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Articles, Behavioral/Cognitive

Morphometric and Histologic Substrates of Cingulate Integrity in Elders with Exceptional Memory Capacity

Tamar Gefen, Melanie Peterson, Steven T. Papastefan, Adam Martersteck, Kristen Whitney, Alfred Rademaker, Eileen H. Bigio, Sandra Weintraub, Emily Rogalski, M.-Marsel Mesulam and Changiz Geula
Journal of Neuroscience 28 January 2015, 35 (4) 1781-1791; DOI: https://doi.org/10.1523/JNEUROSCI.2998-14.2015
Tamar Gefen
1Cognitive Neurology and Alzheimer's Disease Center,
2Department of Psychiatry and Behavioral Sciences,
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Melanie Peterson
1Cognitive Neurology and Alzheimer's Disease Center,
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Steven T. Papastefan
1Cognitive Neurology and Alzheimer's Disease Center,
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Adam Martersteck
1Cognitive Neurology and Alzheimer's Disease Center,
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Kristen Whitney
1Cognitive Neurology and Alzheimer's Disease Center,
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Alfred Rademaker
1Cognitive Neurology and Alzheimer's Disease Center,
3Department of Preventive Medicine,
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Eileen H. Bigio
1Cognitive Neurology and Alzheimer's Disease Center,
4Department of Pathology, and
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Sandra Weintraub
1Cognitive Neurology and Alzheimer's Disease Center,
2Department of Psychiatry and Behavioral Sciences,
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Emily Rogalski
1Cognitive Neurology and Alzheimer's Disease Center,
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M.-Marsel Mesulam
1Cognitive Neurology and Alzheimer's Disease Center,
5Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611
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Changiz Geula
1Cognitive Neurology and Alzheimer's Disease Center,
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  • Figure 1.
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    Figure 1.

    Three cingulate ROIs. Medial ROIs of the cingulate cortex in the Desikan-Killiany (Desikan et al., 2006) cortical labeling protocol are color-coded with their corresponding parcellations characterized by Vogt (2009).

  • Figure 2.
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    Figure 2.

    A–C, Cingulate ROI cortical thickness from superagers, middle-aged controls, and elderly controls. A, Bar graphs demonstrate the distribution of mean (average of left and right hemisphere) cortical thickness values in SuperAgers, middle-aged controls, and elderly controls and SE bars are shown. B, C, Scatterplots show individual cortical thickness measures in left hemisphere (LH) and right hemisphere (RH) in all three ROIs across subject groups. Black bars indicate means of each scatterplot column. SuperAger 3 is indicated to emphasize high caudal anterior thickness. *p < 0.05; **p < 0.01.

  • Figure 3.
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    Figure 3.

    Thioflavin-S staining of NFTs and APs at 20× magnification. The photomicrographs above show no (or extremely sparse) Alzheimer neuropathology (APs and NFTs) in the anterior aspects of cingulate cortex (aMCC) in a 90-year-old SuperAger (SuperAger 3) compared with an age-matched elderly control (middle), and an individual diagnosed clinically with aMCI (bottom). Scale bar in bottom left corner indicates 50 μm at 20×.

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    Figure 4.

    A–F, Heights of the bars represent mean estimated counts of NFTs, APs, VENs, total neurons, and size of neurons, respectively, per cubic millimeter in subject groups (n = 5 per group). A, B, Mean numerical estimates of NFT and AP density were lowest in SuperAgers, followed by the elderly control and aMCI groups across all cingulate regions, with the exception of AP density in aMCC. Significantly lower NFT density in anterior cingulate regions (prACC and aMCC) in SuperAgers compared with the other groups were found, whereas AP density was more variable, with differences reaching statistical significance between SuperAgers and elderly controls in anterior cingulate regions. C, The inverse pattern was demonstrated in VEN counts across regions, where SuperAgers showed highest counts, especially in anterior cingulate regions (aMCC), followed by elderly controls and aMCI individuals. D, There were no differences in total neuronal counts across the subject groups. E, When total neuronal count was accounted for, patterns of VEN distributions (illustrated as the ratio of VEN counts to total neuronal counts) remained similar to the distribution illustrated in VEN counts alone (C); this is due to generally equal counts of total neurons within regions and across groups. F, No differences in total mean neuronal size (area is in mean squared micrometers) across groups were found. *p < 0.05; **p < 0.01.

  • Figure 5.
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    Figure 5.

    A–D, Nissl stain at 20× magnification in aMCC shows higher density of VENS (green arrows) in a SuperAger (A, SuperAger 3) compared with an elderly control (C) and an individual with aMCI (D). Photomicrograph B displays very densely packed VENs in SuperAger 3, clearly visible in abundance at 10× magnification; selected dashed region highlights the same region that is displayed in higher power in 5A. Scale bar in bottom right corner indicates 50 μm in photomicrographs A, C, and D at 20×, and 100 μm in photomicrograph B at 10×.

Tables

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    Table 1.

    MRI study: subject demographic information and neuropsychological test scores with ANOVA comparisons

    SA (n = 31)MAC (n = 18)EC (n = 21)ANOVA post hoc comparisons
    SA vs MACEC vs MACSA vs EC
    Age at baseline (y)82.52 (2.93)58.39 (3.70)83.76 (4.0)SA > MACaEC > MACaNS
    Education (y)15.52 (2.51)15.67 (2.25)16.19 (3.44)NSNSNS
    Gender (% male)32%33%62%NSNSNS
    % of subjects with ≥1 ApoE-4 allele15%NA18%——NS
    RAVLT Delay-Recall Raw (total = 15)11.32 (1.62)10.80 (2.70)5.57 (0.98)NSMAC > ECaSA > ECa
    RAVLT Delay-Recall (ss)*11.68 (1.22)11.27 (2.28)7.05 (0.59)NSMAC > ECaSA > ECa
    MMSE Raw (total = 30)29.23 (0.88)29.67 (0.49)28.86 (1.06)NSMAC > ECbNS
    Category Fluency Raw22.26 (5.16)23.72 (4.64)18.95 (4.54)NSMAC > ECbSA > ECc
    BNT-30 Raw28.68 (1.47)28.89 (1.13)27.57 (2.82)NSNSNS
    Trail-Making Test Part A Raw (sec)35.45 (12.95)29.28 (6.88)38.52 (14.10)NSNSNS
    Trail-Making Test Part B Raw (sec)87.81 (32.72)67.17 (24.69)118.38 (72.91)NSMAC < ECbSA < ECc
    • Values and scores are represented as mean (SD).

    • ↵aSignificant at p < 0.0001.

    • ↵bSignificant at p < 0.01.

    • ↵cSignificant at p < 0.05.

    • ↵*Scores were translated into scaled scores (ss; M = 10; SD = 3), based on normative values for younger individuals in their 50s and 60s.

    • NS, Not significant by ANOVA; SA, SuperAgers; MAC, middle-aged controls; EC, elderly controls; NA, not available.

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    Table 2.

    Postmortem study: case information on SuperAgers, elderly controls, and aMCI subjects

    CaseAge at death (y)SexEducation (y)Cognitive scoreTesting obtained ante mortem (mo)Barona premorbid intelligence (M = 100; SD = 15)PMI (hours)ApoEBrain weight (g)Braak staging
    SA 187F1813/15a4119.1311ϵ3/ϵ31090III
    SA 290F1411/15a9108.914.5ϵ2/ϵ31100II
    SA 390F1812/15a2119.64ϵ3/ϵ3990III
    SA 481F189/10b8106.769.5ϵ3/ϵ312690
    SA 595F1849/50c12113.815NA12410-I
    EC 195F126b4108.343.25ϵ2/ϵ31096III
    EC 289F168b9116.659ϵ3/ϵ31180II
    EC 372F13–15Chart reviewChart review110.227.5ϵ3/ϵ31310III-IV
    EC 488M125b11100.8112NA1250III-IV
    EC 589F168a21115.836ϵ2/ϵ31160III-IV
    aMCI 189F182b16103.54.5NA1280II
    aMCI 299F131b1114.465ϵ3/ϵ31060IV
    aMCI 392F122b7107.083.5ϵ3/ϵ31084IV
    aMCI 490M142b2115.753ϵ3/ϵ31380III
    aMCI 592M163b12118.884.5ϵ3/ϵ41100V
    • Cognitive measures were not identical for all participants. Cognitive scores are provided as actual/total possible score.

    • ↵aDelayed recall score from the RAVLT (Schmidt, 2004).

    • ↵bDelayed recall score from the Consortium to Establish a Registry for Alzheimer's Disease word list; total possible = 10 (Morris et al., 1989).

    • ↵cTotal score from the telephone interview for cognitive status (Brandt et al., 1988),[A] which includes immediate and delayed recall of a 10-word list. All subjects were right handed. Braak staging followed published guidelines (Braak and Braak, 1991, 1993).

    • PMI, Postmortem interval (hours); NA, not available; SA, SuperAgers; EC, elderly controls.

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The Journal of Neuroscience: 35 (4)
Journal of Neuroscience
Vol. 35, Issue 4
28 Jan 2015
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Morphometric and Histologic Substrates of Cingulate Integrity in Elders with Exceptional Memory Capacity
Tamar Gefen, Melanie Peterson, Steven T. Papastefan, Adam Martersteck, Kristen Whitney, Alfred Rademaker, Eileen H. Bigio, Sandra Weintraub, Emily Rogalski, M.-Marsel Mesulam, Changiz Geula
Journal of Neuroscience 28 January 2015, 35 (4) 1781-1791; DOI: 10.1523/JNEUROSCI.2998-14.2015

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Morphometric and Histologic Substrates of Cingulate Integrity in Elders with Exceptional Memory Capacity
Tamar Gefen, Melanie Peterson, Steven T. Papastefan, Adam Martersteck, Kristen Whitney, Alfred Rademaker, Eileen H. Bigio, Sandra Weintraub, Emily Rogalski, M.-Marsel Mesulam, Changiz Geula
Journal of Neuroscience 28 January 2015, 35 (4) 1781-1791; DOI: 10.1523/JNEUROSCI.2998-14.2015
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Keywords

  • aging
  • Alzheimer's pathology
  • cingulate cortex
  • cognition
  • histology
  • structural MRI

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