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The premild cognitive impairment, subjective cognitive impairmentstage of Alzheimers disease

Barry Reisberga,*, Leslie Prichepb, Lisa Mosconic, E. Roy Johnb, Lidia Glodzik-Sobanskac,Istvan Boksaya, Isabel Monteiroa, Carol Torossiana, Alok Vedvyasa, Nauman Ashrafa,

Imran A. Jamila, Mony J. de Leonc

aSilberstein Aging and Dementia Research Center, New York University School of Medicine, New York, NY, USAbBrain Research Laboratories, New York University School of Medicine, New York, NY, USA

cCenter for Brain Health, Department of Psychiatry, New York University School of Medicine, New York, NY, USA

Abstract Background: Subjective cognitive impairment (SCI) has been a common, but poorly understoodcondition, frequently occurring in older persons.

Methods: The past and the emerging literature on SCI and synonymously named conditions is reviewed.

Results: Findings include: (1) There is support from at least one longitudinal study for a long-standing

concept of SCI as a premild cognitive impairment (MCI) condition lasting 15years. (2) There are

complex relationships between SCI and depression and anxiety. (3) Differences in SCI subjects from

age-matched non-SCI persons are being published in terms of cognitive tests, hippocampal gray matter

density, hippocampal volumes, cerebral metabolism, and urinary cortisol levels. Psychometric and

dementia test score differences between SCI and MCI subjects have long been evident. (4) Predictive

electrophysiologic features of subsequent decline in SCI subjects are being published.

Conclusions: Studies of therapeutic agents in SCI treatment and resultant Alzheimers disease

prevention appear to be feasible. These trials are also necessary from a public health perspective.

2008 The Alzheimers Association. All rights reserved.

Keywords: Subjective cognitive impairment; Cognitive complaints; Brain aging; Mild cognitive impairment; Dementia;

Alzheimers disease

1. Background

Studies of the course of Alzheimers disease (AD) from

its earliest antecedents are presently producing new insights

in terms of the earliest behavioral manifestations of AD and

in terms of the basic etiopathogenesis of AD. This brief

perspective will focus on the most salient and important

recent observations from our perspective and the therapeutic

opportunities and challenges associated with these findings.

2. Overview of the behavioral course of incipient and

progressive AD

A schema of our current understanding of the typical be-

havioral course of AD in terms of major staging and mental

status methodologies is shown in Figure 1. The legend for

Figure 1 refers to some of the most important references

supporting this characteristic course of AD [18].

This perspective will focus on the earliest manifest stage

of this characteristic course of AD, which, while requiring

continuing elucidation, is also potentially a very fertile area

for therapeutic intervention.

3. Subjective cognitive impairment, the incipient stage of

AD (before mild cognitive impairment) when the

patient knows, but [presently] the doctor doesnt know

As illustrated inFigure 1, the Global Deterioration Scale

(GDS) [7,8] and the related Functional Assessment Staging

(FAST) procedure [9,10] each contain 7 major stages. The

FAST staging procedure also contains a total of 11 sub-

stages in the FAST stage 6 to 7, advanced dementia, range.

Hence, FAST staging identifies a total of 16 stages and*Corresponding author. Tel.: 212-263-8550; Fax: 212-263-6991.

E-mail address:[email protected]

Alzheimers & Dementia 4 (2008) S98S108

1552-5260/08/$ see front matter 2008 The Alzheimers Association. All rights reserved.

doi:10.1016/j.jalz.2007.11.017
http://mail%20to:[email protected]/http://mail%20to:[email protected]/http://mail%20to:[email protected]/


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been suggested [16], was hypothesized more than 20 years

ago to be a stage in the evolution of AD [1]. More specif-

ically, it was estimated in 1986 that this SCI stage lasts a

mean of approximately 15 years before the subsequent MCI

stage in the evolution of AD pathology [1]. If this estimate

of a 15-year duration for SCI were true, and if a surveyed

population of persons with SCI is evenly distributed acrossthe SCI spectrum, then it would be anticipated that approx-

imately 1/15 of persons with SCI would decline to an MCI

or a more severe diagnosis per year. Hence, a longitudinal

study that included healthy persons with SCI, who are

normally distributed across the severity spectrum, would

show approximately a 6.67% rate of decline to MCI or

dementia per annum. However, SCI symptoms can also be

associated with conditions other than the progression of AD,

notably anxiety, depression, and non-AD neurologic pathol-

ogy such as head trauma, strokes, etc. Therefore, a study

that seeks to examine this hypothesis of a 15-year duration

of the SCI stage in ultimately manifest MCI and dementiaassociated with AD would have to exclude persons with

significant non-ADrelated pathology at baseline and would

have to be conducted prospectively for a sufficient period of

time. Such studies are beginning to be published [6,17].

3.1.2. Observed duration of the SCI stage of incipient AD

Prichep et al [6] enrolled normal older, otherwise

healthy, community-residing subjects with SCI (GDS stage

2) and with baseline electroencephalographic studies during

a period from 1980 to 1997. Of 118 normal older subjects

enrolled, 44 subjects completed longitudinal follow-up after

a 7-year minimal time interval and formed the study popu-lation. Subjects lost to follow-up (n 74) generally died

during the follow-up interval, moved from the area, refused

follow-up, or were unlocatable. There were no significant

differences in age or gender between the subjects longitu-

dinally followed and those who were lost to follow-up. The

44 subjects followed comprised 22 men and 22 women,

with a mean baseline age of 72.0 years (range, 64 to 79

years). During the follow-up period, 20 subjects declined to

an MCI diagnosis (GDS stage 3) [13], and 7 declined to a

dementia diagnosis either of AD or, in one case, vascular

dementia [18]. For the subjects who exhibited decline, the

maximum deterioration period of observation within the7-year minimum observation interval was used for the anal-

yses. For the non-decliners, the mean standard deviation

(SD) period of observation was 8.9 1.8 years. Hence,

assuming SCI is a stage in which all subjects eventually

decline and that this stage lasts 15 years, we would antici-

pate that approximately 59.33% of subjects would have

been observed to decline during the 8.9-year observation

interval. The actual observed percentage of subjects who

declined was 61.36% (Figure 2). Clearly, this study is very

supportive of (1) the hypothesis that SCI, as defined with

the GDS stage 2 terminology/methodology and the appro-

priate inclusion and exclusion criteria, is a stage in the

evolution of MCI and, ultimately, AD, and (2) that this

pre-MCI stage has a total duration of15 years before

manifest decline to MCI and, ultimately, dementia associ-

ated with AD.

3.2. Affective and anxiety interrelationships with SCI

3.2.1. Effect of affective and anxiety symptomatology on

SCI outcome

As noted, conditions other than incipient AD can also

produce SCI symptomatology. For example, many prior

studies have shown associations between depressed mood

and other affective and anxiety symptoms and SCI symp-

tomatology. However, until recently, these studies did not

rigorously exclude MCI subjects (Table 1). Recent studies

that do rigorously exclude MCI subjects continue to find

interesting interrelationships between SCI, anxiety, and de-

pression. For example, Lautenschlager et al [23] found that

elderly (70 years of age) community-residing women withsubjective memory complaints (mean MMSE SD, 28.2

1.5) had higher depression and anxiety scores than a com-

parison group of healthy community-residing women that

was closely matched in terms of the level of cognitive

scores (mean MMSE SD, 28.3 1.4).

These interrelationships can affect outcome. For exam-

ple, it has long been known that treatment of depression, in

subjects with a diagnosis of depression, can reduce memory

complaints [24].

A recent longitudinal study of Glodzik-Sobanska et al

[25] illustrated the very profound relationship between af-

fective symptoms, memory complaints, and subsequent out-come in older persons. This study examined large cohorts of

normal, healthy, community-residing subjects, free of major

depression or other significant psychiatric, neurologic, or

medical morbidities. Two cohorts were examined. The

larger cohort comprised 230 subjects (66% women) with a

mean age of 67 8.0 years, a mean MMSE score of 29.1

1.3, and a mean Hamilton Depression Rating Scale

(HDRS) score of 3.4 3.6. These MMSE scores are, of

course, indicative of a normal level of cognition in these

very well-educated subjects (mean, 15.9 2.5 years of

education), and the HDRS scores indicate a very low level

of affective symptomatology, well within the normal rangeand well below the range traditionally associated with dys-

phoria, as well as major depression. The subjects comprised

81% SCI subjects (GDS stage 2) and 19% non-SCI normal

subjects (GDS stage 1). Subjects were followed for a mean

period of 8.4 3.9 years.

It was found that the presence of SCI (GDS stage 2 at

baseline) was associated both with subsequent decline and

with being in a diagnostically unstable group that declined

to an MCI diagnosis but subsequently reverted to a normal

diagnosis. In addition, being in the unstable outcome group

was associated with a significantly higher baseline HDRS

score, although the magnitude of the HDRS score at base-

S100 B. Reisberg et al / Alzheimers & Dementia 4 (2008) S98S108


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line was still low (mean baseline HDRS, 4.6 4.8). In the

unstable diagnostic group, the five HDRS items with the

highest standardized mean values were those describing (1)

psychological symptoms of anxiety, (2) problems with

maintaining sleep, (3) general somatic symptoms (including

loss of energy), (4) problems with falling asleep, and (5)impairment in work and activities (including fatigue, weak-

ness, and loss of interest). Importantly, these same items

were also those contributing to the Hamilton scores in the

broader baseline subject cohort comprising non-decliners

and stable declining subjects, as well as the unstable out-

come cohort.

A second cohort was also studied by Glodzik-Sobanska

et al [25], which consisted of a subset of the 230 subjects

who had an evaluation of the severity of memory com-

plaints assessed on the Memory Complaints Questionnaire

(MAC-Q) [26]. This is a self-rated questionnaire with five

questions addressing daily activities and one question ad-

dressing overall memory functioning. Functioning is com-

pared with that at 18 to 20 years. The characteristics of this

83-subject subgroup did not differ significantly from the

broader 230-subject cohort on any parameter. Analysis of

this cohort subset indicated that in addition to the prior

finding of the presence of subjective complaints of memoryimpairment and of a higher HDRS score being associated

with membership in the unstable group, (1) a greater mag-

nitude of complaints on the MAC-Q was associated with

being in the unstable diagnostic group, which declined to an

MCI diagnosis but ultimately reverted to a normal diagno-

sis, and (2) the magnitude of complaints on the MAC-Q did

not add to the other variables in predicting membership in

the declining subject group.

Important findings from this study of Glodzik-Sobanska

et al [25] are that increased intensity of memory complaints,

as well as increased affective and anxiety symptomatology,

can be associated with a potentially reversible decline in

Fig 2. The hypothesized mean duration of the subjective cognitive impairment (SCI) stage, synonymous with Global Deterioration Scale (GDS) stage 2, was

published in Reisberg, B. (1986). Dementia: a systematic approach to identifying reversible causes. Geriatrics, 41(4), 30-46. The observed results for the

duration of the SCI stage, synonymous with GDS stage 2, are calculated from Prichep, L.S., et al. (1994). Quantitative EEG correlates of cognitive

deterioration in the elderly. Neurobiology of Aging, 15, 85-90. Result: For a stage with a 15 year duration, the observed result differed from the hypothesized

result by 2 %. Copyright 2007 Barry Reisberg, M.D. All rights reserved.



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SCI subjects. Hence, this study supports the very complex

relationship between anxiety and symptoms sometimes

identified as being affective, such as sleep disturbances, and

SCI, as well as the association of SCI with subsequent

cognitive decline to MCI and to dementia.

3.2.2. Pathophysiologic relationship between affective

disorder and ADRecent studies of the pathophysiologic basis both of AD

and of affective disorder and related conditions have re-

vealed fundamental interrelationships that appear to provide

an explanation for the findings in SCI studies (Table 2). As

outlined inTable 2, both depression and AD are character-

ized by hippocampal volumetric losses [3,2733]. Both con-

ditions have been associated with neuronal and/or gray

matter losses in the hippocampus and elsewhere in the brain

[4,3439].Interestingly, with respect to cell-cycle reactivation, the

findings appear to be different in affective disorder and in

Table 1

Relationships between affective and anxiety symptoms and SCI

Finding Reference Exclusion of MCI Subjects

Presentation

Complaints of poor memory more associated with depressed mood than

objective disabilities

Bolla et al [19], 1991 No

Older depression subjects report more memory problems thancommunity-residing subjects or dementia subjects

OConnor, et al [20], 1990; Feehanet al [21], 1991

No

Anxiety and depressive symptoms are most strongly associated with

memory complaints

Jorm et al [22], 2001 No

Older women with subjective memory complaints had higher anxiety

and depression scores than healthy older subjects

Lautenschlager et al [23], 2005 Yes

Outcome

Treatment of depression, in depressed subjects, reduces memory

complaints

Plotkin et al [24], 1985 NA

Presence of memory complaints is associated both with subsequent

decline and with an unstable outcome wherein subjects decline but

subsequently return to a normal diagnosis

Glodzik-Sobanska et al [25], 2007 Yes, MCI was excluded at baseline.

MCI was studied as an outcome

measure.

Increased intensity of memory complaints and a higher level of affective

symptoms in nondepressed, healthy older persons, GDS stage 1 or 2,

was associated with an unstable outcome, wherein subjects, whenfollowed, received a diagnosis of MCI but subsequently reverted back

to a normal (GDS stage 1 or 2) diagnosis.

Glodzik-Sobanska et al [25], 2007 Yes, MCI was excluded at baseline.

MCI was studied as an outcome

measure.

Abbreviations: SCI, subjective cognitive impairment; MCI, mild cognitive impairment; GDS, Global Deterioration Scale; NA, not applicable.

Table 2

Pathophysiologic relationships between affective disorder, and related predisposing conditions to affective disorder, and AD

Pathophysiologic Condition Affective DisorderRelated Findings AD Pathology

Volumetric loss in the hippocampus Post-traumatic stress disorder [27] and depression [28]

have been associated with hippocampal volume losses

Hippocampal volumetric losses are visible with

neuroimaging [2933] and with neuropathologic

study [3].

Neuronal cellular loss in the

hippocampus and elsewhere in

the brain

Cortical gray matter reductions in major depression [34].

Requirement of hippocampal neurogenesis for

behavioral effects of antidepressants [35].

Neuronal loss in various specific brain regions

[36] including, notably, in the hippocampus

[4,3739].Neuronal cell-cycle reactivation Various antidepressants increase neurogenesis in the

subgranular zone of the dentate gyrus of the

hippocampus [35,40]. Conversely, stress, a risk factor

for depression, has been associated with a decrease in

hippocampal granule cell neurogenesis [41].

Reactivation of the cell cycle in pathologically

involved brain regions, including the

hippocampus, without associated cell division

[4246].

Tau phosphorylation Stress, a physiologic condition associated with depression,

has been associated with tau phosphorylation [47].

Cerebral ischemia and infarction, conditions that are

strongly associated with and/or can produce depression,

have been associated with hyperphosphorylated tau

[48].

Hyperphosphorylated tau is a characteristic feature

of AD, resulting in neurotubular dysfunction

and neurofibrillar pathology [49,50]. AD has

been strongly associated with cerebrovascular

pathology and with cerebrovascular risk factors

[51].

Cerebral white matter changes (eg,

hyperintensities, leukoariosis)

Association with depression [52]. Association with AD [53].

Abbreviation: AD, Alzheimers disease.



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AD, particularly in outcome. As noted above, there is neu-

ronal loss in both conditions. In depression, the treatment

for the neuronal loss is cell-cycle reactivation, specifically

in the form of antidepressant treatment, which appears to

induce neurogenesis in the subgranular zone of the dentate

gyrus of the hippocampus [35,40]. In depression, this suc-

cessful cell-cycle reactivation and cell division are associ-ated with remission. The reason antidepressant treatments

appear to take time to be effective is that the hippocampal

cellular restoration is believed to take some weeks before

the effects of this restoration are fully manifest.

In AD, neuronal cellular loss is also associated with

cell-cycle reactivation in the hippocampus and elsewhere

[4246]. However, this reactivation does not produce neu-

rogenesis (so far as is known) and is believed to be delete-

rious to the terminally differentiated neurons. The cell-cycle

reactivation in AD has been related to both hyperphospho-

rylation of tau with resultant neurotubular dysfunction [42]

and to cellular death.In addition to the association already noted between

affective disorder and AD, both conditions have been

strongly related to the occurrence of cerebrovascular disease

and cerebrovascular risk factors [48,51] and to the occur-

rence of cerebral white matter changes [52,53]. Some of

these changes, notably cerebral ischemia and cerebral in-

farction, as well as stress models of affective disorder,

indicate possible relationships between depression and tau

hyperphosphorylation [47,48], a fundamental pathologic

change in AD [49,50].

3.3. Need for a new diagnostic entity, primary idiopathicSCI

Given the numerous and complex interrelationships be-

tween SCI and anxiety and depression, as well as with AD

and many other potential pathologic entities, eg, cerebro-

vascular disease, head trauma, for research to proceed ef-

fectively, new definitions that can be commonly agreed on

might be necessary. In AD, despite or, actually, because of

intimate associations with, for example, cerebrovascular

pathology [51], categories of probable and possible AD

have been created to permit research to proceed expedi-

tiously [18]. Analogous procedures need to be followed

with a proposed definition of primary idiopathic SCI. Stud-

ies need to be conducted that apply the criteria of McKhann

et al [18] for probable and possible AD, with the exception

that dementia and also MCI need to be excluded. As noted

earlier, evidence already exists and is accruing that indicates

that this primary idiopathic SCI entity might be associated

with eventual AD. However, until such evidence becomes

more definitive, an etiopathogenic basis of this primaryidiopathic SCI entity should not be assumed.Table 3 out-

lines an initial proposed definition for this entity.

The SCI terminology for the proposed entity is itself

somewhat novel. Most commonly, this condition has been

referred to in the literature as subjective memory com-

plaints. The term cognitive is preferable to memory,

because the range of presentations of this entity is pres-

ently not clearly known and should be studied. For ex-

ample, many persons with these symptoms complain of

concentration disturbances. Also, the role of visuospatial

deficits and language deficits as possible modes of pre-

sentation of this condition should be explored beforeprematurely limiting this SCI entity to the memory do-

main of presentation.

Also, the term impairment, as opposed to complaints,

appears to be preferable. These persons do not necessarily

complain of deficits. Rather, they acknowledge perceived

deficits in cognition when queried. In fact, persons with

these symptoms might, or might not, share their perceived

deficits with their spouses or other intimates, and they

might, or might not, present in memory clinic settings. Also,

the term complaints is somewhat pejorative and should be

eschewed for this reason. These persons are not, in general,

complainers.

3.4. Primary idiopathic SCI: Differences from age-

matched, cognitively normal persons without SCI and

differences from MCI cohorts

There is emerging information on differences from oth-

erwise healthy, SCI cohorts and age-matched persons who

are free of SCI (Table 4). Differences in psychometric

assessments [54], hippocampal gray matter [55], hippocam-

pal volumes [56], cerebral metabolism [57], and urinary

cortisol levels [58] are presently being reported.

Perhaps the most clear, dramatic, and interpretable

changes are being reported in terms of cerebral metabolism.

Table 3

Proposed criteria for primary idiopathic subjective cognitive impairment

1. Presence of subjective cognitive deficits.

2. Belief that ones cognitive capacities have declined in comparison with 5 or 10 years previously.

3. Absence of significant medical, neurologic, or psychiatric conditions, including depression and anxiety disorders, that might interfere with cognition.*

4. Absence of overt cognitive deficits. These overt deficits might be elicited in the context of a detailed clinical interview. They might also be evident

to the spouse or other informants.

5. Cognitive performance in a general normal range.

6. Absence of dementia.

* This condition must be met for a categorization as probable. The presence of one or more of these conditions in persons fulfilling the other inclusion

and exclusion criteria is compatible with a possible diagnostic categorization.



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Table 4

Cross-sectional studies indicating differences between primary idiopathic SCI subjects and hierarchically adjacent diagnostic categories

Modality Subject Selection Finding (reference)

Studies of normal, non-SCI subjects in comparison with SCI subjects

Neuropsychologic tests Individuals with other neurologic, medical, or

psychiatric conditions excluded

Subjects with symptoms of memory loss but no cognitive

impairment (S NCI) performed significantly worse than age

matched controls on 6 of 18 cognitive tests. These were (1)Wechsler Abbreviated Scale of Intelligence matrices; (2)

delayed recall, (2 versions); (3) immediate recall; (4) the trail

making test B; and (5) the trail making test difference score

(Archer, et al., 2006) [54]

Hippocampal gray matter

density on MRI

Exclusion criteria included medical, psychiatric,

or neurologic conditions that could adversely

effect brain structure or cognition

Subjects with cognitive complaints show reduced gray matter

hippocampal density on MRI in comparison with healthy

controls (Saykin et al [55], 2006)

Medial temporal lobe

volumes assessed with

MRI

No neurologic or psychiatric comorbidity.

Subjects with memory complaints had higher

education levels and more depressive

symptoms than age-matched controls.

Subjects with subjective memory complaints had smaller left

hippocampal volumes than controls. No differences were

found in right hippocampal volumes or parahippocampal gyrus

volumes (van der Flicr et al [56], 2004)

Positron emission

tomography study of

cerebral metabolism

Individuals without (GDS stage 1) or with

(GDS stage 2) SCI were studied. Individuals

with other medical, neurologic, or psychiatricconditions known to affect cognitive

functioning were excluded.

Subjects with subjective memory complaints showed cerebral

metabolic rates for glucose reductions bilaterally in the

parahippocampal gyrus and in the middle temporal gyrus; inthe left hemisphere; in the inferior parietal lobe, in the inferior

frontal gyrus, fusiform gyrus, and thalamus; and in the right

putamen. The parahippocampal gyrus showed the greatest

reduction (18%) (Mosconi et al [57], in press)

Interaction of cerebral

metabolic change with

apolipoprotein E allele

status

Same as above. Subjects with subjective complaints (GDS stage 2) with an

apolipoprotein E, e4 allele, had lower cerebral glucose

metabolism rates than e4 negative SCI subjects, e4 positive

non-SCI subjects, or e4 negative non-SCI subjects. The most

severe reductions in the e4 positive SCI subjects were in the

parahippocampal gyrus (18% decrease in comparison to the

average of the metabolism of the other 3 groups) (Mosconi, et

al [57], in press)

Urinary cortisol levels Subjects with significant neurologic, medical, or

psychiatric disease were excluded. Also,

subjects taking glucocorticoids, with MCI, orwith diabetes, were excluded. Subjects with

SCI (GDS stage 2) and healthy non-SCI

subjects (GDS stage1) were studied.

Subjects who were free of memory complaints (GDS stage 1),

had lower 12-hour urinary cortisol levels than SCI (GDS stage

2) subjects (Wolf et al [58], 2005)

Studies of SCI subjects in comparison with MCI subjects

Mental status, dementia scale

(including functioning and

personality), and

psychometric test battery

evaluations

Subjects with significant medical, psychiatric,

neurologic, or neuroradiologic conditions

apart from brain agingrelated SCI or MCI

were excluded. Subjects with SCI (GDS

stage 2) or MCI (GDS stage 3) were studied.

MCI subjects were significantly more impaired than SCI subjects

on the MMSE; the Blessed et al dementia scale; the Blessed et

al information test, memory test, and concentration test; in

WAIS vocabulary scores; on the paragraph, initial and delayed

recall tests and the paired associates, initial and delayed recall

tests; on the designs test; on the shopping list selective

reminding task; on performance in digits backwards recall; on

the digit symbol substitution test; and on finger tapping speed

(the mean of the right and left sides). There was also

significantly more impairment for the MCI subjects incomparison with the SCI subjects on a comprehensive

psychometric test battery score. (Reisberg et al [12], 1988)

Mental status and

neuropsychological tests

Individuals with other neurologic, medical, or

psychiatric conditions excluded.

MCI subjects showed significantly more impairment than

subjects with symptoms of memory loss but no cognitive

impairment on the MMSE; on tests of immediate and delayed

recall, on the California Verbal Learning Test Recognition

assessment, on the Washington Recognition Memory Test, and

on the Rey-Osterreich figure copy test, immediate recall test

and the delayed recall test (Archer et al [54], 2006)

Brain gray matter density on

MRI

Subjects with medical, psychiatric, or

neurologic conditions that would adversely

affect brain structure or cognition were

excluded.

Subjects with MCI showed significantly lower gray matter

density in the left middle frontal gyrus and in the right inferior

frontal gyrus (Saykin et al [55], 2006)

Abbreviations: MRI, magnetic resonance imaging; SCI, subjective cognitive impairment; MCI, mild cognitive impairment; GDS, Global DeteriorationScale; MMSE, Mini-Mental State Examination.



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There is an 18% decrement in cerebral metabolism in the

parahippocampal gyrus that is observed in the SCI subjects

in comparison with comparably aged, healthy persons who

are free of SCI. A similar difference is seen for the inter-

action between SCI and the presence of the apolipoprotein

E(APOE), e4 allele. SCI, APOEe4 positive persons have an

18% metabolic rate decrement in the parahippocampal gy-rus in comparison with all other subject groups (ie, APOE

e4 (), no-SCI; APOEe4 (), no-SCI; and APOE e4 (),

with SCI, subject groups).

Differences between SCI subjects and MCI subjects on

mental status, dementia scale, and numerous test measures

have long been recognized [12]. These differences are once

again being recognized with the renaissance of interest in

this important area of behavioral investigation [54]. Differ-

ences between SCI and MCI subject groups in terms of

neuroimaging observations are beginning to be observed

[55].

3.5. Predicting outcome in subjects with SCI

Remarkably, seemingly excellent, reliable, and nonin-

vasive predictors of outcome of SCI subjects are begin-

ning to emerge. This is very important because this ap-

pears to be a stage that lasts about 15 years before MCI.

Therefore, treatment intervention studies might, of ne-

cessity, need to rely on sensitive, surrogate markers of

change. Positron emission tomographic studies of brain

glucose utilization, particularly in the hippocampal re-

gion, have shown great promise in this area [57,59].

However, such measures entail some radiation exposurefor healthy older persons with SCI.

Prichep et al [6] examined outcome in 44 subjects with

SCI (GDS stage 2) followed for a minimum of 7 years.

Subjects were studied at baseline with quantitative elec-

troencephalograms (QEEGs). Outcome was defined di-

chotomously as (1) decline to either MCI or dementia

during the follow-up period or, alternatively, (2) the

absence of decline. Of the 44 subjects studied, 27 de-

clined at follow-up. We found that the baseline QEEGs of

decliners differed significantly from those of the non-

decliners. Differences were categorized by increases in

theta power, slowing of mean frequency, and changes incovariance among regions in the decliners in comparison

with the non-decliners. In a logistic regression analysis

baseline QEEG measures predicted future decline with an

overall accuracy of 90% (R2 0.9, P .001). These

findings indicate that baseline QEEG measures might

prove useful not only in prognostic assessments but also,

perhaps, in the measurement of therapeutic responses to

proposed interventions for persons with these commonly

occurring SCI symptoms.

Recently we conducted a different study with the ar-

chived data from Prichep et al [6]. Specifically, three out-

come groups were studied: (1) no change, (2) decline to

MCI, and (3) decline to dementia. Data were converted to

standardized low-resolution electromagnetic tomographic

analysis (sLORETA) images. Five subjects were randomly

selected by computer from each of the three outcome

groups. Images for maximal theta frequency were pro-

duced. These images are shown in Figure 3, which shows

clear differences between these outcome groups at base-line. Progressive increments in maximal theta frequency

in specific brain regions are seen with the following

outcome hierarchy: SCI MCI dementia [60]. These

differences are particularly remarkable considering that

they are baseline images grouped by subsequent outcome

nearly a decade later. Hence, it appears these sLORETA

images could likely be useful in future therapeutic SCI

trials.

3.6. Treating SCI

At the present time there are no approved treatments for

MCI. Therefore, should investigators begin to contemplate

treating the even earlier SCI stage? There are many reasons

for a positive answer. These include the following:

(1) It might, in fact, prove to be less difficult finding

treatments at earlier points in the evolution of ulti-

mate AD.

(2) Persons are already self-medicating for these symp-

toms. The scientific community has an obligation to

comment on the efficacy and safety of these proce-

dures.

(3) As briefly reviewed, the methodologies that can sup-

port such studies are becoming available andaccessible.

4. Conclusion

SCI has been an underrecognized entity on the part of

the professional community. Although persons with this

condition frequently come to memory clinics, there are

no current pharmacologic treatment trials for these per-

sons. However, a long-term follow-up study is now pub-

lished confirming less systematic observations indicating

that this condition, when properly defined, is a stage

lasting about 15 years before the presently well-recog-nized MCI condition. However, in the clinic setting, this

can be seen as the stage when the patient knows but the

doctor doesnt know.

Similarly, persons with SCI presently try to treat their

symptoms themselves. This condition, perhaps more than

any other, is a reason for persons self-medicating, generally

with various non-prescription substances. The level of pub-

lic discourse is extraordinarily low. For example, presently

in the United States, a product that we will call by the

pseudonym Concentration is advertised widely and regu-

larly on national television network stations. The constitu-

ents of Concentration are never stated. However, there is



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a person in the advertisement who says, They are giving it

away free. It must be good. There is also a man whointroduces himself as the president of the company who

says, I take [Concentration] everyday and I wouldnt go a

day without it.

There is an opportunity at present to raise the intellectual

level of discourse. Basic studies on the nature of SCI need

to continue to be conducted. Simultaneously, the first treat-

ment trials of SCI should be initiated.

Acknowledgments

Supported in part by United States Department of Health

and Human Services (DHHS) grants P30 AG08051,

AG03051, AG09127, AG11505, AG022374, AG13616,

and AG12101 from the National Institute on Aging and bygrant MH32577 from the National Institute of Mental

Health of the U.S. National Institutes of Health, by grants

90AZ2791, 90AM2552, and 90AR2160 from the U.S.

DHHS Administration on Aging, by grant M01 RR00096

from the General Clinical Research Center Program of the

National Center for Research Resources of the U.S. Na-

tional Institutes of Health, by the Fisher Center for Alzhei-

mers Disease Research Foundation, and by grants from Mr

William Silberstein and Mr Leonard Litwin. Additional

support is acknowledged from the Hagedorn Foundation,

the Harry and Jennie Slayton Foundation, and the Sonya

Samberg Family Trust.

Fig 3. Standardized low resolution electromagnetic tomographic analyses (sLORETA) images at maximal theta frequency at baseline for subjects with

subjective cognitive impairment (SCI) (Global Deterioration Scale [GDS] stage 2). Shown are sLORETA images at maximal theta frequency at baseline for

subjects who were followed for outcome at 7 years. From a pool of 44 subjects in the study [6], five subjects from three outcome groups were randomly

chosen by computer. The outcome groups shown in the figure are (1) No change (top row) (n 5), if the subjects remained in a normative diagnostic category

either with or without SCI (GDS stage 1 or 2) at the time of follow-up; (2) Decline (middle row) (n 5), if the subjects declined to mild cognitive impairment

(MCI) (GDS stage 3) during the follow-up period; and (3) Convert (bottom row) (n 5), if the subjects converted to dementia (GDS stage 4) during the

follow-up period. Clear and highly significant differences are seen at baseline for maximal theta frequency in the three outcome groups. Progressive

increments are seen in maximal theta frequency in specific brain regions with the following outcome hierarchy: SCI MCI dementia. It appears that

outcome in normal SCI subjects can be predicted many years later from baseline sLORETA readings. These sLORETA procedures are noninvasive (Adapted

from Reisberg et al, Alzheimers & Dementia 2007;3:S1856).



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Memoriam to my dear colleague, Professor Leon Thal,

MDThis publication is written to honor the memory of our

dear and valued colleague, Dr Leon Thal. With his many

activities and his leading role in the U.S. National Institute

on Aging consortium on pharmacologic trials in the treat-

ment of Alzheimers disease, Leon was an inspiration for all

of us who are actively working toward the improved treat-

ment and, ultimately, the prevention of this disease.

On a personal note, I would like to acknowledge that

Leon and I come from similar backgrounds and grew up

very close to each other in Brooklyn, New York. Leon went

to medical school at the State University of New York

Downstate Medical Center, located less than a mile downthe road, on New York Avenue, from where my parents and

I lived contemporaneously. Later, of course, we both chose

very similar medical and scientific challenges.

Leons work with early pharmacotherapeutic trials of

cholinesterase inhibitors, in organizing and successfully

running the first and only U.S. Alzheimers Disease Coop-

erative Studies group, and in many other areas were galva-

nizing events that significantly advanced our field. I will

always remember his perceptive comment after I presented

the then novel data from our multicenter memantine trial at

the World Alzheimers Congress in Washington, DC, in

2000. It is hard for all of us to imagine that Leon is gone.We miss him. We endeavor to honor him with these works,

which his life inspired.

Barry Reisberg, MD


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