Risk of neurodegenerative diseases in patients with sleep disorders: A nationwide population-based case-control study.

OBJECTIVE: Our study aimed to explore the associative relationship between neurodegenerative diseases and sleep disorders. PATIENTS: This 15-year retrospective longitudinal nationwide population-based matched case-control study used data extracted from the National Health Insurance Research Database. We evaluated 25,589 patients diagnosed with neurodegenerative diseases between 2000 and 2015 and a matched control of 102,356 patients without neurodegenerative diseases. RESULTS: Sleep disorders were an independent risk factor for the development of neurodegenerative diseases (adjusted odds ratio (OR): 1.794, 95% confidence interval (CI): 1.235-2.268, P < 0.001), with a positive dose-effect relationship (adjusted OR (95% CI): <1 year: 1.638 (1.093-2.872), P < 0.001; 1-5 years: 1.897 (1.260-3.135), P < 0.001; >5 years: 2.381 (1.467-3.681), P < 0.001. Moreover, patients with sleep disorder and comorbid depression had a significantly higher risk of neurodegenerative disorders (adjusted OR: 5.874). Subgroup analysis showed that insomnia was associated with Alzheimer's disease, Pick's disease and essential tremor (adjusted OR (95% CI): 1.555 (1.069-1.965), 1.934 (1.331-2.445) and 2.089 (1.439-2.648), respectively). Obstructive sleep apnea was associated with Parkinson's disease, essential tremor, and primary dystonia (adjusted OR (95% CI): 1.801 (1.239-2.275), 5.523 (3.802-6.977), and 4.892 (3.365-6.178), respectively). Other specific sleep disorders were associated with Pick's disease, Parkinson's disease, essential tremor, and primary dystonia (adjusted OR (95% CI): 8.901 (6.101-11.010), 1.549 (1.075-1.986), 2.791 (1.924-3.531), and 9.114 (6.283-10.506), respectively). CONCLUSION: Sleep disorders are associated with the subsequent development of neurodegenerative disorders. Moreover, sleep disorder patients with comorbid depression have a higher risk of neurodegenerative diseases.

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.

Nueva observación de la protección relativa que las enfermedades neurodegenerativas y el cáncer se confieren entre sí / New evidence of the relative protective effects of neurodegenerative diseases and cancer against each other

Introducción: El cáncer y las enfermedades degenerativas constituyen trastornos con algunos mecanismos compartidos que actúan en sentido opuesto, produciendo un fenómeno incontrolado de proliferación o pérdida de células. Observaciones diversas apuntan que los pacientes con enfermedad de Alzheimer tienen menor riesgo de desarrollar tumores y viceversa. En este artículo se expone la prevalencia de tumores (activos o superados) en pacientes de neurología cognitiva con y sin una enfermedad degenerativa demenciante. Pacientes y método: En 1.164 pacientes se analizó la frecuencia y topografía de tumores y la presencia o ausencia de enfermedad neurodegenerativa, que se clasificó en 4 grupos (enfermedad de Alzheimer, sinucleinopatía, enfermedad del complejo Pick y del complejo de poliglutamina). Se comparó la frecuencia de tumor en los subgrupos con y sin enfermedad degenerativa, y de esta en los pacientes con y sin trastorno tumoral. Resultados: Se registró proceso tumoral en el 12,1% de los pacientes con enfermedad neurodegenerativa y en el 17,3% del resto del grupo. En el grupo del estudio, un 14,8% de los que tienen antecedente tumoral fue diagnosticado de enfermedad neurodegenerativa, frente al 20,8% entre los que no tienen ese antecedente. Estas diferencias y las observadas en la comparación de subgrupos (tipo de enfermedad degenerativa y topografía del tumor) no alcanzaron significación estadística, excepto al contrastar enfermedades neurodegenerativas con tumores del sistema nervioso central y sinucleinopatías con neoplasias. Conclusiones: Las enfermedades neoplásicas y las neurodegenerativas demenciantes no son excluyentes, aunque muestran menor asociación de la esperada por su respectiva prevalencia

Background: Cancer and degenerative diseases share some pathogenic mechanisms which act in opposition to one another to produce either uncontrolled cell proliferation or cell death. According to several studies, patients with Alzheimer disease have a lower risk of neoplasia, and vice versa. This study describes the prevalence of tumours (active or successfully treated) in a series of patients with and without a dementing degenerative disease treated at a cognitive neurology unit. Patients and method: We analysed the frequency and topography of tumours and the presence or absence of a neurodegenerative disease in a group of 1,164 patients. Neurodegenerative diseases were classified in 4 groups: Alzheimer disease, synucleinopathies, Pick complex, and polyglutamine complex. We subsequently compared tumour frequency in patients with and without a degenerative disease, and prevalence of neurodegenerative diseases in patients with and without tumours. Results: Tumours were detected in 12.1% of the patients with a neurodegenerative disease and in 17.3% of the remaining patients. Around 14.8% of the patients with a history of neoplasia and 20.8% of the patients with no history of neoplasia were diagnosed with a neurodegenerative disease. Except for these differences and the differences between subgroups (type of degenerative disease and tumour location) were not statistically significant, except when comparing neurodegenerative diseases to central nervous system tumours, and synucleinopathies to neoplasms. Conclusion: Dementing degenerative diseases and neoplastic disorders are not mutually exclusive. Nevertheless, the rate of co-occurrence is lower than would be expected given the prevalence rate for each group

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.

Squaring the round: An unusual progressive graphomotor impairment with post-mortem findings.

Investigations of neurodegenerative disorders may reveal functional relationships in the cognitive system. C.S. was a 63-year-old right-handed man with post-mortem confirmed Pick's disease with a range of progressive impairments including non-fluent aphasia, speech, limb, oculomotor, and buccofacial apraxia, but mostly intact intelligence, perception, orientation, memory, semantics, and phonology. During progression, agrammatism in writing with impairments in syntactic comprehension emerged in parallel with an unusual graphomotor deficit in drawing and writing, with an increasing deterioration of graphic short-term memory. We investigated C.S.'s graphomotor deficit longitudinally using tests of writing and drawing on letters, words, and sentences and drawing to command and copying. We also tested C.S.'s short-term graphemic buffer experimentally. Analysis showed deficits on selective aspects of graphomotor implementation of writing and drawing, mainly affecting the production of circles and curves, but not short straight lines in drawing and writing, and graphomotor short-term memory, which paralleled impairments of written syntax and syntactic comprehension. We believe this to be the first detailed analysis of such an unusual progressive impairment in graphomotor production, which may be related to problems with agrammatic agraphia and impairments affecting shared components of cognition reflecting damage to shared neural networks. Alternatively, they may simply reflect the effects of coincidental damage to separate mechanisms responsible for aspects of writing, drawing, and syntactic processing. Longitudinal investigations of emerging deficits in progressive conditions like C.S.'s provides an opportunity to examine the progressive emergence of symptoms in an individual with multiple progressive impairments as they appear and examine putative relationships between them.

Pick and Alzheimer diseases: a rare comorbidity presenting as corticobasal syndrome.

We describe a patient with corticobasal syndrome in whom neuropathological examination on autopsy revealed Pick and Alzheimer diseases in comorbidity. Corticobasal degeneration is a tauopathy usually associated with asymmetric parkinsonism, parietal lobe involvement, and cognitive impairment. Corticobasal syndrome is the clinical presentation of corticobasal degeneration without neuropathological confirmation. A 66-year-old right-handed man slowly developed speech difficulties, right-hand clumsiness, and forgetfulness. His speech apraxia progressed to mutism with preserved comprehension, and his clumsiness progressed to severe apraxia involving both hands. He developed behavioral changes and severe amnesia. All of these features were consistent with corticobasal syndrome. His loss of episodic, verbal, and visuospatial memory suggested Alzheimer disease; however, beyond his frontotemporal neuropsychological profile, he had few symptoms characteristic of frontal lobe dementia. Magnetic resonance imaging scans showed worsening temporal, frontal, and parietal atrophy, predominant in the left hemisphere. Neuropathological examination at autopsy revealed abundant neuritic plaques and neurofibrillary tangles consistent with fully developed Alzheimer disease, as well as numerous intraneuronal Pick bodies in the frontotemporal lobes. Our findings confirm the importance of clinical and neuropathological correlations in patients with atypical neurodegenerative dementias.

Primary progressive apraxia of speech (AOS) in a patient with Pick's disease with Pick bodies: a neuropsychological and anatomical study and review of literatures.

A 56-year-old right-handed man suffered from progressive apraxia of speech (AOS), characterized by agrammatism and buccofacial apraxia. He also became mute at the later stages of the disease progression. At autopsy, the left precentral gyrus, pars opercularis, and hippocampus showed severe atrophy. Pick bodies and Pick cells were observed. In this report, we also review previous case reports of AOS. Pick's disease is among the most commonly associated of the major diseases. Brain lesions associated with AOS may be found in regions such as the precentral gyrus and the pars opercularis in the left hemisphere.

Nonfluent/agrammatic PPA with in-vivo cortical amyloidosis and Pick's disease pathology.

The role of biomarkers in predicting pathological findings in the frontotemporal dementia (FTD) clinical spectrum disorders is still being explored. We present comprehensive, prospective longitudinal data for a 66 year old, right-handed female who met current criteria for the nonfluent/agrammatic variant of primary progressive aphasia (nfvPPA). She first presented with a 3-year history of progressive speech and language impairment mainly characterized by severe apraxia of speech. Neuropsychological and general motor functions remained relatively spared throughout the clinical course. Voxel-based morphometry (VBM) showed selective cortical atrophy of the left posterior inferior frontal gyrus (IFG) and underlying insula that worsened over time, extending along the left premotor strip. Five years after her first evaluation, she developed mild memory impairment and underwent PET-FDG and PiB scans that showed left frontal hypometabolism and cortical amyloidosis. Three years later (11 years from first symptom), post-mortem histopathological evaluation revealed Pick's disease, with severe degeneration of left IFG, mid-insula, and precentral gyrus. Alzheimer's disease (AD) (CERAD frequent/Braak Stage V) was also detected. This patient demonstrates that biomarkers indicating brain amyloidosis should not be considered conclusive evidence that AD pathology accounts for a typical FTD clinical/anatomical syndrome.

The influence of psycholinguistic variables on articulatory errors in naming in progressive motor speech degeneration.

We describe an analysis of speech errors on a confrontation naming task in a man with progressive speech degeneration of 10-year duration from Pick's disease. C.S. had a progressive non-fluent aphasia together with a motor speech impairment and early assessment indicated some naming impairments. There was also an absence of significant phonological or semantic impairment. In order to examine naming difficulties and the factors that influence his speech production errors, we selected 210 words varying in frequency, age of acquisition (AoA), imageability, phonemic length and syllable length and conducted a logistic regression analysis on a range of speech production error types (phone omissions, additions, substitutions, response delays, overall errors). No significant naming errors due to lexical access were found. The only significant predictor of speech articulation errors was phonemic length, with none of the other lexical variables influencing speech production error. The only error type predicted was phone omissions. Results suggest that C.S.'s speech and naming errors indicate compromised speech programming/planning rather than lexical selection and we conclude that this pattern of findings is indicative of problems with motor speech production.

Frontotemporal dementia, Pick's disease.

A significant expansion of knowledge in the last few years, especially in the molecular biology of frontotemporal dementia (FTD) is summarized. This condition, formerly known as Pick's disease and considered rare, is estimated to be 12-15% of all dementias and 30-50% early onset ones. The clinical picture is protean, mainly a behavioural and language impairment, but the extrapyramidal syndromes of CBD and PSP also belong. These seemingly different presentations converge, as one or other areas in the brain are affected. Less than half of the cases are tauopathies, the majority has been discovered to have a TDP-43 and most recently a FUS proteinopathy, shared with ALS, opening potential opportunities for pharmacological approaches to treatment. Tau and progranulin mutations on Ch-17 and some others, point to molecular mechanisms. A glossary is provided to navigate the complex terminology.

Clinical entity of frontotemporal dementia with motor neuron disease.

Non-Alzheimer-type dementias occur in association with a variety of pathological conditions that include a group of diseases characterized by atrophy of the frontal and temporal lobes. Frontotemporal dementia (FTD) is a clinical entity that comprises at least two distinct diseases: Pick's disease with Pick bodies and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). The vast majority of FTLD-U is now referred to as FTLD-TDP, following the recent discovery of TAR DNA-binding protein of 43 kDa (TDP-43) as the major constituent of the ubiquitin-positive inclusions. FTLD-TDP, but not Pick's disease with Pick bodies, is often associated with motor neuron disease (MND). MND is a group of diseases in which the central nervous system lesions were long believed to be confined to the motor neuron system. In other words, MND was not considered to be associated with other neurological symptoms such as dementia. Nevertheless, more than 200 FTD cases associated with clinical MND have been reported in Japan since 1964. Neuropathologically, MND in such FTD cases was essentially similar to MND in cases without dementia. The combination of FTD and MND was so characteristic that we considered these cases comprise a unique clinicopathological subgroup of FTD. FTD with MND and the classical MND without dementia share the occurrence of ubiquitinated TDP-43-positive inclusions, a finding that could be a key to unlock the pathological backgrounds of both diseases.

Tauopathies with parkinsonism: clinical spectrum, neuropathologic basis, biological markers, and treatment options.

Tauopathies with parkinsonism represent a spectrum of disease entities unified by the pathologic accumulation of hyperphosphorylated tau protein fragments within the central nervous system. These pathologic characteristics suggest shared pathogenetic pathways and possible molecular targets for disease-modifying therapeutic interventions. Natural history studies, for instance, in progressive supranuclear palsy, frontotemporal dementia with parkinsonism linked to chromosome 17, corticobasal degeneration, and Niemann-Pick disease type C as well as in amyotrophic lateral sclerosis/Parkinson-dementia complex permit clinical characterization of the disease phenotypes and are crucial to the development and validation of biological markers for differential diagnostics and disease monitoring, for example, by use of neuroimaging or proteomic approaches. The wide pathologic and clinical spectrum of the tauopathies with parkinsonism is reviewed in this article, and perspectives on future advances in the understanding of the pathogenesis are given, together with potential therapeutic strategies.

Clinicopathological characterization of Pick's disease versus frontotemporal lobar degeneration with ubiquitin/TDP-43-positive inclusions.

Although frontotemporal lobar degeneration with ubiquitin/TDP-43-positive inclusions (FTLD-TDP) and Pick's disease are common pathological substrates in sporadic FTLD, clinical differentiation of these diseases is difficult. We performed a retrospective review of medical records and semiquantitative examination of neuronal loss of 20 sporadic FTLD-TDP and 19 Pick's disease cases. Semantic dementia as the first syndrome developed only in FTLD-TDP patients. Impaired speech output in the early stage was five times more frequent in Pick's disease than in FTLD-TDP. The total frequency of asymmetric motor disturbances (e.g., parkinsonism, pyramidal signs, and contracture) during the course was significantly more frequent in FTLD-TDP (78%) than in Pick's disease cases (14%). Asymmetric pyramidal signs were found in 7 of 13 FTLD-TDP cases with corticospinal tract degeneration similar to primary lateral sclerosis. Frontotemporal dementia as the first syndrome was noted in both FTLD-TDP (28%) and Pick's disease cases (64%); however, only FTLD-TDP cases subsequently developed asymmetric motor disturbances, and some of the cases further exhibited hemineglect. Concordant with these clinical findings, degeneration in the temporal cortex, caudate nucleus, putamen, globus pallidus, substantia nigra, and corticospinal tract was significantly more severe in FTLD-TDP, and degeneration in the frontal cortex tended to be more severe in Pick's disease. Given these findings, the initial impairment of semantic memory or comprehension and subsequent asymmetric motor disturbances in sporadic FTLD patients predict sporadic FTLD-TDP rather than Pick's disease, while initial behavioral symptoms or non-fluent aphasia without subsequent asymmetric motor disturbances predict Pick's disease rather than sporadic FTLD-TDP.

[Current diagnostic, clinical and therapeutic conceptions of frontotemporal dementia]. / Wspólczesne koncepcje diagnostyczne, kliniczne i terapeutyczne otepienia czolowo-skroniowego.

The authors present a review of the selected publications on frontotemporal dementia. Frontotemporal dementia (FTD) is a progressive degeneration of the central nervous system. The typical symptoms of FTD are behavioural disorders, affective symptoms and speech disorders. Neuroimaging methods reveal atrophic lesions and hypometabolism of the frontal and temporal lobes.

[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.

TDP-43 pathology in familial frontotemporal dementia and motor neuron disease without Progranulin mutations.

Frontotemporal dementia is accompanied by motor neuron disease (FTD + MND) in approximately 10% of cases. There is accumulating evidence for a clinicopathological overlap between FTD and MND based on observations of familial aggregation and neuropathological findings of ubiquitin-positive neuronal cytoplasmatic inclusions (NCI) in lower motor neurons, hippocampus and neocortex in both conditions. Several familial forms exist with different genetic loci and defects. We investigated the familial aggregation and clinical presentation of FTD + MND cases in a large cohort of 368 FTD patients in The Netherlands. Immunohistochemistry of available brain tissue of deceased patients was investigated using a panel of antibodies including ubiquitin, p62 and TAR DNA-binding protein of 43 kDa antibodies. A total of eight patients coming from six families had a family history positive for FTD + MND (mean age at onset 53.2 +/- 8.4 years). Five patients presented with behavioural changes and cognitive changes followed by motor neuron disease, whereas symptoms of motor neuron disease were the presenting features in the remaining three patients. Other affected relatives in these families showed dementia/FTD, MND or FTD + MND reflecting the clinical interfamilial variation. No mutations were identified in any of the candidate genes, including Superoxide Dismutase 1, dynactin, angiogenin, Microtubule-Associated Protein Tau, valosin-containing protein and progranulin. Available brain tissue of five patients with familial FTD + MND showed NCI in hippocampus, neocortex and spinal cord in all, and neuronal intranuclear inclusions (NII) in two brains. TDP-43 antibody showed robust staining of neuronal inclusions similar in distribution and morphology to NCI and NII. Additionally, TDP-43 antibody also stained ubiquitin-negative glial inclusions in the basal striatum of one case. In conclusion, there exists considerable clinical variation within families with FTD + MND, which may be determined by other genetic or environmental factors. NII are also found in some cases of familial FTD + MND without Progranulin mutations. The observation of glial TDP-43 positive inclusions in one brain is very interesting, although their pathophysiological significance is yet unknown.

Pick's disease with Pick bodies: an unusual autopsy case showing degeneration of the pontine nucleus, dentate nucleus, Clarke's column, and lower motor neuron.

We report a 51-year-old female with Pick's disease with Pick bodies (PDPB) showing a brainweight of 530 g. This case was considered to be a very rare case of PDPB, in which the lesion developed in the temporal and frontal lobes and later spread to the parietal lobe, occipital lobe, brainstem, cerebellum and spinal cord. This case showed very atypical clinicopathological findings. Clinically, bulging eyes and myoclonus were observed. Neuropathologically, Pick bodies were widely distributed beyond the usual distribution areas to the parietal cortices, occipital cortices, dentate nuclei, motor neuron nuclei in the brain stem, and spinal cord. The atypical clinical symptoms and the widespread neuropathological abnormalities observed in this case seem to represent an extremely extended form of PDPB.