Marchiafava-Bignami disease: why not Marchiafava-Bignami-Carducci disease?

The Marchiafava-Bignami disease has a curious backstory, namely, the publication in 1898 of the Contribution to the Study of Nonsuppurative Encephalitis (Carducci A in Riv Psicol Psichiat Neuropat 8-9:125-135, 1898), in which the neo-graduate Agostino Carducci described the disease that the pathologists Ettore Marchiafava and Amico Bignami would report 5 years later.

Delirium and Dementia in the Elderly: Sometimes Associated or Always Together?

BACKGROUND: In the elderly, the association of delirium and dementia can cause diagnostic problems because they share the same symptom of confusion. Delirium is often misdiagnosed as dementia and treated inappropriately, ignoring that it could be successfully addressed, which can lead to increased health risks up to death. SUMMARY: Confusion indicates that functional reserve fails to compensate for the action of stressors. The decline in reserve is linked to aging-related changes in blood flow, mitochondria, cerebrospinal fluid, and immune function, as well as the appearance of structural precursors of disease. It is greater in dementia that adds a large burden of pathology, especially degenerative and vascular. KEY MESSAGES: Based on their common background linking normal and pathological brain aging, it can be argued that delirium and dementia are always associated to some extent and can aggravate each other. The clinical approach to their association, which currently relies on the preliminary diagnosis of delirium according to ad hoc protocols, could be simplified by taking delirium for granted so that its causative stressors, usually the most common diseases of old age and/or drug abuse, could be addressed immediately. This approach would benefit all demented patients: not only those who are in such a serious condition that they need to be hospitalized due to the risk of death, but also those with clouded delirium.

The cognitive phenotypes of Creutzfeldt-Jakob disease: comparison with secondary metabolic encephalopathy.

BACKGROUND: Rapidly progressive cognitive impairment is a diagnostic criterion in Creutzfeldt-Jakob disease (CJD), but the diagnosis is usually reached when an analysis of cognitive aspects is no longer possible. OBJECTIVE: This study aims to delineate the cognitive phenotypes preceding severe dementia in CJD compared to secondary metabolic encephalopathies (SME) with rapid cognitive impairment. METHODS: Patients with rapidly progressive neurological symptoms underwent neuropsychological evaluation, analysis of cerebrospinal fluid (CSF) and codon 129 polymorphism of the prion protein gene (PRNP), magnetic resonance imaging (MRI), and single positron emission computed tomography (99mTcSPECT). CSF real-time quaking-induced conversion analysis was applied in CJD patients. Based on literature and clinical expertise, cognitive profiles were correlated with brain areas. RESULTS: Thirty-one patients were diagnosed with CJD (n = 17) or SME; 77 cases of CJD were extracted from the literature. In patients with CJD, verbal initiative, lexical search, long-term memory, attention, and abstract reasoning were the most frequently impaired abilities. Cognitive profiles were mainly related to dysfunction in fronto-temporal areas. Furthermore, they were consistent with areas of hypoperfusion detected by 99mTc SPECT in six patients and cortical and subcortical MRI hyperintensities in eight and 14 patients, respectively, and were similar to those described in the literature. In contrast, cognitive profiles were different from those in SME characterized by visuospatial and constructive deficits relating to posterior brain areas. CONCLUSION: In CJD, clinical and neuropsychological analyses outline a salient cognitive phenotype suggestive of fronto-temporal dysfunction preceding severe dementia. This phenotype is different from that observed in other rapidly progressive encephalopathies.

Why is delirium more frequent in the elderly?

An aging-related reduction in the brain's functional reserve may explain why delirium is more frequent in the elderly than in younger people insofar as the reserve becomes inadequate to cover the metabolic requirements that are critically increased by stressors. The aim of this paper is to review the normal aging-related changes that theoretically compromise complex mental activities, neuronal and synaptic densities, and the neurocomputational flexibility of the functional reserve. A pivotal factor is diminished connectivity, which is substantially due to the loss of synapses and should specifically affect association systems and cholinergic fibres in delirious patients. However, micro-angiopathy with impaired blood flow autoregulation, increased blood/brain barrier permeability, changes in cerebrospinal fluid dynamics, weakened mitochondrial performance, and a pro-inflammatory involution of the immune system may also jointly affect neurons and their synaptic assets, and even cause the progression of delirium to dementia regardless of the presence of co-existing plaques, tangles, or other pathological markers. On the other hand, the developmental growth in functional reserve during childhood and adolescence makes the brain increasingly resistant to delirium, and residual reserve can allow the elderly to recover. These data support the view that functional reserve is the variable that confronts stressors and governs the risk and intensity of and recovery from delirium. Although people of any age are at risk of delirium, the elderly are at greater risk because aging and age-dependent structural changes inevitably affect the brain's functional reserve.

Deciphering delirium through semantics: a selective synopsis.

During the course of the more than 2000 years of its recorded history, delirium has been given a very large number of different names, including phrenitis and paraphrenitis, mania and délire maniaque, (febrile, agitated, asthenic, lethargic, reversible toxic, symptomatic, exogenous) psychosis, inattention, acute and reversible dementia and insanity, amentia and sensorial phrenosis, reversible cognitive dysfunction, paralepsia, confusion and mental confusion, disorientation, dysergasia, and incoherence. Such a wide range of names with related definitions and pathogenic hypotheses not only bears witness to the interest that delirium has aroused in clinical investigators, but also reflects the difficulties in scientifically investigating its intrinsic nature. Furthermore, these difficulties have raised doubts about making a diagnosis that may explain why its incidence is reported to be under-estimated.

The puzzle of preserved cognition in the oldest old.

Although epidemiological studies predict an exponential increase in the prevalence of dementia with age, recent studies have demonstrated that the oldest old are actually less frequently affected by dementia than the younger elderly. To explain this, I suggest a parallel between brain ageing and Alzheimer's disease (AD) and assume that theories concerning the brain's vulnerability to AD and its individual variability may also explain why some of the oldest old remain cognitively efficient. Some theories argue that AD is due to the continuing presence of the immature neurones vulnerable to amyloid beta protein (Aß) that are normally involved in brain development and then removed as a result of cell selection by the proteins associated with both brain development and AD. If a dysfunction in cell selection allows these immature neurones to survive, they degenerate early as a result of the neurotoxic action of Aß accumulation, which their mature counterparts can withstand. Consequently, age at the time of onset of AD and its clinical presentations depend on the number and location of such immature cells. I speculate that the same mechanism is responsible for the variability of normal brain ageing: the oldest old with well-preserved cognitive function are people genetically programmed for extreme ageing who have benefited from better cell selection during prenatal and neonatal life and therefore have fewer surviving neurones vulnerable to amyloid-promoted degeneration, whereas the process of early life cell selection was less successful in the oldest old who develop dementia.

Analyzing theory of mind impairment in patients with behavioral variant frontotemporal dementia.

OBJECTIVE: Behavioral variant frontotemporal dementia (bvFTD) and theory of mind (ToM) have common neuroanatomical aspects. This pilot study analyzed the qualitative features of ToM relatively to the site of prefrontal atrophy, aiming to identify a neurobehavioral pattern of bvFTD. METHOD: Fourteen bvFTD patients were compared with 14 healthy subjects with similar age, years of schooling, gender distribution, and social background. The faux pas task (FPT) measured the recognition and comprehension of faux pas (FP) and awareness of the factual details on 20 stories. Magnetic resonance assessed prefrontal atrophy. RESULTS: The bvFTD patients were significantly impaired in FP recognition and comprehension and in attribution of non-existent FP. Qualitative analysis revealed five types of errors: misidentification of characters, misidentification of emotions, excessive cohesiveness to the factual context, delusional interpretations, and non-responses. The FPT recognition and comprehension scores were unrelated to story factual details or other neuropsychological performance. Conversely, the FP comprehension scores related to disease duration, the delusional errors to disease duration and prefrontal orbital atrophy, and the cohesiveness errors to age and prefrontal dorsolateral atrophy. CONCLUSIONS: In bvFTD, ToM is characterized by misinterpretation of mental states and concrete thinking, which is related to disease severity and distinct areas of prefrontal atrophy. This neurobehavioral pattern may be a marker for bvFDT.

Neuro-Behçet's disease presenting as an isolated progressive cognitive and behavioral syndrome.

Behçet's disease is a chronic inflammatory disorder manifesting as a vasculitis that affects arteries and veins of any size. Up to 44% of cases may also present with neurological symptoms, thus defining Neuro-Behçet's disease. We describe a case of Neuro-Behçet's disease characterized by progressive behavioral and cognitive deterioration prevailing over other neurological symptoms, without evident systemic involvement.

An In Vivo 11C-(R)-PK11195 PET and In Vitro Pathology Study of Microglia Activation in Creutzfeldt-Jakob Disease.

Microgliosis is part of the immunobiology of Creutzfeldt-Jakob disease (CJD). This is the first report using 11C-(R)-PK11195 PET imaging in vivo to measure 18 kDa translocator protein (TSPO) expression, indexing microglia activation, in symptomatic CJD patients, followed by a postmortem neuropathology comparison. One genetic CJD (gCJD) patient, two sporadic CJD (sCJD) patients, one variant CJD (vCJD) patient (mean ± SD age, 47.50 ± 15.95 years), and nine healthy controls (mean ± SD age, 44.00 ± 11.10 years) were included in the study. TSPO binding potentials were estimated using clustering and parametric analyses of reference regions. Statistical comparisons were run at the regional and at the voxel-wise levels. Postmortem evaluation measured scrapie prion protein (PrPSc) immunoreactivity, neuronal loss, spongiosis, astrogliosis, and microgliosis. 11C-(R)-PK11195-PET showed a significant TSPO overexpression at the cortical level in the two sCJD patients, as well as thalamic and cerebellar involvement; very limited parieto-occipital activation in the gCJD case; and significant increases at the subcortical level in the thalamus, basal ganglia, and midbrain and in the cerebellum in the vCJD brain. Along with misfolded prion deposits, neuropathology in all patients revealed neuronal loss, spongiosis and astrogliosis, and a diffuse cerebral and cerebellar microgliosis which was particularly dense in thalamic and basal ganglia structures in the vCJD brain. These findings confirm significant microgliosis in CJD, which was variably modulated in vivo and more diffuse at postmortem evaluation. Thus, TSPO overexpression in microglia activation, topography, and extent can vary in CJD subtypes, as shown in vivo, possibly related to the response to fast apoptotic processes, but reaches a large amount at the final disease course.

Neuropathological assessments of the pathology in frontotemporal lobar degeneration with TDP43-positive inclusions: an inter-laboratory study by the BrainNet Europe consortium.

The BrainNet Europe consortium assessed the reproducibility in the assignment of the type of frontotemporal lobar degeneration (FTLD) with TAR DNA-binding protein (TDP) 43 following current recommendations. The agreement rates were influenced by the immunohistochemical (IHC) method and by the classification strategy followed. p62-IHC staining yielded good uniform quality of stains, but the most reliable results were obtained implementing specific Abs directed against the hallmark protein TDP43. Both assessment of the type and the extent of lesions were influenced by the Abs and by the quality of stain. Assessment of the extent of the lesions yielded poor results repeatedly; thus, the extent of pathology should not be used in diagnostic consensus criteria. Whilst 31 neuropathologists typed 30 FTLD-TDP cases, inter-rater agreement ranged from 19 to 100 per cent, being highest when applying phosphorylated TDP43/IHC. The agreement was highest when designating Type C or Type A/B. In contrast, there was a poor agreement when attempting to separate Type A or Type B FTLD-TDP. In conclusion, we can expect that neuropathologist, independent of his/her familiarity with FTLD-TDP pathology, can identify a TDP43-positive FTLD case. The goal should be to state a Type (A, B, C, D) or a mixture of Types (A/B, A/C or B/C). Neuropathologists, other clinicians and researchers should be aware of the pitfalls whilst doing so. Agreement can be reached in an inter-laboratory setting regarding Type C cases with thick and long neurites, whereas the differentiation between Types A and B may be more troublesome.

A mutation in the 5'-UTR of GRN gene associated with frontotemporal lobar degeneration: phenotypic variability and possible pathogenetic mechanisms.

Frontotemporal lobar degeneration (FTLD) is a very heterogeneous disorder. It is genetically linked to three major genes: microtubule-associated protein tau (MAPT), progranulin (GRN), and C9ORF72. In particular, mutations in GRN account for 5-10% of all cases and give rise to a wide spectrum of clinical phenotypes, ranging from behavioral frontotemporal dementia (bvFTD) to primary progressive aphasia, including progressive non-fluent aphasia (PNFA) and semantic dementia, and corticobasal syndrome (CBS). We studied a family affected by FTLD whose members showed three different phenotypes: bvFTD, PNFA, and CBS. We performed plasma progranulin measurement before any genetic analyses and, due to the low level detected, we sequenced GRN and found the new mutation EX0-5' splice site A > G in the 5'-UTR region, where no pathogenic mutations had been previously demonstrated. Genetic analyses of MAPT and C9ORF72 were normal. GRN mRNA expression showed about 50% reduction caused by this mutation, and similar results were found for progranulin level. Testing of nonsense mediated RNA decay gave negative results, suggesting a different mechanism of mRNA degradation. In summary, the EX0-5' splice site A > G mutation widens the GRN regions affected by null mutations, including the 5'-UTR, and confirms once more the large phenotypic variability linked to GRN mutations.

APP mutations in the Aß coding region are associated with abundant cerebral deposition of Aß38.

Aß is the main component of amyloid deposits in Alzheimer disease (AD) and its aggregation into oligomers, protofibrils and fibrils is considered a seminal event in the pathogenesis of AD. Aß with C-terminus at residue 42 is the most abundant species in parenchymal deposits, whereas Aß with C-terminus at residue 40 predominates in the amyloid of the walls of large vessels. Aß peptides with other C-termini have not yet been thoroughly investigated. We analysed Aß38 in the brains of patients with Aß deposition linked to sporadic and familial AD, hereditary cerebral haemorrhage with amyloidosis, or Down syndrome. Immunohistochemistry, confocal microscopy, immunoelectron microscopy, immunoprecipitation and the electrophoresis separation of low molecular weight aggregates revealed that Aß38 accumulates consistently in the brains of patients carrying APP mutations in the Aß coding region, but was not detected in the patients with APP mutations outside the Aß domain, in the patients with presenilin mutations or in subjects with Down syndrome. In the patients with sporadic AD, Aß38 was absent in the senile plaques, but it was detected only in the vessel walls of a small subset of patients with severe cerebral amyloid angiopathy. Our results suggest that APP mutations in the Aß coding region favour Aß38 accumulation in the brain and that the molecular mechanisms of Aß deposition in these patients may be different from those active in patients with familial AD associated with other genetic defects and sporadic AD.

The need to unify neuropathological assessments of vascular alterations in the ageing brain: multicentre survey by the BrainNet Europe consortium.

Here, we summarise the results after carrying out a large survey regarding the assessment of vascular alterations, both vessel changes and vascular lesions in an inter-laboratory setting. In total, 32 neuropathologists from 22 centres, most being members of BrainNet Europe (BNE), participated by filling out a questionnaire with emphasis on assessment of common vascular alterations seen in the brains of aged subjects. A certain level of harmonisation has been reached among BNE members regarding sectioning of the brain, harvesting of brain tissue for histology and staining used when compared to the survey carried out in 2006 by Pantoni and colleagues. The most significant variability was seen regarding the assessment of severity and of clinical significance of vascular alterations. Two strategies have recently been recommended regarding the assessment of vascular alterations in aged and demented subjects. The National Institute on Aging - Alzheimer's Association (NIA-AA) recommends the assessment of hippocampal sclerosis, vascular brain injury and microvascular lesions in 12 regions. Although this strategy will be easy to follow, the recommendations do not inform how the load of observed alterations should be assessed and when the observed lesions are of significance. Deramecourt and his colleagues recommend an assessment and semiquantitative grading of various pathologies in 4 brain regions. This strategy yielded a total score of 0 to 20 as an estimate of pathology load. It is, however, not clear which score is considered to be of clinical significance. Furthermore, in several BNE trials the semiquantitative assessment has yielded poor agreement rates; an observation that might negatively influence the strategy proposed by Deramecourt and his colleagues. In line with NIA-AA, a dichotomised approach of easily recognisable lesions in a standardised set of brain regions harvested for neuropathological assessment and applying reproducible sampling and staining strategies is recommended by BNE. However, a simple strategy regarding assessment of load of alteration is urgently needed to yield reproducible, and at the same time, comparable results between centres.

Alzheimer's disease: ageing-related or age-related? New hypotheses from an old debate.

The view that Alzheimer's disease (AD) is a fatal outcome of ageing prevails over the view that it mainly affects people aged 75-95. The former is based on the exponential increase in the incidence of AD with ageing, while the latter on AD prevalence rates. Both views share the idea that neurofibrillary degeneration (NFD) is secondary to the loading of ß-protein (Aß) and its more toxic species in nervous tissue that occurs with ageing in everybody, but is greater in people predisposed to AD. They differ in terms of the complexity attributed to the concept of neuronal vulnerability to Aß. In the ageing-related hypothesis, it is seen as a phylogenetic characteristic of neurons that predisposes some of them to Aß-dependent NFD, which spreads from the more vulnerable allocortex to the less vulnerable neocortex and accordingly causes memory decline progressing to dementia. To adapt this to the discontinuity of AD prevalence, it is necessary to see neuronal vulnerability as being modulated by additional ontogenetic factors that make some vulnerable neurons more or less sensitive to Aß toxicity. This may give the Aß/NFD relationship enough flexibility to explain the cognitive reserve of the oldest old and the phenotypical variability of AD, in particular why it is that the clinical onset of AD may be characterised by focal signs other than memory loss. Introducing this concept offers a new perspective of AD pathogenesis based on the role played by Aß and related proteins in nerve cell selection during brain development and adult neurogenesis.