (ERT) usage among women diagnosed with Frontotemporal dementia (FTD). The usefulness of ERT in the prevention of certain neurodegenerative diseases has been of great interest during the past decade and a half. Alzheimer’s disease (AD) is the most common form of neurodegenerative disease, and has been the most extensively studied with regards to ERT.
* Corresponding author. E-mail address: [email protected] (A.J. Levine).
AD usually has an onset after the age of 65 and is characterized by early memory loss, thought to be due to the selective early neuropathological changes in the mesial temporal lobes. Large epidemiological studies have consistently shown that women who take ERT have a lowered risk of developing AD (see [1,2] for reviews). This is further evidenced when the ratio of men and women who develop AD is examined. Women, who develop AD with up to twice the frequency of men even when the higher number of women in the at-risk elderly population is taken into consideration [3], slowly lose the ability to produce adequate amounts of a particular endogenous estrogen, 17 beta-estradiol, during perimenopause. Men also have small amounts of estrogen circulating
0378-5122/03/$ - see front matter # 2003 Elsevier Science Ireland Ltd. All rights reserved. doi:10.1016/S0378-5122(03)00142-7
84
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through their bodies and are physiologically capable of converting testosterone into estrogen. Though the cause of AD is uncertain, at least five neuroprotective mechanisms have been identified through which estrogen may act to prevent or delay the disease. 17 beta-estradiol has direct restorative action on nerve cells, including neuronal arborization and increasing the number of synapses [4,5], and has been found to induce and increase the activity of choline acetyltransferase, the rate-limiting enzyme for acetylcholine synthesis [6]. It modulates the effects of nerve growth factor and other factors such as brain-derived neurotropic factor [7], and has been shown to have anti-oxidant effects, protecting neurons against oxidative damage induced by beta-amyloid as well as other oxidants such as hydrogen peroxide and glutamate [8]. Finally, estrogen has been found to increase the expression of the antiapoptotic protein Bcl-XL in rat brains [9]. Although there has been an abundance of research into the relationship between ERT and AD, the relationship between ERT and another common neurodegenerative disease, FTD, has not been specifically examined. FTD is the most common form of a group of related neurodegenerative diseases that primarily affect the frontal and/or temporal lobes. The others include semantic dementia (SD) and progressive nonfluent aphasia (PA). In addition, there may be an associated amyotrophic form of motor neuron disease [10]. Collectively, these have been called frontotemporal lobar degenerative diseases, or FTLD [11], and they are believed to account for an estimated 20% of dementia cases with presenile onset [10]. Furthermore, genetic studies have identified a number of families who have autosomal dominant disorders, many of which are clinically and pathologically related to FTD. Because these disorders often involve some form of motor disturbance or subcortical pathology, and since about half have been found linked to mutations in a specific region of chromosome 17, they are termed FTD with Parkinsonism linked to chromosome 17 (FTDP-17). The subjects used in the current paper were diagnosed according to the criteria put forth by the Lund and Manchester Groups [12]. Clinically, the hallmarks of this
disease typically include a presenile onset and early changes in social conduct and personality. Behavioral changes vary, and may consist of disinhibition, loss of insight, inertia, apathy, neglect of personal hygiene, and lack of concern for others. Cognitively, there is early loss of ‘‘frontal’’ and ‘‘executive’’ abilities, such as abstract thinking and problem solving, while memory functioning is well preserved. The frontotemporal involvement of the disease is further evidenced by hypoperfusion of these areas as seen on SPECT and atrophy seen on MRI and CT scans. Although the common areas of neuropathological change are the frontal and anterior temporal lobes, the specific type of lesions found varies. There are three general patterns seen [10]. The most common is loss of large cortical nerve cells and microvacuolation. Another consists of Pick type inclusion bodies with widespread gliosis, as well as enlarged neurons in some cases. The third type is typically seen in patients with motor neuron disease and lobar degeneration, and consists of loss of large cortical nerve cells, microvacuolation, and gliosis. As with AD, the exact cause of FTD is unknown. A complex protein called tau is highly suspected of being a primary player in the pathogenesis of some types of FTD. Tau is in fact a conglomerate of microtubule associated proteins (MAPS) derived from a single gene on chromosome 17. It is involved in microtubule support within neurons, although exactly how its dysfunction leads to neurodegeneration is unclear. Tau may also have other roles within the brain, though these have not been confirmed [13]. Most, if not all, FTDP-17 families have tau deposits in their brains [13]. Linkage analysis studies have identified 26 kindreds that have FTD heritable disorders [14]. Of these, approximately half are linked to chromosome 17. Investigation into the role of tau, as well as further genetic studies of families with FTDP-17 illness, will hopefully shed more light on the etiology of FTD over the next few years. It may be of no surprise that the relationship between ERT and FTD has not been examined. First, while the drop of 17 beta-estradiol in postmenopausal women is believed to be related
A.J. Levine, L. Hewett / Maturitas 45 (2003) 83 /88
to the fact that they develop AD twice as often as men, the rates of developing FTD are equal in men and women, suggesting that a drop in estrogen does not increase one’s risk of developing FTD. Second, the average age of onset of symptoms for FTD has been found to be around 50 years in some studies, when the average woman is going through perimenopause. Therefore, one would not expect a drop in estrogen to be associated with FTD, since the disease process likely starts some time before the actual time symptom’s surface. Whether or not estrogen’s use is associated with FTD, risk remains to be clarified. The current exploratory study, therefore, is an attempt to add to our knowledge of possible preventative or etiological factors associated with FTD.
85
usage rate in those women living in the Western United States. Greatest rates of use were found among those in Caucasian women (26%) in the 50/59 (39%) age range who were living in the Southern or Midwest regions, and who had completed some college (31%). The typical woman in our sample was Caucasian, 70-year-old at the time of their evaluation, and with an education of approximately 12 years. Rates of estimated population use based on this source were compared with the observed rate of use among the FTD group using a Chi-square (x2) analysis. The characteristics of the women in the current study are illustrated in the table below Table 1.
3. Results 2. Methods Patient files of all females diagnosed with FTD at the UCSF Alzheimer’s Disease Research Center (UCSF-ADRC) since 1994 were reviewed. These patients were self-referred, physician-referred, referred by social and community agencies, or referred by friends and family. Patients had undergone an extensive, multifaceted evaluation. This evaluation included physical examination, neurological examination including CT or MRI scan of the brain, neuropsychological testing, laboratory tests, and thorough review of medical and family history. Patients were diagnosed according to criteria put forth by the Lund and Manchester groups [12]. Total number of patients was 30. The subject’s charts were reviewed to assess for estrogen use at the times of their evaluations. Estimates of estrogen use for women in the general population vary according to different studies, ranging from as low as 5% to as high as 59.8%, depending on such factors as socioeconomic status, occupation ethnicity, and education [15 /18]. For the purposes of the current study, we chose to use a national estimate of 24% from The Commonwealth Fund study [19]. In that study, based on a national survey that included 2010 women, it was found that peak estrogen use occurs between 50 and 59 years of age, with a decline in those over 60. They also found a relatively lower
Seventy percent (70%) of the women (21 of 30) diagnosed with FTD at the UCSF-ADRC between the years of 1994 and 2000 were on ERT at the time of their evaluation. When compared with the estimated use among healthy individuals of a similar age cohort (24%) in a x2 analysis, this difference was found to be significant (x2[df /1, N /30] /34.803, P B/0.01). To ensure that this finding was not simply a result of sampling bias at the UCSF-ADRC, we used frequencies of estrogen use among women diagnosed with probable Alzheimer’s disease (AD) that were obtained for another study (Levine and Battista, unpublished data). The records of 100 such women, evaluated during the same period, were examined, and revealed a 20% (20 of 99) rate of estrogen use at the time of initial evaluation. This finding indicates a slightly lower rate of estrogen use in the Alzheimer’s cohort as compared with the healthy population estimate, congruent with the lowered risk of AD among estrogen users found in previous studies [1,2]. More importantly, it Table 1
Education Age of onset Age at evaluation
Mean
Minimum
Maximum
11.95 64.95 70
7 46 51
20 87 91
86
A.J. Levine, L. Hewett / Maturitas 45 (2003) 83 /88
strengthens the finding of significantly heightened incidence of estrogen use among those diagnosed with FTD.
4. Discussion The findings of the current study indicate that a relationship exists between ERT use and the diagnosis of FTD. The direction of this relationship is not supportive of a preventative effect. In fact, the evidence here indicates a high correlation between estrogen use and the development of FTD. The fact that a greater rate of ERT use was found in those diagnosed with FTD is quite compelling. Although the current exploratory study is admittedly small, the findings should be investigated further in larger studies. Three hypotheses are now put forward that may help to explain the findings and to give direction for future research. 1) Diagnostic accuracy of neurodegenerative diseases has been the focus of numerous studies [20,21]. With regards to the current findings, it may be that estrogen use results in an atypical symptom presentation in those that in fact have AD. Numerous past studies of estrogen receptor distribution in animals, and more recent studies of the distribution in humans (Goka and Chang, unpublished data), have shown that the hippocampus is densely populated with estrogen receptors, and therefore, a candidate for the neuroprotective effects of estradiol. This area is among those first affected in AD, and is believed to be associated with the learning and short-term memory loss that are hallmark symptoms of early AD. It is not unreasonable to conceive that estrogen may protect areas in which there are dense estrogen receptors (e.g. hippocampus), while the disease process progresses in other areas, thereby resulting in an atypical symptom presentation where memory is not primarily affected. Findings of another study from this center support this hypothesis (Levine and Battista, manuscript submitted). However, it is a long leap from neurobiology
to clinical symptomology, especially in a disease with such global neuropathological changes. Furthermore, recent research has found that it is, in fact, FTD that often gets misclassified as AD [21]. In that study, the diagnostic criteria used for the differential diagnosis of FTD, AD, and other dementias were found to result in frequent misdiagnoses of FTD. Specifically, the NINCDS-ADRDA criteria for AD [22] were often fulfilled by those eventually verified as having FTD on post-mortem examination. Finally, even if it were possible that AD patients taking ERT present differently, the extensive, multifaceted evaluation performed at the UCSF-ADRC is unlikely to have misdiagnosed enough patients to account for the present findings. However, the possibility of misdiagnosis should not be dismissed. 2) Estrogen’s beneficial effects on mood have been well documented [23 /25]. As the initial symptoms of FTD can appear as mood disturbance such as depression [26], it may be that physicians prescribe ERT to women with FTD more often than those with AD or those in the general population. One significant limitation of the current study is that information regarding our patients’ hormone replacement use at the time of symptom onset was not available. As our databases become more comprehensive, this variable will ideally be accounted for in future studies. 3) The prime suspect in the pathogenesis of some forms of FTD is tau. Tau deposits are the major component of neurofibrillary tangles and of the other unusual pathological features of some FTDs, such as Pick bodies [27]. Tau is actually a collection of MAPs expressed from a single gene on chromosome 17, and it comes in six known isoforms [13]. At least twelve mutations in the tau gene have been identified and linked with various FTDP-17 disorders. Some have hypothesized that each mutation may result in a different clinical disease. In support of this idea, differences in the neuropathological sequelae of different mutations have been identified [13]. Most, if not all, FTDP-17 disorders show tau deposits on
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neuropathological examination, though not all involve a mutated form. The tau mutations found thus far account for only a small percentage of FTD cases, suggesting that faulty tau is not a direct cause of these diseases. In fact, one researcher has found that no phenotypic abnormalities are seen in a strain of mice that lack the tau gene altogether [28]. They suggested that the disease process may not be due to mutated tau being unable to carry out its usual functions, but rather the disruption of binding of tau, due to mutations or other reasons, leads to an excessive buildup of the compound, which results in disruption of cellular function. Others have suggested that over production of any one of the six tau isoforms may result in an accumulation of tau, which could polymerize into filaments, again disrupting cellular functioning [13]. Furthermore, these authors found that the expression of the tau isoforms can be cell-type specific. Therefore, should a misbalance of tau or the overproduction of any of the tau isoforms occur, whether mutated or not, this may result in the accumulation of tau and the disruption of cellular functioning, and this can occur in specific cell types. In 1991, it was found that the in-vitro administration of estrogen, specifically estradiol beta-17, to embryonic hypothalamic neurons of rats resulted in a selective 3-fold increase of tau levels over those observed in control cells [29]. This was found for cells that had already differentiated as well. The expression of other MAPs did not increase with estrogen. Furthermore, other forms of estrogen used in the study did not result in a significant increase of tau. Recall that it is 17 betaestradiol that ERT replaces. It is not inconceivable, therefore, that the administration of exogenous estrogen may result in a significant increase of tau expression. In prone individuals (e.g. those with mutated tau) this increase could result in the accumulation of tau to levels that may result in the dysfunction of specific neuronal populations, which in turn may be related to the greater percentage of women diagnosed with FTD observed here. If this relationship between tau and
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estrogen is also present in humans, these findings suggest that ERT may be contra-indicated in those with early FTD symptoms, family history of FTD, or a known tau mutation.
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