The underlying mechanisms of verbal fluency deficit in frontotemporal dementia and semantic dementia

Verbal fluency tasks are commonly used to explore semantic memory and executive functions. The aim of this study was to gain a better understanding of the cognitive and neural mechanisms underlying verbal fluency impairment in the frontal variant of frontotemporal dementia (fv-FTD) and in semantic dementia (SD). Semantic and phonemic fluency tasks were performed by 36 fv-FTD and SD patients and 18 elderly controls. We also carried out a neuropsychological investigation of semantic memory, working memory and shifting and updating processes. We performed correlative and regression analyses of fluency scores and neuropsychological data. In addition, patients underwent a resting positron emission tomography examination, and statistical parametric mapping was used to establish correlations between resting-state FDG uptake in the whole brain and fluency scores for each patient group. Both patient groups displayed impaired performances on both fluency tasks compared with controls, but with different patterns. While fv-FTD patients scored higher than SD patients on semantic fluency, their performances on the phonemic task did not differ. Correlation and regression analyses clearly demonstrated that the fv-FTD patients’ performances on both fluency tasks depended on their executive abilities, while those of the SD patients were hampered by the impairment of their semantic memory store. Correlations with resting FDG uptake were consistent with the results of the cognitive study. In fv-FTD, both fluency performances were related to the metabolism of the frontal lobes, while we observed significant correlations between performances on both fluency tasks and the left temporal lobe metabolism in SD.     

Clustering strategies on tasks of verbal fluency in Parkinson's disease.

The verbal output of patients with Parkinson's disease (PD) was analyzed for semantic and phonemic clusters on tasks of verbal fluency. One task required cued retrieval by semantic category (i.e. animals), and one required non-cued retrieval by initial letter (e.g. words beginning with 'F'). Nondemented PD patients (N = 25) produced significantly fewer words on the cued semantic retrieval task than age-, gender- and education-matched normal control subjects (N = 22), but were not impaired on the non-cued letter retrieval task. However, overall, PD patients were able to form more semantic clusters than phonemic clusters. These results are discussed in light of other studies of verbal fluency deficits in patients with PD.     

Cerebral glucose metabolism in Parkinson's disease with and without dementia.

Although cognitive impairment is commonly associated with Parkinson's disease, the relative importance of cortical and subcortical pathologic changes to the development of dementia is controversial. Characteristic abnormalities in cortical glucose metabolism have been reported previously in Alzheimer's disease, a disease in which cortical changes predominate. We measured cerebral glucose metabolism with positron emission tomography in 20 control subjects and in 14 patients with PD with mental status ranging from normal to severely demented to determine whether changes in cortical glucose metabolism occur in early PD and whether the degree and pattern of metabolic change relate to the severity of dementia. The patients were divided into demented and nondemented groups according to the results of neuropsychological assessment. Age-adjusted covariance analyses were performed, since the age distribution varied between groups. The nondemented patients with PD showed widespread cortical glucose hypometabolism without any selective temporoparietal defects. The pattern of glucose hypometabolism seen in the demented patients with PD resembled that described in patients with Alzheimer's disease; ie, there was a global decrease in glucose metabolism, with more severe abnormalities observed in the temporoparietal regions.     

Release signs in Parkinson's disease with and without dementia

Summary Release signs have been described in both age-associated diseases and in the healthy elderly. We investigated the palmomental, snout, grasp, corneomandibular and glabellar reflexes in demented and non-demented Parkinson-patients compared to Alzheimer's disease and age-matched controls. The palmomental reflex and a persisting glabellar reflex were linked to parkinsonism irrespective of dementia and were found also in Alzheimer's disease. A corneomandibular reflex was observed more frequently in demented than non-demented Parkinson-patients and in Alzheimer's disease. The snout-reflex was present in nearly all individuals irrespective of diagnosis. Thus, various release signs react quite differentially to degenerative brain disease and dementia.     

Localization of motor and verbal fluency effects in subthalamic DBS for Parkinson's disease

IntroductionSubthalamic nucleus deep brain stimulation (STN DBS) improves cardinal motor symptoms of Parkinson's disease (PD) but can worsen verbal fluency (VF). An optimal site of stimulation for overall motor improvement has been previously identified using an atlas-independent, fully individualized, field-modeling approach. This study examines if cardinal motor components (bradykinesia, tremor, and rigidity) share this identified optimal improvement site and if there is co-localization with a site that worsens VF.MethodsAn atlas-independent, field-modeling approach was used to identify sites of maximal STN DBS effect on overall and cardinal motor symptoms and VF in 60 patients. Anatomic coordinates were referenced to the STN midpoint. Symptom severity was assessed with the MDS-UPDRS part III and established VF scales.ResultsSites for improved bradykinesia and rigidity co-localized with each other and the overall part III site (0.09 mm lateral, 0.93 mm posterior, 1.75 mm dorsal). The optimal site for tremor was posterior to this site (0.10 mm lateral, 1.40 mm posterior, 1.93 mm dorsal). Semantic and phonemic VF sites were indistinguishable and co-localized medial to the motor sites (0.32 mm medial, 1.18 mm posterior, 1.74 mm dorsal).ConclusionThis study identifies statistically distinct, maximally effective stimulation sites for tremor improvement, VF worsening, and overall and other cardinal motor improvements in STN DBS. Current electrode sizes and voltage settings stimulate all of these sites simultaneously. However, future targeted lead placement and focused directional stimulation may avoid VF worsening while maintaining motor improvements in STN DBS.     

Anterior lead location predicts verbal fluency decline following STN-DBS in Parkinson's disease

IntroductionVerbal fluency (VF) decline is a well-documented cognitive effect of Deep Brain Stimulation of the subthalamic nucleus (STN-DBS) in patients with Parkinson's disease (PD). This decline may be associated with disruption to left-sided frontostriatal circuitry involving the anteroventral non-motor area of the STN. While recent studies have examined the impact of lead location in relation to functional STN subdivisions on VF outcomes, results have been mixed and methods have been limited by atlas-based location mapping.MethodsParticipants included 59 individuals with PD who underwent bilateral STN-DBS. Each participant's active contact location was determined in an atlas-independent fashion, relative to their individual MR-visualized STN midpoint. Multiple linear regression was used to examine lead location in each direction as a predictor of phonemic and semantic VF decline, controlling for demographic and disease variables.ResultsMore anterior lead locations relative to the STN midpoint in the left hemisphere predicted greater phonemic VF decline (B = −2.34, B SE = 1.08, β = −0.29, sr² = 0.08). Lead location was not a significant predictor of semantic VF decline.ConclusionUsing an individualized atlas-independent approach, present findings suggest that more anterior stimulation of the left STN may uniquely contribute to post-DBS VF decline. This is consistent with models in which the anterior STN represents a “non-motor” functional subdivision with connections to frontal regions, e.g., the left dorsal prefrontal cortex. Future studies should investigate the effect of DBS lead trajectory on VF outcomes.     

Everyday action impairment in Parkinson's disease dementia

This study examined everyday action impairment in participants with Parkinson's disease dementia (PDD) by comparison with participants with Parkinson's disease-no dementia (PD) or Alzheimer's disease (AD) and in reference to a neuropsychological model. Participants with PDD (n = 20), PD (n = 20), or AD (n = 20) were administered performance-based measures of everyday functioning that allowed for the quantification of overall performance and error types. Also, caregiver ratings of functional independence were obtained. On performance-based tests, the PDD group exhibited greater functional impairment than the PD group but comparable overall impairment relative to the AD group. Error patterns did not differ between PDD and PD participants but the PDD group demonstrated a higher proportion of commission errors and lower proportion of omission errors relative to the AD group. Hierarchical regression analyses showed omission errors were significantly predicted by neuropsychological measures of episodic memory, whereas commission errors were predicted by both measures of general dementia severity (MMSE) and executive control. Everyday action impairment in PDD differs quantitatively from PD but qualitatively from AD and may be characterized by a relatively high proportion of commission errors-an error type associated with executive control deficits. (JINS, 2012, 18, 1-12).     

Apolipoprotein E genotypes in Parkinson's disease with and without dementia

The apolipoprotein E gene (Apo E) type 4 allele is a genetic risk factor influencing the development and age of onset of Alzheimer's disease. Because Parkinson's disease shares many characteristics of Alzheimer's disease, we studied the frequencies of Apo E genotypes in a cohort of 52 Parkinson's disease patients with dementia and 61 patients without dementia. Dementia was determined per National Institute of Neurological and Communicative Disorders and Stroke criteria and Mattis Dementia Rating Scale (DRS) < 126. Normal cognition was defined as DRS > 132. Apo E genotype and allele frequencies did not differ between demented and nondemented parkinsonian patients. Neither group's genotype and allele frequencies differed from that of a nondemented population of 78 controls. We conclude that the Apo E ε4 allele influences neither the development of Parkinson's disease nor the dementia associated with Parkinson's disease nor the dementia associated with Parkinson's disease.     

Quantified electroencephalographic changes in Parkinson's disease with and without dementia

We examined the presence of quantified electroencephalographic (qEEG) differences between Parkinson's disease (PD) patients with and without dementia, and a group of age-comparable normal controls. While there were no significant differences in relative power in any of the qEEG bands between PD patients without dementia and normal controls, PD patients showed a significantly greater reactivity in the alpha band. On the other hand, PD patients with dementia showed significantly less alpha and more theta relative power than both the normal control and the PD without dementia groups. When PD patients with dementia were compared with a group of patients with Alzheimer's disease (AD) and a similar severity of dementia, no significant between-group differences were found in any of the qEEG bands. In conclusion, while our study demonstrated no significant qEEG differences between non-demented PD patients and normal controls, PD patients with dementia showed qEEG changes similar to those observed in patients with AD.     

Cognitive impairment in Parkinson's disease without dementia

Some degree of cognitive impairment appears frequently in Parkinson's disease (PD) patients, even at the onset of the disease. However, due to the heterogeneity of the patients and the lack of standardized assessment batteries, it remains unclear which capacities are primarily affected by this disease. Fifty PD patients were assessed with 15 tests including executive functions, attention, temporal and spatial orientation, memory, and language tasks. Their results were compared with those of 42 age‐ and education‐matched healthy seniors. Semantic fluency, along with visual search appeared to be the most discriminant tasks, followed by temporal orientation and face naming, as well as action naming and immediate recall. PD patients studied showed an impairment of frontal‐ to posterior‐dependent capacities. Executive functions, attention, and recall tasks appeared to be significantly impaired in the patients. Nevertheless, significantly poor scores in tasks like action and face naming, as well as semantic fluency, also reveal a mainly semantic deficit. © 2010 Movement Disorder Society     

Hippocampal,caudate, and ventricular changes in Parkinson's disease with and without dementia

Parkinson's disease (PD) has been associated with mild cognitive impairment (PDMCI) and with dementia (PDD). Using radial distance mapping, we studied the 3D structural and volumetric differences between the hippocampi, caudates, and lateral ventricles in 20 cognitively normal elderly (NC), 12 cognitively normal PD (PDND), 8 PDMCI, and 15 PDD subjects and examined the associations between these structures and Unified Parkinson's Disease Rating Scale (UPDRS) Part III:motor subscale and Mini‐Mental State Examination (MMSE) performance. There were no hippocampal differences between the groups. 3D caudate statistical maps demonstrated significant left medial and lateral and right medial atrophy in the PDD vs. NC, and right medial and lateral caudate atrophy in PDD vs. PDND. PDMCI showed trend‐level significant left lateral caudate atrophy vs. NC. Both left and right ventricles were significantly larger in PDD relative to the NC and PDND with posterior (body/occipital horn) predominance. The magnitude of regionally significant between‐group differences in radial distance ranged between 20–30% for caudate and 5–20% for ventricles. UPDRS Part III:motor subscale score correlated with ventricular enlargement. MMSE showed significant correlation with expansion of the posterior lateral ventricles and trend‐level significant correlation with caudate head atrophy. Cognitive decline in PD is associated with anterior caudate atrophy and ventricular enlargement. © 2010 Movement Disorder Society     

Brain 3D-SSP SPECT analysis in dementia with Lewy bodies, Parkinson's disease with and without dementia, and Alzheimer's disease

OBJECTIVES: Cerebral blood flow was compared among patients with dementia with Lewy bodies (DLB), Parkinson's disease with dementia (PDD), Parkinson's disease without dementia (PD), and Alzheimer's disease (AD) using three-dimensional stereotactic surface projection (3D-SSP) analysis. PURPOSE: We attempt to clarify the difference of reduction pattern on SPECT among patients having DLB, PDD, PD, AD. PATIENTS AND METHODS: Six patients with DLB, 7 patients with PDD who were matched with the DLB patients for age, unified Parkinson's disease rating scale-III (UPDRS-III) score, and degree of cognitive function disorders, 21 patients with PD who were matched with the DLB patients for age, UPDRS-III score, 12 patients with AD who were matched with the DLB patients for age and degree of cognitive function disorders, and 12 control subjects. All patients were examined by N-isopropyl-p[123I] iodoamphetamine single photon emission computed tomography (123I-IMP SPECT), and obtained images were analyzed with 3D-SSP using an image-analysis software, iSSP ver. 3.5. RESULTS: Although DLB and PDD showed similar cerebral perfusion reduction pattern at the lateral parietal association and lateral temporal association and precuneus on SPECT by the pixel-by-pixel comparison, greater perfusion reduction was observed in DLB than in PDD. Cerebral perfusion was decreased at the occipital lobe of the DLB patients compared with the AD patients. CONCLUSIONS: The regional pattern of blood flow reduction in the brain was found to be different among DLB, PD, and AD. Greater blood flow reduction was observed in DLB, although DLB and PDD showed similar reduction pattern. These regional differences were considered to suggest different and disease-specific combinations of underlying pathological and neurochemical processes.     

Acute low frequency dorsal subthalamic nucleus stimulation improves verbal fluency in Parkinson's disease

BackgroundParkinson's disease (PD) is a common neurodegenerative disorder that results in movement-related dysfunction and has variable cognitive impairment. Deep brain stimulation (DBS) of the dorsal subthalamic nucleus (STN) has been shown to be effective in improving motor symptoms; however, cognitive impairment is often unchanged, and in some cases, worsened particularly on tasks of verbal fluency. Traditional DBS strategies use high frequency gamma stimulation for motor symptoms (∼130 Hz), but there is evidence that low frequency theta oscillations (5–12 Hz) are important in cognition.MethodsWe tested the effects of stimulation frequency and location on verbal fluency among patients who underwent STN DBS implantation with externalized leads. During baseline cognitive testing, STN field potentials were recorded and the individual patients’ peak theta frequency power was identified during each cognitive task. Patients repeated cognitive testing at five different stimulation settings: no stimulation, dorsal contact gamma (130 Hz), ventral contact gamma, dorsal theta (peak baseline theta) and ventral theta (peak baseline theta) frequency stimulation.ResultsAcute left dorsal peak theta frequency STN stimulation improves overall verbal fluency compared to no stimulation and to either dorsal or ventral gamma stimulation. Stratifying by type of verbal fluency probes, verbal fluency in episodic categories was improved with dorsal theta stimulation compared to all other conditions, while there were no differences between stimulation conditions in non-episodic probe conditions.ConclusionHere, we provide evidence that dorsal STN theta stimulation may improve verbal fluency, suggesting a potential possibility of integrating theta stimulation into current DBS paradigms to improve cognitive outcomes.     

Neuropsychological profile of patients with Parkinson's disease without dementia

Cognitive deficits are often associated with Parkinson's disease (PD), although their prevalence in PD patients without dementia is still unknown. In order to describe the neuropsychological profile of PD patients without dementia, a sample of 103 PD patients was compared with a control group consisting of 38 healthy elderly subjects. Psychometric assessment consisted of the Mini Mental State Examination, the Dementia Rating Scale and a battery of neuropsychological tests. The Beck Depression Inventory was used to assess depression in PD patients. Dementia was diagnosed in 27 patients. Among non-demented subjects, 34 (45%) had no cognitive impairment and 42 (55%) had a mild cognitive impairment. Subjects with mild cognitive impairment were older, had a later onset of the disease, and more severe motor symptoms than cognitively intact subjects. Identification of mild cognitive impairment is important, since these symptoms are important for patient management and may also facilitate to determine prognosis.     

Relearning of verbal labels in semantic dementia

Semantic dementia is a degenerative disorder of temporal neocortex characterised by loss of word and object concepts. There is limited evidence that temporary relearning of lost vocabulary may be possible, attributed to sparing of hippocampal structures. However, learning is variable across patients and factors underlying learning success are poorly understood. The study investigated relearning of object names in two severely anomic semantic dementia patients. Following memory models that assume that hippocampal memories require some neocortical representation to underpin them it was predicted that relearning would be influenced by patients' residual semantic information about stimuli. Experiment 1 confirmed that residual knowledge influenced learning success. On the assumption that neocortical knowledge encompasses concepts of space and time, as well as words and objects, it was predicted that learning would be affected by the availability of contextual (temporo-spatial) information. Experiment 2 demonstrated effective learning of object names, attributed to the patient's use of temporal order and spatial position knowledge. Retention of object names over months was linked to the patient's capacity for autobiographical experiential (temporo-spatial contextual) association. The findings indicate that relearning of lost vocabulary is possible in semantic dementia, indicating a role of the medial temporal lobes in the acquisition of semantic information. Effective learning does not imply reinstatement of lost concepts, but, it is argued, does involve some reacquisition of meaning. The findings challenge the traditional semantic-episodic memory dichotomy and are consistent with a "levels of meaning" account of semantic memory.     

Differential verbal fluency deficits in the preclinical stages of Alzheimer's disease and vascular dementia

We examined patterns of early and late word generation in category and letter fluency among persons in the preclinical stages of Alzheimer's disease (AD) and vascular dementia (VaD). The sample consisted of 20 preclinical VaD persons, 66 preclinical AD persons, and 267 control persons, sampled from the community. Persons in the preclinical phase of AD and VaD were similarly impaired in letter fluency, although the preclinical VaD group outperformed their AD counterparts in category fluency. This pattern of results is consistent with the notion that category fluency is relatively more dependent on the medial-temporal lobe, whereas letter fluency relies more on frontal regions. The patterns of fluency impairment in preclinical AD and VaD generalized across early and late word retrieval.     

Category verbal fluency predicted changes in behavioral and psychological symptoms of dementia in patients with Alzheimer's disease

Aim: Alzheimer's disease (AD) is characterized by cognitive symptoms and behavioral symptoms, and their association is inconsistent. The aim of this study was to investigate the relationship between cognitive function and the changes in behavioral and psychological symptoms of dementia (BPSD) in patients with AD. Methods: A total of 101 patients with probable AD were enrolled (57 women and 44 men, mean age 77.6 ± 7.7 years). The Category Verbal Fluency Test (CVFT), the Mini‐Mental State Examination (MMSE), the Constructional Praxis Test, the Delayed Word Recall Test, the Clinical Dementia Rating Scale, and the Neuropsychiatry Inventory (NPI) were administered at baseline. The NPI was reassessed with a median follow‐up duration of 10 months (range 6–18 months). The change in the NPI scores was defined as the end‐point score of the NPI minus the initial one. The associations between the changes in NPI total score, its four subdomains (hyperactivity, psychosis, affection, and apathy), and cognitive function were examined using multivariate linear models. The results were adjusted for confounders including demographics, baseline NPI, and duration of follow up. Results: The mean MMSE was 18.6 ± 5.6, the CVFT score was 7.1 ± 3.9, and the NPI score was 10.9 ± 13.8. Regression analyses found that the CVFT score (β = ?0.32, P = 0.004) was significantly associated with the change in NPI score, but not the MMSE, the Delayed Word Recall score, or the Constructional Praxis score. The CVFT score was significantly associated with changes in the psychosis subdomain (β = ?0.34, P = 0.001), but not the other subdomains. Conclusions: Our study showed that CVFT was predictive of the changes in behavior disturbance in patients with AD, particularly in the psychosis domain.     

Motor subtype and cognitive decline in Parkinson's disease, Parkinson's disease with dementia, and dementia with Lewy bodies

BACKGROUND: A previous cross sectional study found over-representation of a postural instability gait difficulty (PIGD) motor subtype in Parkinson's disease patients with dementia (PDD) and dementia with Lewy bodies (DLB), compared with Parkinson's disease (PD). AIMS: (1) To examine rates of cognitive and motor decline over two years in PD (n=40), PDD (n=42) and DLB (n=41) subjects, compared with age matched controls (n=41), (2) to record whether motor phenotypes of PD, PDD, and DLB subjects changed during the study, (3) to find out if cognitive and motor decline in PD was associated with baseline motor subtype, and (4) to report the incidence of dementia in PD patients in relation to baseline motor subtype. RESULTS: Most of PDD and DLB participants were PIGD subtype at baseline assessment. In the non-demented PD group, tremor dominant (TD) and PIGD subtypes were more evenly represented. Cognitive decline over two years was greater in PDD and DLB groups (mean decline in MMSE -4.5 and -3.9, respectively), compared with PD (-0.2) and controls (-0.3). There was an association between PIGD subtype and increased rate of cognitive decline within the PD group. Of 40 PD patients, 25% of the 16 PIGD subtype developed dementia over two years, compared with none of the 18 TD or six indeterminate phenotype cases (chi2=6.7, Fisher's exact test p<0.05). CONCLUSION: A PIGD motor subtype is associated with a faster rate of cognitive decline in PD and may be considered a risk factor for incident dementia in PD.     

Action and object naming in Parkinson's disease without dementia

The present study aimed to assess the ability in objects and actions naming in Parkinson's disease (PD) patients. Further, we wished to assess the effect of a particular conceptual dimension, i.e. manipulability, on the naming of object and actions. Patients were recruited from the Department of Neurology, University of Brescia. Thirty-two were diagnosed as PD, according to published criteria, and 15 healthy volunteers matched in age and education to patients' sample. All patients underwent a detailed clinical and neurological evaluation. The stimuli used in the action–object picture naming task were taken from the Center for Research in Language-International Picture Naming Project corpus. To assess the effect of manipulability (or the involvement of fine hand movements) the noun–verb stimuli were re-categorized into manipulable and non-manipulable items (i.e. objects which can or cannot be manipulated and actions which do or do not involve fine hand movements). Patients showed a deficit both in action and object naming, compared with controls. In addition, patients with PD but not controls were significantly more impaired in action than in object naming. The current study supports the view that action naming is affected in patients with PD, possibly reflecting the presence of prefrontal dysfunction.