Frontal Dysexecutive Syndrome Research Articles

Patterns of brain volume and metabolism predict clinical features in the progressive supranuclear palsy spectrum.

Progressive supranuclear palsy (PSP) is a neurodegenerative tauopathy that presents with highly heterogenous clinical syndromes. We perform cross-sectional data-driven discovery of independent patterns of brain atrophy and hypometabolism across the entire PSP spectrum. We then use these patterns to predict specific clinical features and to assess their relationship to phenotypic heterogeneity. We included 111 patients with PSP (60 with Richardson syndrome and 51 with cortical and subcortical variant subtypes). Ninety-one were used as the training set and 20 as a test set. The presence and severity of granular clinical variables such as postural instability, parkinsonism, apraxia and supranuclear gaze palsy were noted. Domains of akinesia, ocular motor impairment, postural instability and cognitive dysfunction as defined by the Movement Disorders Society criteria for PSP were also recorded. Non-negative matrix factorization was used on cross-sectional MRI and fluorodeoxyglucose-positron emission tomography (FDG-PET) scans. Independent models for each as well as a combined model for MRI and FDG-PET were developed and used to predict the granular clinical variables. Both MRI and FDG-PET were better at predicting presence of a symptom than severity, suggesting identification of disease state may be more robust than disease stage. FDG-PET predicted predominantly cortical abnormalities better than MRI such as ideomotor apraxia, apraxia of speech and frontal dysexecutive syndrome. MRI demonstrated prediction of cortical and more so sub-cortical abnormalities, such as parkinsonism. Distinct neuroanatomical foci were predictive in MRI- and FDG-PET-based models. For example, vertical gaze palsy was predicted by midbrain atrophy on MRI, but frontal eye field hypometabolism on FDG-PET. Findings also differed by scale or instrument used. For example, prediction of ocular motor abnormalities using the PSP Saccadic Impairment Scale was stronger than with the Movement Disorders Society Diagnostic criteria for PSP oculomotor impairment designation. Combination of MRI and FDG-PET demonstrated enhanced detection of parkinsonism and frontal syndrome presence and apraxia, cognitive impairment and bradykinesia severity. Both MRI and FDG-PET patterns were able to predict some measures in the test set; however, prediction of global cognition measured by Montreal Cognitive Assessment was the strongest. MRI predictions generalized more robustly to the test set. PSP leads to neurodegeneration in motor, cognitive and ocular motor networks at cortical and subcortical foci, leading to diverse yet overlapping clinical syndromes. To advance understanding of phenotypic heterogeneity in PSP, it is essential to consider data-driven approaches to clinical neuroimaging analyses.

Whole-Brain Magnetic Resonance Spectroscopy Reveals Distinct Alterations in Neurometabolic Profile in Progressive Supranuclear Palsy.

Progressive supranuclear palsy (PSP) is an atypical Parkinsonian syndrome characterized by supranuclear gaze palsy, early postural instability, and a frontal dysexecutive syndrome. Contrary to normal brain magnetic resonance imaging in Parkinson's disease (PD), PSP shows specific cerebral atrophy patterns and alterations, but these findings are not present in every patient, and it is still unclear if these signs are also detectable in early disease stages. The aim of the present study was to analyze the metabolic profile of patients with clinically diagnosed PSP in comparison with matched healthy volunteers and PD patients using whole-brain magnetic resonance spectroscopicimaging (wbMRSI). Thirty-nine healthy controls (HCs), 29 PD, and 22 PSP patients underwent wbMRSI. PSP and PD patients were matched for age and handedness with HCs. Clinical characterization was performed using the Movement Disorder Society Unified Parkinson's Disease Rating Scale, PSP rating scale, and DemTect (test for cognitive assessment). In PSP patients a significant reduction in N-acetyl-aspartate (NAA) was detected in all brain lobes. Fractional volume of the cerebrospinal fluid significantly increased in PSP patients compared to PD and healthy volunteers. In PSP much more neuronal degeneration and cerebral atrophy have been detected compared with PD. The most relevant alteration is the decrease in NAA in all lobes of the brain, which also showed a partial correlation with clinical symptoms. However, more studies are needed to confirm the additional value of wbMRSI in clinical practice. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

An Iatrogenic Model of Brain Small-Vessel Disease: Post-Radiation Encephalopathy.

We studied 114 primitive cerebral neoplasia, that were surgically treated, and underwent radiotherapy (RT), and compared their results to those obtained by 190 patients diagnosed with subcortical vascular dementia (sVAD). Patients with any form of primitive cerebral neoplasia underwent whole-brain radiotherapy. All the tumor patients had regional field partial brain RT, which encompassed each tumor, with an average margin of 2.6 cm from the initial target tumor volume. We observed in our patients who have been exposed to a higher dose of RT (30–65 Gy) a cognitive and behavior decline similar to that observed in sVAD, with the frontal dysexecutive syndrome, apathy, and gait alterations, but with a more rapid onset and with an overwhelming effect. Multiple mechanisms are likely to be involved in radiation-induced cognitive impairment. The active site of RT brain damage is the white matter areas, particularly the internal capsule, basal ganglia, caudate, hippocampus, and subventricular zone. In all cases, radiation damage inside the brain mainly focuses on the cortical–subcortical frontal loops, which integrate and process the flow of information from the cortical areas, where executive functions are “elaborated” and prepared, towards the thalamus, subthalamus, and cerebellum, where they are continuously refined and executed. The active mechanisms that RT drives are similar to those observed in cerebral small vessel disease (SVD), leading to sVAD. The RT’s primary targets, outside the tumor mass, are the blood–brain barrier (BBB), the small vessels, and putative mechanisms that can be taken into account are oxidative stress and neuro-inflammation, strongly associated with the alteration of NMDA receptor subunit composition.

Acquired Hemicerebral Atrophy Secondary to Chronic Internal Carotid Steno-Occlusive Disease: A Case Series.

Cerebral atrophy is a common finding in elderly patients; however, cerebrovascular disease causing progressive focal cerebral atrophy and dysfunction is unusual. In this report, we present 3 cases of hemicerebral atrophy due to ipsilateral internal carotid artery (ICA) stenosis or occlusion mimicking neurodegenerative conditions. Patient 1 had a frontal dysexecutive syndrome potentially consistent with a diagnosis of behavioral variant frontotemporal dementia; however, neuroimaging revealed a chronically occluded left ICA and a pattern of atrophy restricted to the left middle cerebral artery territory, suggestive of a vascular etiology. Patient 2 presented with progressively worsening seizures and right-sided weakness consistent with left hemispheric dysfunction, with radiographic evidence of left hemicerebral atrophy. Angiography revealed a chronic dissection of the left ICA leading to left cerebral hypoperfusion. Patient 3 had asymmetric parkinsonism, alien limb, and cognitive impairment consistent with a diagnosis of corticobasal syndrome. His imaging, however, revealed atrophy and encephalomalacia within the anterior circulation watershed territories with chronic, severe stenosis of the left ICA suggestive of a chronic hypoperfused state. In this case series, we report 3 examples of hemicerebral atrophy secondary to chronic ipsilateral ICA vascular disease with diverse progressive clinical symptoms mimicking primary neurodegenerative conditions. This case series highlights the importance of considering chronic hypoperfusion and large-vessel severe stenosis or occlusion in patients with cognitive impairment and evidence of asymmetric brain atrophy. In addition to symptomatic treatment, the management of vascular risk factors including treatment with antiplatelet agents, statins, and revascularization procedures can be considered.

The novel PSEN1 M84V mutation associated to frontal dysexecutive syndrome, spastic paraparesis, and cerebellar atrophy in a dominant Alzheimer's disease family

We identified the novel PSEN1 pathogenic mutation M84V in 3 patients belonging to a large kindred affected by autosomal dominant Alzheimer's disease (AD). The clinical phenotype was characterized by early onset dementia in 14 affected subjects over 3 generations. Detailed clinical, imaging and genetic assessment was performed. We highlighted the presence of unusual symptoms such as frontal executive syndrome, psychosis and spastic paraparesis in these patients. Spastic paraparesis has been reported in other PSEN1 mutations in adjacent codons, suggesting that the position of the genetic defect may affect the clinical expression, although this phenotype can occur in mutations throughout the whole PSEN1 gene. Brain magnetic resonance imaging showed diffuse cortical atrophy, but also atrophy of cerebellar lobules, mainly involving Crus I, in 2 patients without cerebellar motor deficits. These neuroimaging results were consistent with recent findings about the association between sporadic AD and distinct and circumscribed cerebellar atrophy. The present work acknowledged the novel PSEN1 pathogenic mutation M84V and might contribute to the ongoing debate about the involvement of cerebellum in AD.

Managing cognition in progressive supranuclear palsy.

Cognitive impairment is integral to the syndrome of progressive supranuclear palsy. It is most commonly described as a frontal dysexecutive syndrome but other impairments include apathy, impulsivity, visuospatial and memory functions. Cognitive dysfunction may be exacerbated by mood disturbance, medication and communication problems. In this review we advocate an individualized approach to managing cognitive impairment in progressive supranuclear palsy with the education of caregivers as a central component. Specific cognitive and behavioral treatments are complemented by treatment of mood disturbances, rationalizing medications and a patient-centered approach to communication. This aims to improve patients’ quality of life, reduce carer burden and assist people with progressive supranuclear palsy in decisions about their life and health, including discussions of feeding and end-of-life issues.

Is the frontal dysexecutive syndrome due to a working memory deficit? Evidence from patients with stroke

Although frontal dysexecutive disorders are frequently considered to be due to working memory deficit, this has not been systematically examined and very little evidence is available for impairment of working memory in frontal damage. The objective of this study was to examine the components of working memory, their anatomy and the relations with executive functions in patients with stroke involving the frontal or posterior cortex. The study population consisted of 29 patients (frontal: n=17; posterior: n=12) and 29 matched controls. Phonological loop (letter and word spans, phonological store; rehearsal process), visuospatial sketchpad (visuospatial span) and the central executive (working memory span, dual task and updating process) were examined. The group comparison analysis showed impairment in the frontal group of: (i) verbal spans (P<0.03); (ii) with a deficit of the rehearsal process (P=0.006); (iii) visuospatial span (P=0.04); (iv) working memory span (P=0.001) that disappeared after controlling for verbal span and (v) running memory (P=0.05) unrelated to updating conditions. The clinical anatomical correlation study showed that impairment of the central executive depended on frontal and posterior lesion. Cognitive dysexecutive disorders were observed in 11/20 patients with central executive deficit and an inverse dissociation was observed in two patients. Receiver operating characteristic curve analysis indicated that cognitive dysexecutive disorders had the highest ability to discriminate frontal lesions (area under curve=0.844, 95% confidence interval: 0.74-0.95; P=0.0001; central executive impairment: area under curve=0.732, 95% confidence interval: 0.57-0.82; P=0.006). This study reveals that frontal lesions induce mild impairment of short-term memory associated with a deficit of the rehearsal process supporting the role of the frontal lobe in this process; the central executive depends on lesions in the frontal lobe and posterior regions accounting for its low frequency and the negative results of group studies. Finally, the frontal dysexecutive syndrome cannot be attributed to central executive impairment, although it may contribute to some dysexecutive disorders.

Frontotemporal Dementia Behavioral Variant: Which Factors Underly Caregiver Strain? (P04.225)

Objective: We intended to find out whether severity of dementia, the frontal dysexecutive syndrome, parkinsonian motor symptoms, impaired instrumental activities of daily living (IADL), deficits in the Barthel index or behavioral and neuropsychiatric abnormalities contribute to caregiver strain in frontotemporal dementia behavioral variant (FTDbv). Background FTDbv is characterised by dementia, neuropsychiatric and behavioral abnormalities, sometimes parkinsonian motor symptoms, impaired IADL, and may be associated with substantial caregiver strain. Design/Methods: Consecutive patients with FTDbv and Alzheimer dementia (AD) were evaluated for cognition (CERAD+; frontal assessment battery, FAB, Dubois 2000), IADL (LawtonB Rivermead, Whiting 1980), Barthel Index, parkinsonian motor symptoms (Unified Parkinson Disease Rating Scale, UPDRS) and behavioral abnormalities (Neuropsychiatric inventory, NPI, Cummings 1994; Frontal Behavioral Inventory, FBI, Kertesz 2000). Results: Thirty-three patients with early FTDbv (Neary 1998) and 29 with probable AD (McKhann 1984) were examined. MMSE was similar in both groups (median 22). Age was higher in the AD group (mean 66 versus 75, p Conclusions: Preliminary data of our series confirms previous studies that caregiver strain is more severe in FTDbv than in AD. Behavioral abnormalities, assessed by NPI and FBI, but not severity of dementia or frontal dysexecutive impairment, parkinsonian motor symptoms, impairment in ADL or depression correlate with caregiver strain. FBI and NPI, informant based inventories, correlated to one another and revealed neuropsychiatric symptoms which probably contribute to caregiver strain in FTDbv. Supported by: Jubilaumsfonds of the Austrian National Bank Project number 13240. Disclosure: Dr. Ransmayr has received personal compensation for activities with Abbot, Allergan, Biogen-Idec, Boehringer-Ingelheim, Cephalon, Esai, GSK, Lundbeck, Merck-Serono, Merz, Novartis, The Austrian Neurological Society, The Austrian Parkinson Society, Austrial Alzheimer Society, BAIL, Sanofi-Aventis and UCB as a consultant, speaker, and board member.Dr. Ransmayr has received research support from Abbot, BIAL, Biogen-Idec, Lundbeck, Novartis, Sanofi-Aventis. Dr. Steffelbauer has nothing to disclose. Dr. Schmidegg has nothing to disclose. Dr. Struhal has nothing to disclose.

Vitamin B12 deficiency associated with symptoms of frontotemporal dementia

We report the case of an elderly patient with cobalamin deficiency who progressively developed cognitive and behavioral symptoms associated with neuropsychiatric disturbances. His neuropsychological profile showed many features suggestive for a frontal-dysexecutive syndrome and was related to a predominant asymmetric (right > left) frontal lobe hypoperfusion. He completely recovered after a treatment with vitamin B12 and follow-up of 7 years showed that his improvement remained stable. Along with the other cases reported in the literature, our case also proves that there are some cases of vitamin B12 deficiency that can manifest with the symptoms of frontotemporal dementia and that they are completely reversible after substitution therapy.

Myotonic dystrophies as a brain disorder

In their article, Romeo et al. [1] emphasize that abnormalities in blood perfusion and/or glucose metabolism are frequent in myotonic dystrophy type 1 (DM1 or Steinert’s disease). I would suggest that these abnormalities and others encompass all myotonic dystrophies. Myotonic dystrophies are autosomal dominant multisystem disorders. These include myotonic dystrophy type 1 (Steinert’s disease or DM1) due to an abnormal CTG expansion on chromosome 19 coding for protein kinase DMPK and myotonic dystrophy type 2 (proximal myotonic myopathy, PROMM or DM2), due to an abnormal CCTG expansion on chromosome 3 coding for a zinc finger protein ZNF9. These abnormal nucleotide expansions cause an abnormal accumulation of mRNA which is sequestered within the nucleus by specific binding proteins thus altering mRNA splicing of proteins involved in the disease process [2]. There are clinical, neuropsychological and neuroimaging data that support the hypothesis of central nervous system involvement also in DM2. The typical cognitive and behavioural abnormalities in DM2 are like those of the classical adult form of DM1 but in DM2 these abnormalities are less severe. Patients with DM2 have a frontal dysexecutive syndrome characterized by apathy, reduced initiative and strategic abilities. Yet global cognitive performances are normal as demonstrated by normal IQ and MMSE test scores. Neuropsychological test have demonstrated a selective involvement of visual spatial functions which do not seem to correlate with hyperintense lesions demonstrated on traditional brain MRI sequences or to the degree of cortical atrophy in the frontal and temporal poles, but indicate a selective frontal lobe involvement and a reduction of cerebral blood flow in these regions as documented by H20 PET studies [3–5]. From a behavioural point of view, the patients DM1 and DM2 have an avoidant personality trait, more rarely a passive personality trait [6]. These personality traits imply the patients tend to avoid regular outpatient visits, minimize their muscle symptoms and rarely seek medical attention. It is rather the unaffected family members who will notice difficulties during walking, stumbling and tripping over with an increase in frequency. A distinctive element between DM1 and DM2 is the absence of a congenital form in DM2 and the excessive daytime sleepiness in DM1. Extrapyramidal features like camptocormia have been described in some patients with DM2 and the dopaminergic pathway does not seem to justify extrapyramidal signs and symptoms in these patients [7]. In spite of the findings described above, advances in the study of DM1 and DM2 nervous system require development of better-designed study models. For instance, modelling of transgenic mice expressing CUG expansion RNA under the control of a strong neuronal-specific promoter, will allow the exacerbation of DM1 and DM2 neuronal manifestations. Such mouse models could serve as a basis for complete studies of DM1 and DM2 nervous system including brain anatomy analysis, behaviour and memory test, and molecular and cellular biology approach using brain samples and neuron cell cultures.

Charcot’s arthropathy secondary to herpetic encephalitis sequelae: an unusual presentation

Neuropathic arthropathy (Charcot's arthropathy) is a progressive articular disease associated with a reduced sensorial and protector proprioceptive reflex. Its etiology includes many different conditions such as syringomyelia, traumatic lesion causing medullary deformity, spina bifida, diabetic neuropathy, leprosy neuropathy, neurofibromatosis, amyloid neuropathy, alcohol, and repetitive injection of hydrocortisone into joints, among others. However, the relationship between Charcot's arthropathy and herpetic encephalitis has not yet been described. Herpes encephalitis causes acute and chronic diseases of the peripheral or central nervous system. It can manifest as subacute encephalitis, recurrent meningitis, or myelitis. It can also resemble psychiatric syndromes, diplopia, sensory changes in the face and limbs, personality changes, frontal dysexecutive syndrome, stiff neck, subclinical alterations of the vestibular function, intracranial hypertension, convulsion, hemiparesis, and generally includes motor components, among others. On the other hand, pure peripheral sensory disturbance has not been described. In this article, we report the clinical case of a patient with Charcot's arthropathy secondary to pure peripheral sensory polyneuropathy as a consequence of progressive herpetic encephalitis sequelae. In this article, the authors report the first case of Charcot's arthropathy secondary to herpetic encephalitis.

Neuropsychological consequences of right thalamic haemorrhage: Case study and review

The neuropsychological performance of a right-handed man is examined following haemorrhage from the anterior sections of the right thalamus. A pattern of temporally graded retrograde amnesia, global anterograde amnesia, impaired short-term memory, behavioural changes, and severe executive deficits were identified. The deficits evident in this case are discussed in reference to existing neuropsychological literature regarding the consequences of thalamic infarction. It is proposed that damage to the anterior thalamic nuclei results in a frontal dysexecutive syndrome and that such a dysexecutive syndrome can explain the neuropsychological deficits observed in this case.

Mania caused by a diencephalic lesion

We describe the case of a young male patient, SN, who suffered a MR-documented ischaemic lesion of both dorsomedial thalami and presented with a transient maniform syndrome. SN's neuropsychological, structural and functional imaging findings are compared with similar reported cases and are discussed in the framework of fronto-subcortical circuits and their proposed behavioural disorders. SN's mania was characterized by restlessness, mood elevation, a tendency for pleasurable activities, inflated self-esteem and loss of disease awareness. Other symptoms were sexual disinhibition, tactlessness, abnormal discourse, and reduced need for food and sleep. His neuropsychological assessment revealed an anterograde amnesia, and an impairment of frontal-executive functions. A SPECT-study showed diaschisis-related areas of hypoperfusion in both prefrontal regions which were interpreted as equivalents of SN's frontal-dysexecutive syndrome. In addition, there was a perfusion deficit in the right orbitofrontal cortex, which was taken as the imaging correlate of SN's secondary mania and personality disorder. These findings suggest that SN's mania and his other symptoms result from the twofold disruption of fronto-subcortical connections, namely of the right orbitofrontal loop which is concerned with mood regulation and socially appropriate behaviour, and of the dorsolateral prefrontal loop which mediates executive cognitive functions.

Random number generation in dementia of the Alzheimer type: A test of frontal executive functions

The quality of attempts at generating a random sequence of the numbers 1–6 was studied in 30 patients with dementia of the Alzheimer type (DAT) and 30 elderly normal control (NC) subjects. Three main findings emerged: (1) DAT patients' subjective random sequences were more stereotyped (contained fewer digit combinations) than those of NC subjects. (2) This difference in response stereotypy was due to patients' enhanced tendency to arrange consecutive numbers in an ascending series (‘counting bias’). (3) In the patient group, degree of sequential nonrandomness was positively correlated with overall severity of dementia and with the extent to which performance on neuropsychological tests specifically assessing executive functions (fluency, naming, error monitoring) was impaired. These results illustrate a loss of behavioral complexity in the course of dementia and are interpreted as reflecting a frontal dysexecutive syndrome in DAT.

Frontal amnesia and the dysexecutive syndrome

This study analyzes the memory deficits shown by an amnesic patient with bilateral frontal damage and a dysexecutive syndrome. He resembles a classic amnesic patient in showing grossly impaired episodic memory for both verbal and nonverbal material, together with normal digit span, and on occasion normal recency in free recall. He differs from the classic amnesic pattern however in showing an impairment in both the speed and accuracy of performance on tests of semantic memory, and in clear evidence for impaired performance on some though not all procedural learning tasks. Finally, his autobiographical memory was poor and subject to substantial confabulation. It is suggested that the pattern of deficits is consistent with a combination of a classic amnesic syndrome with the additional problems associated with the frontal dysexecutive syndrome, rather than exhibiting a qualitatively different form of amnesia.