La atrofia cerebral como hallazgo o factor predictor del deterioro cognitivo en el envejecimiento normal / Cerebral Atrophy as a Finding of Predictive Factor for Cognitive Impairment in Normal Aging

Introducción: En el curso del envejecimiento es conocida la existencia de un patrón complejo de cambios estructurales cerebrales, conductuales y cognitivos, en ocasiones relacionados con enfermedades neurológicas y psiquiátricas. Objetivo: Determinar la posible relación de causalidad de la atrofia cerebral en la aparición del deterioro cognitivo en el curso del envejecimiento normal. Métodos: Se desarrolló un estudio retrospectivo, transversal, descriptivo y observacional. El universo estuvo conformado por el total de los pacientes de ambos sexos con edades comprendidas entre 35-74 años de edad, con indicaciones previas de tomografía computarizada de cráneo y cuyos resultados fueron informados con signos de atrofia cerebral, cuya cifra ascendió a 733. Resultados: El grupo de edad que predomino fue el de 45-54 años (35,3 por ciento), así como las pacientes del sexo femenino (66,3 por ciento). El 27,7 por ciento tenía como nivel de escolaridad el técnico medio superior y 36,2 por ciento fueron pacientes amas de casa. El 99,7 por ciento fueron diestros. Un total de 368 voluntarios presentaron deterioro cognitivo y 365 sujetos no evidenciaron declive en las funciones exploradas. Las funciones de atención y cálculo y retención verbal a corto plazo fueron las que se vieron más afectadas, seguidas de orientación espacial y memoria verbal de fijación. Conclusiones: No se logró establecer una relación de causalidad significativa entre el diagnóstico radiológico de atrofia cerebral y la presencia de deterioro cognitivo(AU)

Introduction: In the course of aging, the existence of a complex pattern of behavioral, cognitive and cerebral structural changes is known, sometimes related to neurological and psychiatric diseases. Objective: To determine the possible causal relationship of cerebral atrophy with the onset of cognitive impairment in the course of normal aging. Methods: A retrospective, cross-sectional, descriptive and observational study was carried out. The study universe consisted of all patients of both sexes aged 35-74 years, with previous indications for cranial computed tomography and whose results were reported with signs of cerebral atrophy, which numbered 733. Results: The predominant age group was 45-54 years old (35.3percent), as well as female patients (66.3percent). The educational level of 27.7percent of the patients was technical high school and 36.2percent were housewife patients. A total of 99.7percent were right-handed. A total of 368 volunteers showed cognitive impairment and 365 subjects showed no decline in the tested functions. The functions of attention and calculation, as well as short-term verbal retention, were the most affected, followed by spatial orientation and speech retention memory. Conclusions: No significant causal relationship was established between the radiological diagnosis of cerebral atrophy and the presence of cognitive impairment(AU)

Clinical, neuroimaging, and neuropathological characterization of a patient with Alzheimer's disease syndrome due to Pick's pathology.

The most common neurodegenerative syndrome associated with Pick's disease pathology (PiD) is behavioral variant frontotemporal dementia (bvFTD), which features profound social behavioral changes. Rarely, PiD can manifest as an Alzheimer's disease (AD)-type dementia with early memory impairment. We describe a patient with AD-type dementia and pure PiD pathology who showed slowly progressive memory impairment, early social changes, and paucity of motor symptoms. Atrophy and PiD were found mainly in frontotemporal regions underlying social behavior. This report may help predict the pathology of patients with atypical AD, which will ultimately be critical for enrolling suitable subjects into disease-modifying clinical trials.

Downstream effects of polypathology on neurodegeneration of medial temporal lobe subregions.

The medial temporal lobe (MTL) is a nidus for neurodegenerative pathologies and therefore an important region in which to study polypathology. We investigated associations between neurodegenerative pathologies and the thickness of different MTL subregions measured using high-resolution post-mortem MRI. Tau, TAR DNA-binding protein 43 (TDP-43), amyloid-ß and α-synuclein pathology were rated on a scale of 0 (absent)-3 (severe) in the hippocampus and entorhinal cortex (ERC) of 58 individuals with and without neurodegenerative diseases (median age 75.0 years, 60.3% male). Thickness measurements in ERC, Brodmann Area (BA) 35 and 36, parahippocampal cortex, subiculum, cornu ammonis (CA)1 and the stratum radiatum lacunosum moleculare (SRLM) were derived from 0.2 × 0.2 × 0.2 mm3 post-mortem MRI scans of excised MTL specimens from the contralateral hemisphere using a semi-automated approach. Spearman's rank correlations were performed between neurodegenerative pathologies and thickness, correcting for age, sex and hemisphere, including all four proteinopathies in the model. We found significant associations of (1) TDP-43 with thickness in all subregions (r = - 0.27 to r = - 0.46), and (2) tau with BA35 (r = - 0.31) and SRLM thickness (r = - 0.33). In amyloid-ß and TDP-43 negative cases, we found strong significant associations of tau with ERC (r = - 0.40), BA35 (r = - 0.55), subiculum (r = - 0.42) and CA1 thickness (r = - 0.47). This unique dataset shows widespread MTL atrophy in relation to TDP-43 pathology and atrophy in regions affected early in Braak stageing and tau pathology. Moreover, the strong association of tau with thickness in early Braak regions in the absence of amyloid-ß suggests a role of Primary Age-Related Tauopathy in neurodegeneration.

Diagnostic Accuracy of Amyloid versus 18 F-Fluorodeoxyglucose Positron Emission Tomography in Autopsy-Confirmed Dementia.

OBJECTIVE: The purpose of this study was to compare the diagnostic accuracy of antemortem 11 C-Pittsburgh compound B (PIB) and 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET) versus autopsy diagnosis in a heterogenous sample of patients. METHODS: One hundred one participants underwent PIB and FDG PET during life and neuropathological assessment. PET scans were visually interpreted by 3 raters blinded to clinical information. PIB PET was rated as positive or negative for cortical retention, whereas FDG scans were read as showing an Alzheimer disease (AD) or non-AD pattern. Neuropathological diagnoses were assigned using research criteria. Majority visual reads were compared to intermediate-high AD neuropathological change (ADNC). RESULTS: One hundred one participants were included (mean age = 67.2 years, 41 females, Mini-Mental State Examination = 21.9, PET-to-autopsy interval = 4.4 years). At autopsy, 32 patients showed primary AD, 56 showed non-AD neuropathology (primarily frontotemporal lobar degeneration [FTLD]), and 13 showed mixed AD/FTLD pathology. PIB showed higher sensitivity than FDG for detecting intermediate-high ADNC (96%, 95% confidence interval [CI] = 89-100% vs 80%, 95% CI = 68-92%, p = 0.02), but equivalent specificity (86%, 95% CI = 76-95% vs 84%, 95% CI = 74-93%, p = 0.80). In patients with congruent PIB and FDG reads (77/101), combined sensitivity was 97% (95% CI = 92-100%) and specificity was 98% (95% CI = 93-100%). Nine of 24 patients with incongruent reads were found to have co-occurrence of AD and non-AD pathologies. INTERPRETATION: In our sample enriched for younger onset cognitive impairment, PIB-PET had higher sensitivity than FDG-PET for intermediate-high ADNC, with similar specificity. When both modalities are congruent, sensitivity and specificity approach 100%, whereas mixed pathology should be considered when PIB and FDG are incongruent. ANN NEUROL 2021;89:389-401.

Longitudinal anatomic, functional, and molecular characterization of Pick disease phenotypes.

OBJECTIVE: To characterize longitudinal MRI and PET abnormalities in autopsy-confirmed Pick disease (PiD) and determine how patterns of neurodegeneration differ with respect to clinical syndrome. METHODS: Seventeen patients with PiD were identified who had antemortem MRI (8 with behavioral variant frontotemporal dementia [bvFTD-PiD], 6 with nonfluent/agrammatic primary progressive aphasia [naPPA-PiD], 1 with semantic primary progressive aphasia, 1 with unclassified primary progressive aphasia, and 1 with corticobasal syndrome). Thirteen patients had serial MRI for a total of 56 MRIs, 7 had [18F]fluorodeoxyglucose PET, 4 had Pittsburgh compound B (PiB) PET, and 1 patient had [18F]flortaucipir PET. Cross-sectional and longitudinal comparisons of gray matter volume and metabolism were performed between bvFTD-PiD, naPPA-PiD, and controls. Cortical PiB summaries were calculated to determine ß-amyloid positivity. RESULTS: The bvFTD-PiD and naPPA-PiD groups showed different foci of volume loss and hypometabolism early in the disease, with bvFTD-PiD involving bilateral prefrontal and anterior temporal cortices and naPPA-PiD involving left inferior frontal gyrus, insula, and orbitofrontal cortex. However, patterns merged over time, with progressive spread into prefrontal and anterior temporal lobe in naPPA-PiD, and eventual involvement of posterior temporal lobe, motor cortex, and parietal lobe in both groups. Rates of frontotemporal atrophy were faster in bvFTD-PiD than naPPA-PiD. One patient was ß-amyloid-positive on PET with low Alzheimer neuropathologic changes at autopsy. Flortaucipir PET showed elevated uptake in frontotemporal white matter. CONCLUSION: Patterns of atrophy and hypometabolism differ in PiD according to presenting syndrome, although patterns of neurodegeneration appear to converge over time.

Pick's Tau Fibril Shows Multiple Distinct PET Probe Binding Sites: Insights from Computational Modelling.

In recent years, it has been realized that the tau protein is a key player in multiple neurodegenerative diseases. Positron emission tomography (PET) radiotracers that bind to tau filaments in Alzheimer's disease (AD) are in common use, but PET tracers binding to tau filaments of rarer, age-related dementias, such as Pick's disease, have not been widely explored. To design disease-specific and tau-selective PET tracers, it is important to determine where and how PET tracers bind to tau filaments. In this paper, we present the first molecular modelling study on PET probe binding to the structured core of tau filaments from a patient with Pick's disease (TauPiD). We have used docking, molecular dynamics simulations, binding-affinity and tunnel calculations to explore TauPiD binding sites, binding modes, and binding energies of PET probes (AV-1451, MK-6240, PBB3, PM-PBB3, THK-5351 and PiB) with TauPiD. The probes bind to TauPiD at multiple surface binding sites as well as in a cavity binding site. The probes show unique surface binding patterns, and, out of them all, PM-PBB3 proves to bind the strongest. The findings suggest that our computational workflow of structural and dynamic details of the tau filaments has potential for the rational design of TauPiD specific PET tracers.

A case of semantic variant primary progressive aphasia with Pick's pathology.

Neurodegenerative diseases are caused by aggregation of specific proteins that catalyze a cascade of changes that ultimately lead to neurodegeneration. This concept guides current diagnostic approaches, as well as clinical trials, that focus on detecting or removing amyloid or tau from the brain. The semantic variant of primary progressive aphasia (svPPA), a clinical syndrome associated with frontotemporal lobar degeneration (FTLD) pathology, is usually associated with the molecular pathology TDP-C, but there are cases with TDP-B and Pick's disease. The existing literature on the clinical differentiation of these pathologies is limited. Here, we present a case study, in conjunction with a cross-sectional voxel-based morphometry (VBM), to elucidate the clinical and imaging features of a patient with svPPA due to Pick's disease.

Clinicopathological correlations in behavioural variant frontotemporal dementia.

Accurately predicting the underlying neuropathological diagnosis in patients with behavioural variant frontotemporal dementia (bvFTD) poses a daunting challenge for clinicians but will be critical for the success of disease-modifying therapies. We sought to improve pathological prediction by exploring clinicopathological correlations in a large bvFTD cohort. Among 438 patients in whom bvFTD was either the top or an alternative possible clinical diagnosis, 117 had available autopsy data, including 98 with a primary pathological diagnosis of frontotemporal lobar degeneration (FTLD), 15 with Alzheimer's disease, and four with amyotrophic lateral sclerosis who lacked neurodegenerative disease-related pathology outside of the motor system. Patients with FTLD were distributed between FTLD-tau (34 patients: 10 corticobasal degeneration, nine progressive supranuclear palsy, eight Pick's disease, three frontotemporal dementia with parkinsonism associated with chromosome 17, three unclassifiable tauopathy, and one argyrophilic grain disease); FTLD-TDP (55 patients: nine type A including one with motor neuron disease, 27 type B including 21 with motor neuron disease, eight type C with right temporal lobe presentations, and 11 unclassifiable including eight with motor neuron disease), FTLD-FUS (eight patients), and one patient with FTLD-ubiquitin proteasome system positive inclusions (FTLD-UPS) that stained negatively for tau, TDP-43, and FUS. Alzheimer's disease was uncommon (6%) among patients whose only top diagnosis during follow-up was bvFTD. Seventy-nine per cent of FTLD-tau, 86% of FTLD-TDP, and 88% of FTLD-FUS met at least 'possible' bvFTD diagnostic criteria at first presentation. The frequency of the six core bvFTD diagnostic features was similar in FTLD-tau and FTLD-TDP, suggesting that these features alone cannot be used to separate patients by major molecular class. Voxel-based morphometry revealed that nearly all pathological subgroups and even individual patients share atrophy in anterior cingulate, frontoinsula, striatum, and amygdala, indicating that degeneration of these regions is intimately linked to the behavioural syndrome produced by these diverse aetiologies. In addition to these unifying features, symptom profiles also differed among pathological subtypes, suggesting distinct anatomical vulnerabilities and informing a clinician's prediction of pathological diagnosis. Data-driven classification into one of the 10 most common pathological diagnoses was most accurate (up to 60.2%) when using a combination of known predictive factors (genetic mutations, motor features, or striking atrophy patterns) and the results of a discriminant function analysis that incorporated clinical, neuroimaging, and neuropsychological data.

Apathy and impulsivity in frontotemporal lobar degeneration syndromes.

Apathy and impulsivity are common and disabling consequences of frontotemporal lobar degeneration. They cause substantial carer distress, but their aetiology remains elusive. There are critical limitations to previous studies in this area including (i) the assessment of either apathy or impulsivity alone, despite their frequent co-existence; (ii) the assessment of behavioural changes within single diagnostic groups; and (iii) the use of limited sets of tasks or questions that relate to just one aspect of these multifactorial constructs. We proposed an alternative, dimensional approach that spans behavioural and language variants of frontotemporal dementia, progressive supranuclear palsy and corticobasal syndrome. This accommodates the commonalities of apathy and impulsivity across disorders and reveals their cognitive and anatomical bases. The ability to measure the components of apathy and impulsivity and their associated neural correlates across diagnostic groups would provide better novel targets for pharmacological manipulations, and facilitate new treatment strategies and strengthen translational models. We therefore sought to determine the neurocognitive components of apathy and impulsivity in frontotemporal lobar degeneration syndromes. The frequency and characteristics of apathy and impulsivity were determined by neuropsychological and behavioural assessments in 149 patients and 50 controls from the PIck's disease and Progressive supranuclear palsy Prevalence and INcidence study (PiPPIN). We derived dimensions of apathy and impulsivity using principal component analysis and employed these in volumetric analyses of grey and white matter in a subset of 70 patients (progressive supranuclear palsy, n = 22; corticobasal syndrome, n = 13; behavioural variant, n = 14; primary progressive aphasias, n = 21) and 27 control subjects. Apathy and impulsivity were present across diagnostic groups, despite being criteria for behavioural variant frontotemporal dementia alone. Measures of apathy and impulsivity frequently loaded onto the same components reflecting their overlapping relationship. However, measures from objective tasks, patient-rated questionnaires and carer-rated questionnaires loaded onto separate components and revealed distinct neurobiology. Corticospinal tracts correlated with patients' self-ratings. In contrast, carer ratings correlated with atrophy in established networks for goal-directed behaviour, social cognition, motor control and vegetative functions, including frontostriatal circuits, orbital and temporal polar cortex, and the brainstem. Components reflecting response inhibition deficits correlated with focal frontal cortical atrophy. The dimensional approach to complex behavioural changes arising from frontotemporal lobar degeneration provides new insights into apathy and impulsivity, and the need for a joint therapeutic strategy against them. The separation of objective tests from subjective questionnaires, and patient from carer ratings, has important implications for clinical trial design.awx101media15448041163001.

Decreased cerebrospinal fluid Abeta(42) correlates with brain atrophy in cognitively normal elderly.

OBJECTIVE: For therapies for Alzheimer's disease (AD) to have the greatest impact, it will likely be necessary to treat individuals in the "preclinical" (presymptomatic) stage. Fluid and neuroimaging measures are being explored as possible biomarkers of AD pathology that could aid in identifying individuals in this stage to target them for clinical trials and to direct and monitor therapy. The objective of this study was to determine whether cerebrospinal fluid (CSF) biomarkers for AD suggest the presence of brain damage in the preclinical stage of AD. METHODS: We investigated the relation between structural neuroimaging measures (whole-brain volume) and levels of CSF amyloid-beta (Abeta)(40), Abeta(42), tau, and phosphorylated tau(181) (ptau(181)), and plasma Abeta(40) and Abeta(42) in well-characterized research subjects with very mild and mild dementia of the Alzheimer type (n = 29) and age-matched, cognitively normal control subjects (n = 69). RESULTS: Levels of CSF tau and ptau(181), but not Abeta(42), correlated inversely with whole-brain volume in very mild and mild dementia of the Alzheimer type, whereas levels of CSF Abeta(42), but not tau or ptau(181), were positively correlated with whole-brain volume in nondemented control subjects. INTERPRETATION: Reduction in CSF Abeta(42), likely reflecting Abeta aggregation in the brain, is associated with brain atrophy in the preclinical phase of AD. This suggests that there is toxicity associated with Abeta aggregation before the onset of clinically detectable disease. Increases in CSF tau (and ptau(181)) are later events that correlate with further structural damage and occur with clinical onset and progression.

[Diagnostic difficulties linked to frontotemporal dementia--case study]. / Trudnosci diagnostyczne otepienia czolowo-skroniowego--opis przypadku.

The authors present the case study of a 47-year-old woman affected by frontotemporal dementia with a 19-year history of mental disorders. Due to increasing intensity of affective and behavioural disorders and spontaneous suicidal attempts the patient was hospitalized 14 times in psychiatric wards. Despite the treatment with drugs of different groups was conducted, no stable positive outcome was obtained.

Slow wave and rem sleep mechanisms are differently altered in hereditary pick disease associated with the TAU G389R mutation.

Sleep disturbances are found in the course of most dementing syndromes. We report a longitudinal polysomnographic and 18FDG-PET study in a 38-year-old male with FTDP17 carrying the Tau gene mutation G389R. All-night sleep EEG and wake cerebral glucose metabolism at rest (eyes/ears covered) of the preceding day were studied twice, eight months (Night 1; PET 1) and sixteen months (Night 2; PET 2) after the initial neurological evaluation. The Night 1 study showed sleep fragmentation associated to a short REM latency and a severe reduction of slow wave sleep, with relatively preserved NREM-REM sleep cycles; daytime PET 1 revealed severe cerebral glucose metabolic reductions in frontal and temporal areas, with relative preservation of remaining cortical regions and subcortical structures. On Night 2, the total sleep time was less than 5 hours, delta sleep and REM latency remained shortened and only two sleep cycles could be identified; daytime PET 2 exam revealed a greater cortical metabolic impairment and an involvement of subcortical brain regions as compared to PET 1. Post-mortem neuropathological data showed severe neuronal loss, spongiosis and gliosis that were mostly marked in cortical layers I, II, V and VI. In vivo, neurometabolic and post-mortem neuropathological data are consistent with and indicative of a severe dysfunction of intra- and trans-hemispheric regional connectivity and of cortico-thalamic circuits. These findings suggest that the decreased cortical and subcortical connectivity may have been the main pathophysiological mechanism responsible for delta sleep reduction and the cognitive decline.

The role of PET imaging in the management of patients with central nervous system disorders.

PET will continue to play a critical role in both clinical and research applications with regard to CNS disorders. PET is useful in the initial diagnosis of patients presenting with CNS symptoms and can help clinicians determine the best course of therapy. PET studies can also be useful for studying the response to therapy. From the research perspective, the various neurotransmitter and other molecular tracers currently available or in development will provide substantial information about pathophysiologic process in the brain. As such applications become more widely tested, their introduction into the clinical arena will further advance the use of PET imaging in the evaluation and management of CNS disorders.

[Algorithm for automatic quantification of brain atrophy with computed tomography].

In this paper, a new, fully-automatic method for the quantification of brain atrophy based on CT volume data is put forward by taking advantage of the characteristics of cerebral CT images in combination with the prior medical knowledge. This algorithm has been verified through the calculation of 2388 cases of normal and brain atrophy subjects.

Primary progressive aphasia and Pick complex.

Ten autopsied patients from a prospectively followed, clinically defined, neuropsychologically and radiologically documented cohort with primary progressive aphasia were histologically characterized. All were variants of frontotemporal degeneration (Pick complex): Pick body dementia, n=3, corticobasals degeneration (CBD), n=4, and tau and synuclein negative ubiquitinated inclusions of the motor neuron disease type, n=3. All shared superficial cortical spongiosis, neuronal loss, and gliosis. Although most patients had fluent anomic aphasia at onset, all progressed to a nonfluent or mute state. Comprehension, episodic memory, and activities of daily living were initially preserved. Three cases with Pick body dementia had verbal apraxia and stuttering at onset. Two of the patients with CBD pathology were older than the average primary progressive aphasia (PPA). All patients developed secondary syndromes either of frontotemporal dementia (FTD) and/or extrapyramidal-apraxic manifestations (CBD). By the time autopsy was obtained, the pathology appeared outside the language areas. Progressive aphasias secondary to Alzheimer's disease (AD) were excluded on the basis of early loss of memory and comprehension.Rather than the previously emphasized histological heterogeneity, clinically probable PPA has a predictive value of a group of related pathologies, collectively named frontotemporal degeneration, or Pick complex. This series of autopsied cases provides evidence for the clinical and pathological overlap of PPA with FTD and CBD, and contributes to the diagnostic and neuropsychological definition of PPA.

Clinicopathological study of two subtypes of Pick's disease in Japan.

We examined the clinical and neuropathological findings in 3 cases of Pick's disease with Pick bodies (PiD) and 7 cases of atypical Pick's disease without Pick bodies (aPiD). PiD and aPiD cases corresponded clinically to frontotemporal dementia and semantic dementia, respectively, based on the clinical diagnostic criteria of frontotemporal lobar degeneration. Brain CT showed that cerebral atrophy was accentuated at an early stage of the illness in the anterior portion of the frontal lobes in PiD cases and in the anterior portion of the temporal lobes in aPiD cases. Neuropathologically, PiD cases showed more circumscribed lobar atrophy than aPiD cases. Both PiD and aPiD cases revealed moderate to severe degeneration with neuronal loss and gliosis in the affected cerebral cortex and subcortical nuclei, but only aPiD cases had pyramidal tract degeneration. Immunohistochemical analyses demonstrated that tauopathy with phosphorylated tau accumulation in the Pick bodies in PiD cases, while aPiD cases showed ubiquitinopathy with ubiquitin accumulation in the intraneuronal and dendritic inclusions. These findings suggested that two subtypes of Pick's disease in Japan can be distinguished not only neuropathologically but also clinically based on differences in pathogenesis.

Argyrophilic grain disease mimicking temporal Pick's disease: a clinical, radiological, and pathological study of an autopsy case with a clinical course of 15 years.

This report concerns an autopsy case of argyrophilic grain disease (AGD) mimicking temporal Pick's disease. The patient was a Japanese woman without hereditary burden who was 89 years old at the time of death. She developed memory impairment and began wandering at the age of 74, followed by prominent character changes about 6 years after disease onset. A neurological examination 5 months before her death revealed poor rapport, unconcern, severe dementia, and double incontinence, without aphasia or muscle rigidity. Serial neuroradiological examination revealed progressive enlargement of the bilateral inferior horns of the lateral ventricle, reflecting progressive atrophy of the medial temporal lobes. Macroscopically, neuropathological examination showed circumscribed atrophy of the bilateral amygdalae, hippocampi, parahippocampal gyri, and lateral occipitotemporal gyri. Histologically, there was neuronal loss in the areas mentioned above, the caudate nucleus, putamen, thalamus, substantia nigra, and locus ceruleus, with ballooned neurons in the cerebral cortex and amygdala. Numerous argyrophilic grains with coiled bodies were present not only in the limbic system, but also in the affected cerebrum. Rare neurofibrillary changes were present in the limbic areas, consistent with Braak stage II, with no senile plaques. Based on these findings and a review of the literature, we note that AGD is clinicopathologically similar not only to mesolimbocortical dementia, but also to atypical senile dementia of Alzheimer type. This report may contribute to the elucidation of the clinicopathological hallmarks of AGD.

Combined semantic dementia and apraxia in a patient with frontotemporal lobar degeneration.

In this study we report neuropsychological and brain-imaging findings in a patient with frontotemporal lobar degeneration. Brain imaging using registration of (18)fluorodeoxyglucose (FDG)-PET data to three-dimensional (3-D) magnetic resonance imaging showed atrophy and highly significant hypometabolism of the left temporal lobe and both frontal lobes. Volumetric measurements of the hippocampi/amygdala showed a reduction in volume of 25% on the left compared to right within cortical areas. Neuropsychological testing revealed semantic dementia with severe anomia as well as apraxia with impairment of both recognition and production of motor acts. The implications of this case of early manifestation of frontotemporal lobar degeneration for our knowledge of dementia are discussed.

Massive impairment in executive functions with partial preservation of other cognitive functions: the case of a young patient with severe degeneration of the prefrontal cortex.

Historical bases for the special role of the prefrontal cortex are outlined and the case of a 27-year-old woman with massive bilateral prefrontal damage of unknown etiology is then described. Frontal lobe degeneration was repeatedly examined with magnetic resonance imaging and fluoro-deoxy-D-glucose-positron emission tomography and was found to include both orbital and dorsolateral aspects of the frontal lobes. While the degeneration initially measured was limited to portions of the orbital, medial and dorsolateral parts of both frontal lobes, with right-sided predominance, a second brain scan 15 months later revealed massive shrinkage of both frontal lobes, together with additional involvement of the posterior association cortices. The patient had completed her high-school education and had superior verbal long-term memory, normal short-term memory, and normal priming, but manifested grossly deficient scores in various frontal lobe-sensitive tests. Though a number of neurological examinations were performed, no plausible cause for the damage was established.