Redefining Amnestic Mild Cognitive Impairment as an Early Form of Alzheimer’s Disease Based on Assessment of Memory Systems

Abstract

Background: It has been suggested that mild cognitive impairment (MCI) can be used to identify patients at risk of developing clinical stages of Alzheimer’s disease (AD).

Objective: The aim of this study was to describe the characteristics of amnesic syndrome of dementia of the Alzheimer’s type (DAT) as a continuous degenerative process from normality to amnesic syndrome and provide a classification of the degrees of amnesia.

Methods: Of 3,800 new incidental cases at the Memory Clinic, 747 were classified as non-demented patients. A 96-month follow-up study was conducted. We described and compared longitudinal outcomes from normality to amnesic syndrome based on immediate memory, verbal learning, free recall, and recognition using the memory scale from the Basic Neuropsychological Battery, version D (BNB-D) and created a new classification of memory impairment.

Results: Based on differences observed in this longitudinal study, we classified patients in four memory stages: M1, Normal episodic memory; M2, mild impairment in learning and/or free recall; M3, clear impairment in learning and/or free recall; and M4, complete amnesic syndrome. With this new amnesia classification, we studied the chronological progression of all patients diagnosed without dementia from baseline to DAT conversion using the Kaplan-Meier estimator of survival probability (Log Rank/Mantel Cox comparison. χ² = 171.84, p = 0.001).

Conclusion: This new classification of memory impairment can help increase the prediction certainty of conversion from amnestic MCI to AD and improve research on AD biomarkers and their relationship with memory as the principal manifestation of AD.

Keywords

Alzheimer’s disease biomarkers in AD memory in dementia mild cognitive impairment neuropsychology prodromal Alzheimer’s disease

INTRODUCTION

The term mild cognitive impairment (MCI) was conceptualized in the 1990 s [1 –5] to fill the gap between the cognitive changes associated with normal aging, which have successively been called benign senescent forgetfulness, age-associated memory impairment, aging-associated cognitive decline, and age-related cognitive decline [6 –9], and those associated with dementia. MCI describes cognitive disturbances that occur before the clinical diagnosis of dementia, primarily but not exclusively in the form of Alzheimer’s disease (AD) [10, 11]. Because memory impairment is essential for a diagnosis of MCI and Dementia of Alzheimer’s Type (DAT), the selection of memory tests has been a subject of debate. Both list learning and story memory tasks are sensitive to the effects of MCI and DAT [12, 13], and findings are mixed as to whether impairment of different memory measures affects conversion to dementia rates [12, 14]. Neuropsychological tests are not standardized for diagnosing MCI and the MCI studies done by different research groups have consequently produced divergent results [15]. Various pathological entities under the MCI label share clinical features, but have different causes. This etiological heterogeneity limits the value of MCI [10] as an indicator. In general, objective evidence of memory impairment is established when test results are 1.5 standard deviations or more below an age- and education-adjusted normative mean [5], although, to date, there is no standardized memory test or battery designed to identify MCI or the different stages of memory loss in DAT. Diagnostic criteria should be developed for the clinical stages of MCI to DAT as a continuum process of Alzheimer’s disease [10 , 16]. Subgroups have been proposed of individuals who demonstrate very subtle decline but do not meet standardized criteria for MCI [16]. Converging evidence from genetic at-risk cohorts and clinically normal older individuals suggests that the pathophysiological process of AD begins years if not decades before the diagnosis of clinical dementia [17]. This long “preclinical” phase of AD could provide a critical opportunity for therapeutic intervention. However, we need to further clarify the link between the pathological cascade of AD and the emergence of clinical symptoms [11]. Another urgent task involves reviewing the neuropsychological factors that best predict the risk of progression from asymptomatic to MCI and DAT [11].

According to the modular theory of organization and functioning of human memory [18, 19], different memory systems are impaired during the evolution of AD (working, episodic and semantic memory, and priming). The initial memory impairment during AD is focused on episodic memory [20 –22]. In early stages of AD, medial temporal lobe (MTL) structures are selectively impaired, including the hippocampal region, which forms part of a large and hierarchical neuronal network [17 , 23–25] but is, perhaps, still temporally sufficient to subserve the remaining episodic memory performance. However, as the burden of the lesions progresses, this network can become progressively inadequate, so it is hypothesized cortical association areas are recruited and MTL structures raise this activation [25 –29] to increase memory performance and constitute a temporal compensatory mechanism [30 –32]. When the hippocampal and parahippocampal regions and called cortex compensatory systems are destroyed by AD, the complete amnesic syndrome ensues.

Pathologically, neurofibrillary tangles first appear in the rhinal cortex, can then be found in the hippocampus, and finally spread to the neocortex [33, 34].

Research in cognitive psychology and the neuropsychology of memory has produced evidence that human memory is not a unitary aspect of human cognition, but is organized in independent systems. Tulving [18] and Van der Linden [19] identified at least five major memory systems. Multiple-system models of human memory and memory processes, encoding, storage and retrieval have been proposed in AD and memory assessment [18 , 36].

Memory is formally assessed at dementia units by tasks that evaluate: (1) the encoding process (phonemic or semantic); (2) time to recall (immediate or delayed); (3) type of content (verbal or nonverbal); (4) type of material (organized or unorganized); and (5) conditions of recall (free or assisted) [19]. The most common memory tests use verbal material, such as the Rey Auditory Verbal Learning Test (RAVLT), the California Verbal Learning Test (CVLT), the Free and Cued Selective Reminding Test, as well as other cognitive batteries such as the Wechsler Memory Scale-Revised (WMS-R) [36].

The mild symptomatic phase of DAT that precedes the fully developed clinical syndrome of dementia has no official clinical standing [8], and diagnostic criteria have been proposed for “prodromal/preclinical AD” [10, 11]. Some cognitive batteries have been recommended, such as the modified Alzheimer’s Disease Cooperative Study Preclinical Alzheimer Cognitive Composite (mADCS-PACC), a modified version of the ADCS-PAC [37].

Amnestic impairment has not been studied in terms of the different phases of memory loss in relation to the destruction of neural networks, which is why MCI is merely defined as below-normal memory performance (specifically in terms of episodic memory) without specifying the phase of the process of recalling facts and events. If we had a description of the process of impairment of learning capacity and memory in AD, we could identify the stages prior to the onset of dementia and the degree of functional impairment, as well as correlation with any biological and neuroimaging markers [11].

The objective of this study was to describe the stages of memory impairment prior to the onset of the amnesic syndrome (full-blown amnesic syndrome) displayed in DAT and to provide a classification of the gradual changes in episodic memory (from normality to amnesic syndrome) to facilitate early diagnosis of DAT as well as biomarker research on the relationship between neuropsychological markers and conversion to DAT.

METHOD

Subjects

A longitudinal study from September 2005 to March 2015 was conducted as a cohort study and a natural experiment [38]. Individuals were referred to the Memory Clinic by their primary care physicians or medical specialists because the patients themselves, their family, or their physician felt that they might have a memory problem. During this period, 3,800 new cases were referred. We selected 747 individuals for this study (330 men, 417 women), who were initially classified as not having dementia [9, 39]: cognitive normal functioning without a subjective memory problem (n = 20; NC group); subjective memory impairment but cognitively normal memory test results [40] (n = 80; SCI group); mild cognitive impairment, amnestic type (aMCIsd and aMCImd; n = 347; aMCI group); non-amnestic multiple domain impairment (naMCImf; n = 150; naMCI group) [41]; and depression (n = 150; D group) [9]. Of these, we selected the non-objective memory problem groups in order to study the amnesic syndrome in AD from normality: NC, D (without memory impairment), and SCI. This new group was called the non-amnestic group (n = 150; NECG group). Of these 150 patients, 45 converted to DAT diagnostic criteria during the follow-up period [39]: 2 were initially classified as NC, 29 were classified as SCI, and 14 were classified as D (with normal memory function). This group of 45 patients was used as the normal episodic memory capacity group that converted to DAT (NECG-AD). Participants’ cognition was assessed every 12 months (±2 months) with a focus on episodic memory.

All of the data included in this report were obtained in compliance with state regulations and the study followed the Declaration of Helsinki guidelines. All participants provided their written informed consent after the procedures of the study had been fully explained.

Neuropsychological assessment

Cognitive performance was assessed annually with the Basic Neuropsychological Battery, version D (BNB-D) [42], which is specially designed to be used in cognitive assessment for dementia with a large normative population and provides excellent age- and education-adjusted results. This cognitive battery includes tests sensitive to orientation, language, verbal learning and episodic memory, visuoperception, praxis, and executive functions. For this study, we focused on memory. We assessed: (1) immediate memory, using the digit span task; (2) verbal learning capacity (encoding), using 10-word lists in 4 trials (Rey word list type); (3) episodic memory free recall (storage capacity), using delayed free recall (20 minutes) of 10-word lists; and (4) recognition (facilitated retrieval), using recognition of 10-word lists: same semantic/frequency word gambling paradigm at a probability of 50%.

Methods and statistical analysis

In the first-level analysis, we described and compared longitudinal outcomes in the NECG-AD group from normality to amnesic syndrome based on immediate memory capacity (IM), verbal learning in each trial (4 trials: R1, R2, R3, and R4), the verbal learning index as the sum of R1 to R4 (LI), episodic free recall (EPFR), and recognition episodic memory (RCOG) using the GLM/ANOVA paired sample model and Student’s t test year-to-year comparison for paired samples in each year of the follow-up period. In the second level, we retrospectively analyzed data using differential scores between the baseline assessment and the follow-up assessments done each year on verbal learning capacity, free recall, and recognition. In all assessments of these 45 patients (NECG-AD), position and dispersion measures (mean and standard deviation), and standardizing scores (z score) were used to classify the patients according to normalized data on each memory outcome and thus describe the characteristic amnesic syndrome of DAT as a continuous degenerative process from normality and provide a classification of amnesic degree. We established a new four-stage classification (M1, M2, M3, and M4) based on the longitudinal study of the NECG-AD group (see Table 5 for criteria). In the third level, we conducted a survival analysis in all baseline non-demented patient groups (NC, SCI, aMCI, naMCI, and D groups; n = 747) using the new amnesia stage classification with the chronological progression from baseline to DAT conversion using the Kaplan-Meier estimator of survival probability and a Cox proportional hazard model based on age, education level, dominant hand, and new classification memory criteria. All the initial subjects in the NECG group were used (n = 747) without removing the 45 in the NECG-AD group, since they represented the group in initial stages M1 and M2 that converted from normality to DAT.

RESULTS

Figure 1 shows the subjects’ flowcharts with baseline diagnosis and cohort specifications. GLM/ANOVA for paired samples (baseline and eight annual longitudinal cut-offs) for IM (F = 35.21, p = 0.042); R1 (F = 56.37, p = 0.001); R2 (F = 58.73, p = 0.001); R3 (F = 67.89, p = 0.001); R4 (F = 76.68, p = 0.001); LI (F = 85.22, p = 0.001); EPFR (F =122.86, p = 0.001); and RCOG (F = 44.67, p = 0.001). Comparisons using the paired samples Student’s t test (comparing baseline and year-to-year outcomes) are shown in Table 1. Based on the statistically significant differences observed in the longitudinal study (see Table 1) and the z score representing this difference in the normalization scores shown in Table 2 and Table 3, we classified the patients in four amnesic stages: M1, normal episodic memory capacity with normal performance in LI, EPFR and RCOG (z score of up to –0.5); M2, mild impairment in LI (between –0.5 and –1z; age- and education-adjusted normative data) or mild impairment in EPFR (between –0.5 and –1z; age- and education-adjusted normative data), and normal RCOG (recognition of more than 7 of 10 words presented.); M3, deficit in LI (between –1.01z and –1.96z; age- and education-adjusted normative data) or deficit in EPFR (between –1.01z and –1.96z; age- and education-adjusted normative data), and normal RCOG (recognition of more than 7 of 10 words presented); M4 (complete amnesic syndrome): deficit in LI (< –1.96z; age- and education-adjusted normative data) or deficit in EPFR (< –1.96z; age- and education-adjusted normative data), and deficit in RCOG (recognition of fewer than 7 of 10 words presented). We used this new amnesic classification to classify all 747 patients with a non-dementia diagnosis at baseline (see Table 4) and studied the chronological progression from baseline to DAT conversion using the Kaplan-Meier estimator of survival probability (Log Rank/Mantel Cox comparison for new classification of four memory groups. χ² = 171.84, p = 0.001 and Log Rank/Mantel Cox comparison for M3 and M4 groups. χ² = 72.48, p = 0.001), as shown in Fig. 2.

The Cox proportional hazard model using age, education level, dominant hand and the new memory classification criteria was only predictive for the new classification criteria and age, dependent memory stage. For M4, only memory stage was predictive (χ² = 155.34, p = 0.001), Hazard Ratio (HR) = 6.59. For M3, the model includes age and the new memory classification criteria; HR for age = 1.029 (χ² = 14.128, p = 0.001), HR for M3 = 0.61 (χ² = 6.96, p = 0.007). For M2, the model includes age and the new memory classification criteria, HR for age = 1.026 (χ² = 21.26, p = 0.001), HR for M2 = 0.30 (χ² = 16.29, p = 0.007). For M1, the model includes only the new memory classification criteria, HR for M1 = 0.065 (χ² = 26.33, p = 0.001).

DISCUSSION

Because AD is a phenomenologically heterogeneous disease, two points should be considered when describing its progression. The first is that the initial clinical symptoms in early-onset forms of the disease are sometimes focal neocortical disorders such as progressive aphasia, progressive apraxia, and complex visual symptoms. These focal neocortical symptoms can be observed in the absence of significant memory disorders, even in moderate stages of DAT, which suggests that the medial temporal lobe is initially unaffected by AD pathology. In cases where the first symptoms of the disease do not involve memory, classification requires a different approach. The second point is that early-onset impairment most commonly affects episodic memory and ends in amnesic syndrome, though by definition a DAT diagnosis calls for more than memory loss. This second point signals the need to increase research into the stages of impairment of episodic memory and the relationship with other cognitive capacities compromised in DAT.

It is now widely known that the development of AD is a long, complex process and that the chances of identifying non-demented subjects at risk of conversion to dementia using neuropsychological tests is particularly high when these subjects reach the aMCI state. There is a clear need for diagnostic criteria for the clinical stages from normality to DAT as a continuum process, not merely when patients show a clear memory deficit. This study confirms that impairment of episodic memory occurs progressively and the capacity for new learning is affected early on due to the initial deterioration of MTL structures. This impairment prompts patients to complain about their own memory loss and is noticed by those around them (family members, primary care physician, etc.), although these patients’ performance on memory tests is still within normal limits, perhaps thanks to extra-MTL structures involved in episodic memory that have been related or hyperactivation of MTL structures [23 –27]. Subjects in the M1 stage show normal performance in memory assessment, but up to –0.5 standard deviation in memory test performance. After stage M1, the first objective clinical manifestation of the degenerative process is the loss of learning performance, called stage M2 (normal performance in memory assessment, but below -0.5 standard deviation). As degeneration progresses with AD, it is suggested these extra-MTL systems are partially affected and the MTL structures themselves become impaired, which makes it impossible for patients to learn and spontaneously remember facts and events, though memories can be retrieved if aid is provided through recognition (which may be more closely related to the ability to feel an event mediated by medial parietal structures as “familiar” [25]). In this stage, M3, the patient is often diagnosed with amnestic MCI. Finally, the last stage, M4, involves the massive destruction of episodic memory networks, which leads to complete amnesic syndrome, when patients no longer have the capacity to acquire new learning and their activities of daily living are compromised. Many patients diagnosed with aMCI remain in this stage for long periods (1–5 years) until their diagnosis is converted to Alzheimer’s disease due to other lobe dysfunctions, such as the onset of speech disorders, apraxia and agnosia, or increased executive dysfunction with the resulting functional disorder and the possible onset and/or worsening of neuropsychiatric symptoms.

Survival analysis clearly shows that subjects classified in stages M1 and M2 are fewer in number and take longer to evolve towards diagnosis of DAT (perhaps the really “pre-clinical” stage of AD), whereas those in stage M4 are more frequent and are diagnosed with DAT more quickly (in a mean of one to two years). The frequency and time-related results for stage M3 lie between stages 1 and 2 and the final stage (M4), but members of this group are often diagnosed with other kinds of dementia (especially subcortical impairment) that also require study, along with other cognitive functions, which means that further study could lead to divisions in this stage. The M3 and M4 stages are a key point as early forms of Alzheimer’s disease; M3 is the most clinically early stage, but not exclusive of AD, and M4 is close to a DAT diagnosis but most specifically for AD.

This study makes data available on progressive memory impairment expressed quantitatively as standardized scores, which can provide an objective perspective when assessing memory impairment in AD at the clinical level. These data enable clinicians to determine whether or not memory impairment is significant or relevant in longitudinal studies of patients with DAT and to assess the therapeutic efficacy of possible pharmacological and non-pharmacological interventions.

We encountered some difficulty classifying subjects diagnosed with depression, because in many cases there was no agreement in their performance between learning capacity and delayed free recall. We therefore decided to use delayed recall as a classification criterion, because these patients usually have an attention deficit that often leads to an impaired learning capacity, but considerable retention. The difference observed in this patient group led us to believe that other neuronal systems not strictly linked to functional episodic memory networks could be involved. Although this is not the topic of this paper, it is relevant as a clinical observation.

This new classification of memory impairment can be useful when studying the biological processes involved in AD, given the increasingly more advanced search for physiological and/or neuroimaging biomarkers. It can help establish a closer correlation between these biomarkers and the amnesic dysfunction experienced, which could increase diagnostic sensitivity and specificity. To date, the groups that have been studied with biomarkers have been made up of control groups, subjects with AD, and an intermediate group of subjects diagnosed with MCI with different levels of impairment caused by the disease and even subjects without AD, with no specification of their level of amnesic impairment, which means that the dispersion of the data in the different biomarkers increases considerably in the same group and compromises their predictive value for diagnosis. This new clinical classification of the stages of impairment of episodic memory could allow for studies of other cognitive skills such as language and praxis, as well as memory functions (semantic memory, procedural memory, etc.) in relation to episodic memory. This would make it possible to build cognitive profiles that provide a more accurate indication of the diagnosis and evolution of AD.

DISCLOSURE STATEMENT

Authors’ disclosures available online (http://j-alz.com/manuscript-disclosures/16-0117r2).

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