A brief neuropsychological assessment for the differential diagnosis between frontotemporal dementia and Alzheimer''s disease

The neuropsychological performance (including measures of language, semantic memory, visual and spatial perception and executive functions) of a group of 14 patients with the clinical diagnosis of probable frontotemporal dementia was compared with that of a group of 14 patients with a clinical diagnosis of probable Alzheimer's disease. The aim was to identify a specific cognitive profile of frontotemporal dementia, which could be used to select a sensitive, short evaluation for the differential diagnosis with Alzheimer's disease. Both groups were severely impaired in most tasks, including those 'frontal lobe' tests which have been suggested to play an important role in differential diagnosis. Significant differences were found only for a minority of tests (oral praxis, visual-spatial perception, and verbal fluency). A logistic regression showed that a shortened testing procedure based on four tests (Rey-Osterreith complex figure test recall, phonemic fluency, oral apraxia, and cube analysis) achieved a 70% sensitivity and 80% specificity for the correct classification of patients in the frontotemporal dementia or Alzheimer's disease group. In conclusion, a brief neuropsychological evaluation including these four tests, as well as other measures sensitive to the frontal impairment, can be useful in the differential diagnosis between the two pathologies, along with the clinical data.     

Differentiating frontal and temporal variant frontotemporal dementia from Alzheimer's disease

OBJECTIVE/BACKGROUND: To determine whether difficulty in the early differentiation between frontotemporal dementia (FTD) and AD may arise from a failure to discriminate between the temporal and frontal variants of FTD. METHODS: Neuropsychological profiles of patients with early dementia of Alzheimer type (DAT; n = 10), the temporal variant of FTD (tv-FTD or semantic dementia; n = 5), and the frontal variant of FTD (fv-FTD; n = 10) were compared to each other and normal controls (n = 10). Structural MRI demonstrated temporal lobe atrophy in the tv-FTD patients and frontal lobe atrophy in the fv-FTD group. RESULTS: Subjects with tv-FTD showed severe deficits in semantic memory with preservation of attention and executive function. Subjects with fv-FTD showed the reverse pattern. Attention and executive function impairment separated the fv-FTD patients from the early DAT subjects, who were densely amnesic. CONCLUSION: The double dissociation in performance on semantic memory and attention/executive function clearly separated the temporal and frontal variants of FTD and aids the early differentiation of FTD from AD. The characteristic cognitive profiles reflect the distribution of pathology within each syndrome and support the putative role of the inferolateral temporal neocortex in semantic memory, the medial temporal lobe structures of the hippocampal complex in episodic memory, and the frontal lobes in executive function.     

Verbal fluency performance in dementia of the Alzheimer's type: a meta-analysis

A meta-analysis of 153 studies with 15,990 participants was conducted to compare the magnitude of deficits upon tests of phonemic and semantic fluency for patients with dementia of the Alzheimer's type (DAT) relative to healthy controls. As has been found for patients with focal temporal cortical lesions (but not for patients with focal frontal cortical lesions), DAT patients were significantly more impaired on tests of semantic relative to phonemic fluency (r=0.73 and 0.57, respectively). Thus, since phonemic and semantic fluency are considered to impose comparable demands upon executive control processes such as effortful retrieval, but the latter is relatively more dependent upon the integrity of semantic memory, these results suggest that the semantic memory deficit in DAT reflects a degradation of the semantic store. Also supporting this conclusion, confrontation naming, a measure of semantic memory that imposes only minimal demands upon effortful retrieval, was significantly more impaired than phonemic fluency (r=0.60 versus 0.55, respectively). However, since semantic fluency was also significantly more impaired than confrontation naming (r=0.73 versus 0.61), deficits in semantic memory and effortful retrieval may be additive. Semantic, but not phonemic fluency, was significantly more impaired than measures of verbal intelligence and psychomotor speed. Thus, the semantic memory deficit in DAT qualifies as a differential deficit, but executive dysfunction as indexed by phonemic fluency does not constitute an additional isolated feature of the disorder. Dementia severity was not significantly related to the relative magnitude of deficits upon phonemic and semantic fluency.     

Patterns of autobiographical memory impairment according to disease severity in semantic dementia

Studies of autobiographical memory in semantic dementia (SD) have yielded either a reversed temporal gradient or spared performances across the entire lifetime. This discrepancy might be owing to the fact that these studies did not take into account disease severity. Our aim was to study patterns of autobiographical memory impairment according to disease severity and to unravel their mechanisms in 14 SD patients, using an autobiographical memory task assessing overall and strictly episodic memories across the entire lifetime. We divided our patients in 2 subgroups of 7 patients each, one mild and one moderate according to their level of disease severity. The results indicated for the mild subgroup selective preserved performances for the most recent time period (last 12 months period) for both autobiographical memory scores. In the moderate subgroup, performances were impaired for both scores whatever the time period. Within-group comparisons across time periods showed a recency effect and a reminiscence bump in the mild subgroup and only a less important recency effect in the moderate subgroup, suggesting that with disease severity, old memories (reminiscence bump) tend to vanish and even recent memories are less well retrieved. A correlation analysis was carried out on the entire group, between the overall autobiographical memory score and performances provided by a general cognitive evaluation (semantic memory, executive functions, working and episodic memory). The results of this analysis reflect that mechanisms of disruption of autobiographical memory in SD predominantly involve a deficit of storage of semantic information in addition to faulty executive retrieval strategies. Finally, our result and those of the literature suggest the existence of 3 distinct autobiographical memory impairment patterns in SD according to disease severity: firstly preserved performances whatever the time period, secondly a reversed temporal gradient with a reminiscence bump and thirdly the appearance of a “step-function”.     

Retrieval mechanisms for autobiographical memories: insights from the frontal variant of frontotemporal dementia

Very few studies have investigated autobiographical memory in the frontal variant of frontotemporal dementia (fv-FTD). The aim of this study was therefore to unravel the mechanisms of autobiographical memory disruption in general and in the anterograde and retrograde components of amnesia in particular, in patients suffering from fv-FTD. An autobiographical memory task assessing overall (AM) and strictly episodic memories (EM) from five lifetime periods covering the entire lifespan revealed the absence of a temporal gradient for both scores, suggesting the existence of a retrieval deficit. An analysis of the correlation between these two scores and a general cognitive assessment of executive function, working, episodic (i.e. new learning ability) and semantic memory, and behavioural changes highlighted the considerable involvement of executive function, semantic memory and, to a lesser degree, episodic memory and behavioural changes. Moreover, step-wise regression analyses performed on the EM score revealed that the executive function was a better predictor of the retrograde component than of the anterograde component, which was linked principally to new episodic learning ability. All these results confirm the impact of executive dysfunction on autobiographical deficits in fv-FTD, and suggest that the mechanisms at the root of autobiographical memory disruption may also involve difficulties in new episodic learning and semantic storage, though this may be due to the fact that we studied an advanced form of fv-FTD.     

语义性痴呆的临床、认知和影像学特征研究-附3例报告

目的 分析语义性痴呆(semantic dementia，SD)患者的临床、认知缺损与保持模式和影像学特征。方法 针对3例SD患者完成详细的病史采集、一系列神经心理测验和头颅核磁共振(MR)检查。结果 SD的临床特点是起病年龄相对较轻、以命名障碍为最早最严重的症状、应用乙酰胆碱酯酶抑制剂治疗有较明显的不良反应。SD的认知特点是呈现语义记忆的选择性损害、物品命名、列举某一范畴的例子、词语的阅读理解和语义相似性判断等项目严重受损；情景记忆、空间知觉、执行功能和非言语的解决问题能力相对正常。SD的影像学特点是在冠状位MR摄片上呈现左颞叶新皮层局限性严重萎缩。结论 SD患者具有独特的临床、认知和影像学特征。     

Frontal Behavioural Inventory in the differential diagnosis of dementia

Objective –  To evaluate diagnostic properties of the Frontal Behavioural Inventory (FBI) in patients suffering from different forms of dementia.
Methods –  The FBI was administered with other psychometric tests investigating cognitive performances and behavioral scales to the caregivers of 35 patients with the frontal variant of frontotemporal dementia (fv-FTD), 22 patients with Alzheimer's disease (AD) and 15 with vascular dementia (VaD). All patients were comparable for degree of dementia severity and level of executive impairment.
Results –  The FBI showed high concurrent validity, internal consistency and good inter-rater and test–retest reliability. The discriminant validity was also very high. A new FBI cut-off score of 23 gave 97% sensitivity and 95% specificity in distinguishing fv-FTD from non-FTD patients. Conversely, the Neuropsychiatic Inventory (NPI) score was unable to differentiate fv-FTD from AD.
Conclusions –  The FBI is a neurobehavioral tool suitable to distinguish fv-FTD from other forms of dementia also when data from cognitive testing or other behavioral scales fail to support the differential diagnosis.     

Neuropsychological performance of right- and left-frontotemporal dementia compared to Alzheimer's disease.

The performance of 16 patients with Alzheimer's disease (AD) was compared to 11 patients with right-frontotemporal dementia (FTD) and 11 patients with left-FTD on a comprehensive neuropsychological battery. Standardized scores (i.e., z scores based on normal control data) were analyzed for 5 cognitive domains. The results revealed that the AD group displayed significant impairment in visual-constructional ability relative to the two FTD groups; however, no significant difference was found between the groups on memory scores (verbal and nonverbal). Patients with left-FTD scored significantly below patients with AD on the language measures (e.g., word retrieval, verbal semantic memory), and verbal executive ability (phonemic fluency); AD patients did not differ from patients with right-FTD on these measures. Patients with right-FTD exhibited significantly more perseverative behavior than AD patients; AD patients did not differ from left-FTD patients on this parameter. These results indicate that the pattern of neuropsychological performance of AD patients is distinguishable from patients with left and right frontal frontotemporal dementia.     

Word-list generation deficits in dementia

Abstract

To evaluate the specificity of the semantic fluency deficit in Alzheimer's disease (AD), we compared the performances of patients with AD, Huntington's disease (HD), vascular dementia (VD), and healthy control subjects on tasks of category (i.e., semantic) and first-letter (i.e., phonemic/lexical) word list generation. As compared to age-appropriate controls, all three patient groups demonstrated relatively more impaired semantic than phonemic fluency. Dementia severity did not affect this relationship. Thus, the greater vulnerability of semantically guided fluency is not specific to AD but occurs in other dementias as well. Deficits in both the organization of semantic memory and retrieval from long-term storage appear to contribute to the relatively poorer performance on semantic than phonemic fluency tasks observed in patients with AD, VD, and HD.     

In search of autobiographical memories: A PET study in the frontal variant of frontotemporal dementia

Patients suffering from frontal variant of frontotemporal dementia (fv-FTD) undergo autobiographical amnesia encompassing all time periods. We previously demonstrated in a group of 20 fv-FTD patients that this impairment involved deficits in executive function and semantic memory for all periods as well as new episodic learning and behavioural changes for the most recent period covering the last 12 months [Matuszewski, V., Piolino, P., de la Sayette, V., Lalevée, C., Pélerin, A., Dupuy, B., et al. (2006). Retrieval mechanisms for autobiographical memories: Insights from the frontal variant of frontotemporal dementia, Neuropsychologia, 44, 2386-2397]. The aim of the present study was to unravel the neural bases of this impairment by mapping in a subgroup of patients correlations between resting-state brain glucose utilization measured by FDG-PET and measures of autobiographical memory (AM) using the TEMPau task which is designed to gauge personal event recollection across five life time periods. Like in our previous report, the group of patients was impaired regardless of time periods compared to healthy subjects providing generic memories instead of event specific sensory-perceptual-affective details, i.e., episodic memories. New data showed that the patients were also impaired in sense of reliving and self-perspective during retrieval. The cognitivo-metabolic correlations between the AM score and resting normalized FDG-Uptake were computed using statistical parametric mapping (SPM2) and controlling for age and dementia severity. They revealed that AM deficits were mainly subserved by the dysfunction of left-sided orbitofrontal and also temporal neocortical areas whatever the period. Additional analysis showed that specific memories were associated with left orbitofrontal areas whereas generic memories were mainly associated with the left temporal pole. This study supports the view that fv-FTD patients undergo a breakdown of generative processes which relies regardless of the remoteness on the left orbitofrontal cortex and temporal neocortex to gain access to AM.     

The underlying mechanisms of semantic memory loss in Alzheimer's disease and semantic dementia

Patients with Alzheimer's disease (AD) and patients with semantic dementia (SD) both exhibit deficits on explicit tasks of semantic memory such as picture naming and category fluency. These deficits have been attributed to a degradation of the stored semantic network. An alternative explanation attributes the semantic deficit in AD to an impaired ability to consciously retrieve items from the semantic network. The present study used an implicit lexical-decision priming task to examine the integrity of the underlying semantic network in AD and SD patients matched for degree of impairment on explicit semantic memory tasks. The AD (n=11) and SD (n=11) patient groups were matched for age, education, level of dementia and impairment on four explicit semantic memory tasks. Healthy elderly participants (n=22) were matched for age and education. Semantic priming effects were evaluated for three types of semantic relationships (attributes, category coordinates, and category superordinates) and compared to lexical associative priming. Healthy controls showed significant priming across all conditions. In contrast, AD patients showed normal superordinate priming, and significant (although somewhat reduced) coordinate priming, but no attribute priming. SD patients showed no priming effect for any semantic relationship. All groups showed significant associative priming. The results indicate that SD patients do indeed have substantial degradation of semantic memory, while AD patients have a partially intact network, accounting for priming in superordinate and coordinate conditions. These findings suggest that AD patients' impairment on explicit semantic tasks is the product of deficient explicit retrieval in combination with a partially degraded semantic network.     

A meta-analytic review of verbal fluency deficits in depression

A prominent view in the neuropsychological literature is that depression is particularly associated with deficits in executive control processes. A meta-analysis of 42 studies with 2306 participants was therefore conducted to investigate the sensitivity of tests of verbal fluency to the pressure of this disorder, as there is a great deal of evidence that theses measures are valid markers of executive dysfunction. When the methodology adopted by other meta-analytic reviews was employed, semantic fluency deficits were found to be substantially larger than the phonemic fluency deficits. However, when a more rigorous method of meta-analysis was adopted, this indicated that the measure are in fact broadly equivalent in their sensitivity to depression, as has been found for patients with focal frontal lobe lesions. However, in contrast to patients with focal frontal lobe injuries, neither deficit qualified as a differential deficit relative to psychomotor speed. Therefore, for patients with depression, deficits on tests of phonemic and semantic fluency may not reflect executive dysfunction, but a more generalized impairment. Evidence is presented that tests of phonemic and semantic fluency may aid in the differential diagnosis of patients with depression and those in the early stages of dementia of the Alzheimer's type.     

Similar subcortical pattern of cognitive impairment in AIDS patients with and without dementia.

The aim of this study was to develop a series of neuropsychological tests that define the cortical and subcortical features of cognitive impairment and the characteristics of memory in demented and mildly cognitively impaired AIDS patients. We attempted to establish a usable method to assess and determine the type and degree of cognitive impairment in individual AIDS patients. We examined 53 patients without central nervous system opportunistic infections. A short battery included two scales of global efficiency (the Mattis dementia rating scale and the Mini Mental State Examination), a psychomotor speed test, an executive control assessment and explicit memory evaluation. Patients were categorized into four groups based on their score on both the Mattis dementia rating scale and the DSM-IV criteria: (1) asymptomatic; (2) having AIDS without cognitive impairment; (3) having AIDS with mild cognitive impairment; and (4) having AIDS dementia. Patients with mildly impaired cognition demonstrated slowed thinking, abnormal initiation and conceptualization, and memory impairment. AIDS dementia patients had slower motor activity and memory recall was more severely affected. The short neuropsychological battery was able to characterize modified cognitive performances in both severely and mildly cognitively impaired AIDS patients. The subcortical pattern of the memory disorder was obvious, regardless of the degree of cognitive impairment.     

Verbal fluency patterns in amnestic mild cognitive impairment are characteristic of Alzheimer's type dementia.

Amnestic mild cognitive impairment (aMCI) represents a high-risk factor for Alzheimer's disease (AD) and is characterized by a selective decline in episodic memory. Although by definition aMCI is not associated with impaired verbal fluency performance, we examined relative differences between fluency tasks because AD is characterized by poorer semantic than phonemic fluency. Phonemic and semantic fluency trials were administered to 46 healthy controls, 33 patients with aMCI, and 33 patients with AD. Results revealed a progressive advantage (controls > aMCI > AD) in semantic, relative to phonemic fluency. Difference scores between tasks distinguished each group from the others with medium to large effect sizes (d) ranging from 0.49 to 1.07. Semantic fluency relies more on semantic associations between category exemplars than does phonemic fluency. This aMCI fluency pattern reflects degradation of semantic networks demonstrating that initial neuropathology may extend beyond known early changes in hippocampal regions.     

Multidimensional measures of person knowledge and spatial associative learning: can these be applied to the differentiation of Alzheimer's disease from frontotemporal and vascular dementia?

Patients with early stage Alzheimer's disease (AD) show deficits in person knowledge and spatial associative memory. The current investigation examined the ability of impairment in these domains to differentiate AD from other overlapping conditions. In experiment 1, 14 AD patients, 21 vascular dementia (VaD) patients, 11 frontal variant frontotemporal dementia (fvFTD) patients and 41 controls were administered a graded faces test. VaD patients demonstrated a level of impairment comparable to the AD group on both the naming and person identification elements of the task. A mild naming deficit was revealed in the fvFTD group. In experiment 2, 22 AD patients, 23 patients with mild cognitive impairment (MCI), 11 fvFTD patients, 13 semantic dementia (SD) patients, and 23 elderly controls were administered the face-place test, a newly developed task that combines naming of famous faces, item recognition and spatial location. The naming component of the face-place test clearly differentiated SD patients from all dementia groups. All patient groups, except those with fvFTD, showed substantial deficits in the item recognition and spatial components. Consistency analyses indicated a fairly robust association between the two episodic components (item recognition and placing), but not between semantic and episodic elements of the FPT. Person knowledge deficits are, therefore, not specific to AD and the employment of face stimuli may influence the performance of SD patients on tasks of episodic memory.     

脑小血管病患者伴发非痴呆血管性认知功能损害情况及尼莫地平疗效的研究

目的探讨脑小血管病(cerebral small vessel disease,SVD)不同亚型伴发非痴呆血管性认知功能损害的情况,评价尼莫地平对SVD的疗效。方法选择SVD患者118例,包括52例腔隙灶脑梗死(LI)和66例白质疏松(WML)患者。分别将LI组和WML组患者随机分组为治疗组(基础治疗加尼莫地平治疗)和对照组(基础治疗),进行6个月治疗。治疗前后对所有患者采用蒙特利尔认知评估量表(MoCA)、简易智能状态检查表(MMSE)、语义分类流畅测验(动物)、Stroop测验(计算错误数)、画钟试验、积木测验、数字广度顺背测验、数字符号测验、逻辑记忆亚测验和再生亚测验进行认知功能评价,并比较各组患者治疗前后认知功能评分。结果治疗前,LI组患者语义分类流畅测验(动物)、数字符号测验、逻辑记忆亚测验、视觉再生亚测验、MoCA、MMSE评分显著高于WML组患者,Stroop测验得分显著低于WML组患者。经过6个月治疗后,LI组和WML组患者中的对照组治疗前后各项认知功能评分均没有统计学差异(P>0.05)。LI组患者中治疗组MoCA、画钟试验和数字广度顺背测验得分升高,Stroop测验得分下降(均P<0.05);WML组患者中治疗组MoCA、MMSE、画钟试验、数字广度顺背测验和视觉再生亚测验得分升高,Stroop测验得分下降(均P<0.05)。结论 SVD两个亚型伴发非痴呆血管性认知功能损害情况不同,LI患者损害程度比WML患者轻。尼莫地平治疗可较好的改善患者的执行功能、视空间结构能力和注意力。     

Distinct neural substrates of affective and cognitive theory of mind impairment in semantic dementia

Using structural MRI, we investigated the brain substrates of both affective and cognitive theory of mind (ToM) in 19 patients with semantic dementia. We also ran intrinsic connectivity analyses to identify the networks to which the substrates belong and whether they are functionally disturbed in semantic dementia. In line with previous studies, we observed a ToM impairment in patients with semantic dementia even when semantic memory was regressed out. Our results also highlighted different neural bases according to the nature (affective or cognitive) of the representations being inferred. The affective ToM deficit was associated with atrophy in the amygdala, suggesting the involvement of emotion-processing deficits in this impairment. By contrast, cognitive ToM performances were correlated with the volume of medial prefrontal and parietal regions, as well as the right frontal operculum. Intrinsic connectivity analyses revealed decreased functional connectivity, mainly between midline cortical regions and temporal regions. They also showed that left medial temporal regions were functionally isolated, a further possible hindrance to normal social cognitive functioning in semantic dementia. Overall, this study addressed for the first time the neuroanatomical substrates of both cognitive and affective ToM disruption in semantic dementia, highlighting disturbed connectivity within the networks that sustain these abilities.     

“Pre-semantic” cognition revisited: Critical differences between semantic aphasia and semantic dementia

Patients with semantic dementia show a specific pattern of impairment on both verbal and non-verbal “pre-semantic” tasks, e.g., reading aloud, past tense generation, spelling to dictation, lexical decision, object decision, colour decision and delayed picture copying. All seven tasks are characterised by poorer performance for items that are atypical of the domain and “regularisation errors” (irregular/atypical items are produced as if they were domain-typical). The emergence of this pattern across diverse tasks in the same patients indicates that semantic memory plays a key role in all of these types of “pre-semantic” processing. However, this claim remains controversial because semantically impaired patients sometimes fail to show an influence of regularity. This study demonstrates that (a) the location of brain damage and (b) the underlying nature of the semantic deficit affect the likelihood of observing the expected relationship between poor comprehension and regularity effects. We compared the effect of multimodal semantic impairment in the context of semantic dementia and stroke aphasia on the seven “pre-semantic” tasks listed above. In all of these tasks, the semantic aphasia patients were less sensitive to typicality than the semantic dementia patients, even though the two groups obtained comparable scores on semantic tests. The semantic aphasia group also made fewer regularisation errors and many more unrelated and perseverative responses. We propose that these group differences reflect the different locus for the semantic impairment in the two conditions: patients with semantic dementia have degraded semantic representations, whereas semantic aphasia patients show deregulated semantic cognition with concomitant executive deficits. These findings suggest a reinterpretation of single-case studies of comprehension-impaired aphasic patients who fail to show the expected effect of regularity on “pre-semantic” tasks. Consequently, such cases do not demonstrate the independence of these tasks from semantic memory.     

Deficits of knowledge versus executive control in semantic cognition: insights from cued naming

Deficits of semantic cognition in semantic dementia and in aphasia consequent on CVA (stroke) are qualitatively different. Patients with semantic dementia are characterised by progressive degradation of central semantic representations, whereas multimodal semantic deficits in stroke aphasia reflect impairment of executive processes that help to direct and control semantic activation in a task-appropriate fashion [Jefferies, E., & Lambon Ralph, M. A. (2006). Semantic impairment in stroke aphasia vs. semantic dementia: A case-series comparison. Brain 129, 2132-2147]. We explored interactions between these two aspects of semantic cognition by examining the effects of cumulative phonemic cueing on picture naming in case series of these two types of patient. The stroke aphasic patients with multimodal semantic deficits cued very readily and demonstrated near-perfect name retrieval when cumulative phonemic cues reached or exceeded the target name's uniqueness point. Therefore, knowledge of the picture names was largely intact for the aphasic patients, but they were unable to retrieve this information without cues that helped to direct activation towards the target response. Equivalent phonemic cues engendered significant but much more limited benefit to the semantic dementia patients: their naming was still severely impaired even when most of the word had been provided. In contrast to the pattern in the stroke aphasia group, successful cueing was mainly confined to the more familiar un-named pictures. We propose that this limited cueing effect in semantic dementia follows from the fact that concepts deteriorate in a graded fashion [Rogers, T. T., Lambon Ralph, M. A., Garrard, P., Bozeat, S., McClelland, J. L., & Hodges, J. R., et al. (2004). The structure and deterioration of semantic memory: A neuropsychological and computational investigation. Psychological Review 111, 205-235]. For partially degraded items, the residual conceptual knowledge may be insufficient to drive speech production to completion but these items might reach threshold when they are bolstered by cues.