Neurol Sci DOI 10.1007/s10072-015-2405-9
QUIZ CASES
Correlated patterns of neuropsychological and behavioral symptoms in frontal variant of Alzheimer disease and behavioral variant frontotemporal dementia: a comparative case study Pan Li1,2 • Yu-Ying Zhou1,2 • Da Lu1,2 • Yan Wang1,2 • Hui-Hong Zhang1,2
Received: 17 October 2014 / Accepted: 17 October 2015 Ó Springer-Verlag Italia 2015
Abstract Although the neuropathologic changes and diagnostic criteria for the neurodegenerative disorder Alzheimer’s disease (AD) are well-established, the clinical symptoms vary largely. Symptomatically, frontal variant of AD (fv-AD) presents very similarly to behavioral variant frontotemporal dementia (bvFTD), which creates major challenges for differential diagnosis. Here, we report two patients who present with progressive cognitive impairment, early and prominent behavioral features, and significant frontotemporal lobe atrophy on magnetic resonance imaging, consistent with an initial diagnosis of probable bvFTD. However, multimodal functional neuroimaging revealed neuropathological data consistent with a diagnosis of probable AD for one patient (pathology distributed in the frontal lobes) and a diagnosis of probable bvFTD for the other patient (hypometabolism in the bilateral frontal lobes). In addition, the fv-AD patient presented with greater executive impairment and milder behavioral symptoms relative to the bvFTD patient. These cases highlight that recognition of these atypical syndromes using detailed neuropsychological tests, biomarkers, and multimodal neuroimaging will lead to greater accuracy in diagnosis and patient management.
& Yu-Ying Zhou [email protected] Pan Li [email protected] 1
Department of Neurology, Tianjin Huanhu Hospital, 122, Qi-Xiang-Tai Road, Hexi District, Tianjin 300060, People’s Republic of China
2
Key Laboratory of Cerebral Vascular and Neurodegenerative Disease, Tianjin, People’s Republic of China
Keywords Alzheimer disease Frontal variant Alzheimer disease Behavioral variant frontotemporal dementia Executive dysfunction Behavioral disturbance Multimodal neuroimaging
Introduction Alzheimer disease (AD), the most common form of dementia, is a progressively debilitating neurodegenerative disorder characterized by impairments in memory, language, executive function, and visuospatial skill. Although AD is well-defined clinically with established diagnostic criteria and characteristic neuropathologic findings, it is not a homogeneous disease, and there are atypical modes of presentation [1]. The frontal variant of AD (fv-AD) represents a subgroup of AD patients with prominent early symptoms of executive dysfunction, language impairment, and behavioral abnormalities. The clinical profile of frontal deficits in fv-AD overlaps with that of behavioral variant frontotemporal dementia (bvFTD), a type of behavioraldysexecutive frontotemporal lobe degeneration (FTLD). Since both fv-AD and bvFTD exhibit early changes in social and personal conduct, it is challenging to differentiate between the two for accurate diagnosis [2]. The clinical similarities between cases of AD with unusual presentation and bvFTD have been long recognized by neurologists [3–5]. Given the propensity to misdiagnose these disorders, we provide herein longitudinal data from two patients who are striking examples of the clinical and anatomical overlap between fv-AD and bvFTD. Both patients exhibited prominent dysexecutive and behavioral phenotypes in addition to other symptoms of apathy, stubbornness, and irritability. We propose that the differential identification of fv-AD and bvFTD should
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begin with a detailed clinical history and follow-up, using a panel of comprehensive neuropsychological measures, neuroimaging, and neurobiological substrates.
Case report Case 1 Clinical history A 71-year-old right-handed woman with 12 years of education presented with chief complaints of personality change and memory loss for 4 years that progressively worsened over the past 3 months. Initial symptoms appeared 4 years ago when she changed living environments. Her husband reported extraordinary aggravation of her behavioral symptoms in recent months. She alienated herself from her older sister, and they were no longer friendly. The patient often asked her husband the same questions repeatedly. She was always looking for her wallet and had delusions that her older sister had stolen it. She was disoriented in time. She not only had trouble learning new skills, but also she gradually lost her ability to do simple things and required step-by-step instructions to perform basic household tasks, such as cooking and using the washing machine. She exhibited signs of character agnosia, always confusing her older sister for her daughter. In the past 6 months, as her condition continued to progress and she became aggressive and irritable, she was admitted to a local psychiatry department and treated with sertraline (50 mg/day), sulpiride (200 mg/day), and alprazolam (0.6 mg/day) and citicoline (0.6 g/day) was added later. She was first referred to our memory clinic in July 2011 with symptoms of apathy and restlessness. Her personal history denied arterial hypertension, diabetes, coronary heart disease (CHD), and other chronic diseases. Her older brother had died with symptoms similar to dementia. Her parents were deceased and had no evidence of dementia. Her baseline neurological examination was unremarkable. Chemistry panel, blood count, thyroid function, and liver function were normal, and triglycerides were slightly elevated. Neuropsychiatric assessment On July 12, 2011, initial detailed neuropsychological assessments were performed. These tests included the Chinese version of the Montreal Cognitive Assessment (MoCA-C) [6, 7]; the Standardized Mini-Mental State Examination (SMMSE, scores range from 0 to 30, where higher scores indicate better cognitive function) [8]; Neuropsychiatric Inventory Brief Questionnaire (NPI-Q, a
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12-item, 144-point scale used to measure the frequency and severity of behavioral disturbances in dementia patients, where higher scores indicate greater impairment) [9]; Frontal Behavioral Inventory (FBI, a standardized behavioral inventory composed of 24-item scales and divided into two subscales for negative (FBI-A) and positive behaviors (FBI-B) for the diagnosis of FTLD and the quantitation of behavior disorders) [10]; Frontal Assessment Battery (FAB, a scale to assess cognitive function, particularly ones with dysexecutive features) [11]; Alzheimer Disease Assessment Scale-cognitive (ADAS-COG) [12]; Boston naming test (BNT) [13]; Clock Drawing Test (CDT); the Alzheimer’s Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) Inventory [14]; the 21-item Hamilton Depression Rating Scale (HADM-21, a standard instrument used to determine emotional state in four domains: anxiety/somatization, items 10–12, 13, 15, 17; cognitive disturbance, items 2, 3, 9, 19–21; psychomotor retardation, items 1, 7, 8, 14; and sleep disturbance, items 4–6) [15, 16], and Hachinski Ischemia Scale (HIS). The scores in the neuropsychological tests are presented in Table 1. Overall, the patient was severely deficient in the frontal lobe functions of judgment, attention (as assessed on MoCA-C), visuoexecutive functions (1/5, as assessed on CDT and 5/18 in FAB subscales), mildly deficient in the temporal lobe functions of verbal recall and recognition (as assessed on ADAS-COG subscales), and Table 1 Neuropsychological assessment of two cases Neuropsychological test (maximum possible score)
Case 1 scores
SMMSE (30) MoCA-C (30)
15 11
CDT (5)
Case 2 scores 9 2
1
1
ADAS-COG (75)
21
55
BNT (15)
15
10
NPI-Q (144)
6
44
FAB (18)
5
4
FBI (72)
14
30
9
20
5
10
FBI-A (36) FBI-B (36) HIS (18) ADCS-ADL (54) HADM-21 (64)
0
0
36
28
4
18
SMMSE Standardized Mini-Mental State Examination, MoCA-C Chinese version of the Montreal Cognitive Assessment, CDT Clock Drawing Test, ADAS-COG Alzheimer Disease Assessment Scalecognitive, BNT Boston Named Test, NPI-Q Neuropsychiatric Inventory Brief Questionnaire Form, FAB Frontal Assessment Battery, FBI Frontal Behavioral Inventory, FBI-A negative item subscale, FBI-B positive item subscale, HIS Hachinski Ischemia Scale, ADCS-ADL the Alzheimer’s Disease Cooperative Study/Activities of Daily Living, HADM-21 21-items Hamilton Depression Rating Scale
Neurol Sci
severely impaired in the parietal–occipital cortex function of orientation (3/10, assessed by SMMSE) and the angular gyrus function calculation (1/5, assessed by SMMSE). She performed very well on the test of immediate memory (3/3, assessed by SMMSE). Behaviorally, she displayed the negative symptoms (9/36) of apathy, inflexibility, and disorganization and the positive symptoms (5/36) of irritability and restlessness. Transcranial magnetic stimulation (TMS) of the central motor pathways induced first motor evoked potentials (MEP) with almost normal stimulus thresholds and central conduction. For P300 event-related potentials (ERPs), the mean P300 latency was prolonged, and the mean P300 amplitude was decreased. Cranial MRI performed in a 3T scanner revealed atrophy in the frontal and temporal regions. T2-weighted horizontal images and T1-weighted coronal images of the patient are shown in Fig. 1. 18F-fluorodeoxyglucose (18F-FDG)-positron emission tomography/computed tomography (PET/CT) found reduced metabolism in the bilateral frontal lobe, lateral cortex of the temporal lobe, parietal lobe, insula, cingulate, precuneus, and bilateral caudate nucleus. Amyloid plaque deposits were localized mainly to bilateral frontal and parietal lobes and partly in the bilateral temporal and occipital lobes using 11Carbon-Pittsburgh compound-B (11C-PIB) PET/CT (Fig. 2). Cerebrospinal fluid (CSF)
Fig. 1 Selected MRI images of patient 1’s brain. T2-weighted horizontal MRI images revealed symmetric atrophy in the frontotemporal lobes and symmetric enlargement of the bilateral lateral ventricle (a, b). T1-weighted coronal sections at the level of the hippocampus (c, d) showed moderate to severe atrophy of the bilateral hippocampal formation
beta-amyloid (1–42) (Ab1–42) was 207.00 ng/L (normal values [500). Apolipoprotein E (APOE) genotype was e3/ e4. Treatment and follow-up We diagnosed this patient with probable fv-AD. Sulpiride, alprazolam, and citicoline were discontinued during the follow-up period, and sertraline (12.5 mg/day) was prescribed to ameliorate her depression and anxiety. Memantine (5 mg/day titrated up by 5 mg per week to 10 mg twice daily maintenance dose) and aricept (2.5 mg/day) were taken orally in the morning due to the effect of night time dosing on her sleep. At 6 months, positive behavior improved by one point on the FBI (her irritability symptom decreased), and cognitive function improved by three points on the MMSE (especially in orientation). However, her cognitive function and daily life ability continued to decline slowly, and she had difficulties in dressing herself and walking alone within 3 years of the diagnosis. Case 2 Clinical history A 61-year-old right-handed female worker with 6 years of education presented to our clinic in July 2012 with a 1-year history of diminished speech output and abnormal behavior. The patient had difficulty speaking in public, refused to communicate with others, and had declining active speech for 1 year. When awake, she spent most of her time sitting impassively and staring blankly. Over time, she became introverted, and her spontaneous speech was very sparse. She began to focus on money matters and did not permit herself or family members to spend money. She had persecutory delusions and believed others would harm her. She began to hoard bottles, paid less attention to personal hygiene, and wore untidy clothing. The patient would binge eat, altering food preferences with cravings for sweets, despite negative health consequences. More recently, she exhibited cognitive decline, memory loss, and personality changes, including stubbornness, irritability, apathy, and selfishness. She no longer cared for her family members. She had no significant medical history, denying arterial hypertension, diabetes, CHD, and other chronic illnesses and was not currently undergoing any drug treatment. No family history of dementia was reported. Apart from decreased active communication and expressionless sitting, the neurological examination was normal. Chemistry panel, blood count, thyroid function, and liver function were normal, whereas cholesterol and low-density lipoprotein cholesterol were elevated.
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Fig. 2 18F-FDG PET/CT images of patient 1 showed hypometabolism in the bilateral frontal lobe, the lateral cortex of temporal lobe, parietal lobe, insula, cingulate, precuneus, and bilateral caudate
nucleus (a). 11C-PIB PET/CT revealed that amyloid plaque deposition was mainly localized to the bilateral frontal and parietal lobes and partly in the bilateral temporal, and occipital lobes (b)
Neuropsychiatric assessment
scores were 9/30 and 2/30, respectively, demonstrating deficits in orientation, confrontation naming, and language and delays in recall, calculations, and abstraction. There was some retention of instant memory function (2/3). The patient exhibited striking neuropsychiatric and behavioral
Neuropsychological assessments were performed, similar to patient 1, on July 12, 2012. Neuropsychological test scores are presented in Table 1. Her SMMSE and C-MoCA
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Fig. 3 Selected MRI images of the patient 2. T2-weighted horizontal MRI images showed asymmetrical atrophy in the frontotemporal lobes that was worse on the right and a symmetric dilatation of the left and right lateral ventricles (a, b). T1-weighted coronal MRI images showed mild to moderate bilateral hippocampal atrophy (c, d)
symptoms (as assessed by NPI-Q), including agitation, depression, anxiety, apathy, and irritability, and all of these created particular challenges for homecare. On the FBI-A, the patient’s husband endorsed the negative behavior items of severe apathy, occasional aspontaneity, indifference, emotional flatness, and personal neglect, yielding a negative behavior subscore of 20/36. On the FBI-B, she exhibited irritability, hoarding, and hyperorality, yielding a positive behavior subscore of 10/36. There was no report of disinhibition or social inappropriateness. The first MEP exhibited almost normal conduction in TMS of the central motor pathway. The mean P300 latency was prolonged, and the mean P300 amplitude was decreased. A brain 3.0 T MRI identified atrophy in the bilateral frontal and temporal lobes that was worse on the right (Fig. 3). There was decreased metabolism in bilateral frontal lobes, insula, cingulate gyrus, right temporal lobe, bilateral caudate nucleus, and the right side of the thalamus, as shown with 18 F-FDG PET/CT. 11C-PIB PET/CT examination revealed almost no amyloid plaque deposition in the cerebral cortex (Fig. 4). CSF Ab1–42 was 322.50 ng/L (normal values [500), and apolipoprotein E (APOE) genotype was e3/e3. Treatment and follow-up Based on the above information, the diagnosis of probable bvFTD was made. To alleviate neuropsychiatric
Fig. 4 Transaxial and coronal 18F-FDG PET/CT images showed reduced metabolism in bilateral frontal lobes, insula, cingulate gyrus, right temporal lobe, bilateral caudate nucleus, and the right side of the thalamus of patient 2 (a). 11C-PIB PET/CT examination showed almost no amyloid plaque deposition in the cerebral cortex (b)
symptoms and to attenuate the speed of cognitive impairment, she was initiated on memantine, titrated to the full dose of 10 mg twice daily. Sertraline (25 mg/day) was prescribed to treat depression. After 6 months of treatment, her global cognitive ability score on the SMMSE was elevated by two points (her instant memory and orientation each increased by one point). She greeted the doctor in this clinic visit, and her temperament was found to be improved. It was reported she occasionally cared about family members. At her last visit in July 2014, her cognitive function and neuropsychiatric and behavioral symptoms had stabilized.
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Discussion Fv-AD, a subtype of atypical AD, shares many clinical features with the bvFTD syndrome [5]. Here, we presented two cases with very similar clinical pictures, consisting of early and prominent behavioral disturbances (delusions, emotional blunting, loss of social skills, and irritability), executive dysfunction, and mood disorders. According to the diagnostic criteria, these traits are sufficient to prompt an initial diagnosis of bvFTD. However, both cases also exhibited global cognitive impairment of visual perceptualspatial function, episodic memory, and anomia, characteristics that extend beyond the frontal lobes and the diagnostic criteria for bvFTD, but fulfill the diagnostic criteria for fv-AD [1, 17]. The fv-AD patient presented with greater executive impairment than behavioral symptoms, and the bvFTD patient showed striking behavioral symptoms and executive dysfunction along with greater neuropsychiatric problems and higher caregiver burden. Further evaluation of these patients with 18F-FDG PET/CT and 11C-PIB PET/CT imaging revealed disease specific abnormalities in cerebral metabolism and distribution of the amyloid molecule, providing key data regarding underlying disease pathophysiology. The natural disease process of dementia from clinical and biological perspectives can be quantitatively documented by a panel of comprehensive neuropsychological measures. On testing, both patients showed additional deficits in mnestic and other cognitive domains, such as language and visuospatial function. Several scales were utilized to assess frontal executive function and frontal neuropsychiatric symptoms to identify significant overall executive dysfunction. Given the similarities between fvAD and bvFTD patients, it is very difficult to differentiate between these patients using solely nonexecutive neuropsychological tests of intelligence, language, memory, and visual-spatial abilities. bvFTD patients, however, are more inclined to demonstrate behavioral changes, neuropsychiatric disturbances, impaired activities of daily living, and greater caregiver burden. It should be noted that as AD progresses, the characteristic neuropathology will become more widespread and the greater involvement of the frontal lobes will lead to more apparent frontal symptoms. Since there is considerable overlap in the clinical features of fv-AD and bvFTD, especially in the early stages of disease, we explored the benefits of imaging in the differential diagnosis. Over the course of both diseases, a heterogeneous profile of preserved and impaired functions is observed, suggesting the involvement of particular cognitive systems or brain regions. For each type of pathology, these impairments correlate with
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specific profiles of cortical atrophy on MRI and appear to forecast a particular anatomical distribution. Differences in the degree of hippocampal and cortical atrophy have important implications in the differential diagnosis. Prominent hippocampal atrophy is the signature pattern of atrophy in AD [18], whereas asymmetrical cortical atrophy is more likely to be present in FTLD [19]. A cross-sectional volumetric MRI study of different dementia phenotypes found that amygdala and hippocampus volumes were reduced in both AD and FTLD groups relative to cognitive normal controls. Indeed, severe patterns of hippocampal atrophy, especially if associated with severe amygdala atrophy or asymmetry, are more consistent with FTLD [19]. If MRI results are inconclusive, then functional neuroimaging modalities with 18F-FDG PET/CT and 11C-PIB PET/CT will provide more objective results and aid in the differentiation and diagnosis of these diseases. We found in the first case (fv-AD patient), using 18F-FDG PET/CT assessment reduced metabolism in the bilateral frontal and lateral orbitofrontal cortex, parietal lobe, insula, cingulate, precuneus, and bilateral caudate nucleus, forecasting a particular anatomical distribution for AD. In contrast, in the second patient (bvFTD), hypometabolism occurred in bilateral frontal lobes, insula, cingulate gyrus, right temporal lobe, bilateral caudate nucleus, and the right side of the thalamus, well-defined brain structures implicated in FTLD. Meanwhile, the 11C-PIB PET/ CT demonstrated symmetric amyloid distribution in the first patient, but not the second. These findings further underscore the need for collection of critical information and clinical diagnostic accuracy when presented with these types of diseases in the clinical setting [20]. Recently, new criteria for the diagnosis of AD, based on the introduction of biomarkers into the core framework, shifted emphasis from AD as a clinicopathological entity to a clinicobiological entity [1, 21]. Two potential biomarkers for AD, decreased Ab1–42 and increased total tau (T-tau) or phospho-tau (P-tau) in CSF, have emerged to differentiate AD from normal controls and FTLD. With this combination of markers, the sensitivity and specificity of AD diagnosis reaches 90–95 and 90 %, respectively, making them important adjunct markers in cases of diagnostic ambiguity [1]. However, the dynamic changes in the levels of these CSF biomarkers need to be monitored during the longitudinal clinical follow-up. Similarly, the identification of relatively common genetic risk variants, such as APOE (specifically, the APOE e4 allele), will provide reference information when determining the risk for development of the neurodegenerative diseases. However, in cases where such genetic factors are absent, diagnostic uncertainty remains.
Neurol Sci
AD pathology has a wider phenotype than previously recognized. Atypical presentations of AD are not rare and collectively contribute to substantial diagnostic confusion. The present diagnostic criteria for AD still have low specificity when differentiating between fv-AD and bvFTD. The above cases serve to illustrate potential differential symptoms, even though they were insufficient to generate an accurate diagnosis. Advances in biomarkers and multimodal neuroimaging approaches may aid in the classification of these conditions, ultimately improving rates of early diagnosis. Acknowledgments The authors sincerely thank Hui-Hong Zhang for patient data collection and follow-up. This work was supported by grants from the Tianjin Health Bureau of Science and Technology Research Foundation (2013KG121), Tianjin Science and Technology Plan Foundation (2013ZCZDSY01600), the Special Fund of National Clinical and Medical Research (L2014071), and Youth Fund of the National Nature Science Foundation of China (81301629). Compliance with ethical standards Conflict of interest All of the authors read the final draft of the manuscript and declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
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8. Molloy DW, Standish TI (1997) A guide to the standardized Mini-Mental State Examination. Int Psychogeriatr 9(Suppl 1):87–94 discussion 143–150 9. Wang T, Xiao S, Li X, Wang H, Liu Y, Su N, Fang Y (2012) Reliability and validity of the Chinese version of the neuropsychiatric inventory in mainland China. Int J Geriatr Psychiatry 27:539–544 10. Konstantinopoulou E, Aretouli E, Ioannidis P, Karacostas D, Kosmidis MH (2013) Behavioral disturbances differentiate frontotemporal lobar degeneration subtypes and Alzheimer’s disease: evidence from the Frontal Behavioral Inventory. Int J Geriatr Psychiatry 28:939–946 11. Slachevsky A, Villalpando JM, Sarazin M, Hahn-Barma V, Pillon B, Dubois B (2004) Frontal assessment battery and differential diagnosis of frontotemporal dementia and Alzheimer disease. Arch Neurol 61:1104–1107 12. Khan A, Yavorsky C, DiClemente G, Opler M, Liechti S, Rothman B, Jovic S (2013) Reliability of the Alzheimer’s disease assessment scale (ADAS-Cog) in longitudinal studies. Curr Alzheimer Res 10:952–963 13. Karrasch M, Myllyniemi A, Latvasalo L, Soderholm C, Ellfolk U, Laine M (2010) The diagnostic accuracy of an incidental memory modification of the Boston Naming Test (memo-BNT) in differentiating between normal aging and mild Alzheimer’s disease. Clin Neuropsychol 24:1355–1364 14. Iijima S (2011) Disability Assessment for Dementia (DAD), Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL). Nihon Rinsho 69(Suppl 8):471–474 15. Faries D, Herrera J, Rayamajhi J, DeBrota D, Demitrack M, Potter WZ (2000) The responsiveness of the Hamilton Depression Rating Scale. J Psychiatr Res 34:3–10 16. Tollefson GD, Holman SL (1993) Analysis of the Hamilton Depression Rating Scale factors from a double-blind, placebocontrolled trial of fluoxetine in geriatric major depression. Int Clin Psychopharmacol 8:253–259 17. Rascovsky K, Hodges JR, Knopman D, Mendez MF, Kramer JH, Neuhaus J, van Swieten JC, Seelaar H, Dopper EG, Onyike CU, Hillis AE, Josephs KA, Boeve BF, Kertesz A, Seeley WW, Rankin KP, Johnson JK, Gorno-Tempini ML, Rosen H, Prioleau-Latham CE, Lee A, Kipps CM, Lillo P, Piguet O, Rohrer JD, Rossor MN, Warren JD, Fox NC, Galasko D, Salmon DP, Black SE, Mesulam M, Weintraub S, Dickerson BC, Diehl-Schmid J, Pasquier F, Deramecourt V, Lebert F, Pijnenburg Y, Chow TW, Manes F, Grafman J, Cappa SF, Freedman M, Grossman M, Miller BL (2011) Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain 134:2456–2477 18. Barnes J, Fox NC (2014) The search for early markers of AD: hippocampal atrophy and memory deficits. Int Psychogeriatr 26:1065–1066 19. Barnes J, Whitwell JL, Frost C, Josephs KA, Rossor M, Fox NC (2006) Measurements of the amygdala and hippocampus in pathologically confirmed Alzheimer disease and frontotemporal lobar degeneration. Arch Neurol 63:1434–1439 20. Wolk DA (2013) Amyloid imaging in atypical presentations of Alzheimer’s disease. Curr Neurol Neurosci Rep 13:412 21. Dubois B, Feldman HH, Jacova C, Dekosky ST, BarbergerGateau P, Cummings J, Delacourte A, Galasko D, Gauthier S, Jicha G, Meguro K, O’Brien J, Pasquier F, Robert P, Rossor M, Salloway S, Stern Y, Visser PJ, Scheltens P (2007) Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS-ADRDA criteria. Lancet Neurol 8:734–746
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Correlated patterns of neuropsychological and behavioral symptoms in frontal variant of Alzheimer disease and behavioral variant frontotemporal dementia: a comparative case study Pan Li1,2 • Yu-Ying Zhou1,2 • Da Lu1,2 • Yan Wang1,2 • Hui-Hong Zhang1,2
Received: 17 October 2014 / Accepted: 17 October 2015 Ó Springer-Verlag Italia 2015
Abstract Although the neuropathologic changes and diagnostic criteria for the neurodegenerative disorder Alzheimer’s disease (AD) are well-established, the clinical symptoms vary largely. Symptomatically, frontal variant of AD (fv-AD) presents very similarly to behavioral variant frontotemporal dementia (bvFTD), which creates major challenges for differential diagnosis. Here, we report two patients who present with progressive cognitive impairment, early and prominent behavioral features, and significant frontotemporal lobe atrophy on magnetic resonance imaging, consistent with an initial diagnosis of probable bvFTD. However, multimodal functional neuroimaging revealed neuropathological data consistent with a diagnosis of probable AD for one patient (pathology distributed in the frontal lobes) and a diagnosis of probable bvFTD for the other patient (hypometabolism in the bilateral frontal lobes). In addition, the fv-AD patient presented with greater executive impairment and milder behavioral symptoms relative to the bvFTD patient. These cases highlight that recognition of these atypical syndromes using detailed neuropsychological tests, biomarkers, and multimodal neuroimaging will lead to greater accuracy in diagnosis and patient management.
& Yu-Ying Zhou [email protected] Pan Li [email protected] 1
Department of Neurology, Tianjin Huanhu Hospital, 122, Qi-Xiang-Tai Road, Hexi District, Tianjin 300060, People’s Republic of China
2
Key Laboratory of Cerebral Vascular and Neurodegenerative Disease, Tianjin, People’s Republic of China
Keywords Alzheimer disease Frontal variant Alzheimer disease Behavioral variant frontotemporal dementia Executive dysfunction Behavioral disturbance Multimodal neuroimaging
Introduction Alzheimer disease (AD), the most common form of dementia, is a progressively debilitating neurodegenerative disorder characterized by impairments in memory, language, executive function, and visuospatial skill. Although AD is well-defined clinically with established diagnostic criteria and characteristic neuropathologic findings, it is not a homogeneous disease, and there are atypical modes of presentation [1]. The frontal variant of AD (fv-AD) represents a subgroup of AD patients with prominent early symptoms of executive dysfunction, language impairment, and behavioral abnormalities. The clinical profile of frontal deficits in fv-AD overlaps with that of behavioral variant frontotemporal dementia (bvFTD), a type of behavioraldysexecutive frontotemporal lobe degeneration (FTLD). Since both fv-AD and bvFTD exhibit early changes in social and personal conduct, it is challenging to differentiate between the two for accurate diagnosis [2]. The clinical similarities between cases of AD with unusual presentation and bvFTD have been long recognized by neurologists [3–5]. Given the propensity to misdiagnose these disorders, we provide herein longitudinal data from two patients who are striking examples of the clinical and anatomical overlap between fv-AD and bvFTD. Both patients exhibited prominent dysexecutive and behavioral phenotypes in addition to other symptoms of apathy, stubbornness, and irritability. We propose that the differential identification of fv-AD and bvFTD should
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begin with a detailed clinical history and follow-up, using a panel of comprehensive neuropsychological measures, neuroimaging, and neurobiological substrates.
Case report Case 1 Clinical history A 71-year-old right-handed woman with 12 years of education presented with chief complaints of personality change and memory loss for 4 years that progressively worsened over the past 3 months. Initial symptoms appeared 4 years ago when she changed living environments. Her husband reported extraordinary aggravation of her behavioral symptoms in recent months. She alienated herself from her older sister, and they were no longer friendly. The patient often asked her husband the same questions repeatedly. She was always looking for her wallet and had delusions that her older sister had stolen it. She was disoriented in time. She not only had trouble learning new skills, but also she gradually lost her ability to do simple things and required step-by-step instructions to perform basic household tasks, such as cooking and using the washing machine. She exhibited signs of character agnosia, always confusing her older sister for her daughter. In the past 6 months, as her condition continued to progress and she became aggressive and irritable, she was admitted to a local psychiatry department and treated with sertraline (50 mg/day), sulpiride (200 mg/day), and alprazolam (0.6 mg/day) and citicoline (0.6 g/day) was added later. She was first referred to our memory clinic in July 2011 with symptoms of apathy and restlessness. Her personal history denied arterial hypertension, diabetes, coronary heart disease (CHD), and other chronic diseases. Her older brother had died with symptoms similar to dementia. Her parents were deceased and had no evidence of dementia. Her baseline neurological examination was unremarkable. Chemistry panel, blood count, thyroid function, and liver function were normal, and triglycerides were slightly elevated. Neuropsychiatric assessment On July 12, 2011, initial detailed neuropsychological assessments were performed. These tests included the Chinese version of the Montreal Cognitive Assessment (MoCA-C) [6, 7]; the Standardized Mini-Mental State Examination (SMMSE, scores range from 0 to 30, where higher scores indicate better cognitive function) [8]; Neuropsychiatric Inventory Brief Questionnaire (NPI-Q, a
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12-item, 144-point scale used to measure the frequency and severity of behavioral disturbances in dementia patients, where higher scores indicate greater impairment) [9]; Frontal Behavioral Inventory (FBI, a standardized behavioral inventory composed of 24-item scales and divided into two subscales for negative (FBI-A) and positive behaviors (FBI-B) for the diagnosis of FTLD and the quantitation of behavior disorders) [10]; Frontal Assessment Battery (FAB, a scale to assess cognitive function, particularly ones with dysexecutive features) [11]; Alzheimer Disease Assessment Scale-cognitive (ADAS-COG) [12]; Boston naming test (BNT) [13]; Clock Drawing Test (CDT); the Alzheimer’s Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) Inventory [14]; the 21-item Hamilton Depression Rating Scale (HADM-21, a standard instrument used to determine emotional state in four domains: anxiety/somatization, items 10–12, 13, 15, 17; cognitive disturbance, items 2, 3, 9, 19–21; psychomotor retardation, items 1, 7, 8, 14; and sleep disturbance, items 4–6) [15, 16], and Hachinski Ischemia Scale (HIS). The scores in the neuropsychological tests are presented in Table 1. Overall, the patient was severely deficient in the frontal lobe functions of judgment, attention (as assessed on MoCA-C), visuoexecutive functions (1/5, as assessed on CDT and 5/18 in FAB subscales), mildly deficient in the temporal lobe functions of verbal recall and recognition (as assessed on ADAS-COG subscales), and Table 1 Neuropsychological assessment of two cases Neuropsychological test (maximum possible score)
Case 1 scores
SMMSE (30) MoCA-C (30)
15 11
CDT (5)
Case 2 scores 9 2
1
1
ADAS-COG (75)
21
55
BNT (15)
15
10
NPI-Q (144)
6
44
FAB (18)
5
4
FBI (72)
14
30
9
20
5
10
FBI-A (36) FBI-B (36) HIS (18) ADCS-ADL (54) HADM-21 (64)
0
0
36
28
4
18
SMMSE Standardized Mini-Mental State Examination, MoCA-C Chinese version of the Montreal Cognitive Assessment, CDT Clock Drawing Test, ADAS-COG Alzheimer Disease Assessment Scalecognitive, BNT Boston Named Test, NPI-Q Neuropsychiatric Inventory Brief Questionnaire Form, FAB Frontal Assessment Battery, FBI Frontal Behavioral Inventory, FBI-A negative item subscale, FBI-B positive item subscale, HIS Hachinski Ischemia Scale, ADCS-ADL the Alzheimer’s Disease Cooperative Study/Activities of Daily Living, HADM-21 21-items Hamilton Depression Rating Scale
Neurol Sci
severely impaired in the parietal–occipital cortex function of orientation (3/10, assessed by SMMSE) and the angular gyrus function calculation (1/5, assessed by SMMSE). She performed very well on the test of immediate memory (3/3, assessed by SMMSE). Behaviorally, she displayed the negative symptoms (9/36) of apathy, inflexibility, and disorganization and the positive symptoms (5/36) of irritability and restlessness. Transcranial magnetic stimulation (TMS) of the central motor pathways induced first motor evoked potentials (MEP) with almost normal stimulus thresholds and central conduction. For P300 event-related potentials (ERPs), the mean P300 latency was prolonged, and the mean P300 amplitude was decreased. Cranial MRI performed in a 3T scanner revealed atrophy in the frontal and temporal regions. T2-weighted horizontal images and T1-weighted coronal images of the patient are shown in Fig. 1. 18F-fluorodeoxyglucose (18F-FDG)-positron emission tomography/computed tomography (PET/CT) found reduced metabolism in the bilateral frontal lobe, lateral cortex of the temporal lobe, parietal lobe, insula, cingulate, precuneus, and bilateral caudate nucleus. Amyloid plaque deposits were localized mainly to bilateral frontal and parietal lobes and partly in the bilateral temporal and occipital lobes using 11Carbon-Pittsburgh compound-B (11C-PIB) PET/CT (Fig. 2). Cerebrospinal fluid (CSF)
Fig. 1 Selected MRI images of patient 1’s brain. T2-weighted horizontal MRI images revealed symmetric atrophy in the frontotemporal lobes and symmetric enlargement of the bilateral lateral ventricle (a, b). T1-weighted coronal sections at the level of the hippocampus (c, d) showed moderate to severe atrophy of the bilateral hippocampal formation
beta-amyloid (1–42) (Ab1–42) was 207.00 ng/L (normal values [500). Apolipoprotein E (APOE) genotype was e3/ e4. Treatment and follow-up We diagnosed this patient with probable fv-AD. Sulpiride, alprazolam, and citicoline were discontinued during the follow-up period, and sertraline (12.5 mg/day) was prescribed to ameliorate her depression and anxiety. Memantine (5 mg/day titrated up by 5 mg per week to 10 mg twice daily maintenance dose) and aricept (2.5 mg/day) were taken orally in the morning due to the effect of night time dosing on her sleep. At 6 months, positive behavior improved by one point on the FBI (her irritability symptom decreased), and cognitive function improved by three points on the MMSE (especially in orientation). However, her cognitive function and daily life ability continued to decline slowly, and she had difficulties in dressing herself and walking alone within 3 years of the diagnosis. Case 2 Clinical history A 61-year-old right-handed female worker with 6 years of education presented to our clinic in July 2012 with a 1-year history of diminished speech output and abnormal behavior. The patient had difficulty speaking in public, refused to communicate with others, and had declining active speech for 1 year. When awake, she spent most of her time sitting impassively and staring blankly. Over time, she became introverted, and her spontaneous speech was very sparse. She began to focus on money matters and did not permit herself or family members to spend money. She had persecutory delusions and believed others would harm her. She began to hoard bottles, paid less attention to personal hygiene, and wore untidy clothing. The patient would binge eat, altering food preferences with cravings for sweets, despite negative health consequences. More recently, she exhibited cognitive decline, memory loss, and personality changes, including stubbornness, irritability, apathy, and selfishness. She no longer cared for her family members. She had no significant medical history, denying arterial hypertension, diabetes, CHD, and other chronic illnesses and was not currently undergoing any drug treatment. No family history of dementia was reported. Apart from decreased active communication and expressionless sitting, the neurological examination was normal. Chemistry panel, blood count, thyroid function, and liver function were normal, whereas cholesterol and low-density lipoprotein cholesterol were elevated.
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Fig. 2 18F-FDG PET/CT images of patient 1 showed hypometabolism in the bilateral frontal lobe, the lateral cortex of temporal lobe, parietal lobe, insula, cingulate, precuneus, and bilateral caudate
nucleus (a). 11C-PIB PET/CT revealed that amyloid plaque deposition was mainly localized to the bilateral frontal and parietal lobes and partly in the bilateral temporal, and occipital lobes (b)
Neuropsychiatric assessment
scores were 9/30 and 2/30, respectively, demonstrating deficits in orientation, confrontation naming, and language and delays in recall, calculations, and abstraction. There was some retention of instant memory function (2/3). The patient exhibited striking neuropsychiatric and behavioral
Neuropsychological assessments were performed, similar to patient 1, on July 12, 2012. Neuropsychological test scores are presented in Table 1. Her SMMSE and C-MoCA
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Fig. 3 Selected MRI images of the patient 2. T2-weighted horizontal MRI images showed asymmetrical atrophy in the frontotemporal lobes that was worse on the right and a symmetric dilatation of the left and right lateral ventricles (a, b). T1-weighted coronal MRI images showed mild to moderate bilateral hippocampal atrophy (c, d)
symptoms (as assessed by NPI-Q), including agitation, depression, anxiety, apathy, and irritability, and all of these created particular challenges for homecare. On the FBI-A, the patient’s husband endorsed the negative behavior items of severe apathy, occasional aspontaneity, indifference, emotional flatness, and personal neglect, yielding a negative behavior subscore of 20/36. On the FBI-B, she exhibited irritability, hoarding, and hyperorality, yielding a positive behavior subscore of 10/36. There was no report of disinhibition or social inappropriateness. The first MEP exhibited almost normal conduction in TMS of the central motor pathway. The mean P300 latency was prolonged, and the mean P300 amplitude was decreased. A brain 3.0 T MRI identified atrophy in the bilateral frontal and temporal lobes that was worse on the right (Fig. 3). There was decreased metabolism in bilateral frontal lobes, insula, cingulate gyrus, right temporal lobe, bilateral caudate nucleus, and the right side of the thalamus, as shown with 18 F-FDG PET/CT. 11C-PIB PET/CT examination revealed almost no amyloid plaque deposition in the cerebral cortex (Fig. 4). CSF Ab1–42 was 322.50 ng/L (normal values [500), and apolipoprotein E (APOE) genotype was e3/e3. Treatment and follow-up Based on the above information, the diagnosis of probable bvFTD was made. To alleviate neuropsychiatric
Fig. 4 Transaxial and coronal 18F-FDG PET/CT images showed reduced metabolism in bilateral frontal lobes, insula, cingulate gyrus, right temporal lobe, bilateral caudate nucleus, and the right side of the thalamus of patient 2 (a). 11C-PIB PET/CT examination showed almost no amyloid plaque deposition in the cerebral cortex (b)
symptoms and to attenuate the speed of cognitive impairment, she was initiated on memantine, titrated to the full dose of 10 mg twice daily. Sertraline (25 mg/day) was prescribed to treat depression. After 6 months of treatment, her global cognitive ability score on the SMMSE was elevated by two points (her instant memory and orientation each increased by one point). She greeted the doctor in this clinic visit, and her temperament was found to be improved. It was reported she occasionally cared about family members. At her last visit in July 2014, her cognitive function and neuropsychiatric and behavioral symptoms had stabilized.
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Discussion Fv-AD, a subtype of atypical AD, shares many clinical features with the bvFTD syndrome [5]. Here, we presented two cases with very similar clinical pictures, consisting of early and prominent behavioral disturbances (delusions, emotional blunting, loss of social skills, and irritability), executive dysfunction, and mood disorders. According to the diagnostic criteria, these traits are sufficient to prompt an initial diagnosis of bvFTD. However, both cases also exhibited global cognitive impairment of visual perceptualspatial function, episodic memory, and anomia, characteristics that extend beyond the frontal lobes and the diagnostic criteria for bvFTD, but fulfill the diagnostic criteria for fv-AD [1, 17]. The fv-AD patient presented with greater executive impairment than behavioral symptoms, and the bvFTD patient showed striking behavioral symptoms and executive dysfunction along with greater neuropsychiatric problems and higher caregiver burden. Further evaluation of these patients with 18F-FDG PET/CT and 11C-PIB PET/CT imaging revealed disease specific abnormalities in cerebral metabolism and distribution of the amyloid molecule, providing key data regarding underlying disease pathophysiology. The natural disease process of dementia from clinical and biological perspectives can be quantitatively documented by a panel of comprehensive neuropsychological measures. On testing, both patients showed additional deficits in mnestic and other cognitive domains, such as language and visuospatial function. Several scales were utilized to assess frontal executive function and frontal neuropsychiatric symptoms to identify significant overall executive dysfunction. Given the similarities between fvAD and bvFTD patients, it is very difficult to differentiate between these patients using solely nonexecutive neuropsychological tests of intelligence, language, memory, and visual-spatial abilities. bvFTD patients, however, are more inclined to demonstrate behavioral changes, neuropsychiatric disturbances, impaired activities of daily living, and greater caregiver burden. It should be noted that as AD progresses, the characteristic neuropathology will become more widespread and the greater involvement of the frontal lobes will lead to more apparent frontal symptoms. Since there is considerable overlap in the clinical features of fv-AD and bvFTD, especially in the early stages of disease, we explored the benefits of imaging in the differential diagnosis. Over the course of both diseases, a heterogeneous profile of preserved and impaired functions is observed, suggesting the involvement of particular cognitive systems or brain regions. For each type of pathology, these impairments correlate with
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specific profiles of cortical atrophy on MRI and appear to forecast a particular anatomical distribution. Differences in the degree of hippocampal and cortical atrophy have important implications in the differential diagnosis. Prominent hippocampal atrophy is the signature pattern of atrophy in AD [18], whereas asymmetrical cortical atrophy is more likely to be present in FTLD [19]. A cross-sectional volumetric MRI study of different dementia phenotypes found that amygdala and hippocampus volumes were reduced in both AD and FTLD groups relative to cognitive normal controls. Indeed, severe patterns of hippocampal atrophy, especially if associated with severe amygdala atrophy or asymmetry, are more consistent with FTLD [19]. If MRI results are inconclusive, then functional neuroimaging modalities with 18F-FDG PET/CT and 11C-PIB PET/CT will provide more objective results and aid in the differentiation and diagnosis of these diseases. We found in the first case (fv-AD patient), using 18F-FDG PET/CT assessment reduced metabolism in the bilateral frontal and lateral orbitofrontal cortex, parietal lobe, insula, cingulate, precuneus, and bilateral caudate nucleus, forecasting a particular anatomical distribution for AD. In contrast, in the second patient (bvFTD), hypometabolism occurred in bilateral frontal lobes, insula, cingulate gyrus, right temporal lobe, bilateral caudate nucleus, and the right side of the thalamus, well-defined brain structures implicated in FTLD. Meanwhile, the 11C-PIB PET/ CT demonstrated symmetric amyloid distribution in the first patient, but not the second. These findings further underscore the need for collection of critical information and clinical diagnostic accuracy when presented with these types of diseases in the clinical setting [20]. Recently, new criteria for the diagnosis of AD, based on the introduction of biomarkers into the core framework, shifted emphasis from AD as a clinicopathological entity to a clinicobiological entity [1, 21]. Two potential biomarkers for AD, decreased Ab1–42 and increased total tau (T-tau) or phospho-tau (P-tau) in CSF, have emerged to differentiate AD from normal controls and FTLD. With this combination of markers, the sensitivity and specificity of AD diagnosis reaches 90–95 and 90 %, respectively, making them important adjunct markers in cases of diagnostic ambiguity [1]. However, the dynamic changes in the levels of these CSF biomarkers need to be monitored during the longitudinal clinical follow-up. Similarly, the identification of relatively common genetic risk variants, such as APOE (specifically, the APOE e4 allele), will provide reference information when determining the risk for development of the neurodegenerative diseases. However, in cases where such genetic factors are absent, diagnostic uncertainty remains.
Neurol Sci
AD pathology has a wider phenotype than previously recognized. Atypical presentations of AD are not rare and collectively contribute to substantial diagnostic confusion. The present diagnostic criteria for AD still have low specificity when differentiating between fv-AD and bvFTD. The above cases serve to illustrate potential differential symptoms, even though they were insufficient to generate an accurate diagnosis. Advances in biomarkers and multimodal neuroimaging approaches may aid in the classification of these conditions, ultimately improving rates of early diagnosis. Acknowledgments The authors sincerely thank Hui-Hong Zhang for patient data collection and follow-up. This work was supported by grants from the Tianjin Health Bureau of Science and Technology Research Foundation (2013KG121), Tianjin Science and Technology Plan Foundation (2013ZCZDSY01600), the Special Fund of National Clinical and Medical Research (L2014071), and Youth Fund of the National Nature Science Foundation of China (81301629). Compliance with ethical standards Conflict of interest All of the authors read the final draft of the manuscript and declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
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