The Effects of Cortical Hypometabolism and Hippocampal Atrophy on Clinical Trajectories in Mild Cognitive Impairment with Suspected Non-Alzheimer’s Pathology: A Brief Report

Abstract

The clinical and structural trajectories of suspected non-Alzheimer’ pathology (SNAP) remain elusive due to its heterogeneous etiology. Baseline and longitudinal clinical (global cognition, daily functioning, symptoms of dementia, and learning memory) and hippocampal volume trajectories over two years were compared between patients with amnestic mild cognitive impairment (aMCI) with SNAP with reduced hippocampal volumes (SNAP+HIPPO) and aMCI patients with SNAP without reduced hippocampal volumes. SNAP+HIPPO showed overall worse baseline cognitive functions. Longitudinally, SNAP+HIPPO showed faster deterioration of clinical symptoms of dementia. Having both hippocampal atrophy and cortical hypometabolism without amyloid pathology may exacerbate symptoms of dementia in aMCI.

Keywords

Functional decline hippocampus mild cognitive impairment suspected non-Alzheimer’s pathology

INTRODUCTION

Suspected non-Alzheimer’s pathology (SNAP) represents individuals with evidence of neurodegeneration (ND) without amyloid-β (Aβ) [1]. SNAP is extremely heterogeneous with many potential causes underlying this condition. ND in patients with amnestic mild cognitive impairment (aMCI) with SNAP is often defined based on presence of cortical hypometabolism or hippocampal atrophy [2, 3]. Hippocampal atrophy without Aβ in aMCI may be caused by other medical conditions like hippocampal sclerosis [4], and frontotemporal lobe degeneration [5]; therefore, patients with SNAP, who were defined based on one of the aforementioned ND criteria, may be heterogeneous.

In order to examine potential differences in clinical outcomes among individuals with SNAP with hippocampal atrophy and those without atrophy, we found patients with aMCI with SNAP showing both cortical hypometabolism and reduced hippocampal volumes (SNAP+HIPPO) and patients with MCI with SNAP with cortical hypometabolism, but without reduced hippocampal volumes (SNAP-HIPPO). In addition to the high agreement between head size adjusted hippocampal atrophy and cortical hypometabolism, having both cortical hypometabolism and hippocampal atrophy was the second most robust at defining individuals with ND followed by having both cortical hypometabolism and cortical thinning [5]. Therefore, SNAP+HIPPO may be valid representatives of SNAP with true ND.

This study is an extended subanalysis from our previous study [6]. To the best of our knowledge, no study has specifically compared clinical and hippocampal volume trajectories between patients with aMCI with SNAP+HIPPO and SNAP-HIPPO. In addition to hippocampal volume trajectories over a 2-year follow-up period, baseline and longitudinal clinical profiles, which assessed patients’ clinical symptoms of dementia, daily functioning, global cognition, and learning memory, were compared between the groups. We hypothesized that the SNAP+HIPPO group would manifest overall worse cognitive and daily functioning at baseline; in addition, they would show faster cognitive and functional exacerbation in comparison to the SNAP-HIPPO group over a 2-year period.

MATERIALS AND METHODS

Participants and assessments

Data used in the preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (http://adni.loni.usc.edu). The ADNI was launched in 2003 as a public-private partnership, led by Principal Investigator Michael W. Weiner, MD. The primary goal of ADNI has been to test whether serial magnetic resonance imaging, positron emission tomography, other biological markers, and clinical and neuropsychological assessment can be combined to measure the progression of MCI and early Alzheimer’s disease (AD). For up-to-date information, see http://www.adni-info.org.

The entire database was downloaded from ADNI-1, ADNI-2, and ADNI Grand Opportunity (ADNI-GO) databases on October 22, 2015. More detailed information about eligibility criteria for participants from ADNI-1, ADNI-2, and ADNI-GO can be found in ADNI website (http://www.adni.loni.usc.edu).

AD severity was assessed using the Alzheimer’s Disease Assessment Scale (ADAS) 11 and 13 item versions [7], and the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) [8]. Higher scores indicate worse severity. Cognition was assessed using the Montreal Cognitive Assessment (MoCA) [9]. Verbal memory performance was assessed using the Rey Auditory Verbal Learning Test (RAVLT) [10], including (i) RAVLT immediate recall score, which requires correctly recalling 15 words across five trials (the maximum score is 60 with a higher score indicating better performance) [11]; (ii) RAVLT learning score, which consists of the difference between the number of words correctly recalled after the fifth trial and the first trial [11]; (iii) RAVLT forgetting score, which represents the difference between the numbers correctly recalled after the fifth trial and a 20-min delay period [11]; and (iv) RAVLT percentage of forgetting, which is calculated by following equation: (RAVLT forgetting score/Trial 5 score)×100 [11]. Overall functioning was assessed using the Functional Activities Questionnaire (FAQ) [12]; higher scores suggest worse functioning.

Positron emission tomography

All imaging data including positron emission tomography (PET) scans were collected from the ADNI database following the standard method listed in previous literature [13]. Global ¹⁸F-Flobetapir (AV-45) standardized uptake value ratios (SUVR) were calculated by dividing the reuptake values of cortical regions-of-interests (ROIs) (frontal, anterior cingulate, precuneus, and parietal) to those of the reference region cerebral grey matter. The sum of SUVR of pre-defined ROIs (the right and left angular gyri, bilateral posterior cingulate gyrus, and left and right middle/inferior temporal gyrus) with pons and vermis as reference regions, were used for the PET-fluorodeoxyglucose (FDG) scans.

Hippocampal volume analysis

All T1 structural images were obtained from the ADNI website. For the estimation of total brain volume (TBV), which is equivalent to the sum of grey matter and white matter, all T1 scans were analyzed using the voxel-based morphometry-8 toolbox (http://www.neuro.uni-jena.de/vbm/) using Statistical Parametric Mapping 8.0 (SPM8 - http://www.fil.ion.ucl.ac.uk/spm/) running on Matlab 6.5.

Using the Multiple Automatically Generated Templates (MAGeT Brain) algorithm [14, 15], fully automated segmentation of the hippocampal subfields was carried out. More details of MAGeT procedure are found within previous literature [16] using MAGeT methods. Hippocampus volumes, determined separately for the left and the right side, were estimated by taking the sums of cornus ammonis (CA) 1, CA2/CA3, CA4/dentate gyrus, stratum radiatum/stratum lacunosum/stratum moleculare, and subiculum volumes.

Suspected non-amyloid pathology

Patients with SNAP were patients with aMCI showing AV-45 SUVR values <1.10 and global FDG SUVR 1 standard deviation (SD) below the baseline global FDG SUVR of controls in ADNI (n = 521; mean = 6.52; SD = 0.56). Therefore, patients with aMCI who had FDG SUVR <5.95 were defined to be cortically hypometabolic. The average SUVR of aforementioned five ROIs <1.19, which equals to 5.95 divided by 5 ROIs, was also used as a threshold for defining ND in previous literature [3]. Based on current literature using AV-45, an SUVR value larger than 1.10 was set as a threshold to define amyloid positivity [17].

We divided patients with aMCI with SNAP into 2 groups based on hippocampal volume: SNAP-HIPPO and SNAP+HIPPO. The latter was defined as individuals with SNAP who have smaller than the summed hippocampal volume (sum of right and left) of all SNAP patients included in this study. The average of summed bilateral hippocampal volume was 4357.54 mm³ (range = 2779.19–5578.80).

Statistical analysis

Independent t-tests and chi-square/Fisher’s Exact tests were performed to compare continuous and discrete baseline clinical and demographic variables, respectively, among different subgroups.

Mixed-effect model repeated measurements (MMRM) were used to observe longitudinal changes: in clinical symptoms of dementia, as assessed by scores on CDR-SB and ADAS-13; daily functioning, as assessed by scores on FAQ; verbal learning and memory, as assessed by different subdomain scores on RAVLT; global cognition, as assessed by scores on MoCA; and structural changes, as assessed by changes in hippocampal volume. Longitudinal changes were compared between the SNAP+HIPPO and SNAP-HIPPO group over the 2-year period.

Statistical analyses were performed using Statistical Package for the Social Sciences Version 21.0 (IBM, New York, US). The threshold for statistical significance was set at p < 0.05.

RESULTS

SNAP-HIPPO versus SNAP+HIPPO

Baseline demographic and clinical profile

Results from t-tests comparing baseline demographic and clinical variables between the SNAP-HIPPO and SNAP+HIPPO group (n = 20 each) showed that latter group was older than the SNAP-HIPPO group at a trend-level significance (t (38) = 1.97; p = 0.06); in addition, the latter showed worse scores on ADAS-11 (t (38) = 2.10; p = 0.04), ADAS-13 (t (38) = 2.30, p = 0.03), MMSE (t (38) = –2.08, p < 0.05), RAVLT-learning (t (38) = –2.24, p = 0.03), and RAVLT-immediate at a trend-level significance (t (38) = –2.02, p = 0.05). No difference in cortical hypometabolism between the SNAP+HIPPO and SNAP-HIPPO was found. Table 1 shows the baseline clinical and demographic variable comparisons between the SNAP+HIPPO and SNAP-HIPPO.

Table 1

Comparison of demographic and clinical profiles between the SNAP+HIPPO and SNAP-HIPPO

	SNAP+HIPPO		SNAP-HIPPO
Demographic/	(n = 20)		(n = 20)
clinical variables	Mean	SD	Mean	SD	t	df	p-value
Age, years^a	78.21	7.91	73.54	7.01	1.97	38	0.06
Education, y^a	14.95	3.03	16.30	2.43	–1.55	38	0.13
MoCA^a	22.85	3.69	24.20	4.12	–1.09	38	0.28
CDRSB^a	1.75	1.02	1.53	0.60	0.85	38	0.40
ADAS-11^a	10.65	5.61	7.55	3.49	2.10	38	< 0.04 ^*
ADAS-13^a	16.70	7.82	11.55	6.25	2.30	38	< 0.03 ^*
MMSE^a	27.10	2.29	28.50	1.96	–2.08	38	< 0.05 ^*
FAQ^a	4.10	4.83	2.60	3.95	1.07	38	0.29
RAVLT_immediate^a	32.00	13.60	40.45	12.87	–2.02	38	0.05
RAVLT_learning^a	4.25	2.38	6.10	2.83	–2.24	38	0.03 ^*
RALVT_forgetting^a	4.50	2.65	4.70	3.36	–0.21	38	0.84
RAVLT_% forgetting^a	60.09	33.00	49.49	34.14	0.98	37	0.34
GDS^a	1.35	1.69	1.75	1.65	–0.76	38	0.45
AV-45 SUVR^a	0.99	0.07	1.01	0.07	–1.04	38	0.31
FDG SUVR^a	5.66	0.25	5.66	0.31	–0.09	38	0.93
TBV (ml)^a	940.82	92.41	964.46	203.04	–0.47	38	0.64
Right hippocampus (mm³)^a	1893.66	272.46	2414.52	189.31	–7.02	38	< 0.001 ^*
Left hippocampus (mm³)^a	1947.26	235.24	2459.65	165.58	–7.97	38	< 0.001 ^*
tau^a	67.33	43.64	53.55	22.14	1.11	28	0.28
p-tau^a	28.81	11.91	22.71	13.65	1.30	28	0.21
Aβ₄₂ ^a	206.64	48.64	212.31	46.09	–0.33	28	0.75
Demographic/	Number		Number		total n		p-value
clinical variables	(frequency [%])		(frequency [%])
Male^b	8		15		40		0.03 ^*
Caucasian^c	20		19		40		1
Non-Hispanic^c	20		18		40		0.49
Married^b	17		16		40		0.89
0 Apolipoprotein E4 allele^b	17		14		40		0.41
1 Apolipoprotein E4 allele^b	3		5		40		0.41
2 Apolipoprotein E4 allele^b	0		1		40		0.41
History of psychiatric disorder^b	9		8		38		0.97
History of neurological disorder^b	7		8		34		0.52
History of CVD^c	17		16		39		1

ADAS-11, Alzheimer’s Assessment Scale 11 items; ADAS-13, Alzheimer’s Assessment scale 13 items; AV-45 SUVR, Florbetapir standardized uptake value ratio; CDRSB, Clinical dementia rating score sum of boxes; CVD, cardiovascular disease; FAQ, Functional Assessment Questionnaire; FDG SUVR, Fludeoxyglucose standardized uptake value ratio; GDS, Geriatric Depression Scale score; MMSE, Mini-Mental State Examination score; MoCA, Montreal Cognitive Assessment; p-tau, phosphorylated tau protein; RAVLT immediate, Rey Auditory Verbal Learning Test immediate recall score (sum of 5 trials); RAVLT forgetting, Rey Auditory Verbal Learning Test forgetting score (trial 5- delayed); RAVLT learning, Rey Auditory Verbal Learning Test learning (trial 5- trial 1); RAVLT_% forgetting, Rey Auditory Verbal Learning Test percentage of forgetting; SNAP+HIPPO, suspected non-Alzheimer’s pathology with reduced hippocampal volumes; SNAP-HIPPO, suspected non-Alzheimer’s pathology without reduced hippocampal volumes; tau, total tau protein; TBV, total brain volume. ^aindependent-samples t-test; ^bchi-square test; ^cFisher’s Exact test; ^*indicates statistical significance p < 0.05.

Longitudinal clinical trajectories

MMRM analysis between the SNAP+HIPPO and SNAP-HIPPO group (n = 20 each) showed that the SNAP+HIPPO group showed more deterioration in daily functioning assessed using scores on FAQ (p = 0.05), at a trend-level significance, after controlling for baseline scores on FAQ, baseline age, and gender. In addition, the SNAP+HIPPO group showed worse trajectories of clinical symptoms of dementia, assessed using scores on CDRSB (p = 0.04), after controlling for baseline scores on CDRSB, baseline age, and gender, in comparison to the SNAP-HIPPO group (Table 2).

Table 2

Summary of clinical and hippocampal trajectories between the SNAP+HIPPO and SNAP-HIPPO group

	SNAP+HIPPO (n = 20)			SNAP-HIPPO (n = 20)
Year	0	1	2	0	1	2	p-value
Variables
CDRSB^a	1.50	1.91	2.17	1.74	1.54	1.63	0.04 ^*
FAQ^a	3.29	6.38	7.64	3.06	2.70	4.01	0.05
MoCA^a	23.56	23.41	23.79	23.65	23.87	23.17	0.47
RAVLT-immediate^a	36.35	39.00	35.49	36.71	34.69	36.49	0.14
RAVLT learning^a	5.07	4.70	4.21	5.41	4.72	4.11	0.84
RAVLT forgetting^a	4.52	5.40	5.64	4.74	4.44	4.03	0.21
RAVLT % forgetting^a	53.84	62.18	70.77	52.42	53.97	51.21	0.15
ADAS-11^a	8.91	9.99	9.29	9.39	11.41	9.77	0.90
ADAS-13^a	13.65	15.00	15.00	14.54	16.96	15.45	0.85
Left hippocampus^b	1941.82	1911.24	1896.44	2466.12	2473.25	2434.81	0.24
Right hippocampus^b	1872.17	1869.60	1850.90	2442.38	2445.93	2425.76	0.95

Superscript “a” refers to the estimated marginal means, which are adjusted for baseline clinical assessments, baseline age and gender. Superscript “b” refers to the estimated marginal means, which are adjusted for total brain volume, baseline age and gender.

Longitudinal hippocampal volume loss

MMRM analysis between the SNAP+HIPPO and SNAP-HIPPO group (n = 20 each) showed no difference in left (p = 0.24) and right (p = 0.95) hippocampal volume changes, after controlling for TBV, baseline age, and gender (Table 2).

DISCUSSION

In this study, as we expected, the SNAP+HIPPO group showed worse cognitive functioning at baseline, assessed using scores on ADAS-11, ADAS-13, MMSE, and RAVLT-learning, in comparison to the SNAP-HIPPO group. Furthermore, our longitudinal data also suggested that the former group showed more rapid exacerbation of symptoms of dementia and daily functioning with a trend-level significance in comparison to the SNAP-HIPPO group over a 2-year period. Nonetheless, no differences in hippocampal volume changes were found between the groups.

The hypothetical model of the biomarkers of AD states that Aβ is the first occurring event that triggers more downstream biomarker cascades in a temporally ordered manner (e.g., ND-like cortical hypometabolism followed by structural deficits), ultimately resulting in cognitive decline [18]. Current literature also shows that cognitive decline is most prominent among patients showing both Aβ and ND or neuronal injury [19, 20]. Likewise, a recent study showed a synergistic effect of tau and Aβ in promoting cortical metabolic decline measured with PET-FDG [21], suggesting that amyloid and tau play essential roles in leading to ND. However, SNAP patients do not necessarily show the temporally ordered occurrence of AD biomarkers. This population still manifests ND and cognitive decline in absence of amyloid and tau pathology. In our previous [6] and current study, SNAP aMCI patients without elevated levels of Aβ and tau underwent symptomatic and functional deterioration. In the original study, despite not showing evidence of cortical Aβ, SNAP patients still underwent worse functional deterioration in comparison to the matched MCI patients without cortical Aβ and hypometabolism and elderly control group. Similarly, Wisse and her colleagues highlighted that SNAP MCI patients with reduced hippocampal volume (i.e., SNAP+HIPPO) had compatible global cognition and clinical symptoms of dementia in comparison to MCI patients with both amyloid and ND [3]. Hence, results from our current study in concordance with previous literature suggests the plausibility to promote exacerbation in clinical symptoms of dementia under the possibly combined or synergistic influence of cortical hypometabolism and hippocampal volume atrophy in absence of amyloid and tau pathology.

Current understanding underlying the heterogeneity among SNAP is elusive; there are various potential causes of SNAP [22]. One of the plausible explanations to ND without Aβ is hippocampal sclerosis of aging (HS-Aging) [4], which is characterized by neuronal cell loss and gliosis in the hippocampus. In addition, it is difficult to clinically differentiate patients with HS-Aging from patients with AD due to their overlapping cognitive deficits [23]. While it is possible that SNAP+HIPPO represent SNAP with more validated evidence of ND due to presence of both cortical hypometabolism and hippocampal volume loss, it is also difficult to rule out the possibility of HS-Aging in these patients. Having comorbid conditions may explain the rapid exacerbation in clinical symptoms of dementia and functioning in comparison to the SNAP-HIPPO group. Furthermore, there was no difference in levels of cortical hypometabolism between these two groups. This finding corroborates that hippocampal atrophies and cortical hypometabolism may have independent pathways. Likewise, there may be different causes other than AD accounting for hippocampal volume loss (e.g., HS-Aging and other forms of dementia). Hence, results from our study brings out the importance of investigating populations, who are defined using different biomarker criteria other than SNAP, such as hippocampal atrophy without cortical hypometabolism or amyloid pathology, to examine the roles of different biomarkers in AD pathophysiology.

Limitations of this study include small sample size, short follow-up period, and investigation of progressive hippocampal volume changes, rather than global atrophy, to observe patterns of structural changes in patients with aMCI [24]. Small sample sizes and short duration of follow-up period may explicate lack of differences in hippocampal volume changes between groups. It is also important to define ND in SNAP using different criteria (e.g., hippocampal atrophy, cortical hypometabolism, cortical thinning). Nonetheless, Jack et al. [5] showed that different ND measures yielded very similar results. However, future studies should incorporate several biomarkers of ND and compare clinical and biomarker (i.e., Aβ, global atrophy, and cortical hypometabolism) trajectories with longer durations of follow-up between different aMCI groups (e.g., patients with aMCI with several biomarkers, patients with aMCI without biomarkers) and SNAP. Going forward, it is important to investigate which of the combined or synergistic effect of AD biomarkers in SNAP promotes cognitive or functional deterioration.

Footnotes

ACKNOWLEDGMENTS

Data collection and sharing for this project was funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California.

Authors’ disclosures available online ().

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