# Thyroid Function and Cognition during Aging

Authors: M. E. Bégin; M. F. Langlois; D. Lorrain; S. C. Cunnane
Journal: Current Gerontology and Geriatrics Research
 (2008)

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## Abstract

We summarize here the studies examining the association between thyroid function and cognitive performance from an aging perspective. The available data suggest that there may be a continuum in which cognitive dysfunction can result from increased or decreased concentrations of thyroid hormones. Clinical and subclinical hypothyroidism as well as hyperthyroidism in middle-aged and elderly adults are both associated with decreased cognitive functioning, especially memory, visuospatial organization, attention, and reaction time.  Mild variations of thyroid function, even within normal limits, can have significant consequences for cognitive function in the elderly. Different cognitive deficits possibly related to thyroid failure do not necessarily follow a consistent pattern, and L-thyroxine treatment may not always completely restore normal functioning in patients with hypothyroidism.  There is little or no consensus in the literature regarding how thyroid function is associated with cognitive performance in the elderly.


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## Body

## 1. Introduction

Adequate thyroid function is essential for
normal development and retention of cognitive function throughout life. The association
between thyroid hormones and cognition has been recognized since the demonstration
that cretinism stems from iodine and thyroid deficiencies. Low thyroid function at any age causes
cognition to deteriorate because hypothyroidism prevents the brain from adequately
sustaining the energy (glucose)-consuming processes needed for neurotransmission,
memory, and other higher brain functions. Low brain uptake of glucose is
commonly associated with deteriorating cognition and Alzheimer's disease and
can be present decades before clinical evidence of Alzheimer's disease occurs [1, 2]. Brain hypometabolism therefore appears to be a precursor
lesion increasing the risk of at least some forms of cognitive decline. Since thyroid hormone concentrations
change with age and since cognitive decline is often concomitant with aging,
physiological changes in thyroid function might be causally related to changes
in cognition during normal aging.Mental activities involved in the acquisition,
storage, retrieval, and use of information are referred to here by the term
“cognition” [3, 4]. Manifestations of cognitive behavior are achieved through
the integration of a variety of processes and activities such as perception, imagery, memory, reasoning, problem solving,
decision-making, and language. A summary of cognitive measurements used in
thyroid function studies are shown in Table 1.Table 1
Cognitive domains and measures (AN: animal naming; CC: cube copying; CoS: Corsi's
span; CST: concept shifting test; CVMT: continuous visual memory test; d2: d2 test; DRS: dementia rating
scale; DS: digit spans forward and backward of WAIS-R; FMT: Milner facial memory test; FR: figure
rotation from the Schaie-Thurstone adult mental abilities test; GNG: Go-NoGo; HT: Hooper test;
IPALT: Inglis paired associates learning test; LDC: letter digit coding test; LMN: Luria m's and n's; LW:
list of words; MHV: Mill Hill Vocabulary Scale; MMSE: Mini-Mental State
Examination; MMMSE: Modified Mini-Mental State Examination; OR: oral reading;
PASAT: paced auditory serial addition task; PM: Porteus maze; RBP: Rivermead behavioral
profile; RCFT: Rey-Osterrieth complex figure test; RPM: raven progressive matrices
test; RW: Rey's words
immediate and delayed recall; ScT: scribble test; SDMT: symbol digit modalities
test; SRT: selective reminding test (Buschke); ST: Stroop test; SVT: Shipley
Vocabulary test; TMTA&B: trail making test A and B; WAIS: Wechsler adult intelligence
scale; WAIS-R: Wechsler adult intelligence scale-revised; WD: word
discrimination; WFT: word fluency test; WLT: word learning task; WMS: Wechsler memory
scale; ZVT: Zahlenverbindungstest).
Cognitive domainMeasuresGeneral intelligenceRPM, MHV, SVT, WAIS, WAIS-R, DRSAttention and concentrationPASAT, TMTA&B, SDMT, ST, DS, CST, d2,MemoryWMS, CVMT, FMT, RCFT, SRT, IPALT, DS, WLT, LW, RBPVisuospatial organizationWAIS-R, CC, TMT(Part A), FR, HT, ScT, CoSLanguageWFT, AN, WD, RW, ORExecutive functionGNG, WFT, LMN, PM, TMTGlobal cognitionMMSE, MMMSECognitive or psychomotor speedWAIS-R, TMT(Part A), WFT,  LDC, ZVTThyroid function has been measured as serum concentrations
of thyroid-stimulating hormone (TSH) or thyroid hormones (total or free thyroxine
[T4], total or free tri-iodothyronine [T3], or T3 resin uptake). Most studies
reported TSH, since it is very reproducible and is commonly believed to be the
best marker of thyroid status, in combination with one or two thyroid hormones
measurements.Our aim here is to summarize the growing
literature on the relationship between cognitive performance and thyroid
function from an aging perspective. Several studies have been carried out to
investigate whether thyroid function can explain the substantial individual
differences in cognitive performance of older individuals. The characteristics
of the association between thyroid function and cognition will be described
first in healthy euthyroid individuals and then in patients with different
degrees of hypothyroidism or hyperthyroidism.


## 2. Age-related Changes in Cognition and  Thyroid Function

Several changes in thyroid function occur
during aging. Normal aging is associated with changes in thyroid hormone production
and metabolism [5, 6]. Secretion of T4 and T3 is reduced in the healthy elderly
(61–90 years old), but serum concentrations of total and free T4 remain relatively
unchanged because T4 degradation is also reduced in the elderly. Circulating
total and free T3 concentrations demonstrate a clear, age-dependent decline
because of both reduced secretion and reduced peripheral conversion from T4. Serum
reverse T3 (rT3) seems to increase with age. The decrease in serum T3 levels
together with the increase in serum rT3 may indicate a decrease in peripheral
hepatic metabolism of iodothyronines during aging.Data on TSH changes during healthy aging are
equivocal: some studies show unchanged TSH concentrations while others show mildly
increased TSH in both men and women. After excluding subjects with subclinical
hypothyroidism, the data suggest that TSH secretion may actually be slightly
decreased in healthy elderly individuals [5]. A decline in both the circadian
patterns and maximal nocturnal levels contributes in decreasing TSH levels in
the elderly [5, 7].The evaluation of normal thyroid function in
the elderly is commonly confounded by subclinical hypothyroidism, by an increased
prevalence of acute or chronic nonthyroidal illness, by drug use, and by nutritional
deficiencies [6]. Some studies on healthy elderly subjects selected by strict
criteria to exclude coexisting diseases suggest that an age-dependent decline in
thyroid function is at least partially independent of nonthyroidal illnesses,
particularly in the oldest/old (>85 years)
population [5, 8]. In the healthy elderly, thyroid
function appears to be well preserved until the eighth decade of life, and a
reduction of serum free T3 is only observed in the extremely old (100–110 years) [8].An increased risk of declining cognitive
function with aging is well-known, especially with regard to working memory,
information processing speed, and long-term memory [4, 9–13]. Working memory is an essential cognitive resource whereby information is
temporarily stored and made readily available to the various processes carrying
on a specific task. Differences in cognitive efficacy can be related to
discrepancies in working memory, including those presumably caused by normal or
pathological aging [4].
Since it plays such a central
role, alterations of working memory can have an effect on language processing,
problem solving, decision-making, and encoding or retrieving of information in
long-term memory.Information processing speed is also an
important resource, defined by the time parameters of a specific cognitive
task. Shortest latencies are usually associated with youth and better
performances. The label “cognitive slowing” has been applied to age-related increases
in those latencies, which in turn can be held responsible for many aspects of
declining cognitive functioning [4].Efficiency of the three main aspects of long term memory—encoding, storage, and retrieval—declines over time
[10]. A possible explanation could be that the elderly
spontaneously deploy less effort at the time of exposure to properly encode
information, thereby diminishing storage capacity and undermining subsequent
retrieval attempts. This might be the reason why, for the elderly, retrieval
tasks are especially difficult when summoned out of context [4]. An important decrease in mnesic performances has been observed, usually
correlating with the complexity of the material, using either verbal or spatial
stimuli, as well as declarative or procedural knowledge.However, not all aspects of memory are equally
affected with age [9]. For example, organization of long-term memory
and priming of the information it contains remain relatively intact. Implicit
inductive reasoning also seems to be well preserved, compared to explicit
learning capacity. Broadly speaking, episodic memory, being the long-term
memory concerned with items associated with a specific context in space and
time, is generally more affected than semantic memory, which is the long-term
memory concerned with general knowledge and values which have become quite
independent of their acquisition context.


## 3. Cognitive Decline in Healthy Euthyroid Elderly

Table2 shows relevant characteristics of five studies
that sought to establish whether reduced thyroid function adversely affects cognitive
function in healthy euthyroid individuals during aging. In a cross-sectional study
involving a random sample of individuals aged from 49 to 71 years (mean age of 60 years), van Boxtel et al.
[14] found that higher levels of TSH
predicted lower levels of memory performance but that this association was not
significant after correcting for mood status and the presence of possible
thyroid dysfunction. Prinz et al. [15] suggested that total T4 levels and
possibly free T4,  but not total T3 nor
TSH, were significantly associated with better cognitive performance in
euthyroid men aged 65–78 years (mean 72 years) who had no overt
physical or mental illness.  In physically
impaired 75–80-years-old euthyroid women,
Volpato et al. [16] demonstrated that lower total T4 levels, (still within the
normal range), but not TSH, were associated with a greater risk of decline in components
of episodic memory over a 3-year period. Women with serum total T4
concentrations of 4.5–6.5 μg/dL had a
twofold risk of cognitive decline compared to women with serum total T4
concentrations of 8.1–12.5 μg/dL. No association was found between baseline TSH level
and change in cognitive function. These results were not substantially modified
after adjustment for potential confounders including age, race, level of education,
medication use, and presence of nonthyroidal illnesses.Table 2
Relation between thyroid function and cognition in euthyroid elderly (>65 years old) (A: attention; BD: block design of WAIS-R; CST: concept shifting test;
DRS: dementia rating scale; DS: digit span forward and backward of WAIS-R; FR: figure
rotation; FT3: free T3; G: global; LDC: letter digit coding test; LW: list of
words; M: memory; MMSE: Mini-Mental State Examination; MRT: median reaction
time tests; NS: not specified; NTI: nonthyroidal illnesses;  O: orientation;  PS: psychomotor speed;  RBP: Rivermead behavioral profile; ST: Stroop
test; TMTA&B: trail making test A and B; TSH: thyroid stimulating hormone;
TT4: total T4; VF: verbal fluency; VSA: visuospatial ability; WAIS-R: Wechsler adult
intelligence scale-revised; WLT: word learning task).
SourceAge, yearsGenderPopulation health statusAltered cognitive domainThyroid function indicatorMeasuresmeanrangewomenmenNvan Boxtel et al. [14]6049–71NSNS120Healthy + hypoMTSHWLT, CST, STPrinz et al. [15]7265–7804444HealthyG, VFTT4WAIS-R, DRS, VF, FR, RBP, MMSE, MRTVolpato et al. [16]7275–804640464Heathy + NTIO, MTT4MMSEWahlin et al. [17]8475–9615941200HealthyMTSHDS-WAIS-R, LW, TMTA&B, BDWahlin et al. [18]NS75–9339645HealthyVF, VSA→ MTSHRT, BD, VF, TMTA&BGussekloo et al. [19]85–89369189558MixedG, A, M, PSFT3MMSE, ST, LDC, WLTConversely, from a cross-sectional study of
euthyroid very old women and men 75–96 years old (mean age = 84 years), Wahlin et al. [17]
reported that, within the normal range, TSH
levels but not free T4 were positively associated with episodic memory
performance. The effects were independent of age, educational level, and
depressive mood symptoms. No significant effects of TSH were depicted on verbal
fluency, short-term memory, perceptual-motor speed, or visuospatial
functioning. From further examination of very old women (n=39) and men (n=6),
respectively, Wahlin et al. [18] provided longitudinal evidence of the impact
of normal TSH variations on cognitive functioning. Their analyses revealed that
declining TSH levels within the normal range were accompanied by a parallel
decline in verbal fluency and visuospatial abilities, predicting episodic
memory deficits after six years followup. Baseline TSH levels did not predict
future decline of cognitive functioning. Conversely, Gussekloo et al. [19]
found that low-free T3, but not TSH or free T4, was associated with an
accelerated decline in global cognitive function as measured by the MMSE in an
unselected general population of 558 individuals aged 85 years, of whom 85% were
euthyroid, 5% were subclinically hypothyroid, 7% were clinically hypothyroid,
and 3% were hyperthyroid, both at baseline and after a followup of 3.7±1.4 years.Clearly, the results from these studies are disparate
and conflicting as to which indicator of thyroid function is the most relevant
marker of specific cognitive function, and which domain of cognitive
functioning is primarily affected by thyroid hormonal variations. However, the
over all findings suggest that, although thyroid hormones may have an impact on
a variety of cognitive functions, only a link to certain memory functions has
been so far highlighted. Differences in results may be due to differences in sample
selection, age ranges, choice of cognitive tests, and to higher TSH and
cognitive variability with increasing age and limited number of thyroid
function indices. More prospective
follow up studies on a well-characterized selected population of healthy
elderly are needed with repeated assessment of multiple indicators of thyroid
function, ample specific cognitive measurements, and adequate assessment of
mood status.


## 4. Cognitive Impairment in Subclinical  Hypothyroidism

Subclinical hypothyroidism is defined as an elevated
TSH levels in the presence of normal circulating T4 and T3 concentrations plus
the absence of features of clinical hypothyroidism [20, 21].  About one-third of subclinically hypothyroid patients
present mild, nonspecific symptoms possibly pointing to a mild hypothyroidism [22, 23] or a subclinical hypothyroidism, the latter being the term most frequently
used in the studies examined.Subclinical hypothyroidism may be a
predisposing factor for cognitive impairment. Table3 shows the results of
different studies of cognitive impairment in subclinical hypothyroidism in order
of increasing age. Patients with subclinical
hypothyroidism for a long time (16±6.2 months) manifested impaired cognitive
activity as evidenced by significantly longer P3 wave latency of event-related
potentials compared to healthy individuals [23]. Five cross-sectional studies
suggest that young adult patients with subclinical hypothyroidism had mild
dysfunction in learning, memory, and selective attention. Monzani et al. [24] found
memory deficits in a group of 13 women and 1 man (29 to 47 years old) with untreated
subclinical hypothyroidism compared to 50 euthyroid control subjects. Similarly,
Baldini et al. [25] found that 19 young and middle-aged women with subclinical
hypothyroidism showed worse memory, but no differences in scores of mental
control, attention, or visuospatial abilities compared with 17 euthyroid
control women. del Ser Quijano et al. [26] identified slower reaction time, reduced verbal
fluency, and impaired visual memory in a group of 15 young adults with subclinical
hypothyroidism compared with a group of 15 euthyroid control subjects. Cook et
al. [27] reported that elderly patients with subclinical hypothyroidism performed
more poorly than euthyroid individuals on measures of verbal recall as well as
on the Mini-Mental State Examination but working memory and processing speed
were unaffected. A decrease in verbal fluency was noted in the study of Manciet
et al. [28] in a population sample of 425
individuals (65–85 years old or older) comprising 89.7%
euthyroid subjects, 4.2% with subclinical hypothyroidism, 1.9% with clinical hypothyroidism,
and 4.2% with hyperthyroidism.Table 3
Cognitive impairment in subclinical hypothyroidism (A: attention; BMT: Bingley's memory test;  BVRT: Benton's visual retention test; CS:
Corsi's span forward and backward; DC: drawing copy; DSB: digit span backward;
DSCT: digit symbol coding test from the WAIS-III;  DSF: digit span forward; DSS: digit symbol
substitution; EF: executive functions; IFT: identical forms test of
Thurstone;  IST: Isaacs' set test of
verbal fluency; LM: logical memory test; M: memory; MMSE: Mini-Mental State Examination;
NBT: N back test;  PS: perceptual speed;
RAVLT: Rey auditory verbal learning test; RF: Rey's figure; RPM: Raven's progressive
matrices; RT: reaction time; RW: Rey's words immediate and delayed recall; S:
speed test; ScT: Scribble test; TMTAB: trail
making test A and B; VF: verbal fluency; VF: verbal fluency test; WAIS:
Wechsler adult intelligence scale; WFT: word fluency test; WLT: word learning test;
WMS: Wechsler memory scale; ZBT: Zazzo's barring test).
SourceParticipantsImpaired cognitive domainTestsTreatment outcomeAge, yearsGenderMean ± SD and/or (Range)womenmenNdel Ser Quijano38 ± 9.512315A, M, VF, EFMMSE, WAIS, RT, BVRT, RF, WLT, VF, TMTABImprovement after 6 monthset al. [26](23–53)Monzani39 ± 913114MWMSImprovement after 6 monthset al. [24](29–47)Baldini55 ± 919019MWMS, ScT, SImprovement after 3 monthset al. [25](28–68)Bono et al. [29]52 ± 13.536036A, VFMMSE, DSF, DSB, CS, RW, TMTAB, RPM, DC, VFImprovement after 6 months(31–70)Nyström et al. [30](51–73)17017PS, M, SIFT, BMT, RTImprovement after 6 monthsJaeschke et al. [31]68 ± 9.428836M, PSLM, WLT, WFT, DSS, TMTImprovement after 10 monthsJensovsky et al. [23]62 ± 6.820020MWMSImprovement after 6 monthsManciet et al. [28](65–85)256169425VFMMSE, BVRT, WAIS, ZBT, ISTNo treatmentCook et al. [27]74 ± 3.9NSNS15M,VFMMSE, RAVLT, DSCT, NBT, DSBNo treatmentIn contrast, three studies failed to find
cognitive impairment associated with subclinical hypothyroidism.  No differences were found by Osterweil et al.
[32] between the 14 patients with subclinical hypothyroidism and 30 controls.
Similarly, in a group of elderly subjects aged 65–92 years, Luboshitzky et al.
[33] reported no significant differences in cognitive impairment measured by
the Mini-Mental State Examination in 39 untreated subclinically hypothyroid patients
compared to 570 euthyroid controls. Bono et al. [29] provided evidence that subclinical
hypothyroidism in 36 women barely affected their cognitive status but may have
caused an age-related impairment of attentive functions.The possibility of reversing some aspects of
the cognitive impairment associated with subclinical hypothyroidism has been
demonstrated after treatment with L-thyroxine. Two single-case studies showed
that L-thyroxine treatment was associated with reversal of the cognitive
impairment in each case [34, 35]. In a larger study, Bono et al. [29] also
obtained a slight but significant improvement of verbal fluency in 36 women
with subclinical hypothyroidism after 6 months treatment with L-thyroxine but
this showed no correlation with TSH changes after treatment. Three uncontrolled
studies showed improvements in memory skills after 3 or 6 months of treatment
with L-thyroxine [24, 25]. The comprehensive study of del Ser Quijano et al.
[26] revealed that L-thyroxine treatment
was associated with significant improvements on multiple cognitive measures
including attention, memory, verbal fluency, and executive functions compared
to control participants.The effects of L-thyroxine treatment were also
investigated in three small randomized, placebo-controlled trials. A modest but
statistically significant improvement in a composite memory score was obtained
in patients treated with L-thyroxine for 10 months compared to placebo control
patients [31]. However, the difference was small enough to be of questionable
clinical importance. Compared to the placebo control group, Nyström et al. [30]
reported that in a 6-month double-blind, crossover study using L-thyroxine
treatment, up to 20% of patients improved their memory scores and reaction time
but only half of them also improved their perceptual speed. Jensovsky et al.
[23] found significant improvement of verbal, visual, and total memory scores
after the normalization of TSH level by L-thyroxine treatment for 6 months in
the treated individuals compared to the control individuals.The interpretation of these studies is difficult
due to variations in both the definition and the etiology of subclinical
hypothyroidism, the presence or absence of symptoms, and to the limited number
of subjects investigated. Nevertheless, taken together, the results suggest
that evaluation and treatment of subclinical hypothyroidism in the elderly may
be beneficial in view of its prevalence and its potential clinical importance.
Indeed, subclinical hypothyroidism is common with estimates ranging from 5% to
17% in the general population, with an age-related increase to as many as 20%
of women and 9.5% of men over the age of 60 years [6, 22, 33, 36–39]. The
prevalence of subclinical hypothyroidism in men over the age of 74 years was 16% which approaches
the 21% prevalence seen in women of the same age [40].The elderly may be more vulnerable to the cognitive
effects of subclinical hypothyroidism than young adults, suggesting that
diagnosis and treatment may protect the aging brain from cognitive
deterioration. However, it is not yet certain
that favorable results obtained with middle-aged patients are predictive of
favorable responses in elderly. Furthermore, different cognitive functions
probably have varying sensitivity to hormonal or metabolic changes. Not all the
cognitive defects related to thyroid failure are completely reversible with L-thyroxine
therapy. Additional controlled studies are required to answer these questions.


## 5. Cognition Deficits in Clinical Hypothyroidism

Adult clinical hypothyroidism is the result of
decreased serum levels of thyroid hormones and has a variety of adverse effects
on cognitive function [32, 41–49]. Common
cognitive deficits observed in middle-aged clinical hypothyroid patients
include diminished general cognition, attention, learning, memory, and
psychomotor speed (see Table 4). However,
language comprehension and possibly sustained auditory attention are less
impaired than other cognitive functions in clinical hypothyroidism. Whether or
not there is a correlation between the cognitive alterations and the degree or
the duration of hypothyroidism still needs to be clarified.Table 4
Cognitive deficits in adult
clinical hypothyroidism (AN: animal naming; BD: block design of WAIS-R; BEC-96: recall and visuoverbal
recognition test; CC: cube copy; COWA: controlled oral word association; CVLT:
California verbal learning test; CVMT: continuous visual memory test; DRS:
Dementia rating scale (Mattis); DS: digit symbol subtest; FMT: Milner facial
memory test; GNG,: Go-No go; HT: Hooper test; IPAL: Inglis paired associates learning;
LMN: Luria m's and n's;  MHV: Mill hill
vocabulary scale; MMSE: minimental sate examination; MMMSE: modified Mini-Mental
State Examination; OAS: object assembly subsets of WAIS-R; OR: oral reading;  PASAT: paced auditory serial addition task; PM:
Porteus mazes; ROCF: Rey-Osterrieth complex figure test; RPM: Raven progressive
matrices test; SDMT: symbol digit modalities test; SRT: selective reminding test
(Buschke);  SVT: Shipley vocabulary test;
TMT(A): Trail making part A; TMT(A,B): Trail making test parts A and B; VLT: verbal
learning test ; WAIS: Wechsler adult intelligence scale; WAIS-R: Wechsler adult
intelligence scale-revised ; WD: word
discrimination; WFT: word fluency test; WMS: Wechsler memory scale).
Cognitive domainSourceAlteredTreatment outcomeMeasuresGeneral intelligenceCapet et al. [43]YesImprovement after 6 monthsWAIS-RMennemeier et al. [46]YesNot generally affectedWAIS-RHaggerty et al. [45]YesNo change after 3 monthsWAIS, DRSCrown [44]YesImprovement after 8 monthsRPM, MHV, SVTAttentionMiller et
al.  [47]NoNo improvementTMT(A)Capet et al. [43]YesImprovement after 6 monthsTMT(A), WMS,Mennemeier et
al. [46]NoImprovement after 7 monthsPASATOsterweil et
al. [32]YesImprovement after 8 monthsTMT(A), SDMTWhybrow et al. [49]YesNo change after 10.5 monthsTMT(A,B)MemoryMiller et al. [47]YesImprovement after 3 monthsWMS, CVLT, RCFTBurmeister et
al. [42]YesImprovementVLTCapet et al. [43]YesImprovement after 6 monthsWMS, BEC-96, WMS,Mennemeier et
al. [46]YesNo change (but treatment may arrest further decline)CVMT, FMT, RCFT, SRT, WMSOsterweil et
al. [32]YesImprovementIPALHaggerty et al. [45]YesNot treatedWMSVisuospatial abilitiesCapet et al.
[43]YesImprovement
after 6 monthsTMT(A), WAIS-R, HTMennemeier et
al. [46]YesImprovementWAIS-R (BD, OAS)Osterweil et al. [32]YesNo improvementCCLanguage (expression)Miller et al. [47]NoNo changeANCapet et al. [43]NoNo improvement after 6 monthsWFTMennemeier et al. [46]NoNot treatedWFTOsterweil et al. [32]YesNo improvementWFT (Animals)Language (reception)Osterweil et al. [32]NoNot treatedWD, ORExecutive functionsMiller et al. [47]NoNo changeTMT(B), COWAMennemeier et al. [46]NoNot treatedGNG, WFT, LMNWhybrow et al. [49]YesNo changePMPsychomotor speedBurmeister et al. [42]NoNo changeWAIS-RCapet et al. [43]YesImprovement after 6 monthsWAIS-R, WFT, TMT(A, B)Global cognitionCapet et al. [43]YesImprovement after  6 monthsMMSEOsterweil et al. [32]YesNo improvementMMMSEPeabody et al. [48]YesProgressive declineMMSEAlthough L-thyroxine successfully treats low
thyroid status in the majority of hypothyroid patients, it is well recognized
that a minority of patients have persistent symptoms. As shown in Table4, several
reports demonstrate that treatment of hypothyroidism during 3, 6, or 10.5
months still appears to be associated with only partial and inconsistent
patterns of recovery of overall cognitive functioning. Similarly, the study of
Wekking et al. [50] showed that cognitive defects, especially involving
attention and verbal memory, persisted in a large group of hypothyroid
patients, given sufficient L-thyroxine treatment over 5.5 years to normalize TSH.  These results indicate that significant memory
deficit in middle-aged adults with hypothyroidism can persist even after “adequate”
thyroid replacement.Three studies investigated the possibility that
the brain becomes more susceptible to thyroid dysfunction in the seventh decade
of life. Capet et al. [43] reported that the mean cognitive functions scores of
treated patients or controls over 70 years old tended to be lower than those of
treated patients or controls less than 60 years old. Osterweil et al. [32]
compared cognitive performance of a group younger than 75 years to a group over
75 years. The older group performed worse on cognitive tests than the younger
group, although there was no interaction between age and thyroid status. In a
population with a prevalence of hypothyroidism of 14%, Luboshitzky et al. [33] reported
that global cognitive impairment increased with age from 5.2% of the
individuals aged 65–70 years to 35.5%
in the age group of 85–90 years. Thus,
age may increase vulnerability on cognitive tests to the effects of
hypothyroidism.


## 6. Cognition Deficits and Hyperthyroidism

Hyperthyroid patients commonly present a
variety of cognitive function deficits, although to a lesser degree than in
hypothyroid patients. As shown in Table5, the most common cognitive deficits
observed in hyperthyroid patients include poorer performance on tests of attention,
memory, mental alertness, and visuomotor speed [49, 51–54]. There are
conflicting results concerning effects of hyperthyroidism on motor speed [55, 56].
Treatment of hyperthyroidism is followed by a partial return to baseline
cognitive functioning [57].Table 5
Cognitive changes in (natural and experimental) hyperthyroidism.
Cognitive domainHyperthyroidismNaturalExperimentalT3(b)T4(d)T4(e)100μg/day300μg/day500μg/dayfor 3 daysfor 21 daysfor 45 daysAttentionImpaired(a)No changeNot reportedNo changeMemoryImpaired(a)No changeNot reportedNo changeVisuospatial abilitiesImpaired(a)No changeImpairedNo changeMotor speedImpaired(a),(b)Not reportedNot reportedNot reportedNo change(c)Verbal fluencyNo change(b)AcceleratedNot reportedNo change(a)Whybrow et al. [49],
MacCrimmon et al. [51], Alvarez et al. [52],
Trzepacz et al. [53], Toft [54];
(b)Kathman et al. [56];
(c)Zeitlhofer et al. [55];
(d)Münte et al. [58];
(e)Baethge et al. [59].The effects of experimentally raising thyroid
hormones on cognitive performance have been reported in three studies. Increasing
serum T3 levels to values within the hyperthyroid range by administrating 100μg
T3 daily over 3 days to 14 young, euthyroid healthy men (20–37 years old) resulted
in no significant change in either attention, memory, or visuomotor
coordination, but a trend towards improved verbal fluency was seen [56]. Administration
of supraphysiologic doses of L-thyroxine (500 μg/d for 45 days on average) to 11
subjects (4 men, 7 women, mean age 37 years) did not change attention, memory,
visuospatial organization, verbal learning, or verbal fluency [59]. In a
placebo-controlled cross-over study in 24 healthy men, Münte et al. [58] found
that administration of L-thyroxine in relatively high doses (300 μg daily for 3
weeks) significantly improved visual processing. That cognitive functioning was
little or not changed in these short-term studies suggests that the normal
regulatory processes that modulate cognition, and which are disturbed in clinical
hyperthyroidism, are not disrupted in healthy subjects by the use of
supraphysiologic doses of thyroid hormones.


## 7. Thyroid Function and Alzheimer's Disease

Given the potentially increased risk
of cognitive decline with thyroid dysfunction and that progressive cognitive
decline is the central clinical feature of Alzheimer's disease, it is possible
that thyroid status contributes, at least in part, to the clinical
manifestation of Alzheimer's disease. Several clinical reports as well as
laboratory and epidemiological studies support a link between thyroid hormones
and Alzheimer's pathophysiology [41, 49, 60–71]. Studies examining
the relationship between TSH and Alzheimer's disease have yielded contradictory
results. Low serum TSH concentrations as well as high thyroxine levels were proposed
as risk factors for Alzheimer's disease in some studies [72–74] but not in others
[75, 76]. In a 6-year prospective follow-up study of mild
cognitive impairment (which represents a transition between normal aging and Alzheimer's
disease), Annerbo et al. [77] found a significant correlation between reduced
TSH concentrations and patients converting from mild cognitive impairment to Alzheimer's
disease. However, no significant correlation was found between TSH or free T4
levels and global cognition in euthyroid patients with Alzheimer's disease [78].


## 8. Discussion

Normal thyroid function appears to be an
important factor in retaining optimal cognition in human aging [79]. Overall, many studies suggest that there may
be a continuum characterizing the impact of thyroid function on cognition in
which cognitive dysfunction results from either chronically increased or
decreased concentrations of thyroid hormones. For example, Table 6 shows such
continuum of specific cognitive defects with the degree of hypothyroidism. Even
thyroid hormones and TSH levels within low-normal range appear to influence
cognition performance, such that low-normal thyroid function appears associated
with cognitive decline over time [16–18].Table 6
Continuum of specific cognitive defects with the degree of
hypothyroidism.
Hypothyroidism statusAttentionMemorySpeedVerbal fluencyVisuospatial abilitiesLow normal0/1(a) (0%)5/6 (83%)1/5 (20%)1/5 (20%)1/4 (25%)Subclinical2/4 (50%)6/8 (75%)2/5 (40%)3/5 (60%)0/3 (0%)Clinical3/5 (60%)6/6 (100%)1/2 (50%)1/4 (25%)3/3 (100%)(a)Number of studies reporting cognitive defects over total number of studies.Many questions remain unresolved. For example, there is disagreement as to which of TSH, T4,
or T3 is the best indicator of thyroid function, and best predictor of cognitive decline, especially in the elderly. The relationship between TSH
and cognitive functioning appears to be inconsistent in euthyroid elderly [15–18]. Although it
is the major modulator of thyroid hormone secretion, circulating TSH may not be
a sufficiently sensitive or direct measure of thyroid hormone sufficiency for brain
function. Moreover, serum TSH is influenced by a negative feedback loop
associated with thyroid hormones and by the effect of other hormones and
bioactive substances, such as cortisol, somatostatin, and cytokines [80]. TSH and cognitive performance may thus change
in parallel, possibly due to a third variable. For example, TSH relationship with
cognition may exist in a more specific or vulnerable population, in older,
lower education, higher prevalence of cognition-related comorbidity.Physiological studies provide support for a
relationship between T4 and cognitive processing. The brain maintains levels of
both T4 and T3 within a very narrow range, even during important fluctuations
of circulating T4 [81]. Thus, possibly, even small changes in brain T4
concentrations could have consequences for cognitive function. Because brain
function might be negatively affected by brain T4 in the lower range of normal,
to function normally, the brain of older persons might have an increased need
for or less efficient capacity to access or utilize T4. The basis for this
shift could derive from aging-induced changes in T4 transport into specific brain
regions, altered brain conversion of T4 to T3, or decreased brain thyroid receptor
number or affinity.An alternative explanation may be that the
apparent paradox reflects differences in thyroid function before and after a
threshold around the age of 80–85 years. Indeed,
an age-dependent decline in thyroid function has been identified that is at
least partially independent from associated nonthyroidal illnesses,
particularly in those older
than 85 years old [82, 83]. It is thus
plausible that the correlation between cognitive decline may be stronger with
T4 than with TSH in euthyroid individuals aged between 61 and 79 years but that
a positive association with TSH appears with individuals older than 80 years old.
This interpretation is supported by the studies reporting that increasing
levels of TSH and decreasing levels of free T4, both representing lower thyroid
function, were associated with a survival benefit [19, 82–84]. This metabolic change may reflect an adaptive
mechanism to preventing excessive catabolism in the oldest elderly.Our overall impression is that there is a substantial
degree of disagreement regarding several aspects of the relationship between
TSH, thyroid hormones, and cognitive performance. Most studies were adjusted
for age, educational level, gender, and mood status, but differences in results
that remain may still be due to differences in sample populations, exclusion
criteria, age range, normal limits of TSH reference values, and choice of
cognitive tests. Moreover, the interpretation of these results is complicated
by the coexistence of age-related nonthyroidal illnesses which may contribute
to serum thyroid hormone and TSH perturbations but for which adequate
correction may not have been made [5, 85]. In turn, these thyroid indices may also affect
cognitive performance by the degree and the duration of hypothyroidism [23, 32, 50], by practice effects [46, 57], by the use of insufficient thyroid function
indices in most studies, by the wide individual variation in the rate at which TSH
and cognitive functions deteriorate with increasing age [17, 18], by the effects of nutritional deficiencies [6],
or by other endocrine perturbations, such as low sex steroids or high stress
hormones, which could lead either directly or indirectly to cognitive
dysfunction [18, 86].No consensus has been reached about the health
impact of subclinical thyroid dysfunction, for which different recommendations
have been made about screening and treatment [20–22, 45, 54, 87, 88].
Different cognitive functions clearly have different sensitivity to hormonal or metabolic changes and not all the
cognitive defects related to thyroid failure are completely reversible with thyroid replacement therapy.Very few studies have examined the mechanism by
which thyroid dysfunction might influence memory performance. There is some
evidence that decreased cerebral blood flow in mild hypothyroidism occurs in
regions mediating attention, motor speed, memory, and visuospatial processing [89].
High TSH concentrations may also decrease
cerebral blood flow and glucose metabolism in clinical hypothyroidism [90]. However, comorbid cerebrovascular disease and
elevated anticholinergic activity did not appear to be involved in memory
impairment in elderly individuals with a mildly elevated serum TSH [27].



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