Symptomatology and Neuropathology of patients presenting with focal cortical signs.

Here, we describe two patients who presented with focal cortical signs and underwent neuropathological examination. Case 1 was a 73-year-old woman with progressive speech disorder and abnormal behavior. She showed agraphia of the frontal lobe type, featured by the omission of kana letters when writing, other than pyramidal tract signs, pseudobulbar palsy, and frontal lobe dementia. Neuropathological examination, including TAR DNA-binding protein 43 (TDP-43) immunohistochemistry, revealed bilateral frontal and anterior temporal lobe lesions accentuated in the precentral gyrus and posterior part of the middle frontal gyrus. Both upper and lower motor neurons showed pathological changes compatible with amyotrophic lateral sclerosis. Case 2 was a 62-year-old man with progressive speech disorder and hand clumsiness. He had a motor speech disorder, compatible with apraxia of speech, and limb apraxia of the limb-kinetic and ideomotor type. Neuropathological examination revealed degeneration in the left frontal lobe, including the precentral gyrus, anterior temporal, and parietal lobe cortices. Moreover, numerous argyrophilic neuronal intracytoplasmic inclusions (Pick body) and ballooned neurons were observed in these lesions and the limbic system. The pathological diagnosis was Pick disease involving the peri-Rolandic area and parietal lobe. In these two cases, the distribution of neuropathological changes in the cerebral cortices correlated with the clinical symptoms observed.

Early diagnosis of prodromal dementia with Lewy bodies using clinical history of probable REM sleep behaviour disorder and cardiac 123 I-MIBG scintigraphy in memory clinics.

BACKGROUND: Rapid eye movement sleep behaviour disorder (RBD) is associated with reduced cardiac 123 I-metaiodobenzylguanidine (MIBG) uptake and often precedes the onset of Lewy body (LB) disorders. We investigated the role of cardiac 123 I-MIBG scintigraphy in relation to probable RBD for the clinical diagnosis of prodromal dementia with Lewy bodies (DLB) in memory clinics. METHODS: We reviewed clinical profiles of 60 consecutive patients who underwent cardiac 123 I-MIBG scintigraphy in our memory clinics. The diagnostic threshold of 2.20 was used as the cut-off for the heart-to-mediastinum ratio at the delayed phase. RESULTS: Cardiac 123 I-MIBG abnormality was identified in 28 patients at baseline; six were cognitively unimpaired, six had mild cognitive impairment (MCI)-LB, and 16 had probable DLB based on the National Institute on Aging and Alzheimer's Association Research Framework. Although the number of core features increased in accordance with the progression of three cognitive categories, there were no differences in the prevalence of probable RBD and the cardiac MIBG scintigraphy indices among them. During the observation period, two cognitively unimpaired patients with probable RBD progressed to MCI-LB, and three MCI-LB patients with probable RBD developed DLB. The prevalence of final diagnosis of probable MCI-LB or DLB was significantly higher in these patients (85%) than the remaining 32 patients without (9%). Of 25 patients with probable RBD, 22 (88%) had a cardiac 123 I-MIBG abnormality regardless of cognitive conditions. Only one patient consulted a sleep centre for the abnormal sleep behaviour before visiting our memory clinics. Regarding the gender differences, male predominance was not identified and sleep-related injury more frequently occurred in men (7/12, 58%) than in women (1/10, 10%). CONCLUSIONS: Proactive detection of probable RBD plus cardiac 123 I-MIBG abnormality provides the opportunity for an early diagnosis of prodromal DLB in memory clinics. This approach warrants further follow-up studies with polysomnographic and pathological verification.

Prevalence and Clinical Implications of the Mirror and TV Signs in Advanced Alzheimer's Disease and Dementia with Lewy Bodies.

OBJECTIVE: To explore the prevalence and clinical implications of the mirror and TV signs in the moderate to advanced stages of Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). METHODS: We retrospectively examined the prevalence of clinical and psychiatric symptoms including the mirror and TV signs in 200 subjects with AD and 200 with DLB and evaluated the relationships among the symptoms. RESULTS: The mirror sign was found in 3.0% of AD and 4.5% of DLB subjects. The TV sign was found in 1.5% of AD and 4.0% of DLB subjects. The prevalence of the mirror and TV signs was not significantly different between the AD and DLB groups. Visual hallucination, visual illusion, misidentification of person, and sleep talking were significantly more frequent in DLB than in AD subjects. The mirror sign was significantly associated with lower Mini-Mental State Examination scores, whereas the TV sign was significantly associated with the misidentification of person. CONCLUSIONS: Both the mirror and TV signs were rare even in the moderate to advanced stages of AD and DLB. The mirror sign may be independent from other delusional misidentification syndromes (DMSs). Being associated mainly with global cognitive decline, the mirror sign is unlikely attributed to any specific cognitive impairment or the dysfunction of localized brain areas. In contrast, the TV sign was significantly more often coexistent with the misidentification of person, suggesting that the TV sign may partly share common neuropsychological mechanisms with DMSs.

Postural Abnormality in Parkinson's Disease: A Large Comparative Study With General Population.

BACKGROUND: Postural abnormalities in Parkinson's disease (PD) patients and unimpaired elderly are not well differentiated. Factors related to postural abnormality associated with PD are controversial. OBJECTIVE: We assessed differences in postural change between PD patients and unimpaired elderly and elucidated factors related to abnormal posture in PD patients. METHODS: We measured the dropped head angle (DHA), anterior flexion angle (AFA), and lateral flexion angle (LFA) of the thoracolumbar spine of an unprecedented 1,117 PD patients and 2,732 general population participants (GPPs) using digital photographs. Two statistical analyses were used for elucidating factors related to these angles. RESULTS: In GPPs, age was correlated with DHA, AFA, and LFA. DHAs, AFAs, and LFAs of PD patients and age-matched GPPs were 21.70° ± 14.40° and 13.13° ± 10.79°, 5.98° ± 12.67,°and - 3.82° ± 4.04°, and 0.86° ± 4.25° and 1.33° ± 2.16°, respectively. In PD patients, factors related to DHA were age, male sex, and H & Y stage during ON time. Factors related to AFA were age, duration of disease, H & Y stage during ON and OFF times, pain, vertebral disease, and bending to the right. A factor related to LFA was AFA. CONCLUSIONS: DHA and AFA of GGPs correlated with age and were larger in PD patients than those with in GPPs. Some PD patients showed angles far beyond the normal distribution. Thus, factors associated with disease aggravation affected postural abnormality in PD patients.

Dementia with Lewy bodies presenting as frontotemporal dementia phenotype.

We herein report two patients with dementia with Lewy bodies (DLB) presenting characteristic symptoms suggestive of the behavioural variant of frontotemporal dementia (bvFTD). Patient 1 presented behavioural and personality changes from the onset, such as restlessness, compulsive behaviours, and stereotypical speech. A neuroimaging study showed preferential frontal involvement, and this patient fulfilled the diagnostic criteria for bvFTD. However, 123 I-metaiodobenzylguanidine cardiac scintigraphy revealed a markedly lowered uptake, suggesting the diagnosis of possible DLB. Patient 2 fulfilled the criteria for probable DLB, but later presented bvFTD-like symptoms similar to those in patient 1. These patients suggest that DLB can be a candidate for differential diagnosis of bvFTD in the clinical setting.

Historical review of academic concepts of dementia in the world and Japan: with a short history of representative diseases.

Expanding our knowledge of the history of dementia may be beneficial for its holistic understanding. This article aims to review the trajectory of the concepts of dementia in the world and Japan. Historical backgrounds of major dementia diseases are also addressed. The first reference to "imbecility" appeared in Greece in 6th century BC. A Japanese term "Mow-roku" (aged and devitalized) first appeared in 11th century, was replaced by "Chee-hou" (absent-minded imbecile) in 1960s, and then by "Ninchee-show" (cognitive impairment) in 2014 for humanistic reasons. In 1970s, dementia was delineated from normal aging, and the present concept of dementia was established.

5-fluorouracil-induced leukoencephalopathy with acute stroke-like presentation fulfilling criteria for recombinant tissue plasminogen activator therapy.

A 61-year-old man underwent systemic chemotherapy with intravenous infusion of nedaplatin and 5-fluorouracil. On the day after the final drug administration, he suddenly experienced difficulty in speaking followed by left-sided weakness. His National Institutes of Health Stroke Scale score was 12. A computed tomographic scan of the brain performed 4 hours after symptom onset revealed no abnormalities. Because all eligibility criteria were fulfilled, he immediately underwent intravenous recombinant tissue plasminogen activator therapy. He recovered from neurologic complications on day 14. An initial magnetic resonance imaging scan of his brain revealed a hyperintense area in the bilateral white matter and corpus callosum, and these abnormalities had improved on the follow-up scan. We diagnosed him with 5-fluorouracil-induced leukoencephalopathy with acute stroke-like presentation. Our experience suggests that 5-fluorouracil-induced leukoencephalopathy potentially fulfills all eligibility criteria for recombinant tissue plasminogen activator therapy.

Prevalence and clinical implication of microbleeds in dementia with lewy bodies in comparison with microbleeds in Alzheimer's disease.

BACKGROUND: Cerebral microbleeds (MBs) have been well investigated in Alzheimer's disease (AD), but not very extensively in non-AD dementias or in dementia with Lewy bodies (DLB). AIMS: To elucidate the clinical significance of MBs in DLB. METHODS: We compared the prevalence, locations and risk factors for MBs in 59 DLB and 81 AD patients. We visually counted MBs in each of the cortical and subjacent areas (frontal, temporal, parietal and occipital), the basal ganglia and the thalamus, and the brainstem and the cerebellar hemispheres on 1.5-tesla T2*-weighted gradient-recalled-echo MRI images. White matter lesions were semiquantified in fluid-attenuated inversion recovery images according to the Fazekas rating scale. RESULTS: While the prevalence of MBs was comparable, MBs tended to be more abundant in DLB than in AD in all brain areas with the exception of the occipital lobes. The number of MBs was positively associated with the severity of white matter lesions but not with other vascular risk factors in either AD or DLB. The presence of MBs could be associated with cognitive impairment at onset. MB-positive DLB patients showed less impairment on (123)I-metaiodobenzylguanidine myocardial scintigraphy (MIBG scintigraphy) images, supporting the notion of an inverse relationship between vascular lesions and Lewy body pathology. CONCLUSION: It was suggested that an intricate association between Lewy body pathology, AD-type pathologies and vascular lesions seems to be related to the initial symptoms and results of MIBG scintigraphy in DLB.

Cerebral microhemorrhage in Marchiafava-Bignami disease detected by susceptibility-weighted imaging.

Marchiafava-Bignami disease (MBD) is a rare alcohol-associated disorder. Clinical features include not only disturbed consciousness, dysarthria, tetraparesis, astasia-abasia, and symptoms of interhemispheric disconnection as initial symptoms but also cognitive deficits as clinical outcomes. The clinical significance of cerebral microhemorrhage (CMH) has been recognized in patients with cognitive deficits; however, the presence of CMH in patients with MBD has not been emphasized. The aim of the present study was to clarify the relationship between CMH and MBD. For this purpose, we report four patients with MBD, who showed asymmetrical hypointense areas in multiple cortico-subcortical regions on susceptibility-weighted imaging (SWI). All cases had a history of chronic alcohol abuse and symmetrical lesions in the entire corpus callosum. These patients' clinical symptoms included not only coma, dysarthria, and astasia-abasia as initial symptoms but also dementia as a clinical outcome. SWI showed asymmetrical hypointense areas in the multiple cortico-subcortical regions, indicating the presence of CMH. Compared with patients with normal cognitive function, demented patients showed higher severity of CMH. Our report would indicate that CMH is an important factor indicating the severity of dementia in patients with MBD.

[Clinical types of FTLD: progressive nonfluent aphasia; comparative discussions on the associated clinical presentations].

Progressive nonfluent aphasia (PNFA) is one of the 3 clinical presentations of frontotemporal lobar degeneration (FTLD), the other 2 being frontotemporal dementia and semantic dementia (SD). PNFA and SD, both representing relentlessly progressive language impairment in the realm of FTLD, may share a large part with primary progressive aphasia (PPA). A salient distinction between PPA and PNFA or SD is that PPA includes another clinical type, namely, logopenic/phonemic aphasia (LPA), which is not represented in FTLD. This is primarily because LPA is usually caused by Alzheimer's disease (AD) and the brunt of the lesion is localized at the left temporo-parietal region of the brain. Further, PNFA/SD should be limited to the clinical consequencies of FTLD while PPA is more generous with regard to its causal pathology. By definition, PNFA is an expressive language impairment which is characterized by effortful speech, phonemic errors, grammatical impairment, and word-finding difficulties. Reading and writing may be comparatively impaired. Comprehension of single word meaning is normal, while comprehension of sentencies may sometimes be impaired. PNFA should be differentiated from SD, LPA, and pure progressive apraxia of speech (AOS or alternatively referred to as aphemia or anarthria). SD may be distinguished from PNFA by virtue of its fluency, characteristic loss of word meaning and absence of agrammatism. LPA is similar to PNFA, yet differs in that there is preservation of grammatical skills and speech motor function that is devoid of AOS and/or dysarthria. AOS is an impairment at the level of speech motor programming without language impairment. Thus, there may be a double dissociation between AOS and PNFA i. e., PNFA may or may not accompany AOS and vice versa. PNFA is associated with a localized lesion in the left frontotemporal area of the brain. Immunohistochemical investigations have revealed that ubiquitin/TAR DNA binding protein-43 (TDA-43) positive and tau negative pathology, mostly FTLD with ubiquitin-positive inclusions (FTLD-U) type 3, accounts for 90% of PNFA cases, while the remaining 10% may be caused by tauopathy. Therapeutic attempts for PNFA are currently unsuccessful.

Visuospatial function is a significant contributor to functional status in patients with Alzheimer's disease.

BACKGROUND: Contribution of visuospatial abilities to the functional status in patients with Alzheimer's disease (AD) has been controversial. AIM: To address whether visuospatial abilities have independent association with functional measures in patients with AD. METHODS: We regressed performances on a global cognitive (the revised Hasegawa Dementia Scale: HDSR), executive/ visuoconstruction (Clock drawing), visuoperception (Clock reading: CRT), simple visuoconstruction (figure copying), and frontal behavioral tasks on measures of basic and instrumental activities of daily living (BADL and IADL) in 57 patients (78.0 + 6.1 years) with AD of various severity (mean HDSR score: 16.0 + 5.9). We sought independent contributions of these visuospatial measures to functional status. RESULTS: Performance on the CRT contributed significantly to BADL and IADL and the results of HDSR contributed to IADL. Results of figure copying related significantly to BADL especially in mild AD. CONCLUSION: Visuospatial ability is one of the important contributors to functional status.

SPECT-identified neuroanatomical predictor of the cognitive effects of donepezil treatment in patients with Alzheimer's disease.

BACKGROUND/OBJECTIVE: We attempted to determine whether the pretreatment regional cerebral blood flow (rCBF) might predict cognitive changes in response to donepezil treatment, as assessed in terms of the Alzheimer Disease Assessment Scale cognitive subscale (ADAS-cog), and in relation to the severity of subcortical hyperintensities (SH). METHOD: Forty-one patients with Alzheimer's disease (AD) were treated with donepezil at baseline. All the patients underwent a single photon emission computed tomography examination before donepezil therapy. They also completed the ADAS-cog at baseline and after 24 weeks of donepezil therapy. SH were assessed semiquantitatively using a recently developed visual rating scale. We analyzed the correlation between the baseline rCBF and changes in the ADAS-cog score using statistical parametric mapping, including the severity of the SH as a covariate. RESULTS: Lower pretreatment rCBF levels in the right orbitofrontal cortex (OFC) predicted a better improvement in the ADAS-cog score in response to donepezil therapy. The severity of SH did not appear to influence this correlation. CONCLUSIONS: This effect may reflect the choline acetyltransferase activity associated with the OFC. The presence of SH did not appear to influence the effect of donepezil therapy on the cognitive function as assessed by ADAS-cog.

[Germinoma presenting with personality and socio-behavioral abnormalities may challenge differential diagnoses].

We described the major diagnostic difficulties encountered in the case of a 25-year-old man with the pathological diagnosis of a germinoma. The patient initially developed an eating disorder at the end of 2003 and a character change ensued since the beginning of 2004. On admission in August 2004, his cardinal symptoms and signs included marked apathy, depersonalization, generalized muscle wasting, and decreased tendon reflexes. Brain T2-weighted (T2-WI) MR and FLAIR images showed high signal intensities in the suprasellar region and at the genu of the corpus callosum that extended along the sub-pia mater of the right anterior horn. These lesions showed mild enhancement on gadolinium-enhanced T1-WI. CSF examination revealed a mildly elevated level of protein and increased cell counts but did not show any malignant cells on repeated spinal tap. The patient's status remained practically unchanged till December 2004 when he developed diabetes insipidus. Soon afterward, the patient collapsed into akinetic mutism and developed corresponding new lesions at the tegmentum of the midbrain. These new lesions disappeared spontaneously and akinetic mutism regressed without any specific therapy. We tentatively diagnosed of neurosarcoidosis based on a characteristic progressive-regressive clinical course, CSF data, and radiological findings. Clinical symptoms and the enhanced masses on MRI were highly responsive to steroid therapy after which the patient was able to return home. However, disturbances in consciousness and tenacious vomiting recurred in September. Brain MRI revealed a markedly re-enlarged and easily enhanced mass at the right anterior horn, which extended into the cerebral aqueduct and resulted in obstructive hydrocephalus. On surgery, histopathological investigation revealed germinoma. This case highlights the need for careful discrimination between a slow growing germinoma and chronic granulomatous diseases of the brain such as neurosarcoidosis. Early histological investigation may be warranted in patients who present difficulties during differential diagnoses.

Progressive agraphia can be a harbinger of degenerative dementia.

By investigating three patients with progressive agraphia, we explored the possibility that this entity is an early sign of degenerative dementia. Initially, these patients complained primarily of difficulties writing Kanji (Japanese morphograms) while other language and cognitive impairments were relatively milder. Impairments in writing Kana (Japanese syllabograms), verbal language, executive function, visuo- and visuospatial cognition and memory were identified by neuropsychological testing. The agraphia was compatible with a peripheral type, based on deficits at the interface between the central letter selection and the graphemic motor execution (Patient 1) or at the stage of central letter selection as well (Patients 2 and 3). Agraphia was generally more prominent, although not exclusive, for Kanji probably because of later acquisition and larger total number of Kanji letters leading to lower frequency of use and familiarity per letter. Concurrent or subsequent emergence of non-fluent aphasia, ideomotor apraxia, executive dysfunction and asymmetric akinetic-rigid syndrome in two patients suggested degenerative processes involving the parietal-occipital-temporal regions, basal ganglia and striato-frontal projections. We propose that progressive agraphia may be one of the early symptoms of degenerative dementia such as corticobasal degeneration.

Do lesions involving the cortical cholinergic pathways help or hinder efficacy of donepezil in patients with Alzheimer's disease?

AIMS: To investigate the influences of vascular lesions detected by MRI, lesions involving the cortical cholinergic pathways and hippocampal thickness on therapeutic responsiveness to donepezil in patients with Alzheimer's disease (AD). METHODS: The study cohort contained 67 patients with probable AD. We used the revised Hasegawa Dementia Rating (HDS-R) and the Clock Drawing Test (CDT) to evaluate drug efficacy for 24 months. The Cholinergic Pathways Hyperintensities Scale (CHIPS), a newly developed visual scale, was used to semiquantify lesions on the cholinergic pathways. RESULTS: Over the 24-month period, the results of the CDT showed more apparent and constant association with white matter hyperintensities (WMH) and lesions on the cholinergic pathways than the HDS-R. WMH may enhance, while lesions on the cholinergic pathways may attenuate sensitivity to donepezil treatment when judged by the CDT. No apparent association between the thicknesses of hippocampi with baseline cognition or therapeutic responsiveness to donepezil was found. CONCLUSION: Donepezil may be more efficacious when further executive dysfunction caused by WMH is added to AD dementia and less so when cholinergic reserves are further impinged upon by lesions involving the cortical cholinergic pathways.