Frontal Lobe Degeneration Research Articles

Degeneration of gray and white matter differs between hypometabolic and hypermetabolic brain regions in a patient with ALS-FTD: a longitudinal MRI − PET multimodal study

Objective [18F]-fluoro-2-deoxy-d-glucose positron emission tomography (18F-FDG PET) imaging and magnetic resonance imaging (MRI) of brain in ALS patients with frontotemporal lobe dementia (ALS-FTD) reveal hypometabolism and hypermetabolism, as well as gray matter (GM) and white matter (WM) abnormalities in different brain regions, respectively. Hypometabolism arising from neuronal dysfunction or loss is the most recognized pathophysiologic change in neurodegeneration, whereas mechanisms underlying hypermetabolism remain unclear. We hypothesize that hypometabolic and hypermetabolic brain regions in ALS-FTD represent differential degeneration of GM and WM structures, as revealed by co-registered MRI in a two time-point longitudinal multimodal study. Methods: A 69-year-old female with ALS-FTD underwent 18F-FDG PET, diffusion tensor imaging (DTI), and T1-weighted MRI at baseline (15 months after symptom onset), and 20.4 months later. Cerebral glucose metabolism rate, cortical thickness, cortical area, and WM network changes were measured longitudinally. Results and conclusion: The patient had symptoms and signs of bulbar-onset upper motor neuron (UMN)-predominant ALS with language and behavioral dysfunction. Evaluation at baseline showed bulbar dysfunction, and impaired language and executive function. At follow-up, worsened bulbar and other motor functions, and prominent FTD both reflected significant progression. Cortical thickness and surface area showed differential involvement in the hypometabolic and hypermetabolic regions. WM connections from frontal regions to other brain regions were completely absent by graph theory-based network analysis when compared to temporal regions indicating prominent frontal lobe degeneration. Structural neuroimaging reveals different patterns of GM and WM involvement in the hypometabolic and hypermetabolic brain regions in a patient with ALS-FTD.

Incidence of frontotemporal disorders in Olmsted County: A population-based study

IntroductionFrontotemporal dementia disorders (FTDs) are heterogeneous phenotypical behavioral and language disorders usually associated with frontal and/or temporal lobe degeneration. We investigated their incidence in a population-based cohort. MethodsUsing a records-linkage system, we identified all patients with a diagnostic code for dementia in Olmsted County, MN, 1995–2010, and confirmed the diagnosis of FTD. A behavioral neurologist verified the clinical diagnosis and determined phenotypes. ResultsWe identified 35 FTD cases. Overall, the incidence of FTDs was 4.3/100,000/year (95% CI: 2.9, 5.7). Incidence was higher in men (6.3/100,000, 95% CI 3.6, 9.0) than women (2.9/100,000; 95% CI: 1.3, 4.5); we observed an increased trend over time (B = 0.83, 95% CI: 0.54, 1.11, P < .001). At autopsy, clinical diagnosis was confirmed in eight (72.7%) cases. DiscussionWe observed an increased incidence and trends of FTDs over time. This may reflect a better recognition by clinicians and improvement of clinical criteria and diagnostic tools.

Detection of Frontotemporal Dementia using Artificial Intelligence Techniques

Atrophy (degeneration) of frontal and temporal lobes in human brain causes a dysfunctionality in Language, Emotion, Executive abilities and these losses are irreversible. If Atrophy is detected at an early age it is beneficial for the patient. A detailed diagnosis of the patient in terms of physical, physiological, psychological and neuropsychological aspects are mandatory to trace the possibility. There is a continuous increase in population of the disease and limited number of specialists. Frontotemporal Dementia (FTD) happens due to the frontal and/or temporal lobe degeneration. The proposed system helps in the identification of the FTD in the brain using various Artificial Intelligence (AI) techniques. The study makes use of the MR brain images for the purpose of the detection of the FTD.

History of Pick's disease

History of Pick's disease

Phenotypic Heterogeneity of Monogenic Frontotemporal Dementia.

Frontotemporal dementia (FTD) is a genetically and pathologically heterogeneous disorder characterized by personality changes, language impairment, and deficits of executive functions associated with frontal and temporal lobe degeneration. Different phenotypes have been defined on the basis of presenting clinical symptoms, i.e., the behavioral variant of FTD, the agrammatic variant of primary progressive aphasia, and the semantic variant of PPA. Some patients have an associated movement disorder, either parkinsonism, as in progressive supranuclear palsy and corticobasal syndrome, or motor neuron disease (FTD–MND). A family history of dementia is found in 40% of cases of FTD and about 10% have a clear autosomal-dominant inheritance. Genetic studies have identified several genes associated with monogenic FTD: microtubule-associated protein tau, progranulin, TAR DNA-binding protein 43, valosin-containing protein, charged multivesicular body protein 2B, fused in sarcoma, and the hexanucleotide repeat expansion in intron 1 of the chromosome 9 open reading frame 72. Patients often present with an extensive phenotypic variability, even among different members of the same kindred carrying an identical disease mutation. The objective of the present work is to review and evaluate available literature data in order to highlight recent advances in clinical, biological, and neuroimaging features of monogenic frontotemporal lobar degeneration and try to identify different mechanisms underlying the extreme phenotypic heterogeneity that characterizes this disease.

Laminar distribution of β-amyloid (Aβ) peptide deposits in the frontal lobe in familial and sporadic Alzheimer's disease.

To determine whether genetic factors influence frontal lobe degeneration in Alzheimer's disease (AD), the laminar distributions of diffuse, primitive, and classic β-amyloid (Aβ) peptide deposits were compared in early-onset familial AD (EO-FAD) linked to mutations of the amyloid precursor protein (APP) or presenilin 1 (PSEN1) gene, late-onset familial AD (LO-FAD), and sporadic AD (SAD). The influence of apolipoprotein E (Apo E) genotype on laminar distribution was also studied. In the majority of FAD and SAD cases, maximum density of the diffuse and primitive Aβdeposits occurred in the upper cortical layers, whereas the distribution of the classic Aβ deposits was more variable, either occurring in the lower layers, or a double-peaked (bimodal) distribution was present, density peaks occurring in upper and lower layers. The cortical layer at which maximum density of Aβ deposits occurred and maximum density were similar in EO-FAD, LO-FAD and SAD. In addition, there were no significant differences in distributions in cases expressing Apo E ε4 alleles compared with cases expressing the ε2 or ε3 alleles. These results suggest that gene expression had relatively little effect on the laminar distribution of Aβ deposits in the frontal lobe of the AD cases studied. Hence, the pattern of frontal lobe degeneration in AD is similar regardless of whether it is associated with APP and PSEN1, mutation, allelic variation in Apo E, or with SAD.

Dramatic impairment of prediction due to frontal lobe degeneration

Prediction is essential for motor function in everyday life. For instance, predictive mechanisms improve the perception of a moving target by increasing eye speed anticipatively, thus reducing motion blur on the retina. Subregions of the frontal lobes play a key role in eye movements in general and in smooth pursuit in particular, but their precise function is not firmly established. Here, the role of frontal lobes in the timing of predictive action is demonstrated by studying predictive smooth pursuit during transient blanking of a moving target in mild frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD) patients. While control subjects and AD patients predictively reaccelerated their eyes before the predicted time of target reappearance, FTLD patients did not. The difference was so dramatic (classification accuracy >90%) that it could even lead to the definition of a new biomarker. In contrast, anticipatory eye movements triggered by the disappearance of the fixation point were still present before target motion onset in FTLD patients and visually guided pursuit was normal in both patient groups compared with controls. Therefore, FTLD patients were only impaired when the predicted timing of an external event was required to elicit an action. These results argue in favor of a role of the frontal lobes in predictive movement timing.

De la maladie de Pick aux démences fronto-temporales

Frontotemporal dementias (FTD) are defined by a gradual change in social conduct, behavior and language, associated with frontal and anterior temporal lobe degeneration. The clinicalfeatures depend on the location of the degenerative process. In the last 20 years, increasingly specific and sensitive operational criteria have been established. Ongoing neuropathological and genetic studies have highlighted overlaps between FTD, motor neuron disease, and atypical parkinsonian syndromes (supranuclear palsy, corticobasal degeneration). They have also provided a better knowledge of the pathophysiology of FTD, and new specific therapeutic targets. These dementias, which usually occur before the age of 65 years, are now better recognized but are still underdiagnosed and often initially mistaken for psychiatric illnesses. Healthcare professionals managing these patients must therefore be better informed Serotonergic agents provide a symptomatic improvement, but environmental adaptation, prevention of language and swallowing difficulties, and information and support for the family and caregivers remain essential.

Genetic Contributors to Frontotemporal Lobar Degeneration: Beyond Monogenic Disease

Frontotemporal Lobar Degeneration (FTLD) is a genetically and pathologically heterogeneous disorder characterized by behavioral change, executive dysfunction and language impairment associated with frontal and temporal lobe degeneration. Three major clinical subtypes have been identified so far, namely behaviour variant Frontotemporal dementia (bvFTD), Semantic Dementia (SD) and Progressive Non-Fluent Aphasia (PNFA). FTLD might also overlap with atypical parkinsonisms or motor neuron disease. Several pathogenetic mutations have been associated with specific pathological and clinical correlates. FTLD associated with either Microtuble Associated Protein Tau (MAPT) or Progranulin (PGRN) mutations is recognised as the most common form of autosomal dominant inherited disorder. However, monogenic mutations account for only about one third of all FTLD cases. Several studies have evaluated the contribution of genetic background in non-monogenic forms of FTLD, with the attempt to establish its role in increasing disease risk and in modulating clinical phenotypes. Specific MAPT and PGRN polymorphisms have been demonstrated to affect disease onset, clinical features and prognosis of FTLD, and genetic variations within other genes appear to play a role in influencing disease risk and clinical expression of FTLD. The aim of the present review is to discuss the impact and the role of genetic background in non-monogenic forms of FTLD, to highlight new potential pathogenetic and therapeutic targets.

Mesial Prefrontal Cortex Degeneration in Amyotrophic Lateral Sclerosis: A High-Field Proton MR Spectroscopy Study

Frontotemporal lobar degeneration is responsible for the cognitive abnormalities seen in patients with ALS. We sought to evaluate the in vivo neurochemical changes associated with this pathology indicative of neuronal loss and gliosis. Twenty-four patients with ALS (2 with ALS-FTD) and 15 healthy controls were studied. High-field proton MR spectroscopy of the mesial prefrontal cortex was used to determine concentrations of NAA and mIns, markers of neuronal integrity and gliosis, respectively. Metabolite concentrations were correlated with cognitive tests (verbal fluency, ACE). NAA/mIns was decreased 17% (P =.002). Abnormalities were present to a lesser degree in the individual metabolites NAA (decreased 9%; P =.08) and mIns (increased 11%; P =.06) than the ratio of the 2 metabolites. These measures did not correlate significantly with verbal fluency or the ACE. Prefrontal lobe degeneration exists in patients with ALS as indicated by an abnormal mesial prefrontal cortex neurochemical profile. Further study is necessary to determine the potential utility of the NAA/mIns ratio as a biomarker for frontal lobe degeneration in ALS.

Hypochondriacal Symptoms as the First Sign of Frontotemporal Dementia

Back to table of contents Previous article Next article LETTERFull AccessHypochondriacal Symptoms as the First Sign of Frontotemporal DementiaÁlvaro Machado M.D.,Sónia Simões M.D.,Álvaro Machado M.D.Search for more papers by this author,Sónia Simões M.D.Search for more papers by this author,Published Online:1 Oct 2010https://doi.org/10.1176/jnp.2010.22.4.451.e3AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Frontotemporal dementia is a clinicopathological entity characterized by prominent changes in behavior and personality resulting from frontal and temporal lobe degeneration. 1 Neuropsychiatric features can be so conspicuous as to completely overshadow cognitive dysfunction, usually leading to diagnostic flaw or delay. 2 Among these, hypochondriacal symptoms can be found, but usually along with other neuropsychiatric core features such as disrupted social and personal conduct, emotional blunting, and striking lack of insight. 3Case ReportA 70-year-old previously healthy woman was seen for progressive behavioral disturbance. Nine years previously she started complaining of having almost all possible diseases. Every time that she saw a documentary or any news article describing a disease, she said she had all its symptoms so she must have the disease. The family started to find this strange because every time she sought medical help and ancillary tests, everything was completely normal. Even stranger was when she feared having completely unusual diseases. On one occasion she thought she had “the blue baby disease” (Fallot tetralogy). There were no other obsessions, and no compulsive behaviors were noticed.Several months after these initial symptoms, the patient started having incomprehensible fears, refused to be left alone, locked all doors and windows, and did not go outside in an overwhelming fear that someone would harm her.Over the next years the frontotemporal dementia picture developed. The patient’s verbal output started to vanish until “she created a kind of a new dialect, [and the family] could only understand some muttered swear-words”; she was sexually uninhibited, impulsive, and aggressive even with her grandchild; and she started to eat without rules, even mayonnaise with butter. She had complete lack of insight to these changes.Upon examination she was coprolalic, inadequate, and perseverant, and all frontal release signs could be easily elicited. A brain MRI showed left-predominant bilateral frontotemporal atrophy, the same region having significant hypoperfusion on SPECT scan. Comprehensive neuropsychological testing was compromised by the striking language dysfunction.Discussion Frontotemporal dementia has been regarded as a clinically and anatomically heterogeneous disorder, and by this way traditionally subdivided in frontal and temporal subtypes by the predominance of behavioral features in the former and of language or semantic knowledge in the latter. 1 Our patient fulfils the proposed criteria for the behavioral variant of frontotemporal dementia. In this, many neuropsychiatric symptoms have been described; the most common are included on the clinical diagnostic criteria for frontotemporal dementia. 4 Hypochondriacal symptoms can on occasion be found in frontotemporal dementia, 3 but they are highly unusual in the first stages of disease and have not been, to our knowledge, reported as the presenting sign. Nevertheless, they preceded by years the diagnosis of Huntington’s disease, 5 and the disruption of fronto-subcortical circuitry seems to be the most reasonable explanation, providing an attractive anatomical background for what we have seen in our patient. Because true hypochondriasis in our patient could not ever be a true diagnostic consideration, the reported case highlights the need to consider this masked diagnosis in all patients presenting with novel and atypical psychiatric symptoms in late life. Neurology Department, Hospital de São Marcos, Braga, PortugalPsychiatry and Mental Health Department, Hospital de São Marcos, Braga, Portugal

Is lesion of Exner's area linked to progressive agraphia in amyotrophic lateral sclerosis with dementia? An autopsy case report.

Agraphia, as a neuropsychological symptom of ALS, especially ALS with dementia (ALS-D), has recently attracted more attention. However, the brain lesion responsible has not been identified. Here we present an autopsy case of ALS-D of a patient with obvious agraphia, without aphasia, that also presented cerebrospinal degeneration with TDP-43-pathology compatible with ALS-D. Of the pre-motor frontal lobe cortices, degeneration and immuno-histochemical pathology were most obvious in the caudal area of the left middle frontal gyrus, or Exner’s area. Assuring this area plays a pivotal role in the kanji and kana formation used in writing the Japanese language, this case of ALS-D showed both agraphia and Exner's area stressed pathological lesions. It may thus be the first case to indicate an intimate relationship between the neuropsychological symptoms and an associated lesion for ALS-D.

Is Lesion of Exner’s Area Linked to Progressive Agraphia in Amyotrophic Lateral Sclerosis with Dementia? An Autopsy Case Report

Agraphia, as a neuropsychological symptom of ALS, especially ALS with dementia (ALS-D), has recently attracted more attention. However, the brain lesion responsible has not been identified. Here we present an autopsy case of ALS-D of a patient with obvious agraphia, without aphasia, that also presented cerebrospinal degeneration with TDP-43-pathology compatible with ALS-D. Of the pre-motor frontal lobe cortices, degeneration and immuno-histochemical pathology were most obvious in the caudal area of the left middle frontal gyrus, or Exner’s area. Assuring this area plays a pivotal role in the kanji and kana formation used in writing the Japanese language, this case of ALS-D showed both agraphia and Exner's area stressed pathological lesions. It may thus be the first case to indicate an intimate relationship between the neuropsychological symptoms and an associated lesion for ALS-D.

Catatonia: Clinical Aspects and Neurobiological Correlates

Catatonia is a neuropsychiatric syndrome that can occur due to medical or psychiatric disorder. This review synthesizes over 20 years of original research and comprehensive review articles with attention to the most recent findings. Though catatonia is common and highly treatable, there have been few research studies investigating the syndrome. Pooled case reports suggest that catatonia due to an underlying general medical condition and catatonia due to a psychiatric illness can be treated similarly and that the catatonic symptoms and the underlying illness must be addressed in both types. Benzodiazepines and ECT continue to be mainstays of treatment. Evidence is mounting for the use of NMDA antagonists in catatonia refractory to lorazepam.

Identification and Characterization of Frontal Lobe Degeneration

This is a historical account of the development of the concept frontotemporal dementia, beginning with our discovery in the late 60s of a simple degenerative form. It was named frontal lobe degeneration of non-Alzheimer type to clearly separate it from the then almost totally dominating diagnosis Alzheimer disease. In the absence of immunohistochemical methods for specific disease markers, we had to rely solely on structural features. Later, from the 80s, the successively introduced methods to show glial acidic protein, tau, synaptophysin, ubiquitin, and other markers confirmed our impression of a simple type of degeneration. These methods also added further forms with additional features, and from the 90s genetics has contributed new disease characteristics, all these advances leading up to the present conceptual structure of frontotemporal lobar degeneration.

Hippocampal sclerosis dementia differs from hippocampal sclerosis in frontal lobe degeneration

Hippocampal sclerosis (HS) is characterized by selective neuronal loss and gliosis in CA1 and the subiculum and has been associated with several disorders, including Alzheimer’s disease, frontotemporal lobar degeneration with ubiquitin immunoreactive inclusions (FTLD-U), vascular dementia and some tauopathies. In some cases, HS is not associated with other degenerative pathologies. Such cases are sometimes referred to as HS dementia (HSD). Differences between HSD and HS in the setting of FTLD-U have not been systematically investigated. To this end, eight cases of HSD and ten cases of HS associated with FTLD-U were studied with Nissl and periodic acid-Schiff stains to assess neuronal loss and corpora amylacea, respectively. Sections were immunostained with antibodies to glial fibrillary acidic protein, HLA-DR and synaptophysin and immunoreactivity was measured with image analysis in CA1 and the subiculum of each case. Additionally, sections were immunostained with antibodies to 4-R tau to determine the presence of argyrophilic grains. HSD was different from HS associated with FTLD-U. Specifically, it was more common in the elderly, and it was associated with more marked neuronal and synaptic loss and with greater reactive gliosis. Corpora amylacea tended to be more frequent in HSD than in FTLD-U, but there was no difference in frequency of argyrophilic grains.

Theory of mind in frontotemporal dementia

Patients with frontotemporal dementia (FTD) exhibit marked changes in social and emotional functioning including lack of empathy, disinhibition, altered emotional reactivity, apathy and lack of insight. These changes are believed to be dependent on progressive frontal and temporal lobe degeneration. In this review, we discuss the nature of defective theory of mind and empathy in this group and relate it to regional dysfunction in the orbitofrontal and medial prefrontal cortex, based on evidence from several recent studies. The role of executive ability and co-existing emotional deficits are also considered.

Neuropathological changes in ten cases of neuronal intermediate filament inclusion disease (NIFID): a study using α-internexin immunohistochemistry and principal components analysis (PCA)

Ten cases of neuronal intermediate filament inclusion disease (NIFID) were studied quantitatively. The alpha-internexin positive neurofilament inclusions (NI) were most abundant in the motor cortex and CA sectors of the hippocampus. The densities of the NI and the swollen achromatic neurons (SN) were similar in laminae II/III and V/VI but glial cell density was greater in V/VI. The density of the NI was positively correlated with the SN and the glial cells. Principal components analysis (PCA) suggested that PC1 was associated with variation in neuronal loss in the frontal/temporal lobes and PC2 with neuronal loss in the frontal lobe and NI density in the parahippocampal gyrus. The data suggest: 1) frontal and temporal lobe degeneration in NIFID is associated with the widespread formation of NI and SN, 2) NI and SN affect cortical laminae II/III and V/VI, 3) the NI and SN affect closely related neuronal populations, and 4) variations in neuronal loss and in the density of NI were the most important sources of pathological heterogeneity.

Metallothionein-I-II and GFAP positivity in the brains from frontotemporal dementia patients

Frontotemporal dementia regards a group of presenile progressive neurodegenerative form of dementias which includes Pick's disease, corticobasal degeneration, frontotemporal dementia with motor neuron disease, frontal lobe degeneration, dementia-parkinsonism-amyotrophy complex, familial non-specific dementia mapping to chromosome 3, non-Alzheimer degenerative dementia lacking distinctive histological features as well as a number other infrequent syndromes with dementia and focal neurological signs. The aim of this study was to investigate the regional distribution of metallothionein-I-II, an ubiquitary group of buffering proteins, in cases of frontotemporal dementia. The aim of the present study was to study the metallothionein-I-II expression in relationship to the expression in astrocytes of glial fibrillary acidic protein (GFAP) as we have already done in previous studies of Alzheimer's and Binswanger's diseases [31,32]. Our findings indicate that metallothionein-I-II expression in the most affected areas is likely to be regionally distinct and layer-dependent, in that it is highest in the deep layers of the frontotemporal cortex and the allocortex (hippocampus) while insignificantly immunopositive in the occipital cortex. In addition, the potential use of metallothionein-I-II as a new pharmacological approach to contrast some deleterious aspects of this disease has been also discussed.

Inhibitory attentional control in patients with frontal lobe damage

The performance of a group of frontal lobe lesion and a group of frontal lobe dementia patients was compared with the performance of their respective matched normal control groups on two tests of inhibitory attentional control—the stop-signal reaction time task and a negative priming task. Both patient groups responded significantly slower than their respective normal control groups, but they showed only marginally significant selective impairments on the measures of inhibition. The data suggest that the specific inhibitory processes evaluated by these two tests are, in general, spared in patients with focal frontal lobe lesions or frontal lobe degeneration.